Clinical trial NCT02918279
Conditions: Metabolism and Nutrition Disorder Obesity
Sponsor: Novo Nordisk A/S
Start date: 2016-09-29; Completion date: 2019-08-08
Enrollment: 251 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 pubertal adolescent subjects with obesity.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Liraglutide intervention 2: Placebo
Intervention descriptions: intervention 1: Administered once daily subcutaneously (s.c., under the skin) intervention 2: Administered once daily subcutaneously (s.c., under the skin)

Protocol documents:
Prot_000.pdf: 
Cover Page for Protocol 
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT02918279 
Sponsor trial ID: 
NN8022-4180 
Official title of study: 
Effect of liraglutide for weight management in pubertal 
adolescent subjects with obesity 
Document date: 
11-December-2019 
 


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CONFIDENTIAL
 
 
 
 
 
Redacted protocol 
Includes redaction of personal identifiable information only. 
 
 
 
. 
 
 


Protocol
CONFIDENTIAL
Date:
01 June 2016
Novo Nordisk
Trial ID: NN8022-4180
Version:
1.0
UTN: U1111-1162-7101
Status:
Final
EudraCT no.: 2014-004353-14
Page:
1 of 110
Protocol
Trial ID: NN8022-4180
Effect of liraglutide for weight management in pubertal
adolescent subjects with obesity
56-week, double-blind, randomised, parallel-group, placebo-controlled
multi-national trial followed by a 26-week period off study-drug
Trial phase: 3a
Protocol originator
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 No unpublished information contained herein may be 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.
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 No unpublished information contained herein may be 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
CONFIDENTIAL
Date:
01 June 2016
Novo Nordisk
Trial ID: NN8022-4180
Version:
1.0
UTN: U1111-1162-7101
Status:
Final
EudraCT no.: 2014-004353-14
Page:
2 of 110
Table of Contents   
Page
Table of Contents..............................................................................................................................................2
Table of Figures................................................................................................................................................7
Table of Tables..................................................................................................................................................7
List of abbreviations.........................................................................................................................................8
1
Summary..................................................................................................................................................13
2
Flowchart .................................................................................................................................................16
3
Background information and rationale for the trial............................................................................20
3.1
Background information..............................................................................................................20
3.2
Rationale for the trial...................................................................................................................23
4
Objectives and endpoints........................................................................................................................24
4.1
Objectives ....................................................................................................................................24
4.2
Endpoints .....................................................................................................................................24
4.2.1
Primary endpoint........................................................................................................24
4.2.2
Secondary endpoints..................................................................................................24
4.2.2.1
Supportive secondary efficacy endpoints............................................24
4.2.2.2
Supportive secondary safety endpoints...............................................25
5
Trial design ..............................................................................................................................................26
5.1
Type of trial .................................................................................................................................26
5.2
Rationale for trial design..............................................................................................................26
5.3
Treatment of subjects...................................................................................................................27
5.4
Treatment after discontinuation of trial product ..........................................................................29
5.5
Rationale for treatment ................................................................................................................29
6
Trial population.......................................................................................................................................31
6.1
Number of subjects......................................................................................................................31
6.2
Inclusion criteria ..........................................................................................................................31
6.3
Exclusion criteria.........................................................................................................................31
6.4
Randomisation criteria.................................................................................................................33
6.5
Criteria for premature discontinuation of trial product................................................................33
6.6
Withdrawal from trial ..................................................................................................................34
6.7
Subject replacement.....................................................................................................................34
6.8
Rationale for trial population.......................................................................................................34
7
Milestones.................................................................................................................................................36
8
Methods and assessments .......................................................................................................................37
8.1
Visit procedures...........................................................................................................................37
8.1.1
Information visit, visit 1.............................................................................................37
8.1.2
Fasting........................................................................................................................37
8.1.3
Screening visit, visit 2................................................................................................38
8.1.4
Run-in visits...............................................................................................................38
8.1.5
Screening failures ......................................................................................................38
8.1.6
Re-screening ..............................................................................................................38
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
01 June 2016
Novo Nordisk
Trial ID: NN8022-4180
Version:
1.0
UTN: U1111-1162-7101
Status:
Final
EudraCT no.: 2014-004353-14
Page:
3 of 110
8.1.7
Randomisation and initial trial product dose .............................................................39
8.1.8
Dose escalation ..........................................................................................................39
8.1.8.1
Dose escalation and tolerability ..........................................................39
8.1.8.2
Tolerability at maximum tolerated dose..............................................40
8.1.8.3
Recording of trial product dose levels in eCRF ..................................40
8.1.9
Withdrawal from trial ................................................................................................40
8.1.10
Premature discontinuation of trial product ................................................................41
8.2
Subject related information/assessments .....................................................................................41
8.2.1
Demography...............................................................................................................41
8.2.2
Concomitant illness and medical history...................................................................41
8.2.2.1
History of psychiatric disorders ..........................................................42
8.2.3
Concomitant medication............................................................................................42
8.2.4
Childbearing potential................................................................................................42
8.2.4.1
Blood sample for pregnancy testing....................................................43
8.2.4.2
Urine-sticks pregnancy testing............................................................43
8.2.5
Tobacco use ...............................................................................................................43
8.3
Efficacy assessments....................................................................................................................43
8.3.1
Body measurements...................................................................................................43
8.3.1.1
Body weight ........................................................................................43
8.3.1.2
Hip and waist circumference...............................................................44
8.3.2
Systolic and diastolic blood pressure.........................................................................44
8.3.3
Patient-reported outcome questionnaire, IWQOL-Kids ............................................45
8.4
Safety assessments.......................................................................................................................46
8.4.1
Height ........................................................................................................................46
8.4.2
Self-measured plasma glucose (SMPG) ....................................................................46
8.4.3
Pulse...........................................................................................................................46
8.4.4
Electrocardiogram – 12 lead......................................................................................47
8.4.5
Recording of menstrual periods.................................................................................47
8.4.6
Physical examination.................................................................................................48
8.4.7
Tanner staging............................................................................................................48
8.4.8
Bone age (x-ray) ........................................................................................................48
8.4.9
Mental health questionnaires .....................................................................................49
8.4.9.1
C-SSRS ...............................................................................................49
8.4.9.2
PHQ-9 .................................................................................................49
8.4.9.3
Potential referral to mental health professional...................................49
8.4.10
Adverse events...........................................................................................................50
8.4.10.1
Medication error..................................................................................50
8.4.10.2
Adverse events requiring additional data collection ...........................50
8.4.10.3
Acute gallstone disease .......................................................................51
8.4.10.4
Neoplasm.............................................................................................51
8.4.10.5
Pancreatitis ..........................................................................................51
8.4.11
Suspicion of acute pancreatitis...................................................................................51
8.4.12
Elevated calcitonin.....................................................................................................52
8.4.13
Hypoglycaemic episodes ...........................................................................................52
8.5
Laboratory assessment.................................................................................................................55
8.5.1
Total blood volume for laboratory assessments.........................................................55
8.5.2
Laboratory reports......................................................................................................55
8.5.3
Laboratory assessments for efficacy..........................................................................56
8.5.4
Laboratory assessments for safety .............................................................................57
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
01 June 2016
Novo Nordisk
Trial ID: NN8022-4180
Version:
1.0
UTN: U1111-1162-7101
Status:
Final
EudraCT no.: 2014-004353-14
Page:
4 of 110
8.5.5
Anti-liraglutide antibodies .........................................................................................58
8.6
Other assessments........................................................................................................................59
8.6.1
Plasma concentration of liraglutide ...........................................................................59
8.6.2
Counselling in healthy nutrition and physical activity...............................................59
8.6.2.1
Counselling in healthy nutrition..........................................................59
8.6.2.2
Counselling in physical activity ..........................................................60
8.6.3
Subject diary ..............................................................................................................60
8.6.3.1
Trial product dosing diary...................................................................60
8.6.3.2
Hypoglycaemic episode diary .............................................................60
8.6.3.3
Menstrual period diary ........................................................................60
8.7
Subject compliance......................................................................................................................60
9
Trial supplies ...........................................................................................................................................62
9.1
Trial products...............................................................................................................................62
9.2
Labelling......................................................................................................................................62
9.3
Storage .........................................................................................................................................63
9.4
Drug accountability and destruction............................................................................................63
9.5
Auxiliary supplies........................................................................................................................64
10 Interactive web response system............................................................................................................65
11 Randomisation procedure and breaking of blinded codes..................................................................66
11.1
Breaking of blinded codes ...........................................................................................................66
12 Adverse events, technical complaints and pregnancies .......................................................................67
12.1
Definitions ...................................................................................................................................67
12.1.1
Adverse event ............................................................................................................67
12.1.2
Serious adverse event.................................................................................................68
12.1.3
Non-serious adverse event.........................................................................................69
12.1.4
Medication errors.......................................................................................................69
12.1.5
Adverse event requiring additional data collection....................................................69
12.1.6
Technical complaints.................................................................................................70
12.2
Reporting of adverse events.........................................................................................................70
12.3
Follow-up of adverse events........................................................................................................72
12.4
Technical complaints and technical complaint samples ..............................................................73
12.4.1
Reporting of technical complaints .............................................................................73
12.4.2
Collection, storage and shipment of technical complaint samples ............................74
12.5
Pregnancies..................................................................................................................................74
12.5.1
Pregnancies in female subjects ..................................................................................74
12.5.2
Pregnancies in female partners of male subjects – US only ......................................75
12.6
Precautions and/or overdose ........................................................................................................76
12.7
Committees related to safety........................................................................................................77
12.7.1
Novo Nordisk safety committee ................................................................................77
12.7.2
Data monitoring committee .......................................................................................77
13 Case report forms....................................................................................................................................78
13.1
Corrections to case report forms..................................................................................................78
13.2
Case report form flow..................................................................................................................79
13.3
Electronic questionnaires.............................................................................................................79
14 Monitoring procedures ...........................................................................................................................80
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
01 June 2016
Novo Nordisk
Trial ID: NN8022-4180
Version:
1.0
UTN: U1111-1162-7101
Status:
Final
EudraCT no.: 2014-004353-14
Page:
5 of 110
15 Data management....................................................................................................................................81
16 Computerised systems.............................................................................................................................81
17 Statistical considerations ........................................................................................................................82
17.1
Sample size calculation................................................................................................................82
17.2
Definitions of analysis sets ..........................................................................................................83
17.3
Primary endpoint..........................................................................................................................84
17.4
Secondary endpoints....................................................................................................................86
17.4.1
Supportive secondary endpoints ................................................................................86
17.4.1.1
Efficacy endpoints...............................................................................86
17.4.1.2
Safety endpoints..................................................................................88
17.5
Pharmacokinetic and pharmacodynamic modelling ....................................................................92
17.6
Health economics and patient reported outcomes........................................................................93
18 Ethics........................................................................................................................................................94
18.1
Benefit-risk assessment of the trial..............................................................................................94
18.2
Informed consent .........................................................................................................................97
18.3
Data handling...............................................................................................................................98
18.4
Information to subjects during trial..............................................................................................98
18.5
Premature termination of the trial and/or trial site.......................................................................98
19 Protocol compliance................................................................................................................................99
19.1
Protocol deviations ......................................................................................................................99
19.2
Prevention of missing data...........................................................................................................99
20 Audits and inspections ..........................................................................................................................100
21 Critical documents ................................................................................................................................100
22 Responsibilities......................................................................................................................................101
23 Reports and publications......................................................................................................................102
23.1
Communication of results..........................................................................................................102
23.1.1
Authorship ...............................................................................................................103
23.1.2
Site-specific publication(s) by investigator(s) .........................................................103
23.2
Investigator access to data and review of results.......................................................................103
24 Retention of clinical trial documentation and human biosamples....................................................104
24.1
Retention of clinical trial documentation...................................................................................104
24.2
Retention of human biosamples.................................................................................................104
25 Institutional Review Boards/Independent Ethics Committees and regulatory authorities............105
26 Indemnity statement .............................................................................................................................106
26.1
For Belgium only.......................................................................................................................106
26.2
For Mexico only.........................................................................................................................106
27 References..............................................................................................................................................107
Appendix A
Body mass index for age
Appendix B
Blood pressure ranges for children
Appendix C
Calcitonin Monitoring
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
01 June 2016
Novo Nordisk
Trial ID: NN8022-4180
Version:
1.0
UTN: U1111-1162-7101
Status:
Final
EudraCT no.: 2014-004353-14
Page:
6 of 110
Attachment I Global list of key staff and relevant departments and suppliers 
Attachment II Country list of key staff and relevant departments
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
01 June 2016
Novo Nordisk
Trial ID: NN8022-4180
Version:
1.0
UTN: U1111-1162-7101
Status:
Final
EudraCT no.: 2014-004353-14
Page:
7 of 110
Table of Figures
Page
Figure 5–1
Trial design.............................................................................................................................26
Figure 12–1
Reporting of AEs....................................................................................................................71
Figure 17–1
Novo Nordisk classification of hypoglycaemia in paediatric subjects...................................90
!Unexpected End of Formula
Table of Tables
Page
Table 5–1
Glycaemic category ................................................................................................................27
Table 9–1
Trial Products .........................................................................................................................62
Table 9–2
Storage conditions ..................................................................................................................63
Table 11–1
Strata.......................................................................................................................................66
Table 17–1
Sample size calculations for different scenarios with total number of randomised 
subjects ...................................................................................................................................83
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
01 June 2016
Novo Nordisk
Trial ID: NN8022-4180
Version:
1.0
UTN: U1111-1162-7101
Status:
Final
EudraCT no.: 2014-004353-14
Page:
8 of 110
List of abbreviations
ACTH
adrenocorticotropic hormone
ADA
American Diabetes Association
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase 
ANCOVA
analysis of covariance 
AST
aspartate aminotransferase 
BG
blood glucose
BOCF
baseline observation carried forward
BMI
body mass index
BUN
Blood urea nitrogen 
CEA
carcinoembryonic antigen 
CI
confidence interval
CRF
case report form
CLAE
clinical laboratory adverse event 
C-SSRS
Columbia Suicidality Severity Rating Scale 
CTX1
type I collagen C-telopeptide
DHEAS
dehydroepiandrosterone sulfate
DMC
data monitoring committee
DUN
dispensing unit number
ECG
electrocardiogram
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
01 June 2016
Novo Nordisk
Trial ID: NN8022-4180
Version:
1.0
UTN: U1111-1162-7101
Status:
Final
EudraCT no.: 2014-004353-14
Page:
9 of 110
eCRF
electronic case report form
FAS
full analysis set
FDAAA
Food and Drug Administration Amendment Act
FFA
free fatty acids 
FPFV
first patient first visit
FPG
fasting plasma glucose
FSH
follicle stimulating hormone
FU
follow-up
GCP
Good Clinical Practice
GLP-1
glucagon-like peptide-1
HbA1c
glycosylated haemoglobin
hCG
human chorionic gonadotrophin
HDL
high density lipoprotein
HOMA-B
homeostasis model assessment of beta-cell 
function 
HOMA-IR
homeostasis model assessment of insulin 
resistance
hsCRP
high sensitivity C reactive protein 
IB
investigator’s brochure
ICH
International Conference on Harmonisation
ICMJE
International Committee of Medical Journal 
Editors
IEC
independent ethics committee
IGF-1
insulin-like growth factor-1 
IMP
investigational medicinal product
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
01 June 2016
Novo Nordisk
Trial ID: NN8022-4180
Version:
1.0
UTN: U1111-1162-7101
Status:
Final
EudraCT no.: 2014-004353-14
Page:
10 of 110
IRB
institutional review board
ISPAD
international society for pediatric and adolescent 
diabetes
ITT
intention-to-treat
IWRS
interactive web response system
IWQOL-Kids
Impact of Weight on Quality of Life-Kids 
LAR
legally acceptable representative
LDL
low density lipoprotein
LH
luteinising hormone 
LLOQ
lower limit of quantification
LOCF
last observation carried forward
LPLV
last patient last visit
MAP
modelling analysis plan 
MedDRA
Medical Dictionary for Regulatory Activities
MEN2
multiple endocrine neoplasia type 2 
MHP
mental health professional 
MI
multiple imputation 
MMRM
mixed model for repeated measurements 
MTC
medullary thyroid carcinoma 
MTD
maximum tolerated dose
NRS
numerical rating scale
NTX1
type I collagen N-telopeptide
P1NP
procollagen 1 N-terminal propeptide
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
01 June 2016
Novo Nordisk
Trial ID: NN8022-4180
Version:
1.0
UTN: U1111-1162-7101
Status:
Final
EudraCT no.: 2014-004353-14
Page:
11 of 110
PD
pharmacodynamic
PDCO
Paediatric Committee
PHQ-9
Patient Health Questionnaire 9
PK
pharmacokinetic
PRO
patient reported outcome
SAE
serious adverse event
SAP
statistical analysis plan
SAS
safety analysis set 
s.c.
subcutaneous(ly)
SD
standard deviation
SDS
standard deviation score
SIF
safety information form
SMPG
self-measured plasma glucose 
SUSAR
suspected unexpected serious adverse reaction
T1DM
type 1 diabetes mellitus 
T2DM
type 2 diabetes mellitus 
T4
thyroxine
TC
total cholesterol 
TEAE
treatment-emergent adverse event 
TG
triglycerides
TMM
Trial Materials Manual
TPD
trial product discontinuation
TSH
thyroid stimulating hormone
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
01 June 2016
Novo Nordisk
Trial ID: NN8022-4180
Version:
1.0
UTN: U1111-1162-7101
Status:
Final
EudraCT no.: 2014-004353-14
Page:
12 of 110
ULN
upper limit of normal
UTN
Universal Trial Number
VLDL
very low density lipoprotein
WBC
white blood cell count 
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
01 June 2016
Novo Nordisk
Trial ID: NN8022-4180
Version:
1.0
UTN: U1111-1162-7101
Status:
Final
EudraCT no.: 2014-004353-14
Page:
13 of 110
1
Summary
Objectives
Primary objective
!
To compare the efficacy of liraglutide versus placebo on weight loss in adolescent subjects with 
obesity after 56 weeks of treatment
Secondary objectives 
!
To compare the efficacy of liraglutide versus placebo on glycaemic control and cardiovascular 
risk factors in adolescent subjects with obesity after 56 weeks of treatment
!
To compare the safety of liraglutide versus placebo in adolescent subjects with obesity after 56 
weeks of treatment
Primary endpoint
Change in body mass index (BMI) standard deviation score from baseline (randomisation) to 56
weeks. 
Key secondary efficacy endpoints:
!
Percent of subjects achieving ≥5% reduction in baseline BMI at week 56
!
Percent of subjects achieving ≥10% reduction in baseline BMI at week 56
!
Change from baseline to 56 weeks
–
BMI
–
Body weight (kilogram [kg], pounds [lb]
–
Body weight (percent [%])
–
Systolic and diastolic blood pressure
–
Glucose metabolism: glycosylated haemoglobin (HbA1c) and fasting plasma glucose
–
Number of treatment emergent adverse events
Trial design:
This is a 56-week double-blind, randomised, parallel-group, placebo-controlled, multi-national trial 
followed by a 26-week period off study-drug. The trial will be conducted in pubertal adolescents 
with obesity aged 12 to less than 18 years. Subjects will be randomised 1:1 to receive liraglutide or 
placebo. The randomisation will be stratified according to pubertal and glycaemic status.
At least 30% of subjects will be from areas with lifestyle and nutrition comparable to those in the 
European Union. All subjects will undergo counselling in healthy nutrition and physical activity for 
weight loss and must be prescribed a structured programme from the beginning of the 12-week 
run-in period and continuing through the 26-week follow-up period off trial drug. 
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
01 June 2016
Novo Nordisk
Trial ID: NN8022-4180
Version:
1.0
UTN: U1111-1162-7101
Status:
Final
EudraCT no.: 2014-004353-14
Page:
14 of 110
Trial population:
A planned total of approximately 342 subjects will be screened. A planned total of 228 subjects will
be randomised.
Key inclusion criteria:
!
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. 
!
Male or female, age 12 to less than 18 years at the time of signing informed consent and less 
than 18 years at date of randomisation
!
BMI corresponding to ≥30 kg/m2 for adults by international cut-off points and ≥the 95th
percentile for age and sex (for diagnosis of obesity)
!
Stable body weight during the previous 90 days before screening V2 (<5 kg self-reported weight 
change)
!
History of failing to lose sufficient weight with lifestyle modification as judged by the 
investigator and documented in subject’s medical record
Key exclusion criteria:
!
Pre-pubertal subjects (Tanner stage 1) at screening V2
!
Type 1 diabetes mellitus (T1DM)
!
Family or personal history of multiple endocrine neoplasia type 2 (MEN2)
!
Medullary thyroid carcinoma (MTC)
!
History of pancreatitis (acute or chronic)
!
Subjects with secondary causes of obesity (i.e., hypothalamic, genetic or endocrine causes) 
!
Treatment with medications within 90 days before screening V2 that, based on the investigator’s 
judgement, may cause significant weight change. This should also include treatment with any of 
the following medications: pramlintide, orlistat, zonisamide, topiramate, lorcaserin, 
phenteremine, bupropion, naltrexone, glucagon-like peptide-1 (GLP-1) receptor agonists, or 
metformin (used as treatment for obesity)
!
Anti-diabetic treatment other than metformin
!
History of major depressive disorder within 2 years before screening V2
Key randomisation criteria:
!
BMI corresponding to ≥30 kg/m2 for adults by international cut-off points and ≥the 95th
percentile for age and sex (for diagnosis of obesity).
!
Compliance with run-in procedures and visit schedule as judged by the investigator.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
01 June 2016
Novo Nordisk
Trial ID: NN8022-4180
Version:
1.0
UTN: U1111-1162-7101
Status:
Final
EudraCT no.: 2014-004353-14
Page:
15 of 110
Assessments:
Efficacy:
!
Body weight
!
Systolic and diastolic blood pressure
!
Patient reported outcome (Impact of Weight on Quality of Life-Kids)
!
HbA1c
!
Fasting plasma glucose
!
Fasting C-peptide
Safety
!
Adverse events
!
Biochemistry and haematology
!
Mental health related questionnaires (Patient Health Questionnaire 9 and Columbia Suicidality 
Severity Rating Scale)
!
Pubertal assessments (Tanner staging)
!
Hormones
!
Antibodies against liraglutide
!
Pulse
!
Bone age (x-ray)
Trial products:
The following trial products will be supplied by Novo Nordisk A/S. Denmark:
!
Liraglutide 6 mg/mL, solution for injection, 3 mL PDS290 pre-filled pen-injector
!
Placebo, solution for injection, 3 mL PDS290 pre-filled pen-injector
CONFIDENTIAL


