Conditions: Diabetes Diabetes Mellitus, Type 2
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 135
Healthy volunteers: no

Brief summary:
This trial is conducted globally. The aim of this trial is to assess the efficacy and safety of liraglutide in the paediatric population in order to potentially address the unmet need for treatment of children and adolescents with type 2 diabetes.

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: liraglutide intervention 2: placebo intervention 3: metformin
Intervention descriptions: intervention 1: Administered subcutaneously (s.c., under the skin) once daily.1.8 mg or maximum tolerated dose (MTD: 0.6 mg, 1.2 mg, 1.8 mg) for 26 weeks. Subjects will continue treatment in a 26 week open-labelled extension. Rescue treatment will be allowed if rescue criteria are met. intervention 2: Administered subcutaneously (s.c., under the skin) once daily for 26 weeks. Subjects will discontinue placebo treatment in the open-labelled extension. Rescue treatment will be allowed if rescue criteria are met. intervention 3: Tablets administered for 26 weeks. Maximum tolerated dose (MTD) between 1000-2000 mg at the discretion of the investigator. Subjects will continue treatment in a 26 week open-labelled extension.

Protocol document:
Prot_000.pdf: 
Cover Page for Protocol 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT01541215 
Sponsor trial ID: 
NN2211-3659 
Official title of study: 
Efficacy and safety of liraglutide in combination with 
metformin versus metformin monotherapy on glycaemic 
control in children and adolescents with type 2 diabetes 
A 26-week double-blind, randomised, parallel group, placebo 
controlled multi-centre trial followed by a 26-week open-label 
extension 
Document date: 
03 April 2017 
 


Protocol
CONFIDENTIAL
Date:
03 April 2017
Novo Nordisk
Trial ID: NN2211-3659
Version:
7.0
UTN:U1111-1121-8743
Status:
Final
EudraCT No.:2011-002605-29
Page:
1 of 113
Protocol version 7.0
Trial ID:NN2211-3659:
Updated protocol including:
-Original protocol, version 1.0, dated 20 January 2012
-Local Substantial protocol amendment no. 1, version 1.0, dated 23 February 2012 (Israel)
-Local Substantial protocol amendment no. 2, version 1.0, dated 30 May 2012 (United States of America)
-Global Substantial protocol amendment no. 3, version 1.0, dated 26 July 2012 (All countries)
-Global Substantial protocol amendment no. 4, version 1.0, dated 11 October 2012 (All countries)
Local Substantial protocol amendment no. 5, version 1.0, dated 29 October 2012 (Sweden)
Global Substantial protocol amendment no. 7, version 1.0 dated 23 May 2013 (All countries)
Global protocol amendment no. 10, version 1.0 dated 09 Feb 2015 (All countries)
Local amendment no 11 version 1.0 dated 22 April 2014 (Sweden)
Global protocol amendment no. 13, version 2.0 dated 28 March 2017 (All countries)
Efficacy and safety of liraglutide in combination with 
metformin versus metformin monotherapy on glycaemic 
control in children and adolescents with type 2 diabetes
A 26-week double-blind, randomised, parallel group, placebo controlled 
multi-centre trial followed by a 26-week open-label extension
Trial phase: 3a
Protocol originator: 
Name: 
, 
Department or business area: Clinical Operations, Victoza
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.
 
 
 
 
 
Redacted protocol 
Includes redaction of personal identifiable information only. 
 
 
 
. 
 


Protocol
CONFIDENTIAL
Date:
03 April 2017
Novo Nordisk
Trial ID: NN2211-3659
Version:
7.0
UTN:U1111-1121-8743
Status:
Final
EudraCT No.:2011-002605-29
Page:
2 of 113
Table of contents   
Page
Table of contents...............................................................................................................................................2
Table of figures.................................................................................................................................................6
Table of tables...................................................................................................................................................6
List of abbreviations.........................................................................................................................................7
1
Summary..................................................................................................................................................12
2
Flow chart ................................................................................................................................................15
3
Background information and rationale for the trial............................................................................22
3.1
Basic information.........................................................................................................................22
3.1.1
Treatment of type 2 diabetes mellitus in the paediatric population ...........................22
3.1.2
Glucagon-like peptide-1 ............................................................................................22
3.1.3
Liraglutide..................................................................................................................22
3.1.4
Rationale for the trial.................................................................................................26
3.1.5
Risk and benefits assessment (Only Applicable for Sweden)....................................26
4
Objectives and endpoints........................................................................................................................29
4.1
Objectives ....................................................................................................................................29
4.2
Endpoints .....................................................................................................................................29
5
Type of trial .............................................................................................................................................32
5.1
Type of trial .................................................................................................................................32
5.2
Rationale for trial design..............................................................................................................33
5.3
Treatment of subjects...................................................................................................................34
5.3.1
Metformin..................................................................................................................34
5.3.2
Liraglutide..................................................................................................................35
5.3.3
Basal insulin...............................................................................................................36
5.3.4
Open Label period .....................................................................................................38
5.3.5
Rescue treatment........................................................................................................38
5.4
Rationale for treatment ................................................................................................................39
6
Trial population.......................................................................................................................................41
6.1
Number of subjects to be investigated.........................................................................................41
6.2
Inclusion criteria ..........................................................................................................................41
6.3
Exclusion criteria.........................................................................................................................42
6.4
Randomisation criteria.................................................................................................................43
6.5
Rescue criteria..............................................................................................................................43
6.6
Withdrawal criteria ......................................................................................................................44
6.7
Subject replacement.....................................................................................................................45
6.8
Rationale for trial population.......................................................................................................45
7
Trial schedule ..........................................................................................................................................46
8
Methods and assessments .......................................................................................................................47
8.1
Visit procedures...........................................................................................................................47
8.1.1
Informed consent and assent procedure.....................................................................47
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
03 April 2017
Novo Nordisk
Trial ID: NN2211-3659
Version:
7.0
UTN:U1111-1121-8743
Status:
Final
EudraCT No.:2011-002605-29
Page:
3 of 113
8.1.2
Investigator site logs ..................................................................................................47
8.1.3
Screening, screening failures and re-screening..........................................................47
8.1.4
Randomisation and run-in failures.............................................................................48
8.1.5
Visits..........................................................................................................................48
8.1.6
Rescue treatment........................................................................................................49
8.1.7
Withdrawal.................................................................................................................50
8.1.8
Subject training..........................................................................................................50
8.1.9
Investigator evaluations and review...........................................................................51
8.2
Concomitant illness and medical history.....................................................................................52
8.3
Concomitant medication..............................................................................................................52
8.4
Laboratory assessments ...............................................................................................................52
8.5
Subject related information and assessments...............................................................................53
8.5.1
Demography...............................................................................................................53
8.5.2
Diabetes history .........................................................................................................53
8.5.3
Smoking habits ..........................................................................................................54
8.5.4
Alcohol and drug screen ............................................................................................54
8.6
Assessments for efficacy..............................................................................................................54
8.6.1
Body measurements...................................................................................................54
8.6.2
Vital signs ..................................................................................................................55
8.6.3
Blood samples............................................................................................................56
8.6.4
Self-measured plasma glucose...................................................................................57
8.7
Assessments for safety.................................................................................................................58
8.7.1
Adverse events...........................................................................................................58
8.7.2
Hypoglycaemic episodes ...........................................................................................58
8.7.2.1
ADA classification of hypoglycaemia ................................................59
8.7.2.2
Additional definitions of hypoglycaemia............................................60
8.7.3
Electrocardiogram – 12 lead......................................................................................61
8.7.4
Eye examination ........................................................................................................61
8.7.5
Physical examination.................................................................................................61
8.7.6
Tanner staging............................................................................................................62
8.7.7
Bone age assessment..................................................................................................62
8.7.8
Blood samples............................................................................................................63
8.7.9
Urine samples ............................................................................................................65
8.8
Other assessments........................................................................................................................65
8.8.1
Blood samples - pharmacokinetic..............................................................................66
8.9
Subject compliance......................................................................................................................67
9
Trial supplies ...........................................................................................................................................68
9.1
Trial products...............................................................................................................................68
9.1.1
Non-investigational medicinal product(s)..................................................................68
9.2
Labelling......................................................................................................................................69
9.3
Storage, accountability and destruction.......................................................................................69
9.4
Auxiliary supply ..........................................................................................................................70
10 Interactive voice and web response system...........................................................................................71
11 Randomisation and unblinding procedures..........................................................................................72
11.1
Breaking of blinded codes ...........................................................................................................72
11.2
Unblinding procedure and laboratory access to blinded data ......................................................72
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
03 April 2017
Novo Nordisk
Trial ID: NN2211-3659
Version:
7.0
UTN:U1111-1121-8743
Status:
Final
EudraCT No.:2011-002605-29
Page:
4 of 113
12 Adverse events, and technical complaints and pregnancies................................................................73
12.1
Definition of adverse events ........................................................................................................73
12.2
Definition of serious adverse events and non-serious adverse events .........................................73
12.3
Definition of medical events of special interest...........................................................................74
12.4
Severity, relationship and outcome of adverse events.................................................................75
12.5
Reporting of adverse events.........................................................................................................76
12.6
Follow-up of adverse events........................................................................................................78
12.7
Technical complaints and technical complaint samples ..............................................................78
12.7.1
Reporting of technical complaints .............................................................................79
12.7.2
Collection, storage and shipment of technical complaint samples ............................79
12.8
Pregnancies..................................................................................................................................80
12.8.1
Pregnancies in partners of trial subjects (only applicable to US) ..............................81
12.9
Precautions and/or overdose ........................................................................................................81
12.10
Committees related to safety........................................................................................................81
12.10.1
Novo Nordisk safety committee ................................................................................81
12.10.2
The external data monitoring committee...................................................................81
13 Case report forms....................................................................................................................................83
13.1
Corrections to case report forms..................................................................................................83
13.2
Case report form flow..................................................................................................................84
14 Monitoring procedures ...........................................................................................................................85
14.1
Source data verification ...............................................................................................................85
15 Data management....................................................................................................................................86
16 Computerised systems.............................................................................................................................87
17 Statistical considerations ........................................................................................................................88
17.1
Sample size calculation................................................................................................................88
17.2
Definition of analysis sets............................................................................................................90
17.3
Primary endpoint..........................................................................................................................90
17.4
Secondary endpoints....................................................................................................................92
17.4.1
Confirmatory secondary endpoint..............................................................................92
17.4.2
Supportive secondary endpoints ................................................................................93
17.4.3
Safety endpoints.........................................................................................................94
17.5
PK modelling...............................................................................................................................96
18 Ethics........................................................................................................................................................97
18.1
Informed consent .........................................................................................................................98
18.2
Data handling...............................................................................................................................99
18.3
Premature termination of the trial and/or trial site.......................................................................99
19 Protocol compliance..............................................................................................................................100
20 Audits and inspections ..........................................................................................................................101
21 Critical documents ................................................................................................................................102
22 Responsibilities......................................................................................................................................104
23 Reports and publications......................................................................................................................105
23.1
Communication of results..........................................................................................................105
23.1.1
Authorship ...............................................................................................................106
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
03 April 2017
Novo Nordisk
Trial ID: NN2211-3659
Version:
7.0
UTN:U1111-1121-8743
Status:
Final
EudraCT No.:2011-002605-29
Page:
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23.1.2
Site-specific publication(s) by investigator(s) .........................................................106
23.2
Investigator access to data and review of results.......................................................................106
24 Retention of clinical trial documentation............................................................................................107
25 Institutional review boards/independent ethics committees and regulatory authorities................108
26 Indemnity statement .............................................................................................................................109
27 References..............................................................................................................................................111
Attachment I – Global List of key staff and relevant departments 
Attachment II – Country List of key staff and relevant departments
Appendix A ! Body mass index for age
Appendix B – Blood pressure ranges for children
Appendix C – Medical events of special interest
Appendix D – Monitoring of calcitonin levels
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
03 April 2017
Novo Nordisk
Trial ID: NN2211-3659
Version:
7.0
UTN:U1111-1121-8743
Status:
Final
EudraCT No.:2011-002605-29
Page:
6 of 113
Table of figures  
Page
Figure 5–1 
Trial diagram ..........................................................................................................................33
Figure 5–2
Dose escalation of liraglutide .................................................................................................36
Figure 8–1
ADA classification of hypoglycaemia....................................................................................60
Table of tables   
Page
Table 5–1
Algorithm for up-titration of basal insulin dose .....................................................................37
Table 5–2
Algorithm for down-titration of basal insulin dose ................................................................38
Table 17–1
Total sample size for a 1:1 randomisation..............................................................................89
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
03 April 2017
Novo Nordisk
Trial ID: NN2211-3659
Version:
7.0
UTN:U1111-1121-8743
Status:
Final
EudraCT No.:2011-002605-29
Page:
7 of 113
List of abbreviations
AB
Antibody
ADA
American Diabetes Association
AE
adverse event
ALAT
alanine aminotransferase
ANCOVA
analysis of covariance
ASAT
aspartate aminotransferase
Anti-GAD
anti-glutamic acid decarboxylase antibodies 
AUC
area under the curve
BG
blood glucose 
BMI
body mass index
BP
blood pressure
CCDS
company core data sheet
CEA
carcinoembryonic antigen
CFR
code of federal regulation
CLAE
clinical laboratory adverse event
CNS
central nervous system
CRF
case report form
CRO
contract research organisation
CTA
clinical trial application
CTX
C-telopeptide
CTR
clinical trial report
DCF
data clarification form 
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
03 April 2017
Novo Nordisk
Trial ID: NN2211-3659
Version:
7.0
UTN:U1111-1121-8743
Status:
Final
EudraCT No.:2011-002605-29
Page:
8 of 113
DHEAS
dehydroepiandrosterone sulfate
DL
detection limit
DMC
data monitoring committee
DUN
dispensing unit number
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
EMA
European Medicines Agency
EU
European Union
FAS
full analysis set
FDA
Food and Drug Administration
FPFV
first patient first visit
FPG
fasting plasma glucose
FSH
follicle stimulating hormone
FU
follow-up visit
GCP
good clinical practice
GLP-1
glucagon-like peptide-1
HbA1C
glycosylated haemoglobin A1c
HDL
high density lipoprotein
HIV
human immunodeficiency virus
HOMA
homeostasis model assessment
IA-2
insulinoma associated-protein 2 
IB
investigator’s brochure
ICH
International Conference on Harmonisation
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
03 April 2017
Novo Nordisk
Trial ID: NN2211-3659
Version:
7.0
UTN:U1111-1121-8743
Status:
Final
EudraCT No.:2011-002605-29
Page:
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ICMJE
International Committee of Medical Journal Editors
ID
identification 
IEC
independent ethics committee
IGF-1
insulin-growth factor-1
IGF BP-3
insulin-growth factor-binding protein-3
IMP
investigational medicinal product
IND
investigational new drug application
IRB
institutional review board
i.v.