Protocol
UTN: U1111-1162-7101
Date:
01 June 2016
Status:
Final
Novo Nordisk
Trial ID: NN8022-4180
EudraCT no.: 2014-004353-14
Version:
1.0
Page:
16 of 110
2
Flowchart
Trial Period
Information
Screening
Run-in
Randomisation
Dose Escalation
Maintenance
End of Treatment
Follow-up (FU)
TPD FU 30 weeks
TPD FU 56 weeks
TPD FU 82 weeks
Visit number
1
2
3
41
5
61
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
19
x
25
x
30
x
Timing of visit 
(weeks)
-15
-14
-12
-10
-8
-6
-4
-2
0
1
2
3
4
8
12
16
20
25
30
34
38
42
46
51
56
58
64
70
76
82
30
56
8
2
Visit window (days)
-6
±2
±2
±2
±2
±2
±2
±2
±2
±2
±
2
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±5
±5
±5
±5
-5
±5
±5
±5
SUBJECT RELATED
INFO/ASSESSMENTS
Informed consent and 
assent 18.2
X
In/exclusion criteria 
6.2 6.3
X
X
Randomisation 
criteria 6.4
X
Criteria for premature 
discontinuation of 
trial product 6.5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Demography 8.2.1
X
Concomitant illness 
and medical history 
8.2.2
X2
History of psychiatric 
disorders 8.2.2.1
X
Concomitant 
medication 8.2.3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Tobacco use 8.2.5
X
X
X
X
Childbearing potential 
8.2.4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
EFFICACY
Body weight 8.3.1.1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hip and waist 
circumference 8.3.1.2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Systolic and diastolic 
blood pressure 8.3.2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Lipids 8.5.3
X
X
X
X
X
X
X


Protocol
UTN: U1111-1162-7101
Date:
01 June 2016
Status:
Final
Novo Nordisk
Trial ID: NN8022-4180
EudraCT no.: 2014-004353-14
Version:
1.0
Page:
17 of 110
Trial Period
Information
Screening
Run-in
Randomisation
Dose Escalation
Maintenance
End of Treatment
Follow-up (FU)
TPD FU 30 weeks
TPD FU 56 weeks
TPD FU 82 weeks
Visit number
1
2
3
41
5
61
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
19
x
25
x
30
x
Timing of visit 
(weeks)
-15
-14
-12
-10
-8
-6
-4
-2
0
1
2
3
4
8
12
16
20
25
30
34
38
42
46
51
56
58
64
70
76
82
30
56
8
2
Visit window (days)
-6
±2
±2
±2
±2
±2
±2
±2
±2
±2
±
2
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±5
±5
±5
±5
-5
±5
±5
±5
hsCRP 8.5.3
X
X
X
X
X
X
X
Glucose metabolism 
8.5.3
X
X
X
X
X
X
X
IWQOL-Kids 8.3.3
X
X
X
X
X
SAFETY
Height 8.4.1
X
X
X
X
X
X
X
X
X
X
X
Adverse events 8.4.10
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Technical complaints 
12.4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Additional safety 
assessments, if 
applicable 8.4.10
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hypoglycaemic 
episodes 8.4.13 and 
SMPG 8.4.2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pulse 8.4.3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECG 8.4.4
X
X
X
Pregnancy test3
8.2.4.1 and 8.2.4.2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
First day of menstrual 
period4 8.4.5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination 
8.4.6
X
X
X
X
X
X
X
Biochemistry 8.5.4
X
X
X
X
X
X
X
Haematology 8.5.4
X
X
X
X
X
X
X
Hormones5 8.5.4
X
X
X
X
X
X
Calcitonin 8.4.12, 
8.5.4 and Appendix C
X
X
X
X
X
X
X
Biomarkers (bone 
age) 8.5.4
X
X
X
X
X
X


Protocol
UTN: U1111-1162-7101
Date:
01 June 2016
Status:
Final
Novo Nordisk
Trial ID: NN8022-4180
EudraCT no.: 2014-004353-14
Version:
1.0
Page:
18 of 110
Trial Period
Information
Screening
Run-in
Randomisation
Dose Escalation
Maintenance
End of Treatment
Follow-up (FU)
TPD FU 30 weeks
TPD FU 56 weeks
TPD FU 82 weeks
Visit number
1
2
3
41
5
61
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
19
x
25
x
30
x
Timing of visit 
(weeks)
-15
-14
-12
-10
-8
-6
-4
-2
0
1
2
3
4
8
12
16
20
25
30
34
38
42
46
51
56
58
64
70
76
82
30
56
8
2
Visit window (days)
-6
±2
±2
±2
±2
±2
±2
±2
±2
±2
±
2
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±5
±5
±5
±5
-5
±5
±5
±5
Anti-liraglutide 
antibodies 8.5.5
X
X
X
X
X
X
Tanner staging 8.4.7
X
X
X
X
X
Bone age (x-ray) 8.4.8
X
X6
PHQ-9 and C-SSRS 
8.4.9
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
OTHER 
ASSESSMENTS
Liraglutide plasma 
concentration 8.6.1
X
X
X
X
X
X
X
X
X
Counselling in healthy 
nutrition and physical 
activity 8.6.2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X7
X7
X
X7
X7
X
X7
X7
X
X7
X7
X
X7
X
X
X
X
Healthy nutrition 
compliance 8.6.2.1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
TRIAL MATERIAL
Dispensing visit 9
X
X
X
X
X
X
X
X
X
X
X
X
X
Hand-out direction for 
use for trial product 
8.1.7, 9.2
X
X
X
X
X
X
X
X
X
X
X
X
X
Drug accountability 
9.4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
IWRS session 10
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
New dose of trial 
product 8.1.8
X
X
X
X
REMINDERS
Training in trial 
product and pen 
handling (including 
injection technique)8
8.1.7
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


Protocol
UTN: U1111-1162-7101
Date:
01 June 2016
Status:
Final
Novo Nordisk
Trial ID: NN8022-4180
EudraCT no.: 2014-004353-14
Version:
1.0
Page:
19 of 110
Trial Period
Information
Screening
Run-in
Randomisation
Dose Escalation
Maintenance
End of Treatment
Follow-up (FU)
TPD FU 30 weeks
TPD FU 56 weeks
TPD FU 82 weeks
Visit number
1
2
3
41
5
61
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
19
x
25
x
30
x
Timing of visit 
(weeks)
-15
-14
-12
-10
-8
-6
-4
-2
0
1
2
3
4
8
12
16
20
25
30
34
38
42
46
51
56
58
64
70
76
82
30
56
8
2
Visit window (days)
-6
±2
±2
±2
±2
±2
±2
±2
±2
±2
±
2
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±5
±5
±5
±5
-5
±5
±5
±5
Hand-out BG meter 
8.4.2
X
BG meter finger prick 
test 8.4.2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hand-out diary, 
females 8.6.3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect diary, females 
8.6.3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hand-out diary, males 
8.6.3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect diary, males 
8.6.3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Attend visit fasting 
8.1.2
X
X
X
X
X
X
X
X9
X9
X
End of trial (EoT)
X
Footnotes:
1 Can be performed as phone visit.
2 At V2, all pre-existing conditions should be reported as medical history or concomitant illness.
3 At V2 and V25 performed as serum pregnancy test and from V3-V24 and  V26-V30 performed as urine-stick pregnancy test, if applicable (see Section 8.2.4.1 and 8.2.4.2 ).
4 At screening the first date of last menstrual period should be collected. For other visits, first date of all menstrual periods since the last visit should be collected. 
5 Estradiol for female subjects only and testosterone for male subjects only
6 An x-ray will not be performed at V25 for subjects for whom the bone age evaluation at randomisation indicates that the epiphyses are fused.
7 Can be performed by phone
8 At V3-V24, training in trial product and pen handling (including injection technique) is at the investigator’s discretion.
9 Only 2 hour fasting before blood sampling.


Protocol
CONFIDENTIAL
Date:
01 June 2016
Novo Nordisk
Trial ID: NN8022-4180
Version:
1.0
UTN: U1111-1162-7101
Status:
Final
EudraCT no.: 2014-004353-14
Page:
20 of 110
3
Background information and rationale for the trial
The trial will be conducted in compliance with this protocol, ICH GCP1 and applicable regulatory 
requirements, and in accordance with the Declaration of Helsinki2.
In the case of Mexico, the above will include the following responsibilities for the head of the 
Institution/Health Care Establishment, Ethics, Research and, when applicable, Biosafety 
Committees and sponsor within their scope of responsibility:
!
Investigation follow-up
!
Damages to health arising from the investigation development; as well as those arising from 
interruption or advanced suspension of treatment due to non-attributable reasons to the Subject;
!
Timely compliance of the terms in which the authorization of a research for health in human 
beings had been issued;
!
To present in a timely manner the information required by the Health Authority.
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
The prevalence of obesity in children and adolescents, as well as in adults, has been increasing 
steadily during the past three decades and has reached alarming proportions worldwide3-5. The 
American Medical Association as well as a number of leading institutions such as the National 
Institutes of Health (1998), The Obesity Society (2008) and the American Association for Clinical 
Endocrinology (2012) now classify obesity as a disease, calling for dedicated efforts in prevention, 
diagnosis and treatment6. Paediatric obesity is associated with a number of complications, including 
hypertension, type 2 diabetes mellitus (T2DM), early puberty, menstrual irregularities, polycystic 
ovary syndrome, steatohepatitis, sleep apnoea, asthma, musculoskeletal disorders and psychological 
problems7. Furthermore, paediatric overweight/obesity is an independent risk factor for obesity in 
adulthood8, thus predisposing to future comorbid conditions and reduced life expectancy9, 10. In 
studies conducted in paediatric subjects with obesity, weight loss has been associated with 
improvements in cardiometabolic risk factors, including measures of glycaemic control, beta-cell 
function, insulin sensitivity/resistance, lipid profile, systolic/diastolic blood pressure and metabolic 
syndrome11-14.
Paediatric obesity remains a major public health challenge as treatment options are limited. 
Although lifestyle modification is the recommended first-line treatment, widespread adoption of 
this treatment method and long-term compliance are problematic15-17 and treatment intensification 
may be needed. Currently, orlistat is the only pharmacotherapy with FDA approval for the 
management of obesity in the paediatric population and is indicated for those aged ≥12 years18.
However, orlistat effects modest weight loss in adolescents and treatment compliance is low due to 
gastrointestinal adverse events (AEs)17-19. No medication is currently approved for the treatment of 
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
01 June 2016
Novo Nordisk
Trial ID: NN8022-4180
Version:
1.0
UTN: U1111-1162-7101
Status:
Final
EudraCT no.: 2014-004353-14
Page:
21 of 110
obesity in individuals <18 years in the European Union. For paediatric subjects with severe obesity, 
long-term success of lifestyle interventions and pharmacotherapy has been disappointing, indicating 
the need for more aggressive options such as bariatric surgery20. However, procedural 
complications and the risk of long-term nutritional deficiencies due to suboptimal compliance with 
post-operative lifestyle changes may outweigh the benefits of surgically-assisted weight reduction21.
Thus, effective weight loss treatments with optimised safety/tolerability profiles which do not 
discourage compliance are urgently needed for the paediatric population.
Liraglutide
Liraglutide is a once-daily glucagon-like peptide-1 (GLP-1) analogue with 97% homology to 
human GLP-122, 23. The derivatisation of a fatty acid to GLP-1 resulted in a compound with 
protracted pharmacokinetic properties and made liraglutide suitable for once-daily injection at any 
time of the day22, 23. Liraglutide has been approved for the treatment of adults with T2DM at doses 
up to 1.8 mg/day in approximately 90 countries under the brand name Victoza®. The moderate 
dose-dependent weight loss observed in the T2DM development programme, together with 
improvements in other cardiometabolic risk factors (e.g., glycaemic parameters, systolic blood 
pressure, lipid profile), have prompted the investigation of liraglutide’s potential use for weight 
management24.
The weight management clinical development programme has shown that liraglutide induces 
weight loss through a decrease in appetite and subsequent energy intake, and not through an
increase in energy expenditure25. In the phase 2 dose-finding trial, the 3.0 mg dose of liraglutide 
was the most efficacious in terms of weight loss and improvements in cardiometabolic and 
health-related quality of life endpoints. The safety profile of liraglutide 3.0 mg was generally 
similar to that of liraglutide at lower doses in the T2DM programme. The only types of AEs found 
to be dose-dependent were gastrointestinal disorders. The 3.0 mg dose was further investigated for 
weight management in adults with overweight and obesity (with and without other weight-related 
co-morbidities) in 4 phase 3 trials.
In the weight management development programme, treatment with liraglutide 3.0 mg, as adjunct to 
diet and exercise, resulted in significantly greater weight loss than diet and exercise alone in 
subjects with overweight and obesity with at least one weight-related co-morbidity. Liraglutide 
3.0 mg met the pre-specified mean and categorical weight-loss endpoints in each of the phase 2 and 
3 individual trials. In each trial, more than 35% of subjects in the group assigned to liraglutide 3.0 
mg achieved the 5% weight loss benchmark set forth in the FDA guidance, and the proportion 
achieving the benchmark was more than twice that of the group assigned to placebo (i.e., diet and 
exercise alone)26, 27. Weight loss with liraglutide 3.0 mg was accompanied by positive effects on 
multiple secondary efficacy parameters, including waist circumference, insulin resistance, fasting 
and postprandial glycaemic control, prevalence of pre-diabetes and progression to T2DM, systolic 
blood pressure, lipids and cardiovascular biomarkers, and health-related quality of life. Apart from a 
small increase in gallbladder disease, the safety profile of liraglutide 3.0 mg in adults was consistent 
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
01 June 2016
Novo Nordisk
Trial ID: NN8022-4180
Version:
1.0
UTN: U1111-1162-7101
Status:
Final
EudraCT no.: 2014-004353-14
Page:
22 of 110
with that observed with doses up to 1.8 mg in T2DM; transient gastrointestinal events were reported 
most frequently26, 27.
Non-clinical studies
Liraglutide has been tested for toxicity in single-dose studies in mice, rats and monkeys, and in 
repeated-dose studies for up to 3 months in mice, 6 months in rats and up to 12 months in monkeys. 
In all studies, reductions in food consumption as well as reductions in body weight gain were 
observed in the first 2 weeks. These effects can be ascribed to the pharmacological effect of 
liraglutide.
In 2-year carcinogenicity studies, liraglutide caused dose-dependent and treatment-duration-
dependent thyroid C-cell tumours at clinically relevant exposures in both genders of rats and mice. 
Liraglutide was negative with and without metabolic activation in the Ames test for mutagenicity 
and in a human peripheral blood lymphocyte chromosome aberration test for clastogenicity. 
Liraglutide was negative in repeat-dose in vivo micronucleus tests in rats. Studies in mice 
demonstrated that liraglutide-induced C-cell proliferation was dependent on the GLP-1 receptor and 
that liraglutide did not cause activation of the REarranged during Transfection (RET) proto-
oncogene in thyroid C-cells.
In a 2-year repeat-dose carcinogenicity study of liraglutide injected subcutaneously (s.c.) once a day 
in CD-1 mice, a treatment-related increase in fibrosarcomas was seen on the dorsal skin and 
subcutis (the body surface used for drug injection) in males in the 3.0 mg/kg/day group. These 
fibrosarcomas were attributed to the high local concentration of drug near the injection site. The 
liraglutide concentration in the clinical formulation (6.0 mg/mL) is 10 times higher than the 
concentration in the formulation used to administer 3.0 mg/kg/day liraglutide to mice in the 
carcinogenicity study (0.6 mg/mL).
Liraglutide had no adverse effect on fertility, but an increase in early embryonic deaths occurred at 
1.0 mg/kg/day in female rats. Embryo-foetal toxicity was observed in rats and rabbits at or below 
human systemic exposures. Liraglutide dose-dependently delayed onset of puberty more markedly 
in juvenile female than male rats. Subcutaneous administration of liraglutide to juvenile rats for 10 
weeks produced adverse signs of toxicity among females at a dose level of 0.25 mg/kg/day and 
above, resulting in a marked delay in the attainment of sexual maturation at 0.25 and 1.0 mg/kg/day. 
Males were lesser affected than females. Ovary weights were slightly reduced at treatment end but 
normal after a 4 week off-study-drug recovery period. Following mating after a 4 week off-study-
drug period, slightly low implantation counts and post-partum litter size were noted in females 
previously dosed at 1.0 mg/kg/day, for which a relationship to treatment could not be discounted. 
There were no toxicologically significant changes observed among liraglutide-treated male rats.
Further information regarding the clinical and non-clinical findings for liraglutide can be found in 
the latest edition of the Liraglutide 3.0 mg (Saxenda®) Weight Management investigator’s brochure 
(IB)28 or any updates hereof.
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For an assessment of benefits and risks of the trial; see Section 18.1.
3.2
Rationale for the trial
This trial is part of a Paediatric Investigation Plan for treatment of obesity submitted to and agreed 
with the Paediatric Committee (PDCO), a committee of EMA.  The trial is also a post marketing 
requirement from the FDA.
Paediatric obesity is associated with multiple complications/co-morbidities and adverse long-term 
health consequences7, 8, 10, 29. In clinical studies, weight loss in paediatric subjects with obesity led to 
improvements in these weight-related complications/co-morbidities11-14.
Liraglutide (Victoza®) is approved for the treatment of T2DM in adults at doses up to 1.8 mg22, 23.
Liraglutide (Saxenda®) is approved for weight management in adults at doses up to 3.0 mg30, 31.
To date, two 5-6 week randomised, controlled trials with liraglutide have been completed in 
paediatric subjects. 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 years32. Liraglutide’s safety/tolerability 
and pharmacokinetic (PK) 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, the present large, longer-term 
trial will investigate the efficacy and safety of liraglutide (doses up to 3.0 mg) in inducing weight 
loss and improving glycaemic control in adolescents with obesity (12 to less than 18 years).
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4
Objectives and endpoints
4.1
Objectives
Primary objective
!
To compare the efficacy of liraglutide versus placebo on weight loss in adolescent subjects with 
obesity after 56 weeks of treatment
Secondary objectives 
!
To compare the efficacy of liraglutide versus placebo on glycaemic control, cardiovascular risk 
factors and Impact of Weight on Quality of Life-Kids (IWQOL-Kids) in adolescent subjects 
with obesity after 30 and 56 weeks of treatment
!
To compare the safety of liraglutide versus placebo in adolescent subjects with obesity after 30 
and 56 weeks of treatment
!
To examine the potential rebound effect from end of treatment at week 56 to week 82
4.2
Endpoints
4.2.1
Primary endpoint
Change in body mass index (BMI) standard deviation score (SDS) from baseline (randomisation) to 
56 weeks33.
4.2.2
Secondary endpoints
4.2.2.1
Supportive secondary efficacy endpoints
!
Percent of subjects achieving ≥5% reduction in baseline BMI at weeks 30, 56* and 8234, 35
!
Percent of subjects achieving ≥10% reduction in baseline BMI at weeks 30, 56* and 82
!
Change in BMI SDS from baseline to 30 and 82 weeks and change from 56 weeks to 82 weeks
!
Change from baseline to 30 and 56 weeks and change from 56 weeks to 82 weeks in:
–
BMI* 
–
Body weight (kilogram [kg], pounds [lb] and percent [%])*
–
Waist circumference 
–
Waist-to-hip circumference ratio
–
Cardiovascular risk factors: high sensitivity C-reactive protein (hsCRP) and 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)
–
Systolic and diastolic blood pressure*
–
Glucose metabolism: glycosylated haemoglobin (HbA1c)*, fasting plasma glucose (FPG)*, 
fasting insulin, fasting C-peptide, glycaemic category and homeostasis model assessment of 
beta-cell function and insulin resistance parameters (HOMA-B and HOMA-IR)
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–
Patient reported outcome (PRO) assessed by Impact of Weight on Quality of Life-Kids 
(IWQOL-Kids)
4.2.2.2
Supportive secondary safety endpoints
!
Number of treatment emergent adverse events*
!
Number of treatment emergent hypoglycaemic episodes:
–
According to ADA/ISPAD classification
–
According to Novo Nordisk/ISPAD classification 
!
Occurrence of anti-liraglutide antibodies
!
Change from baseline to 56 weeks in bone age assessment
!
Change from baseline to 30 and 56 weeks and change from 56 weeks to 82 weeks in:
–
Pulse
–
Electrocardiogram (ECG)a
–
Laboratory parameters:
o
Haematology: haemoglobin, haematocrit, thrombocytes, erythrocytes, 
leucocytes, differential count (eosinophils, neutrophils, basophils, lymphocytes, 
monocytes)
o
Biochemistry: creatinine, creatinine kinase, urea (BUN), albumin, bilirubin 
(total), alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
alkaline phosphatase (ALP), sodium, potassium, calcium total, calcium, 
albumin- corrected, amylase, lipase, and carcinoembryonic antigen (CEA)
o
Hormone levels: calcitonin, insulin-like growth factor-1 (IGF-1), thyroid 
stimulating hormone (TSH), free thyroxine (free T4), dehydroepiandrosterone 
sulfate (DHEAS), luteinising hormone (LH), follicle stimulating hormone 
(FSH), estradiol (females), testosterone (males), prolactin, adrenocorticotropic 
hormone (ACTH), cortisol
o
Bone metabolism markers: Type 1 collagen N-telopeptide (NTX1), type 1 C-
telopeptide (CTX1), procollagen 1 N-terminal propeptide (P1NP), alkaline 
phosphatase (bone)
–
Pubertal status
–
Physical examination
–
Height standard deviation score (SDS)
–
Mental health assessed by Columbia Suicidality Severity Rating Scale (C-SSRS) and 
Patient Reported Health Questionnaire 9 (PHQ-9)
aNot assessed at week 82 and does not have associated endpoints.
Key supportive secondary endpoint prospectively selected for disclosure (e.g., clinicaltrials.gov and 
EudraCT) are marked with an asterisk (*)
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5
Trial design
5.1
Type of trial
This is a 56-week double-blind, randomised, parallel-group, placebo-controlled, multi-national trial 
followed by a 26-week period off study-drug. The trial will be conducted in pubertal adolescents 
with obesity aged 12 to less than 18 years. Subjects will be randomised 1:1 to receive liraglutide or 
placebo. The randomisation will be stratified according to pubertal and glycaemic status (see 
Sections 5.2 and 11).
At least 30% of subjects will be from areas with lifestyle and nutrition comparable to those in the 
European Union. All subjects will undergo counselling in healthy nutrition and physical activity for 
weight loss and must be prescribed a structured programme from the beginning of the 12-week 
run-in period and continuing through the 26-week follow-up period off trial drug. The trial design is 
shown schematically below:
Figure 5–1
Trial design
5.2
Rationale for trial design
This trial is designed in accordance with regulatory requirements35 and guidelines34 ,36
The primary endpoint, change in BMI SDS, is selected based on EMA’s recommendation for a 
primary endpoint in the assessment of efficacy of new medicinal products for the treatment of 
obesity in children34. The primary endpoint is assessed at the end of the 56 week double blind 
period. Secondary endpoints are assessed at the end of 30, 56, and 82 weeks. The assessment of 
secondary endpoints at 30 weeks, including BMI SDS, is included as there is a likelihood of a high 
attrition rate in this population of adolescents. Efforts will be made to encourage retention.
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First-line therapy in primary obesity should always be lifestyle modification, rather than 
pharmacotherapy. To reflect this, a 12-week run-in period has been included in the trial design. 
During the run-in period, a structured counselling programme in healthy nutrition and physical 
activity is implemented in alignment with CHMP guidelines34.
The 56-week treatment period is designed to be double-blind in order to avoid/minimise bias during 
the assessment of the primary endpoint. Randomisation is another measure used to minimise bias 
and is expected to lead to comparable subject populations at baseline in the liraglutide and placebo
groups. Stratification according to Tanner staging as described in Section 8.4.7 will be used to 
enable the examination of treatment effect consistency across trial population subgroups. 
Stratification will also be performed according to glycaemic status: normoglycaemia versus 
dysglycaemia (pre-diabetes and T2DM).
Table 5–1
Glycaemic category
Normoglycaemia
FPG <5.6 mmol/L (<100 mg/dL) and/or HbA1c <5.7%
Pre-diabetes
FPG 5.6−6.9 mmol/L (both inclusive), FPG 100–125 mg/dL (both inclusive) or
HbA1c 5.7−6.4% (both inclusive)
Type 2 diabetes (T2DM)
FPG ≥7.0 mmol/L (≥126 mg/dL) and/or HbA1c ≥6.5%
Adapted from37
The stratification is controlled by interactive web response system (IWRS); see Section 11.
Dysglycaemia is expected to occur frequently in this trial population. No interaction was observed 
between glycaemic status and body weight in the adult trial (NN8022-1839: Effect of liraglutide on 
body weight in non-diabetic subjects with obesity or overweight subjects with co-morbidities), and 
a similar pattern of AEs was observed in sub-populations by pre-diabetes status at screening.
The 56-week duration of liraglutide treatment is consistent with regulatory authorities’ 
recommendations for the estimation of safety and stabilisation of treatment effect of a weight-
management product (1 year) and also includes a 4-8 week dose escalation period34, 38.
The 26-week duration of the off-study-drug follow-up period is aligned with regulatory 
recommendations34 and is considered to be sufficient to assess effect maintenance and any evidence 
of rebound, as well as to monitor post-treatment safety. 
5.3
Treatment of subjects
Subjects will undergo a 12-week run-in period during which they will receive counselling in healthy 
nutrition and physical activity. This counselling will continue throughout the 56-week blinded 
period and the 26-week off-study-drug follow-up period.
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Subjects who are eligible for randomisation will be administered liraglutide or placebo by a once-
daily s.c. injections. Placebo contains the same excipients as liraglutide, but no active drug 
substance. Subjects randomised to receive placebo will receive s.c. injections with injection 
volumes corresponding to the liraglutide dose.
The injections can be done either in the abdomen, thigh, or upper arm. Injection region consistency 
is not required throughout the trial.
Injections can be administered at any time of day irrespective of meals. It is recommended that the 
time of injection for a subject is consistent throughout the trial. 
Based on the results of the NN8022-3967 PK trial in pubertal adolescents with obesity (aged 12-17 
years), including model-estimated steady-state exposure, treatment with liraglutide will be initiated 
with 0.6 mg daily for one week and increased in weekly steps of 0.6 mg until a maximum tolerated 
dose (MTD) or the 3.0 mg dose of liraglutide (highest allowed liraglutide dose) is reached. Dose 
escalation will be based on tolerability as judged by the investigator and the duration will be from 
4-8 weeks (see Section 8.1.8.1).
Subjects and their legally acceptable representative (LAR) will be instructed in symptom
recognition and handling of hypoglycaemia, and in blood glucose measurements at randomisation
(see Section 8.4.13). 
Medications that should not be used within 90 days before screening and during the trial are listed 
in Sections 6.3 and 6.5.
Subjects who at screening have a diagnose of T2DM can enter the trial. The only allowed anti-
diabetic treatment is metformin. 
If a subject develops T2DM (Table 5–1) during the course of the trial, he/she will be allowed to 
remain on trial product if glycaemic control can be achieved through healthy nutrition and physical 
activity, according to local standard of care. Furthermore, additional treatment with metformin is 
allowed, at the discretion of the investigator. 
If diabetes treatment other than healthy nutrition, physical activity and metformin is required for 
glycaemic control, the trial product must be discontinued (see Sections 6.5 and 8.1.10).
If a dose is missed, treatment should be resumed as prescribed at the next scheduled dose. An extra 
dose or increase in dose should not be taken for the missed dose. If more than 3 consecutive days 
have elapsed since the last dose, subject should resume dosing at the discretion and direction of the 
investigator.
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5.4
Treatment after discontinuation of trial product
In the 26-week off-study-drug follow-up period, subjects will continue to receive counselling in 
healthy nutrition and physical activity.
After the end of the trial, subjects will be encouraged to continue following healthy nutrition and 
physical activity guidance, at the discretion of their healthcare provider. If trial product is 
discontinued prematurely (see Sections 6.5 and 8.1.10), this also applies.
5.5
Rationale for treatment
As liraglutide will be administered by s.c. injections the same route of administration will be used 
for placebo in order to maintain blinding. The relatively slow absorption and half-life of 
approximately 13 hours make liraglutide suitable for once-daily administration, at any time of the 
day22, 23.
The 3.0 mg dose of liraglutide is chosen as the target maintenance dose in the present trial. In the 
phase 2 dose-finding trial (NN8022-1807) in adults, the 3.0 mg dose of liraglutide (as adjunct to 
diet and exercise) was the most efficacious in terms of weight loss and improvements in 
cardiometabolic and quality of life endpoints. The safety profile of liraglutide 3.0 mg was generally 
similar to that of liraglutide at lower doses; the only types of AEs found to be dose-dependent were 
gastrointestinal disorders that were generally transient. In the subsequent phase 3 trials, liraglutide 
3.0 mg, as an adjunct to a reduced calorie diet along with increased physical activity, induced a 
mean weight loss from baseline of ≥5% that was superior to placebo (i.e., diet and exercise alone). 
Weight loss with liraglutide 3.0 mg was accompanied by positive effects on multiple glycaemic and 
non-glycaemic secondary endpoints. 
Clinical trials in adults with or without obesity and with or without T2DM have demonstrated that 
liraglutide should be initiated at a daily dose of 0.6 mg, with subsequent dose escalation in 0.6 mg 
weekly increments in order to improve gastrointestinal tolerability. Based on the results of the 
NN8022-3967 PK trial in adolescents with obesity aged 12-17 years, liraglutide treatment will be 
initiated at the 0.6 mg dose and will be escalated in weekly increments of 0.6 mg. Given the more 
vulnerable nature of the pediatric population, the liraglutide dose will be escalated only if the 
present dose is tolerated.
In case of tolerability issues, the investigator has an option of prolonging the dose escalation period 
or reducing the trial product dose as described in Section 8.1.8.1. The dose may also be reduced to 
previous dose level in case of intermittent illness as described in Section 8.1.8.2.
Lifestyle modification is the recommended first-line treatment for overweight/obesity in the 
paediatric population15,16. Therefore a 12-week run-in period with structured counselling in healthy 
nutrition and physical activity is included in the trial. Only subjects who, after this lifestyle 
modification attempt, still fulfil the definition of obesity can be randomised (as defined by inclusion 
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and randomisation criteria). Currently, no pharmacologic agents are approved for weight 
management in the paediatric population with obesity in the European Union. Although orlistat has 
FDA approval for the above-mentioned indication in adolescents aged ≥12 years, its weight loss 
efficacy is modest and treatment compliance is low due to gastrointestinal adverse effects17-19.
Therefore, a placebo comparator group will be used to evaluate whether liraglutide, in combination 
with healthy nutrition and physical activity, is more efficacious for the treatment of obesity than 
healthy nutrition and physical activity alone.
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6
Trial population
6.1
Number of subjects 
Number of subjects planned to be screened:
342
Number of subjects planned to be randomised:
228 (~ 33% screening failure rate)
For Mexico only: Out of the 228 subjects, approximately 40 subjects are planned to be randomised 
in Mexico.
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. Male or female, age 12 to less than 18 years at the time of signing informed consent and less 
than 18 years at date of randomisation
3. BMI corresponding to ≥30 kg/m2 for adults by international cut-off points and ≥the 95th
percentile for age and sex (for diagnosis of obesity)
4. Stable body weight during the previous 90 days before screening V2 (<5 kg self-reported 
weight change)
5. History of failing to lose sufficient weight with lifestyle modification as judged by the 
investigator and documented in subject’s medical record
6.3
Exclusion criteria
For an eligible subject, all exclusion criteria must be answered "no".
1. Pre-pubertal subjects (Tanner stage 1) at screening V2
2. Body weight ≤ 60 kg
3. Type 1 diabetes mellitus
4. Calcitonin ≥50 ng/L
5. Family or personal history of multiple endocrine neoplasia type 2 (MEN2) 
6. Medullary thyroid carcinoma (MTC)
7. History of pancreatitis (acute or chronic)
8. Subjects with secondary causes of obesity (i.e., hypothalamic, genetic or endocrine causes) 
9. Treatment with medications within 90 days before screening V2 that, based on the investigator’s 
judgement, may cause significant weight change. This should also include treatment with any of
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the following medications: pramlintide, orlistat, zonisamide, topiramate, lorcaserin, 
phenteremine, bupropion, naltrexone, GLP-1 receptor agonists, or metformin (used as treatment 
for obesity)
10. Anti-diabetic treatment other than metformin
11. Diet attempts using herbal supplements or over-the-counter medications within 90 days before 
screening V2
12. Participation in an organised weight reduction program (e.g., Weight Watchers®) within 90 days 
before screening V2
13. Previous surgical treatment for obesity (excluding liposuction if performed >1 year before 
screening V2)
14. History of major depressive disorder within 2 years before screening V2
15. Any lifetime history of other severe psychiatric disorder (e.g., schizophrenia, bipolar disorder)
16. PHQ-9 score of ≥ 15 at screening V2
17. Any suicidal ideation of type 4 or 5 based on the baseline C-SSRS questionnaire at screening 
V2
18. Any suicidal behaviour within 30 days before screening V2
19. Any lifetime history of suicidal attempt
20. Uncontrolled treated or untreated hypertension >99th percentile for age and gender in children. 
If white-coat hypertension is suspected at screening V2, a repeated measurement at V3 prior to 
other trial-related activities is allowed (last measurement being conclusive)
21. Surgery scheduled for the trial duration period, except for minor surgical procedures, at the 
discretion of the investigator 
22. Subjects with confirmed bulimia nervosa disorder 
23. Diagnosis of malignant neoplasms within the last 5 years prior to screening V2 (except basal 
and squamous cell skin cancer)
24. Known or suspected abuse of alcohol or narcotics
25. Language barrier, mental incapacity, unwillingness or inability to adequately understand or 
comply with study procedures
26. Known or suspected hypersensitivity to trial product or related products
27. Previous participation in this trial. Participation is defined as signed informed consent.
28. Subjects from the same household participating in the trial 
29. Participation in any clinical trial of an approved or non-approved investigational medicinal 
product within 30 days before screening V2
30. Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing 
potential and not using an adequate contraceptive method (adequate contraceptive measure as
required by local regulation or practice)
For Sweden only: Oral (except low-dose gestagen [lynestrenol and norestisteron]), injectable, 
or implanted hormonal contraceptives, intrauterine device, intrauterine system (for example, 
progestin-releasing coil), vasectomized male (with appropriate postvasectomy documentation of 
the absence of sperm in the ejaculate). Use of contraception is not required for female subjects 
who have not yet made their sexual debut and/or are not sexually active.
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For Belgium only: Highly effective methods of birth control are defined as those, alone or in 
combination, that result in a low failure rate (i.e., less than 1% per year) when used consistently 
and correctly; such as implants, injectables, combined oral contraceptives, some intrauterine 
devices, true sexual abstinence (i.e., refraining from heterosexual intercourse during the entire 
period of risk associated with the study treatments) or vasectomised partner.
31. Any condition which, in the opinion of the investigator, might jeopardise subject’s safety or 
compliance with the protocol
6.4
Randomisation criteria
To be randomised, all randomisation criteria must be answered “yes”. 
1. BMI corresponding to ≥30 kg/m2 for adults by international cut-off points and ≥the 95th
percentile for age and sex (for diagnosis of obesity).
2. Compliance with run-in procedures and visit schedule as judged by the investigator.
3. PHQ-9 score < 15 at randomisation
4. No suicidal ideation of type 4 or 5 since last visit based on the C-SSRS questionnaire at 
randomisation
6.5
Criteria for premature discontinuation of trial product 
Efforts must be made so that subjects attend and complete all scheduled visit procedures. 
Randomised subjects should stay in the trial irrespective of lack of adherence to randomised 
treatment, lack of adherence to visit schedule or missing assessments. Only in case a subject or 
subject’s LAR decline any further contact with the site in relation to the trial this will be considered 
as withdrawn from the trial.
The subject may be prematurely discontinued from trial product, at the discretion of the 
investigator, due to a safety concern. The subject must be prematurely discontinued from trial 
product if the following applies:
1. Safety concern (not covered by any of below criteria) or unacceptable intolerability to trial 
product, as judge by the investigator.
2. Included in the trial in violation of the inclusion and/or exclusion criteria and/or randomisation 
criteria 
3. Pregnancy
4. Intention of becoming pregnant
5. In case of code break (see Section 11.1)
6. Suspicion of pancreatitis (see Sections 8.4.10.5 and 8.4.11). Subjects may restart on trial 
product should the suspicion not be confirmed.
7. Diagnosis of medullary thyroid carcinoma
8. Weight loss attempts other than what is agreed with the dietitian as part of the trial intervention
9. If diabetes treatment other than healthy nutrition, physical activity and metformin addition is 
initiated.
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10. Initiation of treatment with medications that, based on the investigator’s judgement, may cause 
significant weight change. This should also include treatment with any of
the following medications: pramlintide, orlistat, zonisamide, topiramate, lorcaserin, 
phenteremine, bupropion, naltrexone, GLP-1 receptor agonists, or metformin (used as treatment 
for obesity)
11. Anti-diabetic treatment other than metformin
12. Initiation of diet attempts using herbal supplements or over-the-counter medications 
13. Inadequate psycho- and/or pharmaco therapeutic treatment of a subject’s psychiatric disorder 
(see Section 8.4.9.3)
14. The subject and/or the subject’s LAR refusal of referral to a mental health professional (MHP) 
and it, in investigator’s opinion, is unsafe for the subject to continue in the trial (see Section
8.4.9.3)
15. Simultaneous participation in another clinical trial of an approved or non-approved 
investigational medicinal product
16. The subject treated with 0.6 mg trial product experiences persistent intolerance as judged by the 
investigator
See Section 8.1.10 for procedures to be performed for subjects discontinuing trial product 
prematurely. 
6.6
Withdrawal from trial
The subject may withdraw consent at will at any time either by the subject and/or by the subject’s 
LAR. The subject’s request to withdraw from the trial must always be respected.
See Section 8.1.9 for procedures to be performed for subjects withdrawing consent.
For Mexico only: Should the subject, his/her family members parents or legal representative decide 
to withdraw the consent for participation in the trial, the subject will be entitled to receive 
appropriate, free of charge medical care and/or trial drug during the follow up period of the protocol 
when it will be established with certainty that no untoward medical consequences of the subject´s 
participation in the research occurred.
6.7
Subject replacement
Subjects who discontinue trial product prematurely or withdraw consent will not be replaced.
6.8
Rationale for trial population
In the weight management programme, liraglutide 3.0 mg as an adjunct to a reduced calorie diet 