intravenous  
IV/WRS
interactive voice/web response system
LAR
legally acceptable representative
LDL
low density lipoprotein
LH
luteinizing hormone
LLOQ
lower limit of quantification
LOCF
last observation carried forward
LPLV
last patient last visit
LSMean
least square Mean
MAR
missing at random
MedDRA
Medical Dictionary for Regulatory Activities
MEN
multiple endocrine neoplasia
MESI
medical event of special interest
MIDF
monitor initiated discrepancy form
MODY
maturity onset of the young
MRHD
maximum recommended human dose 
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
03 April 2017
Novo Nordisk
Trial ID: NN2211-3659
Version:
7.0
UTN:U1111-1121-8743
Status:
Final
EudraCT No.:2011-002605-29
Page:
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MTC
medullary thyroid carcinoma
MTD
maximum tolerated dose  
N
number of subjects 
NIMP
non-investigational medicinal product
NTX
N-telopeptide
OAD
oral antidiabetic drug
P1NP
serum type 1 procollagen
PD
pharmacodynamics
PDCO
European Paediatric Committee
PG
plasma glucose
PP
per protocol
PPG
postprandial glucose
PK
pharmacokinetics
REML
restricted maximum likelihood
RMA
repeated measurement analysis
SAE
serious adverse event
SAP
statistical analysis plan
s.c.
Subcutaneous
SD
standard deviation
SDS
standard deviation score 
SDV
source data verification
SIF
safety information form
SmPC
summary of product characteristics
SMPG
self-measured plasma glucose
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
03 April 2017
Novo Nordisk
Trial ID: NN2211-3659
Version:
7.0
UTN:U1111-1121-8743
Status:
Final
EudraCT No.:2011-002605-29
Page:
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SOP
standard operational procedure
SUSAR
suspected unexpected serious adverse reaction
T½
half life
TC
telephone contact 
TMM
trial materials manual
TSH
thyroid stimulating hormone
UNR
upper normal range
US
United States
UTN
universal trial number
VDLV
very low density lipoprotein 
WHO
World Health Organisation 
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
03 April 2017
Novo Nordisk
Trial ID: NN2211-3659
Version:
7.0
UTN:U1111-1121-8743
Status:
Final
EudraCT No.:2011-002605-29
Page:
12 of 113
1
Summary
Objectives and endpoints
Primary objective
To confirm the superiority of liraglutide at the maximum tolerated dose (0.6 mg, 1.2 mg or 1.8 mg) 
versus placebo when added to metformin with or without basal insulin treatment in controlling 
glycaemia in children and adolescents (ages 10–17 years) with type 2 diabetes.
Primary endpoint
∀
Change in HbA1c from baseline to week 26
Key secondary objectives  
To assess and compare the effect of liraglutide versus placebo in combination with metformin with 
or without basal insulin treatment on:
∀
Parameters of glycaemic control  
∀
Safety and tolerability
Key secondary endpoints 
At 26 and 52 weeks of treatment:
∀
HbA1c <7.0% (yes/no)
∀
HbA1c #6.5% (yes/no)
∀
HbA1c <7.0% without severe or minor hypoglycaemic episodes (yes/no)
Change from baseline at 26 and 52 weeks of treatment in:
∀
Fasting plasma glucose (FPG)
∀
7-point self-measured plasma glucose 
∀
Body weight 
∀
BMI standard deviation score (SDS)
Safety
∀
Adverse events (AEs) and serious adverse events (SAEs)
∀
Safety follow-up after 1 and 2 years: AEs and SAEs, growth velocity and pubertal 
progression 
Primary endpoint and key secondary endpoints will be used for clinical trial registers as 
www.clinicaltrials.gov.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
03 April 2017
Novo Nordisk
Trial ID: NN2211-3659
Version:
7.0
UTN:U1111-1121-8743
Status:
Final
EudraCT No.:2011-002605-29
Page:
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Trial design
This is a multi-centre, 26-week randomised double-blind, parallel-group, placebo-controlled clinical 
trial followed by a 26-week open-label extension in subject’s ages 10–17 years with type 2 diabetes. 
After being titrated to 2000 mg of metformin or maximum tolerated dose (MTD) (metformin dose 
must be ≥1000 mg and ≤2000 mg) subjects will be randomised 1:1 to receive liraglutide (1.8 mg or 
MTD) or liraglutide placebo. Subjects treated with basal insulin will continue treatment with basal 
insulin.
Subjects already treated with 2000 mg or more of metformin and with a stable dose for at least 56 
days prior to Visit 1 may advance directly to randomisation (Visit 7) when eligibility according to 
the inclusion and exclusion criteria has been confirmed. Subjects who are treated with basal insulin 
should in addition to the stable dose of metformin have a stable dose of basal insulin for at least 56 
days in order to advance directly to Visit 7.
After 26 weeks of blinded treatment, the treatment allocation will be unblinded. Subjects treated 
with liraglutide will continue their trial medication until end of treatment. Subjects treated with 
liraglutide placebo will discontinue their liraglutide placebo treatment. Rescue treatment will be 
allowed for subjects in both treatment groups experiencing confirmed hyperglycaemia. Subjects on 
rescue medication will stay in the trial.
Subjects treated with liraglutide for more than 3 months will complete 1 and 2 year follow-up visits. 
Trial population
It is planned to randomise 94 subjects in this trial.
Key inclusion criteria
∀
Children and adolescents between the ages of 10–16 years. Subjects cannot turn 17 and 11 
months before the end of treatment (52 weeks)
∀
Diagnosis of type 2 diabetes mellitus and treated for at least 30 days with:
o
diet and exercise alone
o
diet and exercise in combination with metformin monotherapy
o
diet and exercise in combination with metformin and a stable* dose of basal insulin.  
o
diet and exercise in combination with a stable* dose of basal insulin. 
*Stable is defined as basal insulin adjustments up to 15%
∀
HbA1c
!
∃7.0% and #11% if diet and exercise treated
!
∃6.5% and #11% if treated with metformin as monotherapy, basal insulin as monotherapy or 
metformin and basal insulin in combination
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
03 April 2017
Novo Nordisk
Trial ID: NN2211-3659
Version:
7.0
UTN:U1111-1121-8743
Status:
Final
EudraCT No.:2011-002605-29
Page:
14 of 113
∀
Body mass index (BMI) >85% percentile of the general age and gender matched population
Key exclusion criteria
∀
Type 1 diabetes 
∀
Maturity onset diabetes of the young (MODY)
∀
Use of any antidiabetic agent other than metformin and/or basal insulin within 90 days prior to 
screening.
∀
Recurrent severe hypoglycaemia or hypoglycaemic unawareness as judged by the investigator
∀
History of chronic pancreatitis or idiopathic acute pancreatitis
∀
Any clinically significant disorder, except for conditions associated with type 2 diabetes history 
which in the investigator’s opinion could interfere with results of the trial
∀
Uncontrolled hypertension, treated or untreated >99th percentile for age and gender in children
∀
Known or suspected abuse of alcohol or drugs/narcotics 
Key assessments
Efficacy:
∀
Glucose metabolism
∀
Body measurements
∀
Blood pressure
∀
Lipids
Safety:
∀
AEs and SAEs
∀
Hypoglycaemic episodes
∀
Biochemistry
∀
Haematology
∀
Growth parameters
∀
Pubertal assessment (Tanner staging)
∀
Hormones
∀
Biochemical parameters of bone metabolism
∀
Formation of anti-liraglutide antibodies  
Trial products
Novo Nordisk will supply the following trial products:
∀
Liraglutide, 6.0 mg/mL, 3 mL pen-injector for s.c. injection
∀
Liraglutide placebo, 3 mL pen-injector for s.c. injection
∀
Metformin, 500 mg tablets (non-investigational medicinal product)
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
03 April 2017
Novo Nordisk
Trial ID: NN2211-3659
Version:
7.0
UTN:U1111-1121-8743
Status:
Final
EudraCT No.:2011-002605-29
Page:
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2
Flow chart
Trial period
Screening and Run-in
Blinded Treatment
Unblinded Treatment
F
U
FU
Type of visit
Screen-
ing
S
TC
TC
S
TC
(Rando-
misation)
S
S
S
TC
TC
S
TC
S
TC
S
TC
S
S
TC
S
TC
S
TC
S
S
S
S
Visit number
1
21
31
41
51
61
7
8
9
10
10A, 
10B21
11, 
12
11A, 
11B21
13
14
15
16
172,3
18
19
20
21
22
23
24
25 3
26
27, 
2819
Time of visit (week)
-13
-11
-10
-9
-8
-4
0
1
2
3
4, 5
6, 
10
7, 8
14
17
20
23
26
30
33
36
39
42
45
48
52
53
104,
156
Visit window (day)
Day -91 
to day -
82
±2
±2
±2
±2
±2
0
±2
±2
±2
±2
±3
±2
±3
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±3
±14
Informed consent4
X
Informed assent4
X
In/exclusion criteria
X
X
Randomisation
X
Randomisation 
criteria
X
Rescue criteria
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Withdrawal criteria
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant illness
X
Medical history
X
Concomitant
medication
X
X
X
X
X
X
X
X
X
X
X5
X5
X5
X5
X5
X5
X5
X5
X5
X5
X5
X5
X5
X5
X5
X5
X6
X6
Attend blood 
sampling fasting
X
X
X
X
X
X
X20
Demography
X
Diabetes history
X
Smoking habits
X
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
03 April 2017
Novo Nordisk
Trial ID: NN2211-3659
Version:
7.0
UTN:U1111-1121-8743
Status:
Final
EudraCT No.:2011-002605-29
Page:
16 of 113
Trial period
Screening and Run-in
Blinded Treatment
Unblinded Treatment
F
U
FU
Type of visit
Screen-
ing
S
TC
TC
S
TC
(Rando-
misation)
S
S
S
TC
TC
S
TC
S
TC
S
TC
S
S
TC
S
TC
S
TC
S
S
S
S
Visit number
1
21
31
41
51
61
7
8
9
10
10A, 
10B21
11, 
12
11A, 
11B21
13
14
15
16
172,3
18
19
20
21
22
23
24
25 3
26
27, 
2819
Time of visit (week)
-13
-11
-10
-9
-8
-4
0
1
2
3
4, 5
6, 
10
7, 8
14
17
20
23
26
30
33
36
39
42
45
48
52
53
104,
156
Visit window (day)
Day -91 
to day -
82
±2
±2
±2
±2
±2
0
±2
±2
±2
±2
±3
±2
±3
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±3
±14
Alcohol screen
X
Urine drug screen
X
EFFICACY
Body weight
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
X
X
X
X
X
BMI
X
Waist circumference
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Glucose 
metabolism7
∀
HbA1c
X
X
X12
X
X
X
∀
Fasting 
plasma 
glucose
X
X
X
X
X
X
∀
Fasting 
insulin
X
X
X
X
∀
Fasting pro-
insulin
X
X
X
X
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
03 April 2017
Novo Nordisk
Trial ID: NN2211-3659
Version:
7.0
UTN:U1111-1121-8743
Status:
Final
EudraCT No.:2011-002605-29
Page:
17 of 113
Trial period
Screening and Run-in
Blinded Treatment
Unblinded Treatment
F
U
FU
Type of visit
Screen-
ing
S
TC
TC
S
TC
(Rando-
misation)
S
S
S
TC
TC
S
TC
S
TC
S
TC
S
S
TC
S
TC
S
TC
S
S
S
S
Visit number
1
21
31
41
51
61
7
8
9
10
10A, 
10B21
11, 
12
11A, 
11B21
13
14
15
16
172,3
18
19
20
21
22
23
24
25 3
26
27, 
2819
Time of visit (week)
-13
-11
-10
-9
-8
-4
0
1
2
3
4, 5
6, 
10
7, 8
14
17
20
23
26
30
33
36
39
42
45
48
52
53
104,
156
Visit window (day)
Day -91 
to day -
82
±2
±2
±2
±2
±2
0
±2
±2
±2
±2
±3
±2
±3
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±3
±14
∀
Fasting C-
peptide
X
X
X
X
X
∀
Fasting 
glucagon
X
X
X
X
Lipids7
X
X
X
X
X
7-point SMPG 
profile 
X
X
X
X
SAFETY
Adverse events
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
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
SMPG 
measurements14
X
X
X
X
X
X14
X
ECG9
X
X
X
Eye examination 9
X
X
X
Physical 
examination
X
X
X
X
X
Tanner staging17
X17
X17
X17
X17
X17
Bone Age
X
X18
X18
Haematology7
X
X
X
X
X
Biochemistry7
X
X
X
X
X
X
Hormones7
∀
Calcitonin
X
X
X
X
X
X
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
03 April 2017
Novo Nordisk
Trial ID: NN2211-3659
Version:
7.0
UTN:U1111-1121-8743
Status:
Final
EudraCT No.:2011-002605-29
Page:
18 of 113
Trial period
Screening and Run-in
Blinded Treatment
Unblinded Treatment
F
U
FU
Type of visit
Screen-
ing
S