along with increased physical activity produced clinically relevant and sustained weight loss in 
adults with overweight or obesity with or without diabetes. Weight loss with liraglutide 3.0 mg was 
accompanied by beneficial effects on multiple secondary efficacy parameters (i.e., glycaemia, blood 
pressure, lipid profile).
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As with adults, the prevalence of overweight/obesity has tripled in the adolescent population during 
the past three decades and current projections predict a further increase3, 7, 39. Paediatric obesity is 
associated with a number of complications, including hypertension, T2DM, early puberty, 
menstrual irregularities, polycystic ovary syndrome, steatohepatitis, sleep apnoea, asthma, 
musculoskeletal disorders and psychological problems7. Furthermore, paediatric overweight/obesity 
is an independent risk factor for obesity in adulthood8, thus predisposing to future comorbid 
conditions and reduced life expectancy10, 29. In the paediatric population, weight loss has been 
associated with improvements in cardiometabolic risk factors, including measures of glycaemic 
control, beta-cell function, insulin sensitivity/resistance, lipid profile, systolic/diastolic blood 
pressure and metabolic syndrome11-14.
No safety/tolerability concerns for adolescents with obesity aged 12−17 years were raised in the 5-6 
week NN8022-3967 trial investigating the safety/tolerability and pharmacokinetics of liraglutide 
doses up to 3.0 mg. Data from the NN8022-3967 trial, as well as the PK modelling analysis based 
on this trial, have resulted in the decision to use a starting dose of 0.6 mg in the current trial. The 
present trial will investigate the efficacy and safety of liraglutide for weight management in the 
same subject population.
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7
Milestones
Planned duration of recruitment period is 52 weeks from global first patient first visit (FPFV).
End of trial is defined as last patient last visit (LPLV).
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 IWRS in order to estimate when 
to stop screening. All investigators will be notified immediately when the recruitment period ends, 
after which no further subjects may be screened and the IWRS will be closed for further screening. 
All subjects screened during the recruitment period and found eligible for randomisation can be 
randomised within the timelines specified in the flowchart (see Section 2).
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 Disclosure40, it will also be disclosed 
according to other applicable requirements such as those of the International Committee of Medical 
Journal Editors (ICMJE) 41, the Food and Drug Administration Amendment Act (FDAAA)42,
European Commission Requirements43-45 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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8
Methods and assessments
The following Sections describe the assessments and procedures that must be performed during this 
trial. The overview of when they must be performed is included in the flowchart (see Section 2).
8.1
Visit procedures
It is the responsibility of the investigator to ensure that all site visits and phone 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.
The investigator must keep a subject screening log, a subject identification code list and a subject 
enrolment log. Only subjects who have signed the informed consent form should be included on the 
logs. The subject screening log and subject enrolment log may be combined in o
8.1.1
Information visit, visit 1
Informed assent and informed consent from the subject’s LAR(s) must be obtained before any 
trial-related activity; 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 IWRS. Each subject will be assigned a unique 6-digit 
subject number which will remain the same throughout the trial.
All subjects must be reminded to attend the screening visit in a fasting state. Screening must take 
place at least 1 day after the information.
8.1.2
Fasting
The subjects must attend some visits fasting; see Section 2. Fasting is defined as having consumed 
no food or drink except for water for the last 8 hours before blood sampling. For V26 and V28, only 
2 hours fasting (i.e. no food or drink except for water) is needed before blood sampling for anti-
liraglutide antibodies and liraglutide plasma concentrations.
Any prescribed medication which should be taken with or after a meal should be withheld on the 
day of the visits attended fasting, until blood sampling and body weight measurements have been 
performed. Trial product can be taken as usual in relation to visits attended fasting except V14, 
V15, V16, V19, V22, and V25; see Section 8.6.1.
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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, visit 2
At screening, subjects will be provided with a card stating that they are participating in a trial and 
giving 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 or to destroy the card after the 
last visit.
All screening assessments as described in Section 2 must be performed and data recorded in the 
eCRF. For screening failures, please refer to Section 8.1.5.
8.1.4
Run-in visits
Subject’s eligibility according to the in- and exclusion criteria must be evaluated before the 
12-week run-in period is initiated. 
V4 and V6 can be performed as phone visits. All subjects must be reminded to attend V8 and the 
randomisation visit in a fasting state.
During the run-in period the investigator should evaluate the subject’s compliance with the run-in 
procedures and visit schedule. If deemed acceptable, as judged by the investigator, the subject can 
proceed to randomisation visit. If not, the subject is a screening failure (8.1.5).
All run-in assessments as described in Section 2 must be performed and data recorded in the eCRF.
For screening failures, please refer to Section 8.1.5.
8.1.5
Screening failures
A screening failure is a subject who does not fulfil one or more of the inclusion and/or exclusion 
and/or randomisation criteria. For screening failures the screening failure form in the electronic case 
report form (eCRF) must be completed with the reason for not continuing in the trial. Serious 
adverse events (SAE) from screening failures must be transcribed by the investigator into the eCRF. 
Follow-up on SAEs must be carried out according to Section 12. A screening failure session must 
be made in the IWRS. The case book must be signed.
8.1.6
Re-screening
Re-screening is NOT allowed if the subject has failed one of the inclusion, exclusion criteria or 
randomisation criteria, this includes re-sampling if the subject has failed one of the exclusion 
criteria related to laboratory parameters.
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8.1.7
Randomisation and initial trial product dose
Subjects’ eligibility according to the randomisation criteria must be evaluated before randomisation. 
To randomise a subject, a randomisation session must be performed in IWRS. Tanner stage, HbA1c
and FPG status from V8 must be entered in IWRS; see Section 11.
All subjects must be instructed in handling of the device and the trial product; see Section 9. This 
should include training in injection site (see Section 5.3) and injection technique. Subjects should be 
instructed to perform an air shot before the use of a new pre-filled pen. At all subsequent visits,
subjects should be re-trained at the investigator’s discretion.
The initial dose of trial product must be injected by the subject or the subject’s LAR at the site and 
this must be documented in the subject’s medical record. The initial dose of trial product must be 
injected post blood sampling.
For training in symptom recognition and handling of hypoglycaemia; see Section 8.4.13. For 
instruction in handling of the BG meter including auxiliary supplies and self-measured plasma 
glucose (SMPG); see Section 8.4.2.
8.1.8
Dose escalation
Treatment with trial product will be initiated at randomisation with 0.6 mg daily for one week and 
increased in weekly steps of 0.6 mg until MTD or the 3.0 mg dose of trial product (highest allowed 
dose) is reached. Ideally, subjects will reach maximum dose of 3.0 mg at V13.
The SMPG measurement performed during dose escalation visits (Section 8.4.2) must be performed 
before instructing the subject in dose escalation. 
8.1.8.1
Dose escalation and tolerability
Dose escalation is based on tolerability as judged by the investigator.
The trial product dose escalation should continue to next dose level only if the present dose is 
tolerated. If, after increasing to next dose level, the dose is poorly tolerated, it is allowed to be 
lowered to the previously dose level.
If a subject has tolerability issues with a given dose level, it is allowed to remain at that 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 
investigators to judge when the subject has reached MTD. 
Escalation of the trial product is not allowed if the subject has a self-measured plasma glucose 
(SMPG) < 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 or during the dose escalation visits, or during contacts (i.e.,
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via telephone). Hypoglycaemic episodes must be reported in the eCRF according to Section 8.4.2, 
8.4.13, 8.5.3 and 12.1.1.
Visits to the clinic occur weekly during the first 4 weeks of dose escalation at V10-V13. Ideally, 
subjects will reach maximum dose of 3.0 mg at V13. 
In those cases where more than one week is needed at any dose escalation step, the subject must 
still follow the visit schedule (V10-V13). For the remaining dose escalation step(s) after V13, is it at 
the discretion of the investigator to be in frequent contact (e.g., by phone) with the subject to ensure 
correct dose settings. The dose escalation process must be finalised no later than V14.
Contacts regarding dose escalation must be documented in the subject’s medical record.
8.1.8.2
Tolerability at maximum tolerated dose
In case a subject experiences tolerability issues at the MTD during the trial, as judged by the 
investigator, the trial product dose may be lowered to the next, lower dose level as needed: 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. 
The reason for lowering the trial product dose must be documented in the subject’s medical record.
If the cause of the subject’s tolerability issues is intermittent illness or otherwise transient, as judged
by the investigator, the subject is allowed to return to MTD again.
If a subject treated with 0.6 mg experiences persistent intolerance, as judged by the investigator, the 
trial product must be discontinued.
8.1.8.3
Recording of trial product dose levels in eCRF
The investigator must record the trial product dose, date of dose level changes and reason for 
changes in the eCRF throughout the trial.
8.1.9
Withdrawal from trial
If a 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 (V25) as soon as possible, and a follow-up visit 
(V26) two weeks later.
If a subject and/or the subjects LAR(s) withdraw consent after end of treatment (V25), the 
investigator must aim to undertake procedures similar to those for the end of trial (V30) as soon as 
possible.
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 
IWRS. The case book must be signed.
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Although a subject is not obliged to give his/her reason(s) for withdrawing consent, 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 withdrawing consent must be specified on 
the end-of-trial form in the eCRF. 
8.1.10
Premature discontinuation of trial product
If a subject prematurely discontinues trial product, the investigator must aim to undertake 
procedures similar to those for the end of treatment (V25) as soon as possible, and a follow-up visit 
(V26) two weeks later.
The subjects must be asked to attend additional visits depending on when the trial product 
discontinuation takes place during the trial:
!
If the trial product is discontinued before V19 subjects must be asked to attend three additional 
visits (V19x, V25x and V30x) taking place weeks 30, 56 and 82 after randomisation, 
respectively.
!
If the trial product is discontinued after V19 and before V25 subjects must be asked to attend 
two additional visits (V25x and V30x) taking place weeks 56 and 82 after randomisation, 
respectively.
The primary reason for premature discontinuation of trial product must be specified on the end of 
trial form in the eCRF, and final drug accountability must be performed. A treatment 
discontinuation session must be made in the IWRS.
8.2
Subject related information/assessments
8.2.1
Demography
Demography will be recorded at screening and consists of:
!
Date of birth (according to local regulation)
!
Sex
!
Ethnicity (according to local regulation)
!
Race (according to local regulation)
8.2.2
Concomitant illness and medical history
A concomitant illness is any illness that is present at the start of the trial (screening visit) or found 
as a result of a screening procedure or other trial procedures performed before exposure to trial 
product. 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 AEs.
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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. Following medical 
history should be reported as a minimum if applicable: diagnose of T2DM, 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.
It must be possible to verify the subject’s medical history in source documents such as subject’s 
medical record. If a subject is not from the investigators own practice; the investigator must make 
reasonable effort to obtain a copy of subject’s medical record from relevant party e.g. primary 
physician. The investigator must document any attempt to obtain external medical information by 
noting the date(s) when information was requested and who has been contacted.
8.2.2.1
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.
8.2.3
Concomitant medication
A concomitant medication is any medication, other than the trial product, which is taken during 
the trial, including the screening, run-in and follow-up periods.
Details of any concomitant medication must be recorded at screening. 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, 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.
8.2.4
Childbearing potential
It must be recorded in the eCRF whether female subjects are of child-bearing potential. 
Female subjects of child-bearing potential must be instructed to use adequate contraceptive methods 
throughout the trial and until 1week after end of treatment.
Pregnancy testing must be performed on female subjects of child bearing potential (females who 
have had their first menstrual period) as described in Sections 8.2.4.1 and 8.2.4.2.
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8.2.4.1
Blood sample for pregnancy testing
At screening and/or V25, a serum pregnancy test must be performed.
If a female subject becomes of child-bearing potential during the trial, a serum pregnancy test must 
be performed as soon as possible or at the latest at the next clinic visit. 
8.2.4.2
Urine-sticks pregnancy testing
Urine-stick pregnancy tests will be performed at the site during the trial if pregnancy is suspected, if 
a menstrual period is missed (unless this is a part of the mode of action of the contraceptive method) 
or if in accordance with local requirements.
Documentation of result of urine-stick pregnancy test must be recorded in the eCRF.
8.2.5
Tobacco use
Details of tobacco use must be recorded according to Section 2. Smoking is defined as smoking at 
least one cigarette or equivalent daily.
Smoking status:
!
Never smoked
!
Previous smoker, smoking stop date
!
Current smoker
8.3
Efficacy assessments
The timing of the assessments is outlined in the flowchart; see Section 2. The assessments 
performed at randomisation are the baseline measurement, unless otherwise specified. 
8.3.1
Body measurements
8.3.1.1
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 digital 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.
Weight should be measured without shoes and only wearing light clothing and the subject should 
have an empty bladder.
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Weight measured at screening is used for the calculation of BMI, whereas weight measured at 
randomisation is used as baseline for assessment of change in body weight. BMI is calculated in the 
eCRF.
8.3.1.2
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 of both hip and waist circumference must be performed in the 
following order: hip, waist, hip, waist, hip, waist; these must be measured in the horizontal plane 
using a non-stretchable measuring tape and rounded up or down to the nearest 0.5 cm or 0.2 inches.
All three measurements must be recorded in the eCRF.
The circumference should be measured when the subject is in a standing position wearing light 
clothing. The subject should have an empty bladder. The subject should be standing, feet together 
with arms down their side and hip and waist 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.
8.3.2
Systolic and diastolic blood pressure
For blood pressure at screening, three measurements must be performed. The mean value is 
calculated by the eCRF and must be used to evaluate eligibility of the subject; see Section 6.3 and 
Appendix B. For the subsequent visits, only one measurement needs to be performed.
If the investigator suspects white coat hypertension at screening one re-assessment at V3 of the 
systolic and diastolic blood pressure (using the same procedure as described below) is allowed as 
described in the exclusion criterion (Section 6.3).
The method for measuring systolic and diastolic blood pressure should follow the standard clinical 
practise at site, but as a minimum, the following guideline must be adhered to: 
!
Caffeine, smoking and exercise at least 30 minutes prior to measuring the blood pressure should 
be avoided.
!
Blood pressure should be measured in a sitting position, with the legs uncrossed, the back and 
arms supported.
!
The subject should be sitting for at least 5 minutes before the first measurement is taken.
!
The subject should not talk during the measurement.
!
The same arm and cuff size should be used for blood pressure measurements at subsequent 
visits.
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Any “abnormal, clinically significant” findings at screening (or V3, if applicable) 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 screening must be 
reported as AEs in accordance with Section 12. 
8.3.3
Patient-reported outcome questionnaire, IWQOL-Kids 
The Impact of Weight on Quality of Life-Kids (IWQOL-Kids) is a disease-specific questionnaire 
which measures the impact of weight on quality of life in adolescents and is validated in youth ages 
11 years and older46. The four concepts captured are:
!
the impact of weight on an individual’s physical mobility and comfort (Physical Comfort)
!
how an individual feels about themselves and their body (Body Esteem)
!
how an individual is treated in their social environment (Social Life)
!
the individual’s perception of what family members may think and feel about them (Family 
Life).
The questionnaire has 27 items and a total, as well as domain-specific score(s), can be derived. The 
scaled scores range from 0–100, with higher scores representing better health-related quality of life.
The questionnaire is a self-administered questionnaire. It must be completed by the subject using an 
electronic device; see Section 13.3, and it must be completed without assistance of the investigator 
or delegated staff. 
At fasting visits, the questionnaire should be completed after all fasting-related activities, but before 
any other visit-related procedures are conducted. Only subjects can make changes in the 
questionnaire.
After completion, the questionnaire must be reviewed by the investigator or delegated staff on the 
same day for potential AEs, including any overall change in health and concomitant medication. 
When reviewing the questionnaires, the investigator should not influence or question the subject on 
the content of the subject’s response to the questionnaire questions. Review of questionnaires must 
be documented in the subject’s medical record.
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8.4
Safety assessments
The timing of the assessments is outlined in the flowchart; see Section 2. The assessments 
performed at randomisation are the baseline measurement, unless otherwise specified. 
8.4.1
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.
8.4.2
Self-measured plasma glucose (SMPG)
At randomisation, subjects will be provided with a blood glucose (BG) meter including auxiliary 
supplies as well as instructions for use. The subjects will be instructed in how to use the device and 
the instruction will be repeated at regular intervals as indicated in the flowchart; see Section 2.
The blood glucose 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. 
Only the blood glucose meter provided by Novo Nordisk should be used for the measurements 
required in the protocol. 
At each visit, the subject must demonstrate how to use the BG meter device by measuring their 
SMPG. The measured SMPG value must be recorded in the subject’s medical record. 
During dose escalation the SMPG measurement must be done before instructing the subject in dose 
escalation; see Section 8.1.8.
Subjects must be instructed to do a SMPG in between visits in case a hypoglycaemic episode is 
suspected and to report hypoglycaemic episodes in the diary (Section 8.6.3.2). Subjects must 
contact the investigator in case of low SMPGs.
8.4.3
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 screening must be 
reported as AEs in accordance with Section 12. 
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8.4.4
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:
!
Normal
!
Abnormal, clinically significant yes/no
If abnormal, a comment must be given. The evaluation should be based on the investigator’s 
judgement.
ECGs performed for any reason unrelated to this trial within 12 weeks prior to screening are 
acceptable, provided no clinical symptoms suggestive of cardiac disease have been identified or 
have 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. 
The ECG from screening is considered baseline. It is allowed to perform the screening ECG after 
screening, but prior to randomisation. 
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.
Any clinically significant worsening or new clinically significant findings after screening must be 
reported as AEs in accordance with Section 12. 
8.4.5
Recording of menstrual periods
Documentation of the first date of the last menstrual period (if applicable) before screening must be 
recorded in subject’s medical record.
First date of all menstrual periods since last visit must be collected from all female subjects (see 
Section 8.6.3.3) and recorded in the eCRF.
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8.4.6
Physical examination
Physical examination must include:
!
General appearance 
!
Head, ears, eyes, nose, throat, neck
!
Respiratory system
!
Cardiovascular system
!
Gastrointestinal system including mouth
!
Musculoskeletal system
!
Central and peripheral nervous system
!
Skin
!
Thyroid gland
!
Lymph node palpation
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 screening must be 
reported as AEs in accordance with Section12. 
8.4.7
Tanner staging
Pubertal development must be assessed by the Tanner staging in accordance with stages 1-547. The 
assessments must be conducted by site staff trained in pubertal assessments. Assessment of 
testicular volume (by orchidometer) stages for males must be included.
Evidence of accelerated pubertal development at screening, as judged by the investigator must be 
recorded as medical history/concomitant illness in the eCRF and in the subject’s medical record 
Acceleration of pubertal development after screening as judged by the investigator must be reported 
as AEs in accordance with Section 12
Tanner staging is not required once the subject reaches the Tanner stage 5, as judged by the 
investigator.
8.4.8
Bone age (x-ray)
An x-ray of left hand and wrist will be performed at randomisation and V25 for all subjects for 
evaluation of bone age. An x-ray will not be performed at V25 for subjects for whom the bone age 
evaluation at randomisation indicates that the epiphyses are fused.
The x-ray imaging data will be submitted to a supplier selected for central medical imaging services 
and will be analysed by an independent paediatric radiology expert assigned by the supplier for 
bone age assessment.
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A bone age x-ray performed within 2 weeks prior to the scheduled assessments is acceptable.
8.4.9
Mental health questionnaires
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, Columbia 
Suicide Severity Rating Scale (C-SSRS) and Patient Health Questionnaire 9 (PHQ-9), have been 
included in the present trial. Data collection will be done using an electronic device (Section 13.3).
8.4.9.1
C-SSRS 
The investigator 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 screening and randomisation 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).
8.4.9.2
PHQ-9
The PHQ-9 should be completed by the subject without interruption. 
The questionnaires completed at screening and randomisation 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 AEs
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.
8.4.9.3
Potential 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 an MHP, if judged relevant by the investigator. If referral is not deemed relevant, this 
must be documented in the subject's medical record.
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A subject must be referred to a MHP if the subject has:
!
a PHQ-9 score ≥ 15 or
!
any suicidal behaviour or
!
any suicidal ideation of type 4 or type 5 on any C-SSRS assessment
!
if, in 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 
why the referral and psychiatric evaluation by an MHP is needed. If the subject refuses to be 
referred to a MHP, the subject’s decision should be documented in subject’s medical record and the 
investigator must assess if the trial product should be discontinued due to safety reasons; see 
Section 6.5.
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.
8.4.10
Adverse events
Adverse events (AEs) must be reported at each visit in accordance with the procedures outlined in 
Section 12. 
8.4.10.1
Medication error
If a medication error is observed during the trial, the following information is required and a 
specific event form must be completed in the eCRF in addition to the AE form: 
!
Trial products involved 
!
Classification of medication error
!
Whether the subject experienced any hypoglycaemic episode and/or AE(s) as a result of the 
medication error 
!
Suspected primary reason for the medication error 
For definition of medication errors; see Section 12.1.4.
8.4.10.2
Adverse events requiring additional data collection
For some AEs additional data collection is required and specific event forms must be completed in 
the eCRF in addition to the AE form:
!
Acute gallstone disease
!
Neoplasm 
!
Pancreatitis
In case any of these events fulfil the criteria for a SAE, please report accordingly; see Section12.
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8.4.10.3
Acute gallstone disease
If an event of acute gallstone disease or clinical suspicion of this is observed during the trial, the
following additional information should be reported if available on the acute gallstone disease form:
!
Signs and symptoms of acute gallstone disease
!
Specific laboratory test supporting a diagnosis of gallstone disease
!
Imaging performed and consistency with gallstone disease
!
Treatment given for the event
!
Relevant risk factors associated with the event
8.4.10.4
Neoplasm
All events of benign, pre-malignant/carcinoma in-situ and malignant neoplasms must be reported
during the trial and the following additional information should be obtained if available as part of
standard of care on the neoplasm form:
!
Type of neoplasm
!
Signs and symptoms leading to identification of event
!
Diagnostic imaging
!
Pathological examination results
!
Treatment given for the event
!
Participation in screening programs
!
Relevant risk factors associated with the event
8.4.10.5
Pancreatitis
If an event of pancreatitis, acute or chronic is observed during the trial, the following information
must be reported, if available on the pancreatitis form:
!
Signs and symptoms of pancreatitis
!
Specific laboratory test supporting a diagnosis of pancreatitis
!
Imaging performed and consistency with pancreatic disease
!
Treatment given for the event
!
Relevant risk factors associated with the event
8.4.11
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 presences of pancreatitis can be excluded. See 
Section 6.5. Appropriate additional examinations must be performed. Measurement of amylase and 
lipase must be done locally. If acute pancreatitis is ruled out, subject should resume dosing at the 
discretion and direction of the investigator. Trial product dose changes must be recorded in the 
eCRF.
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Pancreatitis is confirmed if as a minimum 2 of 3 criteria are met: 
!
Severe acute abdominal pain
!
Blood amylase and/or lipase >3x upper limit of normal (ULN)
!
Characteristic findings on relevant imaging (e.g., computerised axial tomography/magnetic 
resonance imaging/ultrasound)
8.4.12
Elevated calcitonin
If any calcitonin value post randomisation is ≥ ULN a repeat 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.
8.4.13
Hypoglycaemic episodes
At randomisation, all subjects must be instructed in symptom recognition and handling of 
hypoglycaemia.
Plasma glucose should always be measured and recorded when a hypoglycaemic episode is 
suspected. 
All plasma glucose values:
!
≤ 3.9 mmol/L (70 mg/dL) or 
!
> 3.9 mmol/L (70 mg/dL) occurring in conjunction with hypoglycaemic symptoms 
should be reported in the diary according to the instructions below throughout the trial from 
randomisation to V25. See Section 8.6.3.2.
Upon onset of a hypoglycaemic episode the subject is recommended to measure plasma glucose 
every 15 minutes until the SMPG value is > 3.9 mmol/L (70 mg/dL) and/or symptoms have been 
resolved in accordance to current guidelines48.
A SMPG value ≤3.9 mmol/L (70 mg/dL) or hypoglycaemic symptoms must trigger a 
hypoglycaemic episode form to be completed by the subject. Repeated SMPG measurements and/or 
symptoms, occurring within a period of 60 min after onset on a hypoglycaemic episode, will by 
default be considered as one hypoglycaemic episode until a succeeding SMPG value is > 3.9 
mmol/L (70 mg/dL) and/or symptoms have been resolved and should be reported on one 
hypoglycaemic episode form. SMPG measurements ≤3.9 mmol/L (70 mg/dL) or hypoglycaemic 
symptoms after the 60 min period shall trigger the reporting of a new hypoglycaemia episode and 
prompt the subject to fill out a new hypoglycaemic episode form until a succeeding measurement is 
> 3.9 mmol/L (70 mg/dL) and/or symptoms have been resolved.
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In case of several low SMPG values within the 60 minutes interval, the lowest value is the one that 
will be reported as the SMPG value for the hypoglycaemic episode but the start time of the episode 
will remain as the time for the first SMPG value and/or symptom.
The record should include the following information:
!
Start date and time of the hypoglycaemic episode. 
!
The plasma glucose level before treating the episode (if available) and any follow up 
measurements. 
The lowest value measured during the hypoglycaemic episode will be reported as the plasma 
glucose value for the episode. The remaining values will be kept as source data in the diary.
!
Whether the episode was symptomatic (Yes/No).
A hypoglycaemic episode starting without symptoms should be updated to symptomatic if the 
subject experience symptoms later during the episode.
!
Was the hypoglycaemic episode associated with severe neuroglycopenia, usually resulting in 
coma or seizure and requiring parenteral therapy (glucagon or intravenous glucose)? 49 (Layman 
language used in the diaries: Was the low blood glucose episode associated with symptoms 
severe enough to result in unconsciousness or a seizure and was glucagon (an injection) or IV 
glucose/sugar (drip) needed for your child to recover?).
If the severity of a hypoglycaemic episode aggravates, only one hypoglycaemic episode should 
be reported reflecting the most severe degree of hypoglycaemia. 
!
Date, time and dose of last trial product administration prior to the episode
!
Date and time of last main meal (not including snacks) prior to the episode
!
Whether the episode occurred in relation to physical activity
!
Change in any concomitant illness.
!
Any sign of fever and/or other acute disease. 
!
Whether the subject was asleep when the episode occurred
–
If yes, whether the symptoms of the episode woke up the subject
If the question "Was the hypoglycaemic episode associated with severe neuroglycopenia, usually 
resulting in coma or seizure and requiring parenteral therapy (glucagon or intravenous glucose)?" is 
answered "YES", the hypoglycaemic episode is classified as “severe”49 and the following 
information should be recorded: 
!
Who assisted in the treatment of the hypoglycaemic episode (i.e. medical person or non-medical 
person)?
!
Where the treatment was administered (in clinic/emergency room/hospital or other. If the 
subject was treated in clinic/emergency room/hospital, whether they were transported in an 
ambulance or not)
!
Type of treatment provided by other person (i.e. oral carbohydrates, glucagon, IV glucose or 
other)
!
Were symptoms alleviated after administration of treatment?
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!
Factors contributing to the episode (i.e. physical activity, missed meal, diet change, medication 
error (i.e. overdose, mix-up between products, incorrect use of device), other factors not listed 
or unknown).
!
Did the subject experience seizure?
!
Did the subject experience loss of consciousness?
!
Did the subject experience any of the following symptoms49 (layman term used in the diary is 
specified in brackets if different from the protocol term)?
–
Autonomic: Shakiness, sweatiness, trembling, palpitations (Rapid and irregular heart beat) 
and pallor (extreme paleness)
–
Neuroglycopenic: Poor concentration, blurred or double vision, disturbed colour vision, 
difficulty hearing, slurred speech, poor judgment and confusion, problems with short-term 
memory, dizziness and unsteady gait
–
Behavioural signs and symptoms: Irritability, erratic behaviour, agitation (restlessness 