TC
TC
S
TC
(Rando-
misation)
S
S
S
TC
TC
S
TC
S
TC
S
TC
S
S
TC
S
TC
S
TC
S
S
S
S
Visit number
1
21
31
41
51
61
7
8
9
10
10A, 
10B21
11, 
12
11A, 
11B21
13
14
15
16
172,3
18
19
20
21
22
23
24
25 3
26
27, 
2819
Time of visit (week)
-13
-11
-10
-9
-8
-4
0
1
2
3
4, 5
6, 
10
7, 8
14
17
20
23
26
30
33
36
39
42
45
48
52
53
104,
156
Visit window (day)
Day -91 
to day -
82
±2
±2
±2
±2
±2
0
±2
±2
±2
±2
±3
±2
±3
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±3
±14
∀
Other 
hormones
X
X
X
X
Pregnancy test7, 10
X
X
X
X
X
Bone metabolism 
markers7
X
X
X
X
Insulin Antibodies7
X
HIV-antibodies7
X
Hepatitis B and 
hepatitis C7
X
Liraglutide 
antibodies7
X
X
X
Urinalysis7
X
X
X
X
OTHER 
ASSESSMENTS
Compliance
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Diet and exercise 
counselling
X
X
X
X
X
X
X
X
X
X
X
X
X
X
First day of most 
recent menstrual 
period13
X
X
X
X
PK Sampling7
X
X
X11
X
X
TRIAL 
MATERIAL
Dispensing visit
X
X
X
X
X
X
X2
X
X
X
X
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
03 April 2017
Novo Nordisk
Trial ID: NN2211-3659
Version:
7.0
UTN:U1111-1121-8743
Status:
Final
EudraCT No.:2011-002605-29
Page:
19 of 113
Trial period
Screening and Run-in
Blinded Treatment
Unblinded Treatment
F
U
FU
Type of visit
Screen-
ing
S
TC
TC
S
TC
(Rando-
misation)
S
S
S
TC
TC
S
TC
S
TC
S
TC
S
S
TC
S
TC
S
TC
S
S
S
S
Visit number
1
21
31
41
51
61
7
8
9
10
10A, 
10B21
11, 
12
11A, 
11B21
13
14
15
16
172,3
18
19
20
21
22
23
24
25 3
26
27, 
2819
Time of visit (week)
-13
-11
-10
-9
-8
-4
0
1
2
3
4, 5
6, 
10
7, 8
14
17
20
23
26
30
33
36
39
42
45
48
52
53
104,
156
Visit window (day)
Day -91 
to day -
82
±2
±2
±2
±2
±2
0
±2
±2
±2
±2
±3
±2
±3
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±3
±14
Metformin dose 
titration16
X
X
X
Liraglutide dose 
escalation 
X
X
(X)
Basal insulin dose 
titration
X
X22
X
Drug accountability
X
X
X
X
X
X
X
X
X
X
X
IV/WRS call
X
X
X
X
X
X
X
X2
X
X
X
X
X
Confirmation of 
liraglutide dose
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Confirmation of 
metformin dose
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Basal insulin dose 
information23
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
Dispense subject ID 
card
X
Diary dispense and 
instruct
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Diary collect, 
review, transcribe8
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
Glucose meter 
dispense and instruct
X15
X
Urine container 
dispense
X15
X
X12
X
X
REMINDERS
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
03 April 2017
Novo Nordisk
Trial ID: NN2211-3659
Version:
7.0
UTN:U1111-1121-8743
Status:
Final
EudraCT No.:2011-002605-29
Page:
20 of 113
Trial period
Screening and Run-in
Blinded Treatment
Unblinded Treatment
F
U
FU
Type of visit
Screen-
ing
S
TC
TC
S
TC
(Rando-
misation)
S
S
S
TC
TC
S
TC
S
TC
S
TC
S
S
TC
S
TC
S
TC
S
S
S
S
Visit number
1
21
31
41
51
61
7
8
9
10
10A, 
10B21
11, 
12
11A, 
11B21
13
14
15
16
172,3
18
19
20
21
22
23
24
25 3
26
27, 
2819
Time of visit (week)
-13
-11
-10
-9
-8
-4
0
1
2
3
4, 5
6, 
10
7, 8
14
17
20
23
26
30
33
36
39
42
45
48
52
53
104,
156
Visit window (day)
Day -91 
to day -
82
±2
±2
±2
±2
±2
0
±2
±2
±2
±2
±3
±2
±3
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±3
±14
End of trial 
X
Case book sign off 
X
Affirmation 
statement
X
Unscheduled visits can be scheduled at any time at the discretion of the investigator.
1.
Visits 2, 3, 4, 5 and 6 are not applicable for subjects already treated with 2000 mg or more of metformin, diet and exercise for at least 56 days prior to Visit 1 These subjects may 
advance directly to Visit 7 and be randomised. 
2.
All assessments at visit 17 should be performed prior to trial medication dispensing as the trial medication dispensing session in IV/WRS at Visit 17 will unblind subjects treatment.
3.
In case a subject is being prematurely withdrawn from the trial prior to Visit 17 the investigator must aim to undertake procedures for Visit 17 (End of blinded treatment visit) as soon 
as possible, if possible. In case a subject is being prematurely withdrawn from the trial after Visit 17 the investigator must aim to undertake procedures for Visit 25 (End of treatment 
visit) as soon as possible, if possible. In addition Visit 26 should in both cases be completed, between 5 and 10 days after the early termination visit, if possible.
4.
Subject will be expected to arrive fasting for Visit 1 blood sampling. The informed consent and assent form must be signed at least one day prior to Visit 1 blood sampling.
Only applicable to Israel: Child assent by signature is not mandatory. Child assent form is not used. A minor may sign the local ICF (form 3A).
5.
Type of rescue medication must be captured in the concomitant medication form in the eCRF. Doses should be captured in relevant forms in the eCRF. In addition diabetes medication 
prescribed at the end of treatment (Visit 25) should be captured in the concomitant medication section of the eCRF.
6.
Concomitant medication will be captured only for subjects reporting AEs and SAEs at Visits 26-28.
7.
Blood and urine samples will be sent to a central laboratory for analysis. PK and anti liraglutide antibody samples will be shipped from the central laboratory to special laboratories for 
analysis. Unblinded subjects not treated with liraglutide should not have a blood sample drawn for determination of anti-liraglutide antibodies.
8.
At telephone contacts (TCs) information from the diary as reported by the subject and not the physical diary will be collected.
9.
At Visit 1 the eye examination (fundoscopy) and ECG can be omitted if the assessments have been performed within 12 weeks of Visit 1. At Visits 17 and 25 the assessments may be 
performed in the two weeks prior to the visits.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
03 April 2017
Novo Nordisk
Trial ID: NN2211-3659
Version:
7.0
UTN:U1111-1121-8743
Status:
Final
EudraCT No.:2011-002605-29
Page:
21 of 113
10. At Visits 1, 7, 13, 17 and 25 a blood pregnancy test will be performed in females of childbearing potential. In addition at Visit 7, prior to randomisation, a urine-stick pregnancy test 
will be performed. During the rest of the trial a urine-stick pregnancy test will be performed if a menstrual period is missed. 
Austria: Urine-stick pregnancy test will be performed at all visits to the clinic.
11. PK sampling will be performed at Visit 11 only.
12. Blood sampling for HbA1c and dispensing of urine container will be performed at Visit 12 only. 
13. First day of the most recent menstrual period should be captured for females of childbearing potential in the diary prior to Visits 7, 13, 17 and 25.
14. Fasting SMPG measurements should be performed and captured in the diary on 3 consecutive days prior to Visits 7, 8, 9 and 10. Subjects treated with basal insulin at screening will be 
asked to perform fasting SMPG measurements on the 3 consecutive days preceding Visits 10A, 10B, 11A and 11B. For all other subjects fasting SMPG measurements should be 
performed 3 times a week (on a weekly basis) between Visits 10 and 11.
15. Subjects already treated with metformin 2000 mg/day for at least 56 days prior to screening may have their BG meter, urine collection container for Visit 7 provided at Visit 1 and 
advance directly to Visit 7. Subjects who are treated with basal insulin should in addition to the stable dose of metformin have a stable dose of basal insulin for at least 56 days to 
advance directly to visit 7.
16. In case an extra week for titrating to 2000 mg or maximum tolerated dose of metformin is needed, the titration period can be extended with an additional week, from 3 to 4 weeks.
An unscheduled visit between Visits 4 and 5 may be performed to ensure compliance and the safety of the subject before the last dose step at the discretion of the investigator. All
subjects who undergo metformin titration including those who require a fourth week to reach a dose of metformin of 2000mg or a maximum tolerated dose, need to undergo the
full 8 weeks maintenance period with 2000 mg or maximum tolerated dose of metformin before randomisation.
17. At Visits 7, 13, 17, 25, 27 and 28 the assessments may be performed in the two weeks prior to the visits. Once the subject reaches the Tanner stage V, the Tanner staging assessment no 
longer requires to be performed.
18. A repeat bone age assessment will not be performed for subjects in whom the bone age assessment at the previous assessments indicates that the epiphyses are fused.
19. Visits 27 and 28 are only applicable for subjects treated with liraglutide for more than 3 months.
20. Prior to blood sampling for liraglutide antibodies subjects must attend without food or drink intake except for water and prescribed medication for at least 2 hours.
21. Visits 10A, 10B, 11A and 11B are only applicable to subjects treated with basal insulin. 
22. Basal insulin titration only applicable at Visit 11.
23. Only applicable to subjects treated with basal insulin.
Explanations: Rand = randomisation; S = site visit; TC= telephone contact 
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
03 April 2017
Novo Nordisk
Trial ID: NN2211-3659
Version:
7.0
UTN:U1111-1121-8743
Status:
Final
EudraCT No.:2011-002605-29
Page:
22 of 113
3
Background information and rationale for the trial
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
Basic information
3.1.1
Treatment of type 2 diabetes mellitus in the paediatric population
Despite the increased prevalence and the potential short and long term risks associated with early 
onset of type 2 diabetes, the most effective regimens to treat adolescents with type 2 diabetes are 
not known, and treatment approaches are often extrapolated from those used for adults1.  
Metformin is currently the most commonly used treatment for type 2 diabetes in children and 
adolescents2, 3. The addition of other therapies including a glucagon-like peptide-1 (GLP-1) receptor 
agonist has been suggested when glycaemic control is not achieved with metformin alone in 
children and adolescents with type 2 diabetes4. However, metformin is the only non-insulin 
treatment with regulatory approval at this time, for use in children and adolescents with type 2 
diabetes, 10 years of age and older.
3.1.2
Glucagon-like peptide-1 
GLP-1 is an incretin hormone secreted from the L-cells in the lower gut in response to meal 
ingestion, which stimulates endogenous insulin secretion in a glucose-dependent manner. GLP-1 
also decreases elevated blood glucagon levels, reduces gastric emptying, and reduces food intake.
The combination of these mechanisms makes GLP-1 a potent blood glucose lowering agent. This, 
together with the glucose dependency of action (i.e., stimulation of insulin secretion only when 
plasma glucose levels are above normal) makes GLP-1 hormone a potential candidate for the 
treatment of type 2 diabetes5-11. However, a major drawback with endogenous GLP-1 with regard to 
administration as a medical treatment is the short elimination half-life (t½ < 1.5 minutes after i.v. 
administration). That is due to rapid degradation by dipeptidyl peptidase (DPP-4), present for 
example, on the capillary endothelium12. From human trials it has become clear that 24-hour 
infusion of native GLP-1 would be necessary to achieve satisfactory glycaemic control13. Hence, 
endogenous GLP-1 treatment has limited clinical value and treatment strategies circumventing this 
limitation have been sought.
3.1.3
Liraglutide
Liraglutide (Victoza%) is a once-daily human GLP-1 analogue marketed and developed by Novo 
Nordisk. Compared to human GLP-1, liraglutide has a C16 fatty (palmitic) acid chain attached at 
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
03 April 2017
Novo Nordisk
Trial ID: NN2211-3659
Version:
7.0
UTN:U1111-1121-8743
Status:
Final
EudraCT No.:2011-002605-29
Page:
23 of 113
position 26 (lysine) of the peptide, and has lysine at position 34 replaced by arginine. When 
administered s.c., these structural modifications result in kinetic properties of the compound 
suitable for once daily administration14. In vitro receptor studies have shown that liraglutide is a 
selective, potent and full agonist of the cloned human GLP-1 receptor. In animal studies liraglutide 
has been shown to lower blood glucose, stimulate insulin secretion, decrease plasma glucagon 
levels, inhibit gastric emptying, inhibit food intake, decrease body weight and improve beta-cell 
function when administered subcutaneously.  
Liraglutide has been approved for treatment of type 2 diabetes in adults in the European Union 
(EU), United States (US) and in a number of other countries. As of July 2011, 52 clinical trials had 
been completed, and the safety database includes more than 11,000 subjects, of whom more than 
7500 were treated with liraglutide15. The 52 completed trials include 31 phase 1 trials, 9 phase 2 
trials, and 12 phase 3 trials. 
Data from finalised trials have shown liraglutide to have a pharmacokinetic (PK) profile suitable for 
once daily administration, as evidenced by a relatively slow absorption ([tmax] =8-12 hours) with a 
terminal elimination half-life of approximately 13 hours. The PK profile is comparable between 
healthy subjects and subjects with type 2 diabetes.
Efficacy
Mode-of-action trials in adult subjects with type 2 diabetes have demonstrated glucose lowering 
(fasting plasma glucose (FPG), postprandial glucose (PPG)), increased insulin secretion, restored 
beta-cell responsiveness to increasing glucose concentrations and delayed gastric emptying after a 
single s.c. dose of liraglutide. Importantly, during hypoglycaemia liraglutide did not impair 
glucagon action or the general counter-regulatory response, indicating a low risk of hypoglycaemia. 
Results from the phase 3a trials in adult subjects with type 2 diabetes showed an improvement of 
glycaemic control after treatment with liraglutide. A substantial and clinically relevant lowering of 
glycosylated haemoglobin A1c (HbA1c) and FPG was observed after 26 weeks and 52 weeks of 
treatment with liraglutide. The various treatment regimens included in the trials were liraglutide 
doses of 0.6 mg, 1.2 mg or 1.8 mg per day as monotherapy or in combination with sulfonylurea, 
metformin or a thiazolidinedione.
Based on the HbA1c assessment it was concluded that treatment with liraglutide in monotherapy
(1.2 or 1.8 mg) was superior to treatment with glimepiride 8 mg. Furthermore, liraglutide in
combination with one or two oral anti-diabetic drugs (OADs) was superior to treatment with the
same OAD(s) alone. Furthermore, the weight loss observed in earlier trials was confirmed by results 
from the phase 3a programme.
Treatment with the combination of basal insulin and liraglutide has been studied in adults with type 
2 diabetes and has obtained regulatory approval in some countries.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
03 April 2017
Novo Nordisk
Trial ID: NN2211-3659
Version:
7.0
UTN:U1111-1121-8743
Status:
Final
EudraCT No.:2011-002605-29
Page:
24 of 113
There are case reports in the literature, published clinical trials and retrospective studies with 
exenatide (another marketed GLP-1 receptor agonist) and liraglutide added to insulin therapy. 
These studies indicate that addition of a GLP-1 receptor agonist to pre-existing insulin therapy can 
favourably affect the daily glucose variability by reducing plasma glucose excursions and provide 
improved glycaemic control with significant reductions in HbA1c in adults. These effects of the 
combination therapy seemed associated with a reduced need for insulin, weight loss and no 
substantial increase in the risk of hypoglycaemic events, in adults16-20.
The efficacy and safety of liraglutide as add on to basal insulin analogues was studied in a 
controlled, double blind setting, demonstrating that treatment with insulin detemir as add-on to 
liraglutide 1.8 mg + metformin resulted in statistically significant reductions in HbA1c and FPG 
compared to treatment with liraglutide 1.8 mg + metformin alone21, 22. 
Safety
The safety profile of liraglutide exhibits the features expected for a GLP-1 analogue and is in
accordance with observations from administration of both native GLP-1 and another GLP-1
receptor agonist (exenatide). More than 400,000 patients with type 2 diabetes are estimated to have 
been treated with Victoza% after its approval and availability in marketed use.
Gastrointestinal adverse events (AEs), including mostly transient events of nausea, diarrhoea and 
vomiting were the most frequently reported events during the overall clinical development 
programme for liraglutide. The highest reporting frequency was seen during initiation of therapy. 
The gastrointestinal AEs could however be mitigated by the use of a dose titration scheme. Signs 
and symptoms of dehydration, including renal impairment and acute renal failure have been 
reported in patients treated with liraglutide. Subjects treated with liraglutide should be advised of 
the potential risk of dehydration in relation to gastrointestinal side effects and take precautions to 
avoid fluid depletion. 
Few cases of acute pancreatitis (inflammation of the pancreas) presenting with persistent severe
abdominal pain (usually accompanied by vomiting) have been reported with liraglutide and
exenatide. Post marketing safety surveillance has not altered the favourable risk-benefit ratio of 
liraglutide in this regard. A causal relation between treatment with liraglutide and pancreatitis has 
not been established. Subjects should be informed of the characteristic symptoms of acute 
pancreatitis. If pancreatitis is suspected, liraglutide and other potentially suspected medicinal 
products should be discontinued, see withdrawal criteria in section 6.5.
In a 2-year repeat subcutaneous dose carcinogenicity study of liraglutide injected 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 mg/kg/day group. These fibrosarcomas were 
attributed to the high local concentration of drug near the injection site. The liraglutide
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concentration in the clinical formulation (6 mg/mL) is 10 times higher than the concentration in the 
formulation used to administer 3 mg/kg/day liraglutide to mice in the carcinogenicity study 
(0.6 mg/mL).
Liraglutide causes dose dependent and treatment-duration-dependent thyroid C-cell tumors at 
clinically relevant exposures in both genders of rats and mice. It is unknown whether liraglutide 
causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as human 
relevance could not be ruled out by clinical or nonclinical studies. Based on the findings in rodents, 
monitoring with serum calcitonin or thyroid ultrasound was performed during clinical trials, but this 
may have increased the number of unnecessary thyroid surgeries. It is unknown whether monitoring 
with serum calcitonin or thyroid ultrasound will mitigate human risk of thyroid C-cell tumors. 
Patients with a personal or family history of MTC and in patients with Multiple Endocrine 
Neoplasia syndrome type 2 (MEN 2) are excluded from this trial.
Liraglutide has been shown to be teratogenic in rats at or above 0.8 times the human systemic 
exposures resulting from the maximum recommended human dose (MRHD) of 1.8 mg/day based 
on plasma area under the time-concentration curve (AUC). Liraglutide has been shown to cause 
reduced growth and increased total major abnormalities in rabbits at systemic exposures below 
human exposure at the MRHD based on plasma AUC.
A five week PK/PD trial in paediatric subjects with type 2 diabetes ages 10-17 years has been 
completed (NN2211-1800). In this 5-week trial, no serious AEs were reported. The most common 
AEs in liraglutide treated subjects were of gastrointestinal origin as seen in trials including adults. 
All AEs seen with liraglutide were classified as mild. A total of 57% of liraglutide treated subjects 
and 29% of placebo treated subjects experienced gastrointestinal AEs. In the pooled data from all 
NN2211 trials including adult subjects with type 2 diabetes, 42% of the liraglutide-treated subjects 
had at least one gastrointestinal related adverse event compared with 19% of the subjects treated 
with placebo and 23% of the subjects treated with active comparators.  
A relationship with dose escalation level was not seen, with the majority of these mild events seen 
at 0.3 and 0.6 mg. In placebo treated subjects, gastrointestinal AEs were mild to moderate.
Three (3) liraglutide treated subjects and 1 placebo treated subject experienced hypoglycaemic 
episodes. Some of the episodes of hypoglycaemia occurred after excessively long periods of fasting, 
as long as approximately 18 hours. The 3 liraglutide treated subjects experienced 4 episodes of 
“minor hypoglycaemia” (confirmed plasma glucose <3.1 mmol/L with or without symptoms). All 
episodes were self-treated and most occurred approximately 2-3 hours after a meal.
An external hormonal safety board of the trial, concluded that there was no evidence of hormonal 
disruption in this short-term trial based on evaluation of the following hormones and biomarkers 
measured during the trial: estradiol (female subjects), testosterone (male subjects), 
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carcinoembryonic antigen (CEA), insulin-growth factor-1 (IGF-I), dehydroepiandrosterone sulfate 
(DHEAS), thyroid stimulating hormone (TSH), luteinizing hormone (LH), follicle stimulating 
hormone (FSH), prolactin, C-peptide and fructosamine. 
Mean FPG, HbA1c and fructosamine decreased during this short-term treatment period, but mean 
body weight did not change.
Further information can be obtained in latest version of the investigator’s brochure (IB) for 
liraglutide or any updates hereof15. 
3.1.4
Rationale for the trial
The first trial to assess safety and tolerability of liraglutide in children and adolescents was the 
pharmacokinetic and pharmacodynamic trial (NN2211–1800), conducted in paediatric subjects with 
type 2 diabetes, ages 10-17 years, in the EU and US.
The liraglutide pharmacokinetics in the paediatric population was similar to that observed in adults.
The NN2211–3659 trial is being conducted to assess the efficacy and safety of liraglutide in the 
paediatric population in order to potentially address the unmet need for treatment of children and
adolescents with type 2 diabetes and also to fulfil the regulatory requirement for paediatric trials 
from the European Paediatric Committee (PDCO) of the European Medicines Agency (EMA) and 
from the U.S. Food and Drug Administration (FDA). 
3.1.5
Risk and benefits assessment (Only Applicable for Sweden)
The nonclinical safety programme of liraglutide reveals no special hazards for humans based on 
conventional studies of safety pharmacology, repeat-dose toxicity or genotoxicity. Nonclinical 
studies have shown that liraglutide lowers blood glucose and body weight in numerous animal 
models. Also, in some models, liraglutide has been shown to have beneficial effects on 
cardiovascular related parameters. 
The current available data on clinical safety and efficacy of liraglutide is summarized in section 
3.1.3. It is assumed that the benefits and risks associated with long-term liraglutide treatment will be 
the same for the paediatric population as for the adult populations with the exception of any 
unforeseen effects on growth and pubertal development. Pubertal and growth related hormonal 
levels, biochemical parameters of bone metabolism and growth and pubertal development will 
therefore be monitored through the clinical trial in this paediatric population. 
Other relevant precautions have also been implemented in the design and planned conduct of this 
trial in order to minimise the risks described in section 3.1.3 and the inconveniences of trial 
participation. All subjects participating in the trial will be monitored closely through frequent site 
visits and telephone contacts. Throughout the trial, subjects will be in regular contact (by telephone 
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or visits) with the investigator or a designated person. Subjects will be monitored for elevated levels 
of amylase and lipase and be informed of the characteristic symptoms of acute pancreatitis. 
Liraglutide causes dose dependent and treatment-duration–dependent thyroid C-cell tumours at
clinically relevant exposures in both genders of rats and mice.
Based on the nonclinical findings of C-cell tumours in rodents, monitoring of serum calcitonin at
regular intervals will be performed in the present trial. Subjects with a personal or family history of
medullary thyroid carcinoma (MTC) and patients with Multiple Endocrine Neoplasia type 2
(MEN2) and/or subjects with a screening calcitonin value >50 ng/L are excluded from this trial.
A few cases of MTC have been reported in patients treated with the marketed product. No cases of
MTC have been reported to date in subjects treated with liraglutide in completed clinical trials. 
Blood sampling and contacts with the clinic are considered an inconvenience for the children 
participating in the trial. On the other hand, the intensified treatment may help to improve 
glycaemic control.
The current standard of care for this paediatric population is metformin and when needed, insulin 
treatment. 
The most common side effect of all available insulin preparations is hypoglycaemia. The 
investigator will explain to the subject how to check blood sugar with the BG meter provided by 
Novo Nordisk and the signs and symptoms of hypoglycaemia. Furthermore, it is encouraged that 
subjects participating in the trial do not miss meals or have a prolonged period of fasting. 
Subjects on basal insulin will have additional telephone visits. Additionally to reduce the risk of 
hypoglycaemia, subjects on basal insulin will have their insulin dose decreased by 20% at 
randomisation. It is anticipated that benefit will be gained from participating in this trial due to the 
closer and more frequent assessments of the subject’s diabetes, focus on diet and exercise and/or 
intensified anti-diabetes therapy.
It has recently been demonstrated that there is a need for improvement of type 2 diabetes treatment 
in children and adolescents. Metformin in combination with life style changes was insufficient for 
maintenance of acceptable glycaemic control in a large proportion of adolescents with type 2 
diabetes23.
All subjects will, in order to ensure adequate treatment, be treated with metformin throughout the 
trial. Subject treatment with liraglutide or liraglutide placebo will be blinded during the first 26 
weeks of randomised treatment. After that the subjects’ treatment allocation will be revealed due to 
the anticipated need for rescue treatment for subjects treated with metformin and liraglutide 
placebo. In the event that a subject treated with liraglutide experiences severe intolerance or 
recurrent hypoglycaemia as judged by the investigator, the liraglutide dose will be lowered. If a 
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subject treated with 0.6 mg liraglutide experiences severe intolerance or recurrent hypoglycaemia as 
judged by the investigator, the subject will be withdrawn from the trial. 