associated with irritability and tension), nightmares, inconsolable crying
–
Non-specific symptoms: Hunger, headache, nausea, tiredness
–
Other symptoms?
Oral carbohydrates should not be given if the subject is unconscious.
If the subject experiences a severe hypoglycaemic episode, the subject or LAR should be instructed 
to contact the investigator as soon as possible after recovery for further guidance. 
The investigator must review the diary for low SMPG values not reported as hypoglycaemic 
episodes. The subject must be questioned whether any of the low values were severe, i.e. whether 
the subject was able to self-treat or not. If the subject was not able to self-treat, it has to be reported 
as a severe hypoglycaemic episode.
Low SMPG values for non-severe hypoglycaemic episodes not having a hypoglycaemic episode 
form completed within 7 days since the SMPG measurement should be reported on a 
hypoglycaemic episode form with as much information as possible. Novo Nordisk will not query 
for additional data except for the start date, SMPG value and whether the subject was able to self-
treat due to decreased validity of such data50, 51.
The subject must be re-trained in how to report hypoglycaemic episodes if the investigator identifies 
low SMPG values not reported as hypoglycaemic episodes.
If the hypoglycaemic episode fulfils the criteria for an SAE then an AE form and a safety 
information form must also be filled in; see Section 12.
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8.5
Laboratory assessment
Blood samples may be drawn on another day than the day of the actual visit, as long as it is within 
the visit window outlinedin the flowchart (see Section 2).
Laboratory assessments will be 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.
Laboratory samples are destroyed on an ongoing basis or,at the latest,at the completion of the 
clinical trial report, except antibody samples.
Only laboratory samples specified in the protocol must be sent to the central laboratory for analysis. 
If additional laboratory sampling is needed, e.g. to follow-up on AEs, this must be done at a local 
laboratory.
All laboratory samplesmust be sent to the central laboratory and the results will be reported to the 
investigator on an ongoing basis.Anti-liraglutide antibody results and the results of the liraglutide 
plasma concentration analysis will not be provided to the investigator, as these results will not be 
used for any clinical evaluation during the trial and would potentially unblind the treatment.
Antibody samples will be stored as described in Section24.2.
HOMA-B and HOMA-IR results (calculated by Novo Nordisk A/S) will not be reported to 
investigators during the trial but will be included in the clinical trial report.
For Mexico only:The handling, transportation and storage of biological samples are described in 
the laboratory manual (for central laboratory details;see Attachment I).
8.5.1
Total blood volume for laboratory assessments
Approximately 197 mL blood will be collected from each subject during the entire trial period. 
Blood collection should be performed in accordance with the guidelines in EU Directive 
2001/20/EC52.
8.5.2
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.
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Review of laboratory reports must be documented (signed and dated) either on the document or in 
the subject’s medical record. The evaluation of screening results must be dated and signed prior to
randomisation 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.
The laboratory reports and evaluations must be retained as source documentation.
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 
Sections 8.2.2 and 12.
8.5.3
Laboratory assessments for efficacy
Any “abnormal, clinically significant” findings at screening 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):
!
Total cholesterol
!
LDL-cholesterol
!
VLDL-cholesterol
!
HDL-cholesterol
!
Triglycerides
!
FFA
!
Non-HDL cholesterol (calculated value from central lab)
Biochemistry:
!
hsCRP
Glucose metabolism (The measurement performed at V8 is considered baseline):
!
HbA1c
!
FPGa
!
Fasting insulin
!
Fasting C-peptide
HOMA-B and HOMA-IR will be calculated on glucose metabolism parameters to asses beta-cell 
function and insulin resistance.
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aFasting plasma glucose
An FPG result ≤3.9 mmol/L (70 mg/dL) should not be reported as a hypoglycaemic episode but as 
a clinical laboratory adverse event (CLAE) at the discretion of the investigator; see Section 12.1.1. 
8.5.4
Laboratory assessments for safety
Any “abnormal, clinically significant” findings at screening (and randomisation for hormones) must 
be recorded as medical history/concomitant illness in the eCRF. The following blood samples must 
be drawn (for frequency, see Section 2):
Pregnancy test:
!
hCG (see Section 8.2.4.1)
Biochemistry:
!
Creatinine
!
Creatine kinase
!
Urea (BUN)
!
Albumin
!
Bilirubin, total
!
ALT
!
AST
!
ALP
!
Sodium
!
Potassium
!
Calcium, total
!
Calcium, albumin corrected
!
Amylase
!
Lipase
!
CEA
Haematology:
!
Haemoglobin
!
Haematocrit
!
Thrombocytes
!
Erythrocytes
!
Leucocytes
!
Differential count: 
–
basophils
–
eosinophils 
–
lymphocytes 
–
monocytes 
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–
neutrophils
Hormones:
!
Calcitonin (values above ULN); refer to Section 8.4.12 and Appendix C
!
Prolactin
!
FSH
!
Estradiol (female subjects)
!
LH
!
Testosterone (male subjects)
!
TSH
!
free T4
!
ACTH
!
Cortisol
!
DHEAS
!
IGF-I
Bone metabolism markers
!
NTX1
!
CTX1
!
P1NP
!
alkaline phosphatase (bone)
8.5.5
Anti-liraglutide antibodies
Blood samples for determination of anti-liraglutide antibodies should be collected from all subjects
and sent via central laboratory to special laboratory for analysis; see Section 2. Only samples from 
subjects treated with liraglutide will be analysed for anti-liraglutide antibody development. A 
randomisation list will be provided to the special laboratory.
Subjects must be instructed to withhold their trial product dose in the morning until blood sampling 
is performed on the visit.
Samples are analysed by the special laboratory for anti-liraglutide antibody formation including 
cross reactivity to endogenous GLP-1. Follow up samples that are found to be positive for anti-
liraglutide antibodies will be analysed for in vitro neutralising effect to liraglutide. Antibody 
positive follow up samples that are found to cross react with endogenous GLP-1 will, in addition, be 
analysed for in vitro neutralising effect against endogenous GLP-1. The last-mentioned analyses 
will be performed by Novo Nordisk A/S. See Sections 8.5.4 and 24.2. 
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8.6
Other assessments
8.6.1
Plasma concentration of liraglutide 
Blood samples for assessment of liraglutide plasma concentration should be collected and sent via 
central laboratory to special laboratory for analysis; see Section 2. A randomisation list will be 
provided to the special laboratory. Samples from randomised subjects will be analysed for 
liraglutide plasma concentration.
Subjects must be instructed to withhold their trial product dose in the morning until blood sampling 
is performed on the visit. Any dose taken by mistake in the morning before the visit must be 
recorded in the eCRF Section made for the purpose.
The subjects must be instructed to complete the dosing diary for liraglutide plasma concentration 
assessment (see Section 8.6.3.1). The doses, dates and exact time for blood sampling must be 
recorded in the eCRF.
The blood samples taken at V26, V28 and V30 for liraglutide plasma concentration assessments are
not part of the liraglutide pharmacokinetic and pharmacodynamic modelling plan (see Section 17). 
The purpose of these assessment are to preclude any false negative antibody results. Hence 
recordings in the subjects’ dosing diary and eCRF are not requested for these samples. 
8.6.2
Counselling in healthy nutrition and physical activity
8.6.2.1
Counselling in healthy nutrition
Subjects (and subjects’ LAR, as applicable) must receive individualised counselling in healthy 
nutrition with the goal of obtaining a weight loss. The counselling must be performed by a certified 
dietitian according to local standard. The focus of the counselling in healthy nutrition must be 
facilitating healthier food choices.
If a BMI corresponding to ≤ 25 kg/m2 for adults by international cut-off point53 is reached, subjects 
should be assigned a maintenance diet, at the discretion of the investigator. For details, refer to 
Appendix A.
Counselling in healthy nutrition can be done by phone and must be documented in subject’s 
medical record.
Healthy nutrition compliance must be evaluated at every visit by the dietitian, using a numerical 
rating scale (NRS), and the results must be provided to the investigator. The investigator or 
delegated staff must record the NRS into the eCRF.
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8.6.2.2
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 with a goal of 60 minutes of moderate to high intensity physical 
activity per day54.
8.6.3
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 either on the document 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. 
All data from the diary must be transcribed into the eCRF.
The diary will include three different Sections as specified in Sections 8.6.3.1, 8.6.3.2 and 8.6.3.3.
8.6.3.1
Trial product dosing diary
Trial product dosing diary pages should be completed by the subject on the last three days before a 
visit including a blood sampling for liraglutide plasma concentration (see Section 8.6.1).
The last 3 doses of trial product should be recorded in the diary with:
!
Dose
!
Date
!
Exact time for dosing
8.6.3.2
Hypoglycaemic episode diary
The hypoglycaemic episode diary pages should be completed if the subject recognises a 
hypoglycaemic episode in between visits (see Section 8.4.2). 
8.6.3.3
Menstrual period diary
The menstrual period diary forms should be completed by all female subjects during the trial. The 
first day of all menstrual periods, if applicable, should be recorded in the diary.
8.7
Subject compliance
Throughout the trial, the investigator will remind the subjects to follow the trial procedures and 
requirements to ensure subject compliance. If a subject is found to be non-compliant, the 
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investigator will remind the subject of the importance of following the instructions given including 
taking the trial products as prescribed.
Treatment compliance: 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 investigational medicinal products (IMP). The investigator 
must assess the amount of IMPs returned compared to what was dispensed at the last dispensing 
visit and, in case of discrepancies, question the subject (see Section 9.4).
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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 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
Strength
Dosage form
Route of 
administration
Delivery device
Liraglutide 
Investigational medicinal 
product (IMP)
6 mg/mL
Solution for 
injection
Subcutaneous 
injection (s.c.)
PDS290 pen-injector for 
liraglutide/placebo (0.6 mg/ 1.2 
mg/1.8 mg/2.4 mg/ 3.0 mg) 
Placebo
Investigational medicinal 
product (IMP)
0 mg/mL
Liraglutide and placebo are visually identical. 
If metformin is used by the subjects, it will be regarded as a concomitant medication and will not be 
provided by Novo Nordisk.
9.2
Labelling
The trial products will be labelled in accordance with Annex 1355, 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 IWRS. Trial product 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 and at all subsequent dispensing visits.
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9.3
Storage 
Table 9–2
Storage conditions
Trial product
Storage conditions
(not-in-use)
In-use conditions
In-use timea
Liraglutide 6 mg/mL 
Store in a refrigerator 
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 2°C to 
8°C
US only: At room 
temperature (59°F-86°F) or 
in a refrigerator (36°-46°F)
Protect from light
Do not freeze
Use within one month
US only: Use within 30 
days
Placebo
a In-use time starts when the product is taken out of the refrigerator at subjects home.
The investigator must ensure that trial product is kept under proper storage conditions and 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). Additional 
details regarding handling of temperature deviations can be found in the TMM.
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 of all trial products received at site is the responsibility of the investigator.
Returned trial product (used/partly used and/or unused), expired or damaged trial product can be 
stored at room temperature and must be stored separately from non-allocated trial product.
Non-allocated trial products including expired or damaged products must be accounted as unused at 
the latest at closure of the trial site.
Drug accountability is performed using the IWRS drug accountability module. The trial products 
must be accounted for at pen level and either recorded as used/partly used, unused or lost. Returned 
pens must be sent for destruction, thus may not be re-allocated to new subjects.
Destruction of trial products can be performed on an on-going basis and will be done according to 
local procedures after accountability is finalised and reconciled by the monitor. Destruction of 
products must be documented in the IWRS.
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9.5
Auxiliary supplies
The following will be provided by Novo Nordisk in accordance with the TMM:
!
Direction for use for PDS290 pen-injector for trial product 
!
Needles for the device (maximum length to be used is 8 mm)
!
BG meters and BG-meter auxiliary supplies
Only needles provided by Novo Nordisk must be used for administration of trial product.
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10 Interactive web response system
A trial-specific IWRS will be set up which can be accessed at any time via the internet or telephone. 
Access to the IWRS must be restricted to and controlled by authorised persons. 
IWRS is used for: 
!
Screening
!
Screening failure
!
Randomisation
!
Medication arrival
!
Dispensing
!
Treatment discontinuation
!
Completion
!
Code break
!
Drug accountability
!
Data change
IWRS user manuals will be provided to each trial site.
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11 Randomisation procedure and breaking of blinded codes
At randomisation, the subjects will be randomised to one of two parallel treatment groups: 
liraglutide 3.0 mg or placebo. The randomisation will be carried out in a 1:1 manner using the 
IWRS.
The randomisation will be stratified according to pubertal and glycaemic status (see Sections 5.2). 
Stratification will be controlled by the IWRS. The strata are:
Table 11–1
Strata
Tanner 2 or 3
Dysglycaemia yes
Tanner 2 or 3
Dysglycaemia no
Tanner 4 or 5
Dysglycaemia yes
Tanner 4 or 5
Dysglycaemia no
Dysglycaemia is defined as T2DMorpre-diabetes with FPG ≥5.6 mmol/L (≥100mg/dL) and/or 
HbA1c≥ 5.7%(see Table 5–1). The laboratory results from V8must be used for this purpose.
11.1
Breaking of blinded codes
The IWRS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 IWRS, 
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 IWRS is not accessible at thetime of code break the 
IWRS helpdesk should be contacted. Contact details are listed in Attachment I.
If the code has been broken, the subject must discontinue treatment with trial product (see Section
6.5) and a treatment discontinuation session must be completed in IWRS.
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12 Adverse events, technical complaints and pregnancies
12.1
Definitions
12.1.1
Adverse event 
An adverse event (AE) is any untoward medical occurrence in a subject administered a medicinal 
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:
!
A clinically significant worsening of a concomitant illness.
!
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:
!
Pre-existing conditions, including those found as a result of screening or other trial procedures 
performed before exposure to trial product (pre-existing conditions should be reported as 
medical history or concomitant illness).
!
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.
!
Non-serious hypoglycaemia is an AE, but is reported on a hypoglycaemic episode form instead 
of on an AE form; see Section 8.4.13.
The following three definitions are used when assessing an AE:
!
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.
!
Causality 
Relationship between an AE and the relevant trial products: 
–
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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!
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.
12.1.2
Serious adverse event
A serious adverse event (SAE) is an experience that at any dose results in any of the following:
!
Death.
!
A life-threateninga experience.
!
In-patient hospitalisationb or prolongation of existing hospitalisation.
!
A persistent or significant disability or incapacityc.
!
A congenital anomaly or birth defect.
!
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
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 
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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 dyscrasia 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:
!
suspicion of transmission of infectious agents via the trial product 
!
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).
12.1.3
Non-serious adverse event
A non-serious AE is any AE which does not fulfil the definition of an SAE.
12.1.4
Medication errors
A medication error concerning trial products is defined as:
!
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), misuse or 
abuse of trial product.
!
Accidental administration of a lower or higher dose than intended. That is a dose lower or 
higher than 0.6, 1.2, 1.8, 2.4 and 3.0 mg respectively (within 24 hours). However the 
administered dose must deviate from the intended dose to an extent where clinical consequences 
for the trial subject were likely to happen as judged by the investigator, although they did not 
occur.
Medication errors must be reported on an AE form and a specific event form (medication error 
form); see Section 8.4.10.1.
12.1.5
Adverse event requiring additional data collection
AEs requiring additional data collection are AEs where the additional data will benefit the
evaluation of the safety of the trial product.
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In this trial the following AEs require the completion of specific event forms in the eCRF:
!
Acute gallstone disease
!
Neoplasm 
!
Pancreatitis
For details; see Section 8.4.10.2.
12.1.6
Technical complaints
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:
!
The physical or chemical appearance of trial products (e.g., discoloration, particles or 
contamination)
!
All packaging material including labelling
!
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 (week 82). The events must be recorded in the applicable eCRF 
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?”
All AEs, either observed by the investigator or subject, must be reported by the investigator and 
evaluated.
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 safety information form 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. 
For all non-serious AEs, the applicable forms should be signed when the event is resolved or at the 
end of the trial at the latest.
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Timelines for initial reporting of AEs:
The investigator must complete the following forms in the eCRF within the specified timelines:
SAEs: The AE form within 24 hours and the safety information form 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. 
For SAEs requiring reporting on a specific event form:In addition to the above the specific 
event form within 14 calendar days from the investigator’s first knowledge of the AE.
If the eCRF is unavailable, the concerned AE information must be reported on a paper AE form 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 form into the 
eCRF. See Section 13.
Contact details (fax, telephone, e-mail and address) are provided in the investigator trial master file. 
AE identified
Does the AE require 
a specific event 
form?
AE form < 24 hours
SIF < 5 calendar days
Specific event form 
For SAEs: 
< 14 calendar days
Is the Adverse Event 
serious or non-
serious?
AE form
Queries and follow-up 
requests to be resolved 
< 14 calendar days
Timelines are for the completion of forms from the time of investigator’s awareness
AEs requiring specific event forms are descibed in Section 12.1.4 and 12.1.5
AE: Adverse event
SAE: Serious adverse event
SIF: Safety information form
No additional action
Serious
Yes
Non-serious
No
Figure 12–1
Reporting of AEs
Novo Nordisk assessment of AE expectedness:
Novo Nordisk assessment of expectedness is performed according to the following reference 
documents: Company Core Data Sheet (CCDS), current version and any updates thereto.
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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 ICH GCP1. In addition, the 
investigator will be informed of any trial-related SAEs that may warrant a change in any trial 
procedure.
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 ICH GCP1
unless locally this is an obligation of the investigator.
Novo Nordisk products used as concomitant medication or non-investigational medicinal 
product:
If an AE is considered to have a causal relationship with a Novo Nordisk marketed product used as 
non-investigational medicinal product or 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 AE 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 must be reported to Novo Nordisk according to the following:
!
SAEs: 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. 
!
Non-serious AEs: 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 recovered/not resolved”. Cases can be closed with the outcome 
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of “recovering/resolving” when the subject has completed the follow-up period and is expected 
by the investigator to recover.
The investigator must ensure that the recording of 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.
SAEs after end of trial: If the investigator becomes aware of an SAE with a suspected causal 
relationship to the investigational medicinal product occurring to a subject after the subject has 
ended the trial, the investigator should report this SAE within the same timelines as for SAEs 
during the trial. 
12.4
Technical complaints and technical complaint samples
12.4.1
Reporting of technical complaints 
All technical complaints on any of the following products:
!
liraglutide PDS290 pre-filled pen injector
!
Placebo PDS290 pre-filled pen injector
!
Novo Nordisk 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 and/or SAEs.
Technical complaints mustbe reported on a separate technical complaint form: 
!
One technical complaint form must be completed for each affected DUN
!
If DUN is not available, a technical complaint form for each batch, code or lot number 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:
!
Technical complaint assessed as related to an SAE within 24 hours
!
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 
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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 copyof the technical complaint form must be included 
in the shipment of the sample. If several samples are returned in one shipment, the individual 
sample and the corresponding technical complaint form must be clearly separated.
The investigator must ensure that the technical complaint sample contains the batch, code or lot 
number and, if available, the DUN. All parts of the DUN should be returned.
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.
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 
product(s).
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.
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.
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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: 
!
AE forma within 14 calendar days of the investigator’s first knowledge of the initial or follow-
up information to the non-serious AE.
SAEs: 
!
AE forma within 24 hours of the investigator’s first knowledge of the SAE.
!
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.
a
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. If the AE occurred in the foetus or newborn infant, the AE 
can only be reported on paper AE and safety information form.
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.
12.5.2
Pregnancies in female partners of male subjects – US only
Male subjects must be instructed to notify the investigator if their female partner becomes pregnant 
during the trial, except in the screening and run-in period. At the last scheduled visit, male subjects 
must be asked if their female partner has become pregnant.
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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.
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). One case of a -fold overdose (
 mg daily) given for  months has 
been reported. Generally, the patients reported severe nausea, vomiting and diarrhoea, but recovered 
without complications. None of the reports included severe hypoglycaemia. In the event of 
overdose, appropriate supportive treatment should be initiated according to the patient’s clinical 
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signs and symptoms. Refer to the latest edition of the Liraglutide 3.0 mg (Saxenda®) Weight 
Management investigator’s brochure (IB)28 or any updates hereof. 
When initiating treatment with liraglutide, the subject may, in some cases, experience loss of 
fluids/dehydration (e.g., in cases of vomiting, nausea or diarrhoea). It is important to avoid 
dehydration by drinking plenty of fluids.
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 an independent, external committee 
composed of members whose expertise covers relevant specialties including statistics. The DMC is 
established to review and evaluate accumulated data from the trial at predefined time points as well 
as ad-hoc. This is in order to protect the safety of the subjects and to evaluate the benefit-risk 
balance. The DMC will have access to unblinded data, and will provide recommendations on trial 
continuation, modification or termination.
Information regarding responsibilities, procedures and workflow to be used by the DMC are 
specified in the DMC charter.
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13 Case report forms 
For 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 EDC Data Entry Guideline.
The following will be provided as paper CRFs:
!
Pregnancy forms
The following will be provided as paper CRFs to be used when access to the eCRF is revoked or if 
the eCRF is unavailable:
!
AE forms
!
Safety information forms
!
Technical complaint forms (also to be used to report complaints that are not subject related [e.g., 
discovered at trial site before allocation]).
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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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.
13.3
Electronic questionnaires
Novo Nordisk will use a SitePad at sites for electronic recording of PROs (see Section 8.3.3) and 
mental health questionnaires (see Section 8.4.9). The SitePad and related support services will be 
provided by an external supplier that will be working under the direction and supervision of Novo 
Nordisk.
Subjects will be instructed in the use of the SitePad before entering any data. The SitePad will 
contain built in edit checks, to ensure that all relevant questions are answered. The SitePad device is 
not intended to support the subsequent review and modification of completed entries. In case of 
need for corrections of the transferred data, a query flow must be initiated by the investigator. An 
audit trail will be maintained.
All data entered will be transferred automatically from the device to an electronic database from 
where a certified copy will be saved on a CD-ROM and shipped to the sites after completion of the 
trial. A secure web portal will be the source data. Data entered on the devices will upon 
confirmation of a successful back-up be deleted from the device.
Data in the electronic database will be viewable to relevant site and Novo Nordisk staff through a 
secure and password-protected web portal. Data will be transferred to Novo Nordisk clinical
database at defined intervals.
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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 eCRFs, the trial site's recruitment rate and the compliance 
of the trial site to the protocol and GCP, 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 all 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 eCRF. 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.
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 of the completed diaries must not be removed from the trial site.
The monitor will ensure that the eCRFs are complete.
The following data will be source data verified for screening failures: 
!
Date for obtaining informed consent
!
Screen failure reason
Monitors will review the subject’s medical records and other source data (e.g., the diaries) to ensure 
consistency and/or identify omissions compared to the eCRF. 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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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.
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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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. The SAP will be finalised before 
database lock.
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 are given in 
Section 17.2.
Laboratory values below the lower limit of quantification (LLOQ) will be set to ½LLOQ. 
The baseline value will be defined as the last measured and available value from randomisation 
(V9) and end of run-in (V8), if not otherwise specified.
17.1
Sample size calculation
This is a superiority trial comparing liraglutide to placebo. Superiority will be claimed if the p-value 
is less than 5% and the treatment favours liraglutide.
It is anticipated that the effect of liraglutide in adolescents with obesity will be similar to the effect 
observed in adults. The anticipated treatment difference for BMI SDS33 is based on the results from 
trial NN8022 1839 in adults with overweight and obesity. For the sample size scenarios, treatment 
differences of -0.24, -0.26, and -0.28 were investigated.
The standard deviation (SD) is assessed based on publications by Reinehr et al. 200913 Berkowitz et 
al. 200356 and trial NN8022-3967 in adolescents with obesity aged 12−17 years. For the sample size 
scenarios, SD of 0.25, 0.35 and 0.45 were investigated.
The effect of withdrawals on the analysis 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 for this paediatric trial is 40% at 
week 56. A higher withdrawal percentage is assumed for this trial than what was seen in trial 
NN8022-1839 in adults, because this trial will include an adolescent trial population. 
The total number of subjects is shown for the investigated scenarios in Table 17–1 for 90% and 
99% power.
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Table 17–1
Sample size calculations for different scenarios with total number of 
randomised subjects
POWER
Treatment difference
(completers)
SD
0.25
0.35
0.45
90%
-0.24
144
266
428
-0.26
124
228
366
-0.28
110
200
318
99%
-0.24
248
462
746
-0.26
216
398
638
-0.28
190
346
554
Based on the above mentioned references, it seems realistic and conservative to assume an SD of 
0.35 and a treatment difference of −0.26. The minimum requirement in the Paediatric Investigation
Plan is 154 randomised subjects while FDA requires a minimum of 100 subjects exposed to 
liraglutide. A sample size of 228 randomised subjects gives a power of 90%. Thus, the number of 
randomised subjects should be 228.
17.2
Definitions of analysis sets
The following analysis sets are defined in accordance with the ICH E9557.
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 (V19x, V25x and V30x) will be used prior to imputation of remaining 
missing data unless otherwise stated. For AEs, summaries will be presented separately for the 
periods “run-in”, “in-trial” and “on-treatment”, as defined in Section 17.4.1.2.
Before data are locked for statistical analysis, a blinded 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 Novo Nordisk trial statistician, the international trial manager and the 
international 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.
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17.3
Primary endpoint
The primary endpoint is change from baseline in BMI SDS after 56 weeks of treatment33. 
The objective is to show that liraglutide is superior to placebo in obtaining weight loss. Let μliraglutide
and μplacebo denote the 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% CI 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) 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. The baseline glycaemic category includes two 
levels: presence and absence of dysglycaemia. The stratification factor for Tanner stage includes 
two levels: stages 2 and 3 together, and stages 4 and 5 together. 
Missing data in the main analysis will be handled by the following multiple imputation (MI) 
method. A pattern mixture model approach is applied where withdrawn subjects without a 
follow-up visit are assumed to respond as if treated with placebo for the entire trial. Multiple copies 
(100 copies) 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:
!
In the first step, 100 copies of the dataset will be generated.
!
In the second step, an enriched ANCOVA model with 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, baseline waist 
circumference, baseline age and baseline HbA1c as covariates will be fitted to the change from 
baseline in BMI SDS at 56 weeks for the completers in the placebo group only.
!
For each of the 100 copies of the dataset, the estimated parameters and their variances from this 
model will be used to impute missing values at 56 weeks for subjects in both treatment arms, 
based on their factor levels and the values of the covariates.
!
For each of the 100 complete datasets, the change from baseline in BMI SDS at 56 weeks will 
be 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. 
!
The estimates and SDs for the 100 data sets are pooled to one estimate and associated SD using 
Rubin’s formula:
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 =
1
100 
 