It is concluded that the potential benefits from participating in the trial outweigh the potential risks. 
The safety profile of liraglutide generated from the nonclinical and clinical studies in adults has not 
revealed any safety issues that should prohibit administration of liraglutide to children and 
adolescents. The results of this trial will contribute to the development of new improved treatments 
for children and adolescents with type 2 diabetes in the future.
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4
Objectives and endpoints
4.1
Objectives
Primary objective
To confirm the superiority of liraglutide at the maximum tolerated dose (0.6 mg, 1.2 mg or 1.8 mg) 
versus placebo when added to metformin with or without basal insulin treatment in controlling 
glycaemia in children and adolescents (ages 10–17 years) with type 2 diabetes.
Secondary objectives 
To assess and compare the effect of liraglutide versus placebo in combination with metformin with 
or without basal insulin treatment on:
∀
Parameters of glycaemic control  
∀
Parameters of beta-cell function 
∀
Parameters of body composition
∀
Vital signs
∀
Growth velocity (if subject is still growing)
∀
Safety and tolerability
∀
Growth and pubertal development at 1 and 2 year follow up after trial drug cessation at week 52  
4.2
Endpoints
Primary endpoint to be assessed at 26 weeks of treatment
∀
Change in HbA1c from baseline to week 26
Confirmatory secondary endpoints to be assessed at 26 weeks of treatment
∀
Change from baseline in FPG 
∀
HbA1c <7.0% (yes/no)
∀
Change from baseline in BMI standard deviation score (SDS)
Secondary endpoints to be assessed at 26 and 52 weeks of treatment unless otherwise stated
∀
HbA1c <7.0% (yes/no) at 52 weeks
∀
HbA1c #6.5% (yes/no)
∀
HbA1c <7.0% without severe or minor hypoglycaemic episodes (yes/no)
∀
HbA1c<7.5% (yes/no)
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Change from baseline at 26 and 52 weeks of treatment unless otherwise stated:
∀
HbA1c at 52 weeks
∀
FPG at 52 weeks
∀
7-point self-measured plasma glucose (SMPG)
!
Mean 7-point SMPG
!
Post-prandial increments
∀
Fasting insulin, fasting pro-insulin, pro-insulin to insulin ratio, fasting glucagon, fasting C-
peptide, and homeostasis model assessment (HOMA-B and HOMA-IR)
∀
Fasting lipid profile (cholesterol, low density lipoprotein (LDL), very low density lipoprotein 
(VLDL), high density lipoprotein (HDL), triglycerides and free fatty acids
∀
Body weight
∀
Waist circumference
∀
Body mass index (BMI)
∀
BMI SDS at 52 weeks
∀
BMI percentile (age and gender adjusted) 
∀
Systolic and diastolic blood pressure
∀
Basal insulin dose
Safety endpoints
Change from baseline at 26 and 52 weeks of treatment unless otherwise stated
∀
Clinical evaluations (physical examination including fundoscopy [fundoscopy at 26 and 52 
weeks])
∀
Electrocardiography (ECG) with rhythm strip (at 26 and 52 weeks)
∀
Pulse
∀
Laboratory tests:
!
Haematology (haemoglobin, haematocrit, thrombocytes, erythrocytes, leucocytes and 
differential count (eosinophils, neutrophils, basophils, lymphocytes and monocytes) 
!
Biochemistry (creatinine, creatine kinase, urea, albumin, bilirubins (total), alanine 
aminotransferase (ALAT), aspartate aminotransferase (ASAT), alkaline phosphatase, 
sodium, potassium, calcium, calcium (albumin corrected), amylase and lipase) 
!
Hormones (calcitonin, prolactin, follicle stimulating hormone (FSH), estradiol, luteinizing 
hormone (LH), testosterone, dehydroepiandrosterone sulfate (DHEAS), carcinoembryonic 
antigen (CEA) and thyroid stimulating hormone (TSH), insulin-like growth factor 1 (IGF-1), 
insulin–like growth factor binding protein 3 (IGFBP-3)
!
First morning urinalysis (micro albumin, creatinine, albumin:creatinine ratio calculated, 
protein, ketone, glucose, pH)
!
Biochemical parameters of bone metabolism: Alkaline Phosphatase, N-telopeptide (NTX),                 
C-telopeptide (CTX), serum type 1 procollagen (P1NP)
!
Formation of anti liraglutide antibodies (at 26 and 53 weeks) 
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∀
Height SDS
∀
Bone age assessment (x-ray of left hand and wrist) at 52 weeks
∀
Pubertal assessment/ progression (Tanner staging) 
In addition the following will be assessed at 26, and 52 weeks:
∀
Assessment of compliance (questioning of subjects and subjects legally acceptable 
representative) 
∀
Growth velocity in cm/year and height velocity SDS (if subject is still growing). A growth 
velocity < 1.0 cm/year is defined as no longer growing.
∀
Hypoglycaemic episodes
∀
AEs and serious adverse events (SAEs)
Safety follow-up at 1 and 2 years after trial drug cessation at week 52 (only applicable for 
subjects on active liraglutide treatment for more than 3 months) 
∀
AEs and SAEs 
∀
Growth velocity in cm/year (if subject is still growing)
∀
Height velocity SDS (if subject is still growing)
Change in: 
∀
Height SDS  
∀
Pubertal assessment/progression (Tanner staging)
∀
Bone Age assessment (x-ray of left hand and wrist)
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5
Type of trial
5.1
Type of trial 
This is a multi-centre 26 week randomised double-blind, parallel-group, placebo-controlled clinical 
trial followed by a 26 –week open-label extension in subjects aged 10 -17 years with type 2 
diabetes. Subjects will be randomised 1:1 to receive liraglutide or liraglutide placebo in 
combination with metformin with or without basal insulin treatment. Subjects will be stratified at 
randomisation by sex and according to their age at end of treatment (with two levels: 1:≤ 14, 2:> 14 
years of age; ≤ 14 years of age is defined as not reaching 14 years and 11 months at the end of 
treatment (52 weeks)).
The trial consists of a 2 weeks screening period where all screening parameters are assessed. 
Screening is followed by 11 to 12-weeks run-in period starting at Visit 2 (3 to 4 weeks metformin 
titration and 8 weeks metformin maintenance). After the run-in period subjects will, if fulfilling the 
randomisation criteria, be randomised to either liraglutide or liraglutide placebo treatment for 26 
weeks. Subjects already treated with a stable dose ≥ 2000 mg of metformin or more for at least 56 
days at the time of screening may skip the run-in period and advance directly to randomisation.
Subjects who are treated with basal insulin should in addition to the stable dose of metformin have a 
stable dose of basal insulin for at least 56 days to advance directly to Visit 7.
At the end of the 26 weeks blinded treatment period, the treatment allocation will be unblinded and 
subjects will continue in a 26 weeks open-labelled treatment period. All subjects will attend a 
follow-up visit one week after end of treatment. 
Further for subjects experiencing confirmed hyperglycaemia according to rescue criterion no. 1(see 
section 6.5) rescue treatment will be allowed. Subjects on rescue treatment will remain in the trial.
Subjects receiving rescue treatment should continue to follow the trial schedule for the remainder of 
the trial.
The maximum duration of the trial including screening and one week follow-up will be up to 67
weeks. 
Subjects treated with liraglutide (active treatment) for more than 3 months will be asked to return 
one and two years after the end of the open label phase of the trial (after trial drug cessation at week 
52).
The trial design is shown schematically below in Figure 5–1.
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Figure 5–1
Trial diagram
1) Screening prior to metformin titration
2) Run-in: metformin titration to 2000 mg daily if possible or maximum tolerated dose (MTD) ≥1000 mg and #2000 mg after verification of 
eligibility according to the inclusion and exclusion criteria. Subjects already treated with a stable dose ≥ 2000 mg of metformin or more for at least 56 
days at the time of screening may skip the run-in period and advance directly to randomisation. Subjects who are treated with basal insulin should in 
addition to the stable dose of metformin have a stable dose of basal insulin for at least 56 days to advance directly to Visit 7.
3) Randomised treatment: Escalation of liraglutide in 0.6 mg increments over 2-3 weeks to 1.8 mg if possible or MTD. Subjects on basal insulin will 
have their insulin dose decreased by 20% at randomisation.
4) All subjects will be unblinded at Visit 17. Subjects treated with liraglutide will continue with unchanged doses of metformin± basal insulin and 
their treatment with liraglutide. Subjects treated with liraglutide placebo will discontinue liraglutide placebo and will continue on metformin ± 
basal insulin.
5) All subjects will complete the Visit 26. Subjects treated with liraglutide for more than 3 months will complete Visits 27 and 28. 
5.2
Rationale for trial design
A randomised double-blind design was chosen for the efficacy endpoints in order to limit the bias in 
the conduct and interpretation of the trial. An effect on HbA1c as well as durability effects should be 
seen by 26 weeks23. Stratification has been implemented in order to avoid bias arising from gender 
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and age at end of treatment (≤ 14 and > 14 years of age) (see section 5.1 for definition of ≤14 years 
of age).
Subjects’ treatment allocation will be unblinded after 26 weeks in order to enable discontinuation of 
the liraglutide placebo injections which are considered a burden to the children and adolescents.
The current standard of care for this population is metformin treatment or insulin if needed. 
Subjects will, in order to ensure adequate treatment, be treated with metformin at a dose ≥1000 mg 
and #2000 mg, throughout the trial. This metformin dose is generally approved for children and 
adolescents. Subjects entering the trial on a dose of metformin >2000 mg will be allowed to remain 
on that dose.
The 26 weeks open label extension has been added in order to assess the safety of liraglutide 
treatment in the paediatric population. The 2 years follow-up for subjects treated with liraglutide for 
more than 3 months is added in order to assess any potential long time effect on growth, pubertal 
development and general safety.
A rescue criterion has been implemented in order to attempt to improve retention in order to obtain 
additional safety information, and to mimic what would likely occur in clinical practice.
5.3
Treatment of subjects
5.3.1
Metformin
Metformin is an oral anti-diabetic agent in the biguanide class. In this trial metformin is 
characterised as background treatment (non-investigational medicinal product [NIMP]).
Subjects will undergo 3-4 weeks of metformin titration to a maximum tolerated dose (MTD) of 
≥1000 mg and ≤2000 mg. Titration and MTD will be at the discretion of the investigator. It must be 
aimed to reach a dose of 2000 mg metformin. The titration period can be extended from 3 to 4 
weeks in total, if needed for tolerability. Once MTD is reached, the metformin dose must stay 
unchanged throughout the trial, unless subjects meet rescue criterion no. 1 (see section 6.5) The 
titration of metformin is followed by 8 weeks maintenance period whereafter subjects may be 
randomised if they fulfil the randomisation criteria (see section 6.4). 
Subjects treated with metformin < 2000 mg at Visit 1, may use their current dose as the starting 
dose for the titration. Subjects with an established MTD of ≥1000 mg and ≤2000 mg may advance 
directly to Visit 5. An established MTD is where previous attempts to escalate the metformin dose 
were not tolerated, and that the Investigator does not consider up-titration possible in the subject 
because of tolerability issues. Subjects treated with 2000 mg or more of metformin for less than 56 
days at Visit 1 may proceed directly to the 8 weeks maintenance period.
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Subjects already treated with 2000 mg or more of metformin and with a stable dose for at least 56 
days prior to Visit 1 may advance directly to randomisation (Visit 7) continuing their current 
metformin dose when eligibility according to the inclusion and exclusion criteria has been 
confirmed. Subjects who are treated with basal insulin should in addition to the stable dose of 
metformin have a stable dose of basal insulin for at least 56 days to advance directly to Visit 7.
Metformin should be temporarily discontinued in subjects undergoing radiologic studies involving 
intravascular iodinated contrast materials (see local label).
5.3.2
Liraglutide
Liraglutide and liraglutide placebo are administered once daily by s.c. injections, either in the 
abdomen, thigh or upper arm. The injection site does not have to be consistent throughout the trial. 
Injections can be done at any time of the day and irrespective of meals. It is recommended that the 
time of injection is consistent throughout the trial. Subjects will be instructed to perform an air shot 
before the first use of a new prefilled pen. Liraglutide vehicle will be used as placebo. In this trial 
liraglutide and liraglutide placebo are characterised as investigational medicinal products (IMPs).
After randomisation, liraglutide or liraglutide placebo will be escalated weekly starting at 0.6 mg 
and increasing with 0.6 mg increments over 2-3 weeks. Dose escalation will be based on tolerability 
(dose should not be increased in case severe intolerability is experienced, as judged by the 
investigator) and the following: the average of 3 measurements of FPG > 6.1 mmol/L (110 mg/dL) 
performed by the subject at home on the three consecutive days preceding the dose escalation visit 
(Visits 8, 9 and 10, please see Figure 5–2). After end of the liraglutide dose escalation period no 
further dose escalations must be performed.
Subjects treated with basal insulin experiencing hypoglycaemia should reduce the dose of basal 
insulin (if needed to 0 units) before the dose of liraglutide/liraglutide placebo is decreased.
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Figure 5–2
Dose escalation of liraglutide 
During the blinded period, escalation at each YES/NO decision point should be determined by 
whether the subjects average FPG is > 6.1 mmol/L (110 mg/dL).
In the event that a subject experiences severe intolerance or recurrent hypoglycaemia as judged by 
the investigator (such as ∃3 unexplained minor hypoglycaemic events or 1 severe unexplained 
hypoglycaemic event in a week) the dose will be lowered to the next decreased level (from 1.8 mg 
to 1.2 mg or from 1.2 mg to 0.6 mg). The reason for down escalation of liraglutide must be 
documented in the subject’s medical record and transferred to the eCRF.
If a subject treated with 0.6 mg experiences severe intolerance or recurrent hypoglycaemia as 
judged by the investigator (such as ∃3 unexplained minor hypoglycaemic events or 1 unexplained 
severe hypoglycaemic event in a week) the subject must be withdrawn from the trial.   
5.3.3
Basal insulin
Subjects may enter the trial on a stable dose of basal insulin. A stable dose of basal insulin 
(intermediate acting human insulin, intermediate acting insulin analogue or long acting insulin 
analogue) is defined as basal insulin adjustments up to 15% at the investigator’s discretion. Subjects 
treated with basal insulin must initiate treatment with metformin as described in section 5.3.). 
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The pre-trial basal insulin regimen will be considered background medication and will not be 
provided by Novo Nordisk.
Subjects treated with basal insulin at screening should reduce their basal insulin dose by 20% at 
randomisation.
Subjects on a stable dose of metformin ≥ 2000 mg as per section 5.3.1 can advance directly to 
maintenance period or randomisation depending on the time on stable insulin:
∀
Subjects with a stable dose of basal insulin for at least 30 days but less than 56 days at screening 
(visit 1) may proceed directly to the 8 week maintenance period (Visit 5)
∀
Subjects on a stable dose of basal insulin for 56 days or more at screening (Visit 1) may advance 
directly to randomisation (Visit 7) when eligibility according to the inclusion and exclusion 
criteria has been confirmed.
After the MTD dose of liraglutide/liraglutide placebo is reached, the dose of basal insulin can be 
up-titrated to no higher than the screening dose level. This up-titration will be based on the average 
of three pre-visit fasting SMPG values before visits between weeks 4 and 8 (Visits 10A -11B). Up-
titration is only allowed between Visits 10A and 11B. Up-titration of basal insulin dose is to be 
performed at the discretion of the investigator in accordance with the algorithm described in Table 
5-1.
Table 5–1
Algorithm for up-titration of basal insulin dose
Average fasting SMPG 
Increase in basal insulin dose 
>10 mmol/L (>180 mg/dL )
+6 units
7.8 to 10 mmol/L (141–180 mg/dL)
+4 units
6.7 to <7.8 mmol/L (121–140 mg/dL)
+2 units
5.6 to <6.7 mmol/L (100–120 mg/dL)
+1 units
SMPG=self-measured plasma glucose 
(adapted from the Texas Diabetes Council 201321)
Basal insulin should be down-titrated for unexplained hypoglycaemia ≤ 3.9 mmol/L (≤70 mg/dL) at 
any time during the trial at the discretion of the investigator in accordance with Table 5-2
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Table 5–2
Algorithm for down-titration of basal insulin dose
PPG
Reduction of basal insulin dose 
One or more values < 3.1 mmol/L (56 mg/dL) 
without obvious explanation
Reduce insulin dose by 4 units 
(if dose >50 units, a dose reduction of 10% is 
suggested)
One or more values between 3.1–3.9 mmol/L 
(56–70) mg/dL) without obvious explanation
Reduce insulin dose by 2 units (if dose > 50 
units, a dose reduction of 5% is suggested).
PG=plasma glucose 
The basal insulin dose can be increased again to the dose the subject was on prior to the 
hypoglycaemic event if safety allows and at the discretion of the investigator. Subjects should 
continue in the trial even if the insulin treatment is down-titrated to 0 U. Subjects will be instructed 
to contact the investigator in case of hypoglycaemia.
No shifts in type of insulin will be allowed during the trial and for the 30 days prior to screening.
5.3.4
Open Label period
After 26 weeks of treatment, treatment allocation will be unblinded. The open-label period will last 
for 26 weeks until the end of treatment (week 52). 
Subjects treated with liraglutide will continue their trial medication under the same circumstances 
as listed above for the blinded period. 
Subjects treated with liraglutide placebo will discontinue liraglutide placebo and continue their 
treatment with MTD of metformin with or without basal insulin.
The total duration of treatment with liraglutide will be 52 weeks for subjects randomised to 
liraglutide. The total duration of treatment with liraglutide placebo will be 26 weeks for subjects 
randomised to liraglutide placebo. 
5.3.5
Rescue treatment
Subjects experiencing confirmed hyperglycaemia as per rescue criterion no. 1 (see section 6.5), will 
be offered rescue treatment. Subjects on rescue treatment will remain in the trial.
Rescue treatment will be as follows:
∀
Subjects treated with metformin and liraglutide/liraglutide placebo may have basal 
insulin added. The start dose and basal insulin titration will be at the discretion of 
the investigator. If subjects continue to experience confirmed hyperglycaemia as 
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per rescue criterion no. 1 a rapid acting insulin may be added and titrated at the 
discretion of the investigator.
∀
Subjects treated with metformin, basal insulin and liraglutide/liraglutide placebo 
may have the basal insulin dose increased; the dose and basal insulin titration will 
be at the discretion of the investigator. If subjects continue to experience 
confirmed hyperglycaemia as per rescue criterion no 1 a rapid acting insulin may 
be added and titrated at the discretion of the investigator.
If hyperglycaemia is persistent and meets the withdrawal criterion no. 5 despite rescue treatment 
having been initiated, the subject must be withdrawn from the trial (see section 6.5)
5.4
Rationale for treatment
Liraglutide escalation and doses used in the present trial have been chosen based on results from the 
NN2211-1800 trial performed in children and adolescents as described below, and on the current 
approved labelling for Victoza®15.
In the NN2211-1800 trial liraglutide treatment or corresponding volume of placebo was initiated 
with 0.3 mg/day for the first week. The dose was escalated weekly to 0.6, 0.9, 1.2 and 1.8 mg/day 
of liraglutide or placebo. Dose escalation took place only if the mean fasting plasma glucose (FPG) 
taken on three consecutive days before the dose escalation visits was above 6.1 mmol/L (110 
mg/dL). Nine (9) liraglutide subjects escalated to the maximum dose of 1.8 mg liraglutide, while 3 
subjects remained on 0.6 mg liraglutide. One (1) subject, who was diet and exercise treated, 
remained on 0.3 mg liraglutide (HbA1c of 
% at screening). The decision to escalate subjects to 
the maximum dose of 1.8 mg was based on FPG measurements, and not on lack of tolerability or 
AEs. All subjects randomised to placebo were escalated to a dose volume corresponding to 1.8 mg 
liraglutide. Two subjects (one treated with liraglutide and one with placebo) withdrew prematurely 
from treatment for other reasons than tolerability (blood draw issue and did not want to undergo 
procedures).
The American Diabetes Association (ADA) recommends the use of metformin in 2000 based on the 
efficacy and safety data for adults24 Metformin is the ADA preferred first oral agent because it does 
not induce hypoglycaemic events. In 2002 a trial demonstrated the safety and efficacy of metformin 
in children and adolescent and concluded that the efficacy and safety profile was similar to the adult 
population2. Metformin doses of ≥1000 mg and #2000 mg have been shown to have an acceptable 
safety and efficacy profile in children and adolescent and these doses were therefore chosen for this 
trial. The use of 2500 mg of metformin has only been tested in adults where FPG was slightly 
reduced. Therefore doses higher than 2000 mg of metformin will only be permitted for subjects 
entering the trial with a dose > 2000 mg at the time, if in accordance with local standard of care.
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Insulin therapy is a key component in the treatment of children and adolescents with type 2 
diabetes25. The SEARCH incidence study identified 119 adolescents between 10-19 years of age, 
31.1% of whom (GAD65 negative) were being treated with insulin26. Recent guidelines recommend 
that insulin therapy be initiated in children and adolescents who have random venous or plasma 
blood glucose levels > 250 mg /dL, or whose HbA1c >9%, and certainly in patients who exhibit 
ketosis or ketoacidosis27. An earlier recommendation was to treat patients with blood glucose >200 
mg/dL, HbA1c more than 8.5%, or severe manifestations of insulin deficiency (e.g. ketosis/diabetic 
ketoacidosis) with insulin initially to achieve metabolic control rapidly. After resolution of ketosis 
(hydration and treatment with insulin, metformin should be started and insulin may be gradually 
weaned if normoglycaemia is maintained28.
Inclusion of children and adolescents with type 2 diabetes with basal insulin in this clinical trial is 
consistent with clinical practice25, 27.
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6
Trial population
6.1
Number of subjects to be investigated
Number of subjects planned to be screened: 
269
Number of subjects planned to be randomised and started on trial products:
94
Number of subjects expected to complete the trial (Visit 26):
63
At least 30% of randomised subjects must be 10-14 years (see section 5.1 for definition of ≤14).
At least 40% of randomised subjects must be female.
6.2
Inclusion criteria
For an eligible subject, all inclusion criteria must be answered “yes”.
1.
Informed consent from a legally acceptable representative (LAR) and child assent from the 
subject must be obtained before any trial-related activities (see section 18.1 for further details). 
Trial-related activities are any procedures that are carried out as part of the trial, including 
activities to determine suitability for the trial (e.g. fasting prior to Visit 1 blood sampling)
Only applicable to Israel: Child assent by signature is not mandatory. Child assent form is not 
used. A minor may sign the local ICF (form 3A).
2. Children and adolescents between the ages of 10 –16 years. Subjects cannot turn 17 years and 
11 months before the end of treatment (52 weeks)
3. Diagnosis of type 2 diabetes mellitus and treated for at least 30 days with:
o
diet and exercise alone
o
diet and exercise in combination with metformin monotherapy
o
diet and exercise in combination with metformin and a stable* dose of basal insulin. 
o
diet and exercise in combination with a stable* dose of basal insulin. 
*Stable is defined as basal insulin adjustments up to 15%
4. HbA1c
-
∃7.0% and #11% if diet and exercise treated
-
∃6.5% and #11% if treated with metformin as monotherapy, basal insulin as monotherapy or 
metformin and basal insulin in combination
5. BMI >85th percentile of the general age and gender matched population (see Appendix A)
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6.3
Exclusion criteria
For an eligible subject, all exclusion criteria must be answered “no”.
1.
Known or suspected hypersensitivity to trial products or related products
2.
Any contraindications to use of metformin according to local label
3.
Previous participation in this trial. Participation is defined as having been randomised. Re-
screening is allowed however there must be at least 3 months between screenings
4.
Female of child-bearing potential who is pregnant, breast-feeding or intend to become pregnant 
or who is sexually active and is not using adequate contraceptive methods (adequate 
contraceptive measures as required by local law or practice). China: Sterilisation, intrauterine 
device (IUD), oral contraceptives or barrier methods. Germany: Adequate contraceptive 
measures are implants, injectables, combined oral contraceptives, hormonal IUD, sexual 
abstinence or vasectomised partner. UK: Contraception requirements as per the MHRA 
guidelines.
5.
Receipt of any investigational medicinal product within 30 days before to Visit 1. Participation 
in another medication related research trial while taking part in this clinical trial. Brazil: 
Participation in other clinical trials within one year prior to Visit 1 unless there is a direct 
benefit to the research subject at the investigator´s discretion
6.
Type 1 diabetes
7.
Positive insulinoma associated-protein 2 (IA-2) or anti-glutamic acid decarboxylase antibodies 
(anti-GAD)
8.
Fasting C-peptide < 0.6 ng/ml
9.
Maturity onset diabetes of the young (MODY)
10. Use of any antidiabetic agent other than metformin and/or basal insulin 90 days prior to Visit 1. 
11. Previous treatment with liraglutide 
12. History of  pancreatitis (acute or chronic)
13. Screening calcitonin value ∃50 ng/L 
14. Subjects with personal or family history MTC or MEN 2
15. Impaired liver function defined as alanine aminotransferase (ALAT) ≥2.5 times upper normal 
range (UNR)
16. Impaired renal function defined as serum-creatinine >UNR for age in children unless renal 
function is proven normal by further assessments at the discretion of the investigator 
17. Known history of heart disease (including history of arrhythmias or conduction delays on ECG) 
within 6 months of Visit 1, new arrhythmias or conduction delays on ECG identified at the 
screening visit
18. Known proliferative retinopathy or maculopathy requiring acute treatment as judged by the 
investigator 
19. Hepatitis B or hepatitis C positive
20. Human immunodeficiency virus (HIV) positive 
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21. Uncontrolled hypertension, treated or untreated >99th percentile for age and gender in children 
(see Appendix B). If “white coat hypertension” is suspected at Visit 1 a repeat blood pressure 
measurement either during Visit 1, or at Visit 2 prior to other trial related activities is allowed, 
with the last measurement being conclusive
22. Any history of or diagnosis/treatment of cancer within the last 5 years (except basal cell skin 
cancer or squamous cell skin cancer)
23. Any clinically significant disorder, except for conditions associated with type 2 diabetes history 
which in the investigator’s opinion could interfere with results of the trial
24. Surgery scheduled for the trial duration period (excluding minor surgical procedures performed 
in local anaesthesia, as judged by the investigator)
25. Recurrent severe hypoglycaemia or hypoglycaemic unawareness as judged by the investigator 
26. Use of any drug (except for metformin and/or basal insulin), which in the Investigator’s opinion, 
could interfere with the blood glucose level (e.g. systemic corticosteroids)
27. Known or suspected abuse of alcohol or drugs/narcotics 
28. Mental incapacity or language barrier precluding adequate understanding or cooperation or 
unwillingness to adhere to protocol requirements
Proportion of subjects above 14 years of age will be restricted to a total of 70% of randomised 
subjects (see section 5.1). Proportion of male subjects will be restricted to a total of 60% of 
randomised subjects. When the individual target is reached, subjects above 14 years of age and 
male subjects respectively may not be randomised into the trial.