,  =  1
100 
 



+ 1 + 1
100 
1
100 −1 
( −)


,
where mi and SDi are the estimated means and SDs for the 100 copies of the dataset, and mMI, 
SDMI are the pooled estimates. From mMI and SDMI , the 95% CI for the treatment difference 
and the associated p-value will be calculated.
The MI method does not assume missing at random. It assumes that withdrawn subjects in the 
placebo arm have a response similar to the completers in the placebo arm given similar baseline 
characteristics. In the active arm, the assumption is that withdrawn subjects behave as if they 
have been in the placebo arm during the entire trial regardless of the time of their 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 ITT estimator or an effectiveness 
estimand of the add-on effect of liraglutide to healthy nutrition and physical activity 
counselling.
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 analysis 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 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 56-week double-blind period of the trial. 
!
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 56 weeks will with this method be imputed by the corresponding 
baseline values. 
!
The same type of ANCOVA as above will be performed without imputation by only including 
subjects who completed the 56 weeks double-blind period. 
!
A mixed model for repeated measurements (MMRM) will be applied where all post baseline 
BMI SDS measurements obtained at planned visits during the 56-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. 
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!
The ANCOVA model with LOCF assumes that post treatment discontinuation, the body weight 
is on average stable in both treatment arms. This assumption can be evaluated over the 26 weeks 
follow-up period in completers. 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 
withdrawal differs between active and placebo, this analysis might provide an optimistic or 
over-conservative estimate, depending on the actual circumstances. The ANCOVA model with 
BOCF assumes that post treatment withdrawn subjects return 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 effect and 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. 
17.4
Secondary endpoints
The planned secondary endpoints will be analysed as outlined in this Section.
17.4.1
Supportive secondary endpoints
17.4.1.1
Efficacy endpoints
BMI SDS at 30 and 82 weeks
The change in BMI SDS from baseline to 30 and 82 weeks and from 56 weeks to 82 weeks will be 
analysed using the same statistical method as used for the main analysis of the primary endpoint.
BMI
The changes in BMI from baseline at 30 and 56 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. Change from 56 weeks to 82 weeks 
will be summarised using descriptive statistics.
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In addition, the following categorical endpoints related to BMI will be evaluated:
!
Percentage of subjects achieving ≥5% reduction in baseline BMI at 30, 56 and 82 weeks
!
Percentage of subjects achieving ≥10% reduction in baseline BMI at 30, 56 and 82 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 results 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.
PRO outcome
The PRO questionnaire IWQOL-Kids will be evaluated similarly to the primary endpoint. That is, 
the change in PRO score from baseline at 30 and 56 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 PRO score instead of the baseline BMI SDS as covariate.
Glycaemic category
The change in glycaemic category (normoglycaemia, pre-diabetes, T2DM) from baseline at 30 and 
56 weeks and change from 56 weeks to 82 weeks will be summarised using descriptive statistics. 
Furthermore, two separate analyses will be performed on the binary variable normoglycaemia 
(yes/no) at 30 and 56 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 covariate. 
Missing data will be handled by an MI method similar to the one used for the main analysis of the 
primary endpoint, but adapted to the logistic regression model. The results will be presented as odds 
ratios together with the associated 95% CIs.
Other supportive secondary efficacy endpoints
The following other efficacy variables will be evaluated:
!
Body weight
!
Waist circumference
!
Waist-to-hip circumference ratio
!
Cardiovascular biomarker (hsCRP)
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!
Fasting lipids (TC, LDL-cholesterol, HDL-cholesterol, non-HDL cholesterol, VLDL 
cholesterol, TG and FFA)
!
Systolic and diastolic blood pressure
!
Quantitative glucose metabolism parameters (HbA1c, FPG, fasting insulin, fasting C-peptide, 
HOMA-Ba and HOMA-IRa)
The changes in these variables from baseline at 30 and 56 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, fasting C-peptide, 
HOMA-B and HOMA-IR, the response and baseline values will be log transformed prior to the 
analysis. The change in these variables from 56 weeks to 82 weeks will be summarised using 
descriptive statistics.
a The calculation of the HOMA endpoints will be done as follows:
!
Beta-cell function (%) = 20·fasting insulin[mU/L]/(FPG[mmol/L]-3.5)
!
Insulin resistance (%) = fasting insulin [mU/L]·FPG [mmol/L]/ 22.5. 
17.4.1.2
Safety endpoints
Adverse events
AEs will be summarised for the safety analysis set separately for three periods: 
!
Run-in period: defined as events with onset date between V2 (included) and the first day of trial 
product administration (not included).
!
In-trial period: defined as events with onset date between the first day of trial product 
administration and the last study visit.
!
On-treatment period: defined as events with onset date between the first day of trial product 
administration and whatever comes first: a) 14 days after the last day on trial product , b) 
follow-up visit (V26 for subjects with trial product discontinued), or c) last study visit (subjects 
withdrawn without follow-up visit).
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 (prior to randomisation) will be presented in listings.
Hypoglycaemic episodes
Hypoglycaemic episodes will be summarised descriptively by severity and treatment in terms of the 
number and percentage of subjects with at least one episode and the total number of episodes. 
Separate summaries will be made by severity (the ISPAD criterion for severe hypoglycaemia49). In 
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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 23:00 and 07:00 both inclusive.
Hypoglycaemic episodes are classified according to ISPAD’s definition of severe hypoglycaemia49
as well as the Novo Nordisk classification of hypoglycaemia; see Figure 17–1 and the ADA 
classification of hypoglycaemia; see Figure 17–2).
Novo Nordisk classification of hypoglycaemia in paediatrics
In normal physiology, symptoms of hypoglycaemia occur below a plasma glucose level of 
3.1 mmol/L (56 mg/dL)58. Therefore, Novo Nordisk has included hypoglycaemia with plasma 
glucose levels below this cut-off point in the definition of BG-confirmed hypoglycaemia.
Novo Nordisk uses the following classification (see Figure 17–1) in addition to the ADA 
classification:
!
Severe hypoglycaemia according to the ISPAD classification49: Was the hypoglycaemic 
episode associated with severe neuroglycopenia, usually resulting in coma or seizure and 
requiring parenteral therapy (glucagon or intravenous glucose)?
!
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.
!
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.
!
Severe or BG-confirmed symptomatic hypoglycaemia: An episode that is severe according to 
the ISPAD classification49 or BG-confirmed by a plasma glucose value <3.1 mmol/L 
(56 mg/dL) with symptoms consistent with hypoglycaemia. 
!
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. 
!
Severe or BG-confirmed hypoglycaemia: An episode that is severe according to the ISPAD 
classification49 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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Hypo-
glycaemic
episode
SMPG
measurement
PG < 3.1 mmol/L
(56 mg/dL)
with symptoms
PG < 3.1 mmol/L
(56 mg/dL)
without
symptoms
Symptomatic BG 
confirmed 
hypoglycaemia
Asymptomatic BG 
confirmed 
hypoglycaemia
No
Yes
Severe or 
BG confirmed 
symptomatic 
hypoglycaemia
BG confirmed 
hypoglycaemia
Severe or BG 
confirmed 
hypoglycaemia
Note: Glucose measurements are performed with capillary blood calibrated to plasma equivalent glucose values
BG: blood glucose  PG: plasma glucose  SMPG: Self-measured plasma glucose
Severe 
hypoglycaemia
(ISPAD 2014)
Was the 
hypoglycaemic 
episode 
associated with 
severe 
neuroglyco-
penia, usually 
resulting in 
coma or seizure 
and requiring 
parenteral 
therapy 
(glucagon or 
intravenous 
glucose)?
Figure 17–1
Novo Nordisk classification of hypoglycaemia in paediatric subjects
ADA/ISPAD classification of hypoglycaemia in paediatric subjects48, 49
!
Severe hypoglycaemia according to the ISPAD classification49:Was the hypoglycaemic episode 
associated with severe neuroglycopenia, usually resulting in coma or seizure and requiring 
parenteral therapy (glucagon or intravenous glucose)?
!
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).
!
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).
!
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.
!
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).
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Hypo-
glycaemic 
episode 
SMPG
measurement
Asymptomatic 
hypoglycaemia
Documented 
symptomatic 
hypoglycaemia
Pseudo-
hypoglycaemia
Probable 
symptomatic 
hypoglycaemia
Yes
No
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
PG: plasma glucose  SMPG: Self-measured plasma glucose
Was the 
hypoglycaemic 
episode 
associated with 
severe 
neuroglyco-
penia, usually 
resulting in 
coma or seizure 
and requiring 
parenteral 
therapy 
(glucagon or 
intravenous 
glucose)?
Severe 
hypoglycaemia
(ISPAD 2014)
Figure 17–2
ADA/ISPAD classification of hypoglycaemia in paediatrics
Anti-liraglutide antibodies
Anti-liraglutide antibodies will be summarised in terms of the number and percentage of subjects 
per visit that are antibody-positive, antibody-negative, cross-reacting and in vitro neutralising.
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.
Bone age assessment
Bone age assessment at baseline and change in bone age assessment will be summarised using 
descriptive statistics.
ECG
Summary statistics and the frequencies of shifts from baseline at 30 and 56 weeks will be tabulated 
for each treatment group.
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Pulse
Summary statistics and the frequencies of shifts from baseline to 30 and 56 weeks and from 56 
weeks to 82 weeks will be tabulated for each treatment group. In addition, statistical analyses 
similar to those made for blood pressure will be performed for change from baseline to 30 and 56 
weeks.
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 ranges. The 
results will be presented as follows:
!
Shifts from baseline at 30 and 56 weeks and from 56 weeks to 82 weeks will be tabulated. The 
shift tables will include the number of subjects below, within and above the reference range at 
each visit
!
The proportion of subjects with laboratory values outside the reference range will be tabulated 
per visit and treatment group
!
Individual values outside the reference range (abnormal values) will be listed by treatment and 
subject
Pubertal status
Tanner stage at screening as well as changes in Tanner stage at 30 and 56 weeks and change from 
56 weeks to 82 weeks, will be summarised using descriptive statistics.
Physical examination
Physical examination at screening and changes in physical examination will be summarised.
Height SDS
Height SDS59 at screening and changes in height SDS will be summarised.
Mental health questionnaires
Results from the mental health questionnaires PHQ-9 and C-SSRS will be summarised using 
descriptive statistics and the frequencies of shifts from baseline to 30 and 56 weeks and from 56 
weeks to 82 weeks will be tabulated for each treatment group.
17.5
Pharmacokinetic and pharmacodynamic modelling
Liraglutide concentrations from samples drawn at site visits will be used to describe the liraglutide 
exposure in pubertal adolescent subjects with obesity (12 to less than 18 years) and to investigate 
the effects of covariates on the pharmacokinetics. Data from pre-defined historical trials in relevant 
populations (i.e., adult 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. 
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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 data base lock.
The pre-specified analysis will explore the effects of covariates on liraglutide exposure. The 
structural model and covariate relationships will be predefined in detail in the MAP. In brief, a 
previously-developed population PK model for liraglutide will be used. For the PK model, the 
apparent clearance will be estimated, while other model parameters may be set to prior pre-defined 
estimates (based on data from other trials). Area under the plasma concentration-time curve in 
steady state will be derived from the apparent clearance. The covariates of interest, such as body 
weight, sex and age group (adolescent/adult), will be tested on the apparent clearance. 
The selected covariates will be incorporated into the population PK model and results will be 
presented using criteria which will be specified in the MAP. The population PK analysis will be 
reported in a separate stand-alone document.
Exposure-response analysis
The PK and pharmacodynamic data may be included in exploratory analyses of PK and exposure-
response relationships, which may also include data from other trials.
17.6
Health economics and patient reported outcomes
The PRO questionnaire IWQOL-Kids 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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18 Ethics
18.1
Benefit-risk assessment of the trial
The trial will be conducted in compliance with ICH GCP1, applicable regulatory requirements and 
in accordance with the Declaration of Helsinki2.
Current treatment options for paediatric 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 reactions15-19. 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 weight26.
Participation in the present trial is restricted to adolescents who have obesity and who have a 
documented history of failing to lose weight with lifestyle modifications. Subjects will have access 
to experimental intensified treatment, liraglutide 3.0 mg, which has been shown to induce weight 
loss and improve cardiometabolic and quality of life parameters in adults with obesity. Subjects in 
the placebo group will have access to counselling in healthy nutrition and physical activity
throughout the duration of the trial.
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 less than 18 years, 
duration of 5-6 weeks) and trial NN8022-3967 (liraglutide 3.0 mg in subjects with obesity without 
T2DM, 12 to less than 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 latest edition of the Liraglutide 3.0 mg (Saxenda®) Weight Management IB28 or any 
updates hereof.
Identified and expected risks
With respect to the key risks of liraglutide, the most frequently reported AEs in subjects treated 
with liraglutide 3.0 mg were gastrointestinal (nausea and diarrhoea), with onset in weeks 1-4; these 
were of mild to moderate severity, and transient. Other gastrointestinal AEs 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 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 s.c.
administration of proteins and peptides, allergic reactions are an identified risk due to the potential 
severity of these events.
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An association between the use of GLP-1 receptor agonists 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-1 receptor agonists. 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/marked weight loss 
and the development of cholelithiasis is present60-63.
Potential risks
There is currently no evidence supporting a causal relationship between liraglutide treatment and 
any of the following potential risks. 
Based on potential cross-reactivity of anti-liraglutide antibodies with an endogenous counterpart 
(GLP-1), anti-liraglutide antibody formation is a potential risk. Based on feedback from EMA, 
immune complex-related AEs are to be considered separately from those related to allergic 
reactions. No imbalance or safety concern has been seen regarding immune complex disorders for 
liraglutide in weight management. However, in alignment with liraglutide for T2DM, immune 
complex disorders are considered a potential risk for liraglutide in weight management. 
It is unknown whether liraglutide causes thyroid C-cell tumours, including MTC, in humans, as 
human relevance has not been determined either by clinical or nonclinical studies. Cases of MTC in 
patients treated with liraglutide have been reported in the post-marketing period; the data in these 
reports are insufficient to establish or exclude a causal relationship between MTC and liraglutide 
use in humans. Data from the intensive monitoring of calcitonin (a marker for MTC) in plasma in 
the liraglutide clinical development programme do not support a liraglutide-effect on calcitonin in 
humans, as mean calcitonin levels remained stable over time and well below the ULN of normal for 
both genders.
Subjects with overweight and obesity have an increased risk of certain types of cancer. In the 
weight management programme, the reporting rate of neoplasm events confirmed by 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. Pancreatic cancer has been added as a 
separate potential risk in the risk management plan as per EMA’s request, although there is 
currently no evidence from clinical trials that GLP-1-based therapies increase this risk.
In the clinical development programme, mean increase in resting pulse (by 2–3 beat per minute), as 
well as a decrease in systolic blood pressure, have 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 
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resting pulse have not been established, cardiovascular disorders are an important potential risk also 
for liraglutide in weight management.
Trial-specific risk mitigation
All participating subjects will be monitored closely through frequent site visits. Blood sampling 
frequency and volume will be minimised for subjects’ safety and convenience. The duration of the 
double-blind trial period is set to 56 weeks in an effort to limit the duration of placebo injections 
and reduce unnecessary subject discomfort/inconvenience (see Section 5.2).
An external independent DMC will be established and will perform review of unblinded safety data 
at regular intervals throughout the trial.
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 adolescent 
subjects, the trial product 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 lower to 
the previously given dose or to prolong a dose step for one additional week (see Section 8.1.8.1). 
Subjects treated with trial product 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.
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 with healthy nutrition, physical activity and 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, the trial product should promptly be interrupted 
until the presences of pancreatitis can be excluded (see Section 8.4.11) and appropriate treatment 
should be initiated. Subjects that are diagnosed with acute pancreatitis must have their trial product 
discontinued. Subjects with a personal or family history of MTC and subjects with MEN2 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 neoplasia. During the trial, calcitonin levels will be measured 
at pre-specified trial visits and levels above ULN 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 as they are for the adult populations with the exception of any 
unforeseen effects on growth and pubertal development. In nonclinical 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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rate that was most pronounced in females. A delay in sexual maturation is known to occur in 
humans under caloric restriction/increased energy expenditure64.
Pubertal- and growth-related hormonal levels, biochemical parameters of bone metabolism and 
growth and pubertal development will be monitored in the present trial.
Conclusion
Given the scarcity and limitations of available treatment options for paediatric obesity, the potential 
weight loss and cardiometabolic benefits of liraglutide and its acceptable safety/tolerability profile 
in the short-term paediatric trials, it is concluded that the potential benefits from participating in the 
present trial outweigh the potential risks. A starting dose of 0.6 mg has been chosen based on the 
tolerability seen in this population and model-estimated steady-state liraglutide exposure. 
18.2
Informed consent 
In seeking and documenting informed consent, the investigator must comply with applicable 
regulatory requirement(s) and adhere to ICH GCP1 and the requirements in the Declaration of 
Helsinki2.
Before any trial-related activity, the investigator must give the subject and the subject’s LAR verbal 
and written information about the trial and the procedures involved in a form that the subject and 
the subject’s LAR can read and understand. The information given to the subjects must always be 
given in according to his/her capacity to understand, always taking into consideration the subject’s 
presumed willingness to participate in a clinical trial. 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.
The investigator must ensure the subject ample time to come to a decision whether or not to 
participate in the trial. The subject must only be included in the trial if both the subject and subject’s 
LAR agree to have the subject participating.
A voluntary, signed and personally dated informed consent must be obtained from the subject and
the subject’s LAR before any trial-related activity. The informed consent/assent must be signed at 
least one day prior to screening as the subject must attend this visit fasting (see Section 8.1.2).
If the minor reaches legal age while participating in the trial and has only signed an age specific 
informed consent/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 
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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 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 withdraws from the trial or is lost to follow up, then the subject’s data will be handled 
as follows:
!
Data already collected and any data collected at the end-of-trial visit including follow up visits
will be retained by Novo Nordisk, entered into the database and used for the clinical trial report. 
!
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 subjects 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, at the 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.
18.5
Premature termination of the trial and/or trial site
Novo Nordisk, 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 the 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 
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participated in the trial. If it has an impact, the actions needed to inform and protect the subjects 
should be described.
19 Protocol compliance
19.1
Protocol deviations
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 trial database. 
Documentation on protocol deviations must be kept in the investigator trial master file and sponsor 
trial master file.
19.2
Prevention of missing data
The importance of subject retention will be addressed by Novo Nordisk in the training and 
communication with the trial sites. 
The subjects will be carefully informed about the trial procedures before signing informed consent, 
so that they know the implications of participating in the trial. 
Close surveillance of subject retention will be performed throughout the trial by Novo Nordisk with 
focus on reasons for premature discontinuation of trial product or withdrawal of consent to secure 
early mitigations in collaboration with the trial sites. 
The investigator will make every effort to ensure that all assessments are performed and data is 
collected. If missing data does occur the reason will be collected via the protocol deviation process;
see Section 19.1. Novo Nordisk will monitor protocol deviations on an on-going basis throughout 
the trial followed by appropriate actions (e.g., re-training of site staff).
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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.
21 Critical documents
Before a trial site is allowed to start screening subjects, written notification from Novo Nordisk 
must be received and the following documents must be available to Novo Nordisk:
!
Regulatory approval and/or acknowledgement of notification as required 
!
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
!
List of IRB/IEC members and/or constitution (or a general assurance number/statement of 
compliance)
!
Curricula vitae of investigator and sub-investigator(s) (current, dated and signed - must include 
documented GCP training or a certificate)
!
Signed receipt of investigator’s brochure or SmPC or similar labelling as appropriate
!
Signed and dated Agreement on Protocol
!
Signed and dated Agreement on Protocol Amendment, if applicable
!
Contract, signed by the investigator and/or appropriate parties on behalf of the investigator’s site 
and Novo Nordisk
!
Source document agreement
!
Central laboratory certification and normal ranges
!
Insurance statement, if applicable
!
Financial disclosure form from investigator and sub-investigator(s)
!
For US trial sites: verification under disclosures per Code of Federal Regulations (CFR) of 
Financial Conflict of Interest
!
For US trial sites: FDA form 1572 must be completed and signed by the investigator at each site
FDA form 1572:
For US sites:
!
Intended for US sites
!
Conducted under the IND
!
All US investigators, as described above, will sign FDA Form 1572
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For sites outside the US:
!
Intended for participating sites outside of the US
!
Not conducted under the IND
!
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 agreement, each investigator agrees to comply fully with ICH GCP1
applicable regulatory requirements and the Declaration of Helsinki2.
By signing the protocol agreement, 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.
22 Responsibilities
The investigator is accountable for the conduct of the trial at his/her site and must ensure adequate 
supervision of the conduct of the trial at the trial 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 and documented 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 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 must be kept in a secure locked facility, so no unauthorized 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.
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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).
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 publications41.
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 Disclosure40.
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 
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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.
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. 
23.1.1
Authorship
Authorship of publications should be in accordance with the Uniform Requirements of the 
International Committee of Medical Journal Editors41 (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.
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24 Retention of clinical trial documentation and human biosamples
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 at least 20 years 
after discontinuation of the marketing authorisation, termination of the trial or cancellation of the 
research project whichever is longest.
The files from the trial site/institution must be retained for 15 years after end of trial as defined in 
Section 7, 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 biosamples
Antibody samples may be retained for later analysis for further characterisation of antibody 
responses towards drug if required by health authorities or for safety reasons.
The samples will be stored either at the special laboratory or at Novo Nordisk AS after end of trial 
and until marketing authorisation approval or until the research project terminates, but no longer 
than 15 years from end of trial after which they will be destroyed.
The subject’s identity will remain confidential and the antibody samples will be identified only by 
subject number, visit number and trial identification number. No direct identification of the subject 
will be stored together with the samples. 
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Only staff from the special laboratory or specialised staff at Novo Nordisk A/S will have access to 
the stored antibody samples. 
Subjects can contact the investigator if they wish to be informed about results derived from stored 
antibody samples obtained from their own body. 
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 
brochure28, 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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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.
26.1
For Belgium only
Law concerning experiments on the human person of 07 May 2004 - Article 29:
§1. Even if without fault, the sponsor is liable for the damage which the subject and/or his rightful 
claimants sustain and which shows either a direct or an indirect connection with the trial.
26.2
For Mexico only
Novo Nordisk carries product liability for its products assumed under the special laws, acts/and/or 
guidelines for conducting trials in any country, including those applicable provisions on the 
Mexican United States.   If the subject feels that something goes wrong during the course of this 
trial, the subject should contact the trial staff in the first instance.
If during their participation in the trial the subject experiences a disease or injury that, according to 
the trial doctor and the sponsor, is directly caused by the trial medication and/or a trial procedure 
that otherwise would not have been part of his/her regular care, the subject will receive from the 
Institution or Medical Care Establishment and free of charge, the appropriate medical treatment as 
required.
In this case, the costs resulting from such treatment  as well as the costs of any indemnification 
established by law will be covered by the trial sponsor in accordance with the terms provided by all 
applicable regulations; even if the  subject discontinues his/her participation in the trial by his own 
will or by a decision from the investigator.
By signing the informed consent, the subject will not renounce to any compensation or 
indemnification he/she may be entitled to by law, nor will he/she will incur any additional expense 
as a result of his/her participation in the trial; any additional expense resulting from the subject’s 
participation in the trial will be covered by the trial sponsor.
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27 References
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Trial ID: NN8022-4180
Version:
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UTN: U1111-1162-7101
Status:
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Version:
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UTN: U1111-1162-7101
Status:
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UTN: U1111-1162-7101
Status:
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8S.
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Liraglutide
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Appendix A
Liraglutide
NN8022-4180
Body mass index (BMI) 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
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
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Version:
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Table of Contents
Page
Table of Contents .............................................................................................................................................2
1
Introduction...............................................................................................................................................3
2
International BMI cut off points..............................................................................................................4
2.1
Cut off points to determine subject’s eligibility ............................................................................4
2.2
Cut off points for diet maintenance ...............................................................................................5
3
Determination of a subject’s BMI > 95th percentile ...............................................................................6
4
References................................................................................................................................................16
Table of tables
Table 1
International cut off points for BMI for obesity by sex for children between 12 and 17 
years old, 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 States....................4
Table 2
International cut off points for BMI for obesity by sex for children between 12 and 17 
years old, 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....................5
Table 3
BMI-for-age-FEMALES (12-18 years old)...................................................................................6
Table 4
BMI-for-age-MALES (12-18 years old)......................................................................................11
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1
Introduction
According to protocol inclusion (Section 6.2in the protocol)and protocol randomisation (Section 
6.4 in the protocol),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.The tables in Section 2 and 3 
must be used to determine subjects eligibility.
The BMI ≥30 kg/m2for adults by international cut-off points aretabulated in Section 2.11. 
The 95th percentile for males and females of different ages aretabulated in Section 32.
According to protocol exclusion (Section 6.3 in the protocol), subjects with a body weight equal to 
or below 60 kg must be excluded.
If a BMI corresponding to ≤ 25 kg/m2for adults by international cut-off point is reached, subjects 
should be assigned a maintenance diet, at the discretion of the investigator. See Section 2.2.
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2
International BMI cut off points
2.1
Cut off points to determine subject’s eligibility
Table 1
International cut off points for BMI for obesity by sex for children between 12 and 17 
years old, 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 States. 
Age: Years
BMI 30 kg/m2
Males
BMI 30 kg/m2
Females
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
Adapted from Cole et al.1
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2.2
Cut off points for diet maintenance 
Table 2
International cut off points for BMI for obesity by sex for children between 12 and 17 
years old, 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.
Age: Years
BMI 30 kg/m2
Males
BMI 30 kg/m2
Females
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
Adapted from Cole et al.1
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3
Determination of a subject’s BMI > 95th percentile
In order to determine whether a subject is eligible according to inclusion criterion no.3, the 
investigator should use Table 2 for females and Table 3 for males. Based on the subject’s age, it can 
be determined if the BMI is above the 95th percentile.
Table 3
BMI-for-age-FEMALES (12-18 years old)
Year: Month
Month
95th percentile
(BMI in kg/m2)
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
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Year: Month
Month
95th percentile
(BMI in kg/m2)
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
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
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Year: Month
Month
95th percentile
(BMI in kg/m2)
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
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Year: Month
Month
95th percentile
(BMI in kg/m2)
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
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
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Year: Month
Month
95th percentile
(BMI in kg/m2)
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
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Table 4
BMI-for-age-MALES (12-18 years old)
Year: Month
Month
95th percentile
(BMI in kg/m2)
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
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Year: Month
Month
95th percentile
(BMI in kg/m2)
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
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
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Year: Month
Month
95th percentile
(BMI in kg/m2)
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
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Year: Month
Month
95th percentile
(BMI in kg/m2)
15:11
191
26.1
16:0
192
26.1
16:1
193
26.2
16:2
194
26.3
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
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Year: Month
Month
95th percentile
(BMI in kg/m2)
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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4
References
1 Cole TJ, Bellizzi MC, Flegal KM, Dietz WH. Establishing a standard definition for child 
overweight and obesity worldwide: international survey. BMJ (Clinical research ed ) 2000; 
320(7244):1240-1243.
2 World Health Organisation. BMI for age, 2007 WHO reference. Web . 22 Jul 2011. 
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Appendix B
Liraglutide
NN8022-4180
Blood pressure ranges for children
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Table of Contents
Page
Table of Contents .............................................................................................................................................2
Table of figures.................................................................................................................................................2
Table of tables...................................................................................................................................................2
1
Introduction...............................................................................................................................................3
2
Determination of a subject’s hypertension > 99th percentile.................................................................4
3
References..................................................................................................................................................9
Table of figures
Figure 1
Height for age percentiles in females.............................................................................................5
Figure 2
Height for age percentiles in males................................................................................................7
Table of tables
Table 1
Blood pressure levels for females by age and height percentile....................................................6
Table 2
Blood pressure levels for males by age and height percentile.......................................................8
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1
Introduction
According to exclusion criterion (Section 6.3 in the protocol),subjects mustbe excluded from the 
trial in cases wherethey have uncontrolled treated or untreated hypertension >99thpercentile for age 
and gender in children, in accordance with “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 in accordance 
with CDC Growth Charts.2
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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 subject’s height percentile according to Figure 1 for females and Figure 2 for males.
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 females and Table 2 for males.
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Figure 1
Height for age percentiles in females
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Table 1
Blood pressure levels for females by age and height percentile
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Figure 2
Height for age percentiles in males
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Table 2
Blood pressure levels for males by age and height percentile
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3
References
1 The fourth report on the: Diagnosis, evaluation, and treatment of high blood pressure in children 
and adolescents. U.S.Department of Health and Human Services, National Institute of Health 
National Heart Lung and Blood Institute. 2012.
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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Appendix C
Liraglutide
NN8022-4180
Calcitonin Monitoring
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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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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 limit of normal 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 (12 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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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 post randomisation will be reviewed monthly by the International Medical Director (IMD) 
for this project or the director’s surrogate. Calcitonin levels above upper limit of normal will be 
flagged by the central laboratory on the laboratory report, and reported to the investigator, the 
International Trial Manager (ITM), and IMD. 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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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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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
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Protocol Amendment no 1
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Date:
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UTN: U1111-1162-7101
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Protocol Amendment
no 1
to Protocol, final version 1.0
dated 01 June 2016
Trial ID: NN8022-4180
Effect of liraglutide for weight management in pubertal
adolescent subjects with obesity
56-week, double-blind, randomised, parallel-group, placebo-controlled
multi-national trial followed by a 26-week period off study-drug
Trial phase: 3a
Applicable to Sweden
Amendment originator:
  