6.4
Randomisation criteria
For subjects to be eligible for randomisation the randomisation criteria must be answered “yes”. 
1. FPG measured prior to the randomisation visit (Visit 7), must be ∃126 mg/dL (7.0 mmol/L) and 
# 220 mg/dL (12.2 mmol/L). The measurement must be based on an average of fasting SMPG 
values taken on the 3 consecutive days leading up to the randomisation visit (Visit 7)
2. Subject must be on a stable dose for at least 56 days of metformin ≥1000 mg and # 2000 mg per 
day (subjects who enter the trial on > 2000 mg may be randomised continuing with that dose)
3. Subjects treated with basal insulin must be on a stable dose for at least 56 days. Stable dose of 
basal insulin is defined as basal insulin adjustments up to 15%
6.5
Rescue criteria
If the fasting SMPG values taken on 3 consecutive days or any of the FPG samples analysed by the 
central laboratory exceeds the limits of >12.2 mmol/L (220 mg/dL) during the first 14 weeks after 
randomisation (after end of liraglutide dose escalation, i.e. the subject has reached 1.8 mg or the 
MTD, and after week 8 for subjects on basal insulin) or >10.3 mmol/L (185 mg/dL) after week 14 
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the subject should be called for an unscheduled visit as soon as possible. A confirmatory FPG 
should be obtained and analysed by the central laboratory. The unscheduled visit should be 
documented in the eCRF. If the FPG exceeds the above described values and no intercurrent cause 
for the hyperglycaemia has been diagnosed rescue treatment should be initiated according to section 
5.3.5. If hyperglycaemia is persistent and meets the FPG limits as set above after rescue treatment 
having been initiated, the subject must be withdrawn from the trial (see section 6.6)
6.6
Withdrawal criteria
A subject must be withdrawn if the following applies:
1. The subject may withdraw at will or be withdrawn by the subject’s LAR at any time 
2. The subject may be withdrawn from the trial at the discretion of the investigator due to a 
safety concern or if judged non-compliant with trial procedures
3. The subject must be withdrawn if randomised in error
4. Pregnancy or intention to become pregnant
5. If the subject experiences persistent hyperglycaemia despite initiation of rescue treatment as 
described in section 6.5 the subject must be withdrawn. Persistent hyperglycamia: If fasting 
SMPG values taken on 3 consecutive days or any FPG samples analysed by the central 
laboratory exceeding the limits set below the subject must be called for an unscheduled visit 
as soon as possible. A confirmatory FPG must be obtained and analysed by the central 
laboratory. If the confirmed FPG exceeds the below described values and no intercurrent 
cause for the hyperglycaemia has been diagnosed the subject is experiencing persistent 
hyperglycaemia. The unscheduled visit must be documented in the eCRF.
FPG limits:
∀
during the first 14 weeks after randomisation (after end of liraglutide dose 
escalation, i.e. the subject has reached 1.8 mg or the MTD): FPG > 12.2 mmol/L 
(220 mg/dL)
∀
after week 14: FPG >10.3 mmol/L (185 mg/dL)
6. Subjects who need to have their dose of metformin reduced due to tolerability after having 
reached their MTD must be withdrawn. 
7. Subjects treated with 0.6 mg of liraglutide who experience severe intolerance or recurrent 
hypoglycaemia as judged by the investigator (such as ∃3 unexplained minor hypoglycaemic 
events or 1 unexplained severe hypoglycaemic event in a week) must be withdrawn 
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8. Calcitonin ≥50 ng/L. A referral to a specialist in thyroid disease is recommended (See 
Appendix D)
9. If the investigator suspects acute pancreatitis, all drugs suspected to relate to this condition 
should be discontinued until confirmatory tests have been conducted and appropriate 
treatment should be initiated. Subjects that are diagnosed with acute pancreatitis and/or 
exhibit at least 2 of the following criteria must be withdrawn from the trial; 1) abdominal pain,  
2) amylase and/or lipase > 3x UNR or 3) characteristic findings on ultrasound, computerised 
axial tomography (CT) or magnetic resonance imaging (MRI) 
10. Initiation of any systemic treatment (other than anti-diabetes treatment) with products which 
in the investigator’s opinion could interfere with glucose metabolism (e.g.: systemic 
corticosteroids)
6.7
Subject replacement
Subjects who are withdrawn will not be replaced.   
6.8
Rationale for trial population
There is an unmet need for treatment of children and adolescents with type 2 diabetes. Metformin is
the most commonly used treatment for type 2 diabetes in children and adolescents2, 3. However, it is 
also the only non-insulin treatment with regulatory approval, for use in children and adolescents.
The addition of other therapies including a GLP-1 analogue has been suggested when glycaemic 
control is not achieved with metformin alone4. 
Children and adolescent ages 10–17 are the target population for this trial since the mean age for 
diagnosis of type 2 diabetes mellitus is 13.5 years4, 29 and the incidence of type 2 diabetes in 
children less than 10 years old is low26. 
The inclusion of subjects on basal insulin is consistent with current clinical practice. Insulin therapy 
is a key component in the treatment of children and adolescents with type 2 diabetes25.
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7
Trial schedule
It is aimed to limit the period of competitive recruitment to a minimum and a recruitment strategy 
will be developed in cooperation with the participating countries.
Planned date for first patient first visit (FPFV)
01-Nov-2012
Planned date for last patient last visit (LPLV) (Visit 26)
15-July 2018 
Planned date for last follow-up visit (Visit 28)
15-July 2020
The end of the clinical trial is defined as LPLV (Visit 26)
Only applicable for Mexico: Mexico can recruit up to 20 subjects
All investigators will be notified immediately when the recruitment period ends, after which no 
further subjects will be screened and the interactive voice/web response system (IV/WRS) will be 
closed for further screening.
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 Disclosure, it will also be disclosed 
according to other requirements such as those of the International Committee of Medical Journal 
Editors (ICMJE)30, the Food and Drug Administration Amendment Act (FDAAA)31, European 
Commission Regulation for EudraCT32 and other relevant recommendations or regulations. If a 
patient 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 patient.
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8
Methods and assessments
8.1
Visit procedures
Introduction
Throughout the trial the investigator should ensure working in accordance with International 
Conference on Harmonisation (ICH) Good Clinical Practice (GCP)33 and local regulations. The 
investigator must ensure that trial procedures are performed as described in the protocol. Any 
discrepancies will result in protocol and/or GCP deviations and the investigator must take 
appropriate actions to avoid recurrence of the detected discrepancies.
8.1.1
Informed consent and assent procedure
The investigator must obtain informed assent and consent for each subject and subject’s LAR 
respectively prior to any protocol related procedures. For information on informed consent 
procedure please refer to section 18.1. 
All subjects and subject’s LAR will be provided with a copy of their own signed and dated 
informed assent and consent form. 
Note: Subjects should arrive fasting for Visit 1 blood sampling. Fasting is considered a trial related 
activity and no trial related activities may be initiated prior to a signed assent and consent form. 
Only applicable to Israel: Child assent by signature is not mandatory. Child assent form is not 
used. A minor may sign the local ICF (form 3A).
8.1.2
Investigator site logs 
The investigator must keep a subject identification code list; a subject screening log and a subject 
enrolment log. The subject screening log and subject enrolment log may be combined in one list 
and may be generated from the IV/WRS. 
In addition the investigator must keep a log of staff and delegation of tasks at trial site. The 
investigator must sign the log of staff and delegation of tasks at trial site at the time of delegation of 
tasks.
8.1.3
Screening, screening failures and re-screening 
At screening, subjects will be provided with a card stating that they are 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.
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At screening subjects must be assigned a unique screening number (the lowest available number 
allocated to the site) which should remain the same throughout the trial. A screening session must 
be performed in the IV/WRS.
Subjects that are found to be eligible for the trial after assessing all in- and exclusion criteria will 
advance to Visit 2, Visit 5 or Visit 7 depending on their metformin treatment at trial entry.
For screening failures a screening failure session must be made in the IV/WRS and the screening 
failure form in the electronic Case Report Form (eCRF) must be completed with the reason for not 
continuing in the trial. Serious and non-serious AEs from screening failures must be transcribed by 
the investigator into the CRFs. Follow-up of serious AEs (SAEs) should be carried out according to 
section 12.
Re-screening of screening and run-in failures is allowed however there must be at least 90 days 
from screening failure date to re-screening. In case of re-screening, a new informed consent and 
assent must be obtained, a new screening number must be allocated and samples and assessments 
must be performed once more as according to the screening procedures.
Only applicable to Israel: child assent form is not applicable.
8.1.4
Randomisation and run-in failures
At Visit 7 subjects fulfilling the randomisation criteria (see section 6.4) will be randomised. A 
randomisation session must be performed in the IV/WRS.
Run-in failures are subjects withdrawn from the trial in the run-in period or not fulfilling the 
randomisation criteria. They are regarded as screening failures and should be treated as such in the 
IV/WRS and eCRF. 
8.1.5
Visits
Procedures for the scheduled site visits and phone contacts are described in the following section 
and in the flow chart (please refer to section 2). In order to secure consistency in data over time it is 
encouraged that assessments are performed consistently (e.g. using the same type of equipment and 
trial site staffs with alike qualifications) during the trial.
For visit numbers, timing of site visits, phone contacts and visit windows during the trial period, 
please refer to the flow chart (section 2). It is the responsibility of the investigator to ensure that all 
site visits and phone contacts occur according to the flowchart. A phone contact may be converted 
to a site visit, if needed. 
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There will be one follow-up visit (Visit 26) for all subjects. Subjects treated with liraglutide for 
more than 3 months should in addition attend a 1 and 2 year follow-up visit (Visits 27 and 28). 
There will be no diaries attached to these visits and hence reporting of AEs and SAEs will be by the 
subject’s and subject’s LAR’s memory.
Visits attended fasting 
Subjects must attend the clinic in a fasting state for Visits 1, 7, 13, 17, 22 and 25 blood sampling. 
Fasting is defined as at least eight hours without food or drink intake except for water and 
prescribed medication other than diabetes medication. 
In addition subjects must be without food or drink intake except for water and prescribed 
medication for at least 2 hours before Visit 26 blood sampling. 
Should a subject attend a fasting blood sampling in a non-fasting state blood sampling must be re-
scheduled, preferably within the visit window. 
Unscheduled and missed visits
If a subject attends the clinic for an unscheduled visit, the unscheduled visit form must be 
completed unless the subject attends the clinic to obtain additional IMP, NIMP, auxiliary supplies 
or to perform a re-test of a blood sample. If the subject needs additional IMP and/or NIMP an 
additional dispensing call should be made in the IV/WRS.
Should a visit be missed, every effort should be made to re-schedule the visit within the allowed 
visit window. If this is not possible the visit should be re-scheduled at the earliest possible date.
8.1.6
Rescue treatment
If a subject fulfils rescue criterion no. 1 as described in section 6.5 the following procedures should 
be performed: 
∀
Body measurements (weight and height)
∀
A blood sample will be drawn and analysed at the central laboratory to determine 
levels of HbA1c 
The following should in addition to result of above assessments be recorded in the eCRF:
∀
SMPG values from 3 consecutive days where this is what led to the confirmatory 
FPG sample
∀
Details of the rescue treatment
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When all assessments have been performed rescue treatment as described in section 5.3.5 should be 
initiated.
8.1.7
Withdrawal
If a subject is withdrawn from the trial prior to Visit 17, the investigator must aim to undertake 
procedures for Visit 17 (End of blinded treatment visit) as soon as possible, if possible. If a subject 
is withdrawn from the trial after Visit 17 the investigator must aim to undertake procedures for Visit 
25 (End of treatment visit) as soon as possible, if possible. In addition Visit 26 should in both cases 
be completed, between 5 and 10 days after the early termination visit, if possible. In addition if the 
subject has been treated with liraglutide for more than 3 months the investigator must aim to have 
the subject return to the clinic for the 1 and 2 year follow up visits.
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 site. In addition a withdrawal session must be performed in the 
IV/WRS and the case book (eCRF) must be signed.
Although a subject is not obliged to give his/her reason(s) for withdrawing from a trial, the 
investigator should make a reasonable effort to ascertain the reason(s), while fully respecting the 
subject’s rights. Where the reasons are obtained, the primary reason(s) (i.e. adverse event, non-
compliance with protocol or other) for discontinuation must be specified in the eCRF.  
8.1.8
Subject training 
Diaries
The subject should be provided with diaries at Visits 1, 2, 5, 7, 8, 9, 11, 12, 13, 15, 17, 18, 20, 22 
and 24 and be instructed in filling in the diary. It is the responsibility of the investigator to review 
the diary for subject notes regarding possible AEs and concomitant medication (please see sections 
12 and 8.3). The investigator must transcribe data from the diary into the eCRF throughout the trial. 