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Protocol Amendment no 1
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Table of Contents   
Page
Table of Contents..............................................................................................................................................2
1
Introduction including rationale for the protocol amendment.............................................................3
2
Changes......................................................................................................................................................3
6       Trial Population..................................................................................................................................3
6.3    Exclusion criteria................................................................................................................................3
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Protocol Amendment no 1
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1
Introduction including rationale for the protocol amendment
The present local substantial amendment for Sweden implements a requirement from the Swedish 
Medical Products Agency (MPA) to specify the definition on adequate contraceptive measures for 
Swedish trial participants in accordance with the Clinical Trial Facilitation Group (CTFG) 
recommendations related to contraception and pregnancy testing in clinical trials, Final Version 
2014-09-15.
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
2
Changes
6       Trial Population
6.3    Exclusion criteria
Changes to exclusion criteria number 30:
For Sweden only: Oral (except low-dose gestagen [lynestrenol and norestisteron]), injectable, or 
implanted hormonal contraceptives, intrauterine device, intrauterine system (for example, progestin-
releasing coil), vasectomized male (with appropriate postvasectomy documentation of the absence 
of sperm in the ejaculate). Use of contraception is not required for female subjects who have not yet 
made their sexual debut and/or are not sexually active. Only highly effective methods of birth 
control are accepted (i.e. one that results in less than 1% per year failure rate when used 
consistently and correctly, such as implants, injectables, combined (estrogen and progestogen 
containing) oral/intravaginal/transdermal contraceptives, progestogen-only 
oral/injectable/implantable contraceptives, intrauterine device (IUD, IUS), sexual abstinence or 
vasectomised partner.
CONFIDENTIAL


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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.


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CONFIDENTIAL

SAP_001.pdf: 
Cover Page for Statistical Analysis Plan  
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT02918279 
Sponsor trial ID: 
NN8022-4180 
Official title of study: 
Effect of liraglutide for weight management in pubertal 
adolescent subjects with obesity 
Document date: 
11-December-2019 
 


Link
Link
List of contents
Statistical analysis plan......................................................................................................................
Sample size calculations.....................................................................................................................
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
Liraglutide 3.0 mg
Trial ID: NN8022-4180
Clinical Trial Report
Appendix 16.1.9
11 December 2019
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:
05 September 2019
Novo Nordisk
Trial ID:NN8022-4180
Version:
1.0
UTN:U1111-1162-7101
Status:
Final
EudraCT No.:2014-004353-14
Page:
1 of 27
Statistical Analysis Plan
Trial ID: NN8022-4180
Effect of liraglutide for weight management in pubertal
adolescent subjects with obesity
56-week, double-blind, randomised, parallel-group, placebo-controlled
multi-national trial followed by a 26-week period off study-drug
Trial Phase: 3a
Author
Name: 
Department: 
 
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.
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:
05 September 2019
Novo Nordisk
Trial ID:NN8022-4180
Version:
1.0
UTN:U1111-1162-7101
Status:
Final
EudraCT No.:2014-004353-14
Page:
2 of 27
Table of contents   
Page
Table of contents.........................................................................................................................................2
List of abbreviations ...................................................................................................................................3
1
Introduction .........................................................................................................................................4
1.1
Trial information.......................................................................................................................4
1.2
Scope of the statistical analysis plan..........................................................................................4
2
Statistical considerations .....................................................................................................................4
2.1
Definitions of analysis sets........................................................................................................5
2.2
Primary endpoint.......................................................................................................................5
2.2.1
Sensitivity analysis ..................................................................................................7
2.3
Handling of missing values .......................................................................................................8
2.3.1
Handling of missing values at baseline.....................................................................8
2.3.2
Handling of missing values at weeks 30, 56 and 82 ..................................................8
2.4
Secondary endpoints ...............................................................................................................13
2.4.1
Supportive secondary endpoints.............................................................................13
2.4.1.1
Efficacy endpoints............................................................................13
2.4.1.2
Safety endpoints...............................................................................15
2.5
Endpoint derivation methods...................................................................................................16
2.5.1
BMI Standard deviation score (BMI SDS) and Height Standard deviation score 
(Height SDS).........................................................................................................16
2.5.2
IWQoL-Kids..........................................................................................................18
2.5.3
C-SSRS questionnaire............................................................................................20
2.5.4
PHQ-9 questionnaire..............................................................................................20
2.6
Pharmacokinetic and Pharmacodynamic modelling .................................................................20
2.7
Reporting Endpoints................................................................................................................20
3
Changes to the statistical analyses planned in the protocol..............................................................20
3.1
Primary endpoint:....................................................................................................................21
3.2
Supportive secondary efficacy endpoints:................................................................................21
3.3
Supportive secondary safety endpoints: ...................................................................................21
3.4
Analysis Rules ........................................................................................................................22
3.4.1
Visit Windowing:...................................................................................................22
3.4.1.1
Visits windows:................................................................................23
3.4.1.2
For parameters which are not collected at every visit (e.g. 
HEIGHT):........................................................................................25
3.4.1.3
For parameters which are collected at ‘x’ visits:................................26
3.4.2
Analysis eligible records:.......................................................................................26
4
References ..........................................................................................................................................27
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
05 September 2019
Novo Nordisk
Trial ID:NN8022-4180
Version:
1.0
UTN:U1111-1162-7101
Status:
Final
EudraCT No.:2014-004353-14
Page:
3 of 27
List of abbreviations
AE
adverse event
ADA 
American Diabetes Association
AD
available droup-out
ANOVA
analysis of variance
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
CTR
clinical trial report
CV
coefficient of variance
EoT
end-of-text
FAS
full analysis set
HbA1c
glycosylated haemoglobin
ISPAD
international society for pediatric and adolescent
LOCF
last observation carried forward
MD
missing drop-out
MedDRA
Medical Dictionary for Regulatory Activities
MT
missing on treatment
PD
pharmacodynamics
PK
pharmacokinetics
PP
per protocol
SAE
serious adverse event
SAP
statistical analysis plan
SAS
safety analysis set
SD
standard deviation
SE
standard error
LAR
legally acceptable representative
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
05 September 2019
Novo Nordisk
Trial ID:NN8022-4180
Version:
1.0
UTN:U1111-1162-7101
Status:
Final
EudraCT No.:2014-004353-14
Page:
4 of 27
1
Introduction
1.1
Trial information
Trial design
This is a 56-week double-blind, randomised, parallel-group, placebo-controlled, multi-national trial 
followed by a 26-week period off study-drug. The trial will be conducted in pubertal adolescents 
with obesity aged 12 to less than 18 years. Subjects will be randomised 1:1 to receive liraglutide or 
placebo. The randomisation will be stratified according to pubertal and glycaemic status (see 
protocol Sections 5.2 and 11).
At least 30% of subjects will be from areas with lifestyle and nutrition comparable to those in the 
European Union. All subjects will undergo counselling in healthy nutrition and physical activity for 
weight loss and must be prescribed a structured programme from the beginning of the 12-week run-
in period and continuing through the 26-week follow-up period off trial drug.
Primary objective
!
To compare the efficacy of liraglutide versus placebo on weight loss in adolescent subjects 
with obesity after 56 weeks of treatment
Secondary objectives
!
To compare the efficacy of liraglutide versus placebo on glycaemic control, cardiovascular 
risk factors and Impact of Weight on Quality of Life-Kids (IWQOL-Kids) in adolescent 
subjects with obesity after 30 and 56 weeks of treatment
!
To compare the safety of liraglutide versus placebo in adolescent subjects with obesity after 
30 and 56 weeks of treatment
!
To examine the potential rebound effect from end of treatment at week 56 to week 82
Further details are described in the protocol section 4.2.
1.2
Scope of the statistical analysis plan
This SAP is based on the protocol “Effect of liraglutide for weight management in pubertal 
adolescent subjects with obesity”, version [final protocol version 1.0].
2
Statistical 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.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
05 September 2019
Novo Nordisk
Trial ID:NN8022-4180
Version:
1.0
UTN:U1111-1162-7101
Status:
Final
EudraCT No.:2014-004353-14
Page:
5 of 27
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 
section 2.1.
Laboratory values below the lower limit of quantification (LLOQ) will be set to ½LLOQ.
The baseline value will be defined as the last measured and available value from randomisation
(V9) and end of run-in (V8), if not otherwise specified.
2.1
Definitions of analysis sets
The following analysis sets are defined in accordance with the ICH E91, 2.
!
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”.
Before data are locked for statistical analysis, a blinded 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 Novo Nordisk trial statistician, the international trial manager and the
international 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.
2.2
Primary endpoint
The primary endpoint is:
!
Change from baseline in BMI SDS after 56 weeks of treatment.
The objective is to show that liraglutide is superior to placebo in obtaining weight loss. Let μliraglutide
and μplacebo denote the 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
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
05 September 2019
Novo Nordisk
Trial ID:NN8022-4180
Version:
1.0
UTN:U1111-1162-7101
Status:
Final
EudraCT No.:2014-004353-14
Page:
6 of 27
The null-hypothesis will be rejected on a 5% level if the two-sided 95% CI of the treatment FAS 
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) model using including 
the factors, covariates and interaction term listed in below table. 
Table 2-1: 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
Europe, North America
Glycaemic category
Factors
Yes, No*
Tanner stage, Glycaemic 
category
Interaction factor
Not applicable
Tanner stage
Factors
Stage 2 and 3 together, Stage 4 
and 5 together
Baseline BMI SDS
Covariate
Not applicable
Age
Covariate
Not applicable
*Yes: dysglycaemic, No: non-dysglycaemic. 
The factors and covariates will be included in the model as main effects in an additive structure.
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 in the main analysis will be handled by the following multiple imputation (MI) 
method. A pattern mixture model approach is applied where withdrawn subjects or treatment 
discontinued subjects without a follow-up visit are assumed to respond as if treated with placebo for 
the entire trial. Multiple copies (100 copies) 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. 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
05 September 2019
Novo Nordisk
Trial ID:NN8022-4180
Version:
1.0
UTN:U1111-1162-7101
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Table 2-2: Taxonomy of week 30, 56 and 82 assessments being available or missing
Assessment at week 
30, 56 and 82
On randomised 
treatment at week 30, 
56 and 82
Type description
Type 
abbreviation
Available
Yes
Available on randomised 
treatment: Subjects who did not 
discontinue randomised 
treatment prematurely. 
AT
No
Available drop-outs: Subjects 
who discontinued randomised 
treatment prematurely but 
returned to have an assessment 
at week 30, 56 and 82; so-
called retrieved drop-outs.
AD
Missing
Yes
Missing on randomised 
treatment: Subjects who did not 
discontinue randomised 
treatment prematurely. 
MT
No
Missing drop-outs: Subjects 
who discontinued randomised 
treatment prematurely and did 
not return to have an 
assessment at week 30, 56 and 
82; so-called non-retrieved 
drop-outs.
MD
2.2.1
Sensitivity analysis
To investigate the sensitivity of the results of the main analysis of the primary endpoint about the 
handling of missing data, a sensitivity analysis will be performed as mentioned below (further 
details refer protocol section 17.3).
!
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
will be included as fixed effect and baseline BMI SDS and baseline age as covariates. The 
response variable will be the last available measurement of BMI SDS obtained within the 
56-week double-blind period of the trial.
!
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 56 weeks will be imputed by the corresponding baseline 
values with this method.
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!
The same type of ANCOVA as above will be performed without imputation by only 
including subjects who completed the 56 weeks double-blind period.
!
A mixed model for repeated measurements (MMRM) will be applied where all post baseline 
BMI SDS measurements obtained at planned visits during the 56-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.
For further details refer protocol section 17.3.
2.3
Handling of missing values 
2.3.1
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.
2.3.2
Handling of missing values at weeks 30, 56 and 82
Missing values at weeks 30, 56 and 82 will be imputed and the relevant endpoints will be analysed
from the imputed values. Several approaches for imputation of missing values at weeks 30, 56 and 
82 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.
Primary approach for handling missing values
The primary approach for multiple imputations of missing values of BMI SDS at week 30, 56 and 
82 (type MT+MD Table 2-2) 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: 100 copies of the dataset will be generated.
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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 2-3. The estimated parameters and their variances from this model were used to 
impute missing values at 56 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 100 complete datasets, the change from baseline in BMI SDS at 
56 weeks will be analysed using the main ANCOVA model with factors and covariates as 
mentioned in Table 2-1.
Pooling: Step 4: Pool the 100 estimation results into a final result using Rubin’s formula.
The imputation model in step 2 uses placebo subjects from FAS with non-missing BMI SDS at 
baseline and week 56. The imputation model is a linear regression of BMI SDS at week 56 on the 
factors and covariates listed in Table 2-3 (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 2-3 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 week 
56 BMI SDS values for both randomised treatment arms.
Table 2-3: Factors and Covariate for imputation model
Factors and 
covariates at baseline
Type
Categories
Order
Sex
Factors
Female, Male
1
Region
Factors
Europe, North America
2
Baseline Glycaemic
category
Factors
Yes, No
3
Tanner stage
Factors
Stage 2 and 3 together, Stage 
4 and 5 together
4
Tanner stage, 
Glycaemic category
Interaction factor
Not applicable
5
Baseline BMI SDS
Covariate
Not applicable
6
Baseline Waist 
circumference
Covariate
Not applicable
7
Baseline Age
Covariate
Not applicable
8
Baseline HbA1c
Covariate
Not applicable
9
The multiple imputations will be generated using Novo Nordisk trial number 80224180 as seed 
number. 
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A similar procedure of imputation will be followed for all the secondary endpoints as mentioned in 
Table 2-4 except while imputing missing values for waist circumference assessment, baseline waist 
circumference which will not be included in the imputation model. Similarly, for HbA1c
assessments, baseline HbA1c will not be included in the imputation model.
For missing glycaemic category, the imputation will be done for missing FPG and HbA1c 
assessments using the imputation model mentioned in Table 2-4 except for HbA1c, baseline 
HbA1c which will not be used while imputing the missing values.
Table 2-4: Statistical analysis to address primary and secondary 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 56
Continuous
J2R-MI 
ANCOVA
FAS
!
ANCOVA 
(LOCF)
!
ANCOVA
(BOCF)
!
ANCOVA 
(no 
imputation, 
with 56 
week 
completers)
!
MMRM 
       Secondary Endpoint
2
Change from 
baseline in 
BMI SDS
Week 30, 
Week 82
Continuous
J2R-MI 
ANCOVA
FAS
NA
3
Change from 
baseline in 
BMI SDS
(%)
Week 30, 
Week 56
Continuous
J2R-MI 
ANCOVA
FAS
NA
4
Change from 
baseline in 
BMI SDS
Week 56 
to 82 
(Week 56 as 
baseline)
Continuous
J2R-MI 
ANCOVA
FAS
NA
5
Change 
from 
baseline 
BMI
Week 30, 
Week 56
Continuous
J2R-MI 
ANCOVA
FAS
NA
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(Kg/m2)
6
Percentage 
of Subjects 
achieving 
>=5% 
reduction in 
baseline 
BMI
Week 30, 
Week 56, 
Week 82
Categorical
J2R-MI 
Logistic 
Regression
FAS
NA
7
Percentage 
of Subjects
achieving 
>=10% 
reduction in 
baseline 
BMI
Week 30, 
Week 56, 
Week 82
Categorical
J2R-MI 
Logistic 
Regression
FAS
NA
8
Change from 
Baseline in 
PRO score
(IWQoL)
Week 30, 
Week 56
Continuous
J2R-MI 
ANCOVA
FAS
NA
9
Change from 
baseline in 
Glycaemic 
category
Week 30, 
Week 56
Categorical
J2R-MI 
Logistic 
Regression
FAS
NA
10
Change from 
baseline in 
Body weight 
(kg and %)
Week 30, 
Week 56
Continuous
J2R-MI 
ANCOVA
FAS
NA
11
Change from 
baseline in 
Waist 
circumferenc
e (cm)
Week 30, 
Week 56
Continuous
J2R-MI 
ANCOVA
FAS
NA
12
Change from 
baseline in 
Waist-to-hip 
circumferenc
e ratio (ratio)
Week 30, 
Week 56
Continuous
J2R-MI 
ANCOVA
FAS
NA
13
Change from 
baseline 
Systolic 
Blood 
Pressure
(mmHg)
Week 30, 
Week 56
Continuous
J2R-MI 
ANCOVA
FAS
NA
14
Change from Week 30, Continuous
J2R-MI 
FAS
NA
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baseline 
Diastolic 
Blood 
Pressure
(mmHg)
Week 56
ANCOVA
15
Change from 
baseline 
Pulse
(beats/min)
Week 30, 
Week 56
Continuous
J2R-MI 
ANCOVA
SAS
NA
16
Change from 
baseline in 
Cardiovascul
ar biomarker 
(hsCRP)
(mg/L)
Week 30, 
Week 56
Continuous
J2R-MI 
ANCOVA
(with log 
transformed 
response and 
baseline values)
FAS
NA
17
Change from 
baseline in 
TC
(mmol/L)
Week 30, 
Week 56
Continuous
J2R-MI 
ANCOVA
(with log 
transformed 
response and 
baseline values)
FAS
NA
18
Change from 
baseline in 
LDL-
cholesterol
(mmol/L)
Week 30, 
Week 56
Continuous
J2R-MI 
ANCOVA
(with log 
transformed 
response and 
baseline values)
FAS
NA
19
Change from 
baseline in 
HDL-
cholesterol
(mmol/L)
Week 30, 
Week 56
Continuous
J2R-MI 
ANCOVA
(with log 
transformed 
response and 
baseline values)
FAS
NA
20
Change from 
baseline in 
non-HDL 
cholesterol
(mmol/L)
Week 30, 
Week 56
Continuous
J2R-MI 
ANCOVA
(with log 
transformed 
response and 
baseline values)
FAS
NA
21
Change from 
baseline in 
VLDL
(mmol/L)
Week 30, 
Week 56
Continuous
J2R-MI 
ANCOVA
(with log 
transformed 
response and 
baseline values)
FAS
NA
23
Change from 
baseline in 
TG
(mmol/L)
Week 30, 
Week 56
Continuous
J2R-MI 
ANCOVA
(with log 
transformed 
response and 
baseline values)
FAS
NA
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24
Change from 
baseline in 
FFA
(mmol/L)
Week 30, 
Week 56
Continuous
J2R-MI 
ANCOVA
(with log 
transformed 
response and 
baseline values)
FAS
NA
25
Change from 
baseline in
HbA1c (%)
Week 30, 
Week 56
Continuous
J2R-MI 
ANCOVA
FAS
NA
26
Change from 
baseline in 
FPG
(mmol/L)
Week 30, 
Week 56
Continuous
J2R-MI 
ANCOVA
FAS
NA
27
Change from 
baseline in 
fasting 
insulin
(pmol/L)
Week 30, 
Week 56
Continuous
J2R-MI 
ANCOVA
(with log 
transformed 
response and 
baseline values)
FAS
NA
28
Change from 
baseline in 
fasting C-
peptide
(nmol/L)
Week 30, 
Week 56
Continuous
J2R-MI 
ANCOVA
(with log 
transformed 
response and 
baseline values)
FAS
NA
29
Change from 
baseline in 
HOMA-B
Week 30, 
Week 56
Continuous
J2R-MI 
ANCOVA
(with log 
transformed 
response and 
baseline values)
FAS
NA
30
Change from 
baseline in 
HOMA-IR
Week 30, 
Week 56
Continuous
J2R-MI 
ANCOVA
(with log 
transformed 
response and 
baseline values)
FAS
NA
2.4
Secondary endpoints
All the secondary supportive efficacy endpoints listed below will be analysed as per protocol 
section 17.4.
2.4.1
Supportive secondary endpoints
2.4.1.1
Efficacy endpoints
!
From Baseline to week 82:
!
Percent of subjects achieving ≥5% reduction in baseline BMI at weeks 30, 56 and 82
!
Percent of subjects achieving ≥10% reduction in baseline BMI at weeks 30, 56 and 82
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!
Change in BMI SDS from baseline to 30 and 82 weeks and change from 56 weeks to 82 
weeks
!
Change from baseline to 30 and 56 weeks in:
o
BMI
o
Body weight (kilogram [kg], pounds [lb] and percent [%])
o
Waist circumference
o
Waist-to-hip circumference ratio
o
Cardiovascular risk factors: high sensitivity C-reactive protein (hsCRP) and 
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)
o
Systolic and diastolic blood pressure
o
Glucose metabolism: glycosylated haemoglobin (HbA1c), fasting plasma 
glucose (FPG), fasting insulin, fasting C-peptide, glycaemic category and 
homeostasis model assessment of beta-cell function and insulin resistance 
parameters (HOMA-B and HOMA-IR)
o
Patient reported outcome (PRO) assessed by Impact of Weight on Quality of 
Life-Kids (IWQOL-Kids)
!
   Change from 56 weeks to 82 weeks in:
o
BMI
o
Body weight (kilogram [kg], pounds [lb] and percent [%])
o
Waist circumference
o
Waist-to-hip circumference ratio
o
Cardiovascular risk factors: high sensitivity C-reactive protein (hsCRP) and 
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)
o
Systolic and diastolic blood pressure
o
Glucose metabolism: glycosylated haemoglobin (HbA1c), fasting plasma 
glucose (FPG), fasting insulin, fasting C-peptide, glycaemic category and 
homeostasis model assessment of beta-cell function and insulin resistance 
parameters (HOMA-B and HOMA-IR)
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.
!
Change from baseline to 30 and 56 weeks:
o
BMI SDS (%)
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!
Glycaemic category will be summarised by frequency count for each treatment group
!
Nutritional compliance will be summarised using descriptive statistics for each treatment 
group.
2.4.1.2
Safety endpoints
Descriptive statistics for all safety endpoints mentioned below will be provided with the aim to 
compare liraglutide 3.0 mg and placebo. All analyses and tabulations will be done using the safety 
analysis set. Unless otherwise stated, no formal statistical analyses are planned for the safety 
endpoints.
!
Number of treatment emergent adverse events
!
Number of treatment emergent hypoglycaemic episodes:
o
According to ADA/ISPAD classification
o
According to Novo Nordisk/ISPAD classification
!
Occurrence of anti-liraglutide antibodies
!
Change from baseline to 56 weeks in bone age assessment
!
Change from baseline to 30 and 56 weeks in:
o
Pulse
o
Electrocardiogram (ECG)
o
Laboratory parameters:

Haematology: haemoglobin, haematocrit, thrombocytes, erythrocytes, 
leucocytes, differential count (eosinophils, neutrophils, basophils, 
lymphocytes, monocytes)

Biochemistry: creatinine, creatinine kinase, urea (BUN), albumin, bilirubin 
(total), alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
alkaline phosphatase (ALP), sodium, potassium, calcium total, calcium, 
albumin- corrected, amylase, lipase, and carcinoembryonic antigen (CEA)

Hormone levels: calcitonin, insulin-like growth factor-1 (IGF-1), thyroid 
stimulating hormone (TSH), free thyroxine (free T4), 
dehydroepiandrosterone sulfate (DHEAS), luteinising hormone (LH), follicle 
stimulating hormone (FSH), estradiol (females), testosterone (males), 
prolactin, adrenocorticotropic hormone (ACTH), cortisol

Bone metabolism markers: Type 1 collagen N-telopeptide (NTX1), type 1 C-
telopeptide (CTX1), procollagen 1 N-terminal propeptide (P1NP), alkaline 
phosphatase (bone)
o
Pubertal status
o
Physical examination
o
Height standard deviation score (SDS)
o
Mental health assessed by Columbia Suicidality Severity Rating Scale (C-SSRS) and 
Patient Reported Health Questionnaire 9 (PHQ-9)
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!
Change from 56 weeks to 82 weeks in:
o
Pulse
o
Laboratory parameters:

Haematology: haemoglobin, haematocrit, thrombocytes, erythrocytes, 
leucocytes, differential count (eosinophils, neutrophils, basophils, 
lymphocytes, monocytes)

Biochemistry: creatinine, creatinine kinase, urea (BUN), albumin, bilirubin 
(total), alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
alkaline phosphatase (ALP), sodium, potassium, calcium total, calcium, 
albumin- corrected, amylase, lipase, and carcinoembryonic antigen (CEA)

Hormone levels: calcitonin, insulin-like growth factor-1 (IGF-1), thyroid 
stimulating hormone (TSH), free thyroxine (free T4), 
dehydroepiandrosterone sulfate (DHEAS), luteinising hormone (LH), follicle 
stimulating hormone (FSH), estradiol (females), testosterone (males), 
prolactin, adrenocorticotropic hormone (ACTH), cortisol

Bone metabolism markers: Type 1 collagen N-telopeptide (NTX1), type 1 C-
telopeptide (CTX1), procollagen 1 N-terminal propeptide (P1NP), alkaline 
phosphatase (bone)
o
Pubertal status
o
Physical examination
o
Height standard deviation score (SDS)
o
Patient Reported Health Questionnaire 9 (PHQ-9)
2.5
Endpoint derivation methods
2.5.1
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 = 
[/(	)](	)  
(	) (	)
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2 : Compute the final z-score (Z*
ind) of the child for the indicator as:
Where:
!
L(t), M(t) and S(t): Box-cox power, median and CV respectively
!
y: Individual BMI or height value
!
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)
!
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)
!
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)
!
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 1.
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Figure 1
Examples of children/adolescents ranked according to the 2007 WHO BMI-for-
age reference.
Child 1: 11 year-old boy with BMI=30
L=1.7862 M=16.9392 S=0.11070
Z=
[./.]^((.)) ()
.∗(.)
= 3.24 > 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+(30 −28.03/5.58) = 3.35 (BMI SDS)
Similar calculation will be done for height SDS.
2.5.2
IWQoL-Kids
The impact of weight on Quality of Life-Kids for Clinical Trials Version contains 27 questions with 
categorical answers (never, rarely, sometimes, usually, always). All these 27 questions are 
categorised into 4 domains (Physical Comfort, Body Esteem, Social Life, Family Life) scores. The 
Total score is the sum of all the 4 domain scores. 
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Table 2-5: Composite scores
Composite score
Items
Total number of items
Physical Comfort
1 - 6 
6
Body Esteem
7 - 15 
9
Social Life
16 - 21 
6
Family Life
22 - 27 
6
Total
1 - 27  
27
The derivation of the composite scores within the ADQSIWQL dataset can be done in several ways, 
but below procedure was followed on this trial.
The categorical values of the questionnaire are converted into numbers (in ADQSIWQL) as below:
Table 2-6: Conversion of categorical values to numeric values
Categorical values
Numeric values
Items 1- 27
Never True
1
Rarely True
2
Sometimes True
3
Usually True
4
Always True
5
The maximum and minimum possible score for each item will be 5 and 1, respectively. Composite 
score will be calculated for all four domains, including a total composite score will be calculated 
including all the domains.
For all four composite scores, at least 50% of the questions within a composite should be answered 
to calculate the score. For the total score, at least 75% of the 27 items should be answered.
The algorithm used for the derivation of a composite score (per subject and per visit):
((T*S_max )-(T*C_avg ))/((T*S_max )-(T*S_min ) )*100%
where,
T is the total number of items in the composite score (see Table 2-5).
C_avg is the average score of the composite (for subject X at visit X).
S_max is the maximum possible score value (5).
S_min is the minimum possible score value (1).
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2.5.3
C-SSRS questionnaire
The Columbia-Suicide Severity Rating Scale questionnaire is used 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 behaviour, 
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
2.5.4
PHQ-9 questionnaire
The Patient Health Questionnaire 9 is used 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. 
2.6
Pharmacokinetic and Pharmacodynamic modelling
The Pharmacokinetic and pharmacodynamic analysis will be done as mentioned in the protocol 
section 17.5.
2.7
Reporting Endpoints
All the continuous endpoints mentioned in section 2.2 and 2.4 will be summarised by treatment 
group for in-trial period using descriptive statistics such as mean, SD, 5th percentile and 95th
percentile, minimum and maximum. 
Lipids will be summarised by treatment group using descriptive statistics such as mean, geometric 
mean, SD, CV, 5th percentile and 95th percentile, minimum and maximum accept HbA1c and FPG
which will be summarised as rest of the continuous endpoints.
For the categorical endpoints mentioned in section 2.2 and 2.4 will summarised by treatment group 
using frequency counts and percentage by treatment groups.  
3
Changes to the statistical analyses planned in the protocol
In this SAP the following changes is been made to the statistical consideration in the protocol are as 
elaborated below for:
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
05 September 2019
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Trial ID:NN8022-4180
Version:
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EudraCT No.:2014-004353-14
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3.1
Primary endpoint
!
Primary analysis will be performed on in-trial period.
!
Tanner stage and glycaemic category collected at randomisation visit will be considered as fixed 
effect while performing ANCOVA for change from baseline to week 56.
!
Tanner stage for each subject at baseline is been derived and grouped using the information 
received from eCRF.
3.2
Supportive secondary efficacy endpoints
!
All the secondary supportive analysis will be performed on in-trial period.
!
To analyse the change in BMI SDS from week 56 to week 82 subjects who have completed the 
treatment (treatment completers), only their assessment at week 56 will be considered as 
baseline. No change from week 56 to 82 will be calculated for treatment discontinued subjects 
and for withdrawn subjects unless they have week 56 visit assessment collected.
!
Multiple imputation will not to be considered for change in BMI SDS from week 56 to 82 
parameter if there is no missing assessment. 
!
Tanner stage and glycaemic category collected at randomisation visit will be considered as fixed 
effect while performing ANCOVA for change from baseline to week 30, 56 and 82 and change 
from week 56 to 82.
!
For “percentage of subjects achieving ≥5% reduction” and “Percentage of subjects achieving 
≥10% reduction” in baseline BMI at week 30, 56 and 82. Missing imputation will be handled as 
mentioned in section 2.3 with the baseline BMI as covariate instead of baseline BMI SDS.
!
Body weight with standard units (Kg) will only be used in all summary and analysis outputs. 
Below additional supportive secondary endpoint is been included in section 2.4
!
Change from baseline to 30 and 56 weeks in:
o
BMI SDS (%)
3.3
Supportive secondary safety endpoints
!
For overall tanner staging, the maximum scale irrespective of the categorical question will be 
considered. 
!
For adverse events in run-in period all the subjects who has attended at least one run-in visit will 
be included in the run-in outputs.
!
C-SSRS will only be summarised using summary statistics (frequency count, percentage) for 
screening, baseline, week 30, week 56 and week 82 and the shift from baseline to 30 and 56 
week and from week 56 to 82 will not be produced.
!
Only standard units will be reported for all laboratory parameters.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
05 September 2019
Novo Nordisk
Trial ID:NN8022-4180
Version:
1.0
UTN:U1111-1162-7101
Status:
Final
EudraCT No.:2014-004353-14
Page:
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!
Boxplots will not be produced for laboratory parameters.
!
ECG and bone age assessment will be summarised using summary statistics (frequency count, 
percentage) by treatment group for each visit will be produced. Shift table will be produced for 
ECG at week 30 and week 56.
!
SAS will be used to analyse change from baseline pulse values at week 30 and 56.
The following text in protocol: 
“Bone age assessment at baseline and change in bone age assessment will be summarised   using 
descriptive statistics”
is replaced to:
“Bone age assessment is summarised using frequencies count and percentages. A shift table will be 
provided for change in baseline to week 56.”  
3.4
Analysis Rules
3.4.1
Visit Windowing:
Primary endpoints analysis is performed at Visit 25 (week 56) and secondary endpoints are 
performed at Visit 19 (week 30), Visit 25 (week 56) and Visit 30 (week 82).
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 like those for the end of 
treatment (V25) as soon as possible, and a follow-up visit (V26) two weeks later.
The subjects were asked to attend additional visits depending on when the trial product
discontinuation takes place during the trial:
!
If the trial product is discontinued before V19 subjects were asked to attend three additional
visits (V19x, V25x and V30x) taking place weeks 30, 56 and 82 after randomisation, 
respectively.
!
If the trial product is discontinued after V19 and before V25 subjects were asked to attend
two additional visits (V25x and V30x) taking place weeks 56 and 82 after randomisation,
respectively.
The end of treatment (V25), and a follow-up visit (V26) collected for prematurely discontinued 
subject and withdrawn subjects did not exactly taken place in respective endpoint weeks (i.e., at 
week 30, week 56 and week 82). Hence these records will be reallocated to the respective weeks 
based on analysis day on when the assessments are done by visit windowing concept.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
05 September 2019
Novo Nordisk
Trial ID:NN8022-4180
Version:
1.0
UTN:U1111-1162-7101
Status:
Final
EudraCT No.:2014-004353-14
Page:
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3.4.1.1
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 4180 the visit windowing will be done only for V25 and V26 visits for prematurely 
discontinued/withdrawn subjects.
The visit windows are shown in Table 3-1.
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 72 to Day 99. 
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.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
05 September 2019
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Trial ID:NN8022-4180
Version:
1.0
UTN:U1111-1162-7101
Status:
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EudraCT No.:2014-004353-14
Page:
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Table 3-1: Assessment windows for scheduled visits
Analysis Visit
Week
Scheduled 
Day
Visit Window
Visit 2 (screening)
week -14
-98
Day -999 to -91
Visit 3 (week -12)
week -12
-84
Day -90 to -70
Visit 5 (week -8)
week -8
-56
Day -69 to -42
Visit 7 (week -4)
week -4
-28
Day -41 to -21
Visit 8 (week -2)
week -2
-14
Day -20 to -7
Visit 9 (week 0)
Randomisation
1
Day -6 to 4
Visit 10 (week 1)
week 1
8
Day 5 to 11
Visit 11 (week 2)
week 2
15
Day 12 to 18
Visit 12 (week 3)
week 3
22
Day 19 to 25
Visit 13 (week 4)
week 4
29
Day 26 to 43
Visit 14 (week 8)
week 8
57
Day 44 to 71
Visit 15 (week 12)
week 12
85
Day 72 to 99
Visit 16 (week 16)
week 16
113
Day 100 to 127
Visit 17 (week 20)
week 20
141
Day 128 to 158
Visit 18 (week 25)
week 25
176
Day 159 to 193
Visit 19 (week 30)
week 30
211
Day 194 to 225
Visit 19x (week 30 follow-up)
week 30
211
Day 194 to 225
Visit 20 (week 34)
week 34
239
Day 226 to 253
Visit 21 (week 38)
week 38
267
Day 254 to 281
Visit 22 (week 42)
week 42
295
Day 282 to 309
Visit 23 (week 46)
week 46
323
Day 310 to 340
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Statistical Analysis Plan
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Date:
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Trial ID:NN8022-4180
Version:
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UTN:U1111-1162-7101
Status:
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EudraCT No.:2014-004353-14
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Analysis Visit
Week
Scheduled 
Day
Visit Window
Visit 24 (week 51)
week 51
358
Day 341 to 375
Visit 25 (week 56)
week 56
393
Day 376 to 400
Visit 25x (week 56 follow-up)
week 56
393
Day 376 to 400
Visit 26 (week 58)
week 58
407
Day 401 to 428
Visit 27 (week 64)
week 64
449
Day 429 to 470
Visit 28 (week 70)
week 70
491
Day 471 to 512
Visit 29 (week 76)
week 76
533
Day 513 to 554
Visit 30 (week 82)
week 82
575
Day 555 to 999
Visit 30x (week 82 follow-up)
week 82
575
Day 555 to 999
3.4.1.2
For parameters which are not collected at every visit (e.g. HEIGHT): 
Visit windows defined in Table 3-1will be combined. For example, Table 3-2show visit windows 
for HEIGHT.
Table 3-2: Assessment windows for scheduled visits
Analysis Visit
Week
Scheduled 
Day
Visit Window
Visit 2 (screening)
week -14
-98
Day -999 to -56
Visit 8 (week -2)
week -2
-14
Day -55 to -7
Visit 9 (week 0)
week 0
   1
Day -6 to 43
Visit 15 (week 12)
week 12
85
Day 44 to 148
Visit 19 (week 30)
week 30
211
Day 149 to 253
Visit 19x (week 30 follow-up)
week 30
211
Day 149 to 253
Visit 22 (week 42)
week 42
295
Day 254 to 344
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
05 September 2019
Novo Nordisk
Trial ID:NN8022-4180
Version:
1.0
UTN:U1111-1162-7101
Status:
Final
EudraCT No.:2014-004353-14
Page:
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Analysis Visit
Week
Scheduled 
Day
Visit Window
Visit 25 (week 56)
week 56
393
Day 345 to 484
Visit 25x (week 56 follow-up)
week 56
393
Day 345 to 484
Visit 30 (week 82)
week 82
575
Day 485 to 999
Visit 30x (week 82 follow-up)
week 82
575
Day 485 to 999
3.4.1.3
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 19x, 25x and 30x, hence if the visit reallocation for these 
parameters and related parameters such as ‘BMI’, ‘BMI_SDS’ and ‘HEIGHT_SDS’ are reallocated 
to x visit instead of normal visit (i.e., visits 19, 25 and 30). Other parameters are reallocated to 
normal visits.
Note: Withdrawal subjects are reallocated to normal visits.
3.4.2
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 19 (week 30)) and x visit (Visit 19x (week 
30)) then the records which are reallocated are not eligible for analysis.
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Statistical Analysis Plan
CONFIDENTIAL
Date:
05 September 2019
Novo Nordisk
Trial ID:NN8022-4180
Version:
1.0
UTN:U1111-1162-7101
Status:
Final
EudraCT No.:2014-004353-14
Page:
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4
References
1. International Conference on Harmonisation. ICH Harmonised Tripartite Guideline. Guideline for 
Good Clinical Practice E6 (R1), Step 4. 10 June 1996.
2. International Conference on Harmonisation. ICH Harmonised Tripartite Guideline. Guideline for 
Statistical principle for clinical trials Step 4. 5 February 1998.
3. Carpenter JR, Roger JH, Kenward MG. Analysis of longitudinal trials with protocol
deviation: a framework for relevant, accessible assumptions, and inference via multiple
imputation. J Biopharm Stat. 2013;23(6):1352-71.
4. Computation of centiles and z-scores for height-for-age, weight-for-age and BMI-for-age. 
(http://www.who.int/growthref/computation.pdf?ua=1)
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Sample size calculation
   
Date:
20 May 2016
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Trial ID: NN8022-4180
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Status:
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Statistical Documentation
Trial ID: NN8022-4180
Program code and results for the sample size calculation in 
trial NN8022-4180
Author 
 
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Trial ID: NN8022-4180 
 
Program code and results for the sample size calculation in trial NN8022-4180, Version 1.0, 
dated 20 May 2016 
 
Overview of deleted pages 
 
Pages 
Title 
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Program code and results for the sample size calculation in trial 
NN8022-4180