The investigator should, if necessary, convert the format of data used by the subject into the format 
used in the eCRF. The subject’s dispensed diaries should be collected at the following clinic visit 
(Visits 2, 5, 7, 8, 9, 11, 12, 13, 15, 17, 18, 20, 22, 24 and 25).
The diaries will contain the below information:
∀
Date, actual clock time and value of all 7-point profile (SMPG) measurements
∀
Date and time of first liraglutide injection
∀
Date and dose of metformin and insulin on the day just prior to each visit 
∀
Date and dose of liraglutide on the day just prior to each visit (not applicable after Visit 17 for 
subjects treated with liraglutide placebo)
∀
Information on fasting SMPG measurements
∀
Details on hypoglycaemic episodes
∀
Date, time and dose of liraglutide injections on two days just prior to Visits 8, 9, 11, 13 and 17
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∀
Date of first day of most recent menstrual period prior to Visits 7, 13, 17 and 25 (only for 
females of childbearing potential)
∀
Adverse events
∀
Concomitant medication
If clarification of entries or discrepancies in the diary is needed, the subject should be questioned 
and a conclusion made in the medical record. Entries in the diary should only be made by the 
subject or the subject’s LAR. Care should be taken not to bias the subject.
Trial product
Investigator should instruct the subject in the use of the pen-injector and the direction for use should 
be handed out at each dispensing visit. Instructions in use should be repeated as necessary. The 
investigator must document that direction for use is given to each subject orally and/or in writing at 
each dispensing visit.
Blood glucose meter
Subjects should also be instructed in the use of the BG meter provided. Subjects should be 
explained that the BG meter is to be used exclusively by them.
8.1.9
Investigator evaluations and review
Review of diary, laboratory reports, ECGs and eye examination (fundoscopy) must be documented 
with investigator’s dated signature.
For ECGs and eye examinations the evaluations must follow the categories:
∀
Normal
∀
Abnormal, not clinically significant (abnormal NCS)
∀
Abnormal, clinically significant (abnormal CS)
For laboratory report values outside the reference range, the investigator must specify whether this 
is clinically significant. 
In case of abnormal clinically significant findings (laboratory reports, ECGs and eye examination) 
the investigator must state a comment in the subject’s medical record and record this on the 
concomitant illness form in the eCRF at Visit 1. At subsequent visits any clinically significant 
changes or new clinically significant findings must be reported as an AE according to section 12.
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8.2
Concomitant illness and medical history 
A concomitant illness is any illness that is present at the start of the trial (i.e. at the first visit). All 
concomitant illnesses should be reported however information on diabetes will be reported 
separately.
If a level of calcitonin ∃20 ng/L is found at Visit 1 this should be reported as concomitant illness.
Medical history is an account of medical events that the subject has experienced in the past. Any 
relevant and significant medical history as judged by the investigator must be reported in the 
medical record and eCRFs. The investigator should consider any medical history that is required to 
properly document that the subject does not fulfil any of the exclusion see section 6.3.
The information collected for concomitant illness and medical history should include diagnosis, 
date of onset, date of resolution or continuation. Any change to a concomitant illness should be 
recorded during the trial. A clinically significant worsening of a concomitant illness must be 
reported as an AE. 
8.3
Concomitant medication
A concomitant medication is any medication, other than metforminand liraglutide which is taken 
during the trial. Diabetes treatment prescribed at the end of trial should be registered in concomitant 
medication form in the eCRF. Medication given for a concomitant illness must be recorded in the 
eCRF. Insulin treatment incl. rescue medication should be registered in concomitant medication 
form in the eCRF. In addition there are specific forms to capture information on insulin dose in the 
eCRF.
Details of any concomitant medication must be recorded at trial entry (i.e. at the first visit). Any 
changes in concomitant medication must be recorded at each visit as they occur.
The information collected for each concomitant medication includes (at a minimum) trade name or 
generic name, indication, start date and stop date or continuation.
If a change is due to an AE, then this must be recorded and reported according to section 12. If the 
change influences the subject’s eligibility to continue in the trial, the monitor must be informed.
8.4
Laboratory assessments
A central laboratory will be responsible for providing laboratory supplies for the analysis of blood 
and urine samples taken during the trial. All samples obtained during the trial will be analysed at a 
central laboratory or a special laboratory (PK and antibody samples). The urine pregnancy test will 
be performed locally during subject visits. Descriptions of assay methods, laboratory supplies and 
procedures for obtaining samples, handling and storage of samples and information on who will 
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perform the assessments, are described in a trial-specific laboratory manual provided by the central 
laboratory.
Laboratory samples can be drawn at another day than on the day of the actual visit as long as it is 
within the visit window stated in the flow chart (section 2). It should be ensured that where fasting 
is required for the sensitivity of the analysis (Visits 1, 7, 13, 17 and 25) that subjects will attend the 
visit in a fasting state for blood draw.
Note: Subjects should arrive fasting for Visit 1 blood sampling. Fasting is considered a trial related 
activity and no trial related activities may be initiated prior to a signed assent and consent form.
Samples will be coded in order to keep subject identity anonymous.
Information on central laboratory results will be available to the investigator on an ongoing basis. 
All laboratory printouts must be dated and signed by the investigator on the day of evaluation. If a 
result is outside the normal range, the investigator must judge whether the abnormality is clinically 
significant and document this. If considered clinically significant the result must be reported as a 
concomitant illness at Visit 1 and as an AE according to section 12 at all other visits.
All samples will be analysed and destroyed on an ongoing basis or at the latest at the completion of 
the clinical trial report (CTR), unless otherwise stated.
The central laboratory equipment may provide analyses not requested in the protocol but produced 
automatically in connection with the requested analyses. Such data will not be transferred to the 
trial database, but may be reported to the investigator according to specifications in the laboratory 
standard operating procedures and requirements. The investigator must review all laboratory results 
for concomitant illnesses and AEs and report these according to this protocol.
8.5
Subject related information and assessments 
8.5.1
Demography
Demography consists of: 
∀
Date of birth (according to local regulations)
∀
Sex
∀
Race (according to local regulations)
∀
Ethnicity (according to local regulations)
8.5.2
Diabetes history
The following information on subject’s diabetes history should be recorded:
∀
Date of diagnosis
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∀
Complications
!
Diabetic retinopathy (incl. date of diagnosis)
!
Diabetic neuropathy (incl. date of diagnosis)
!
Diabetic nephropathy (incl. date of diagnosis)
!
Macroangiopathy including peripheral vascular disease (incl. date of diagnosis)
∀
Diabetes treatment
!
Current diabetes treatment 
!
Dose of current diabetes treatment 
!
Start date of current diabetes treatment 
8.5.3
Smoking habits
It should be recorded at Visit 1 if the subject:
∀
Never smoked
∀
Is a previous smoker
∀
Is a current smoker
8.5.4
Alcohol and drug screen
A urine drug screen will be performed to test for the presence of therapeutic and drugs of abuse at 
Visit 1. Subjects testing positive for commonly abused substances or alcohol must not be enrolled in 
this trial.
8.6
Assessments for efficacy
8.6.1
Body measurements 
Body measurements consist of the following parameters:
!
Body weight (Visits 1, 7, 11, 12, 13, 15, 17, 18, 20, 22, 24, 25, 27 and 28)
!
Height (safety endpoint) (Visits 1, 7, 13, 17, 25, 27and 28)
!
BMI (calculated at Visit 1)
!
Waist circumference (Visits 1, 7, 13, 17 and 25)
Body weight
Body weight should be measured (kilogram or pound [kg or lb], one decimal) without shoes and 
only wearing light clothing. Preferably the same set of scales should be used throughout the trial.
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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.
Waist circumference
The waist circumference is defined as the minimal abdominal circumferences located midway 
between the lower rib margin and the iliac crest. 
Three consecutive measurements of waist circumference should be taken and recorded in the eCRF. 
The waist circumferences will be measured to the nearest 0.5 cm (0.2 inches) using a non-
stretchable measuring tape. 
The subject should be measured in a standing position with an empty bladder and wearing light 
clothing with accessible waist. The subject should be standing with arms down their side and feet 
together. The tape should touch the skin, but not compress soft tissue and twist in tape should be 
avoided. The subjects should be asked to breathe normally and the measurement should be taken 
when the subject is breathing out gently.
BMI
The BMI will be calculated by the eCRF based on the height and weight as described above. At the 
screening visit the investigator must verify subject’s eligibility for the trial according to the BMI 
inclusion criteria see section 6.2 and Appendix A.
8.6.2
Vital signs
Vital signs will be measured at Visits 1, 5, 7, 8, 9, 11, 12, 13, 15, 17, 18, 20, 22, 24, 25 and 26. Vital 
signs consist of the following parameters:
!
Pulse (safety endpoint) 
!
Systolic blood pressure, sitting
!
Diastolic blood pressure, sitting
Pulse
Pulse (beats per minute) should be recorded at site visits after resting for 5 minutes in a sitting 
position. 
Systolic and diastolic blood pressure
For measurement of systolic and diastolic blood pressure the following method should be used. 
Avoid caffeine, smoking and exercise at least 30 minutes prior to blood pressure measurement. The 
measurement should be taken in a sitting position, with legs uncrossed, the back and arm supported. 
Subjects should be sitting for at least 5 minutes before the first measurement is taken. The subject 
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should not talk during the measurement. The site should measure blood pressure using their usual 
method, the method should be consistent throughout the trial using the same devices. For blood 
pressure at screening visit (Visit 1) three measurements need to be performed and all three values 
should be entered into the eCRF. The mean value will be calculated by the eCRF system and must 
be in accordance with exclusion criterion 21 (see section 6.3 and Appendix B). It is recommended 
to use the same arm used at Visit 1 for measurements of pulse and blood pressure at subsequent 
visits. 
If investigator suspects white coat hypertension at the screening visit one re-assessment of the 
systolic and diastolic blood pressure (using the same procedure as described above) is allowed as 
described in exclusion criterion 21.
In case of an “abnormal, clinically significant” finding, the investigator must comment in the 
medical records and, if it occurs at Visit 1, record this on the concomitant illness form. Any 
clinically significant worsening from baseline during the trial must be reported as an AE.
8.6.3
Blood samples
Blood samples will be drawn at site at the specified time-points (section 2) and analysed at the 
central laboratory to determine levels of the following efficacy laboratory parameters:
∀
Glucose metabolism
!
HbA1c
!
FPG
!
Fasting C-peptide
!
Fasting insulin
!
Fasting pro-insulin
!
Fasting glucagon
∀
Lipids
!
Cholesterol
!
LDL cholesterol
!
HDL cholesterol
!
VLDL cholesterol
!
Triglycerides
!
Free fatty acids
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8.6.4
Self-measured plasma glucose
At Visit 2, subjects should be supplied with a glucose meter and oral and written instruction on use 
of the device including regular calibration according to the manufacturer’s instructions. Sites should 
as necessary, repeat the instruction of use at visits to the clinic. Subjects already treated with 
metformin 2000 mg/day at a stable dose for at least 56 days prior to screening may have their BG 
meter for Visit 7 provided at Visit 1. 
The glucose meters use test strips calibrated to plasma values. Therefore, all glucose measurements 
performed with drawn capillary blood are automatically calibrated to plasma equivalent glucose 
values, which will be shown on the display and are values to be used. 
Subjects should be instructed in how to record the results of the SMPG values (including date) in 
the provided diaries and should only record the SMPG values based on glucose meter 
measurements. 
Self-measured plasma glucose 
Subjects will be asked to perform fasting SMPG measurements on the 3 consecutive days preceding 
Visit 7. The average of these 3 measurements will be used to evaluate subject’s eligibility according 
to randomisation criterion no. 1 (see section 6.4). 
After randomisation, subjects will be asked to perform fasting SMPG measurements on the 3 
consecutive days preceding Visits 8, 9 and 10. Subjects treated with basal insulin will be asked to 
perform fasting SMPG measurements on the 3 consecutive days preceding Visits 10A, 10B, 11A 
and 11B for adjustment of insulin dose. For all other subjects fasting SMPG measurements should 
be performed 3 times a week (on a weekly basis) between Visits 10 and 11. The measurements 
should be captured in the subjects’ diary. These measurements are used to evaluate the safety of the 
subject during their first weeks of treatment with liraglutide. In addition the first two to three 
weeks’measurements are used for dose escalation of liraglutide. 
In addition all subjects are encouraged to measure their FPG on a regular basis as agreed with the 
investigator. Also subjects should measure their plasma glucose at least every time the subject has 
symptoms of hypoglycaemia or hyperglycaemia. Hypoglycaemic episodes should be recorded in the 
diary (see section 8.1). The investigator may ask the subject to perform additional SMPGs if needed 
for any safety reason.
The subject should be instructed to contact the Investigator if:
∀
self-measured FPG falls below 3.9 mmol/L (70 mg/dL), 
or if:
∀
During the first 14 weeks after randomisation: FPG increases above 12.2 mmol/L (220 mg/dL) 
on three consecutive days, or if:
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∀
After Week 14 (Visit 13): FPG increases above 10.3 mmol/L (185 mg/dL) on three consecutive 
days
The outcome of the contact will be recorded on an Unscheduled Visit Form.
7-point self-measured plasma glucose profile
Subjects will be instructed to perform a 7-point SMPG profile preferably within one week prior to 
Visits 7, 13, 17 and 25 on days where the subject do not anticipate unusual strenuous exercise. 
The plasma glucose levels should be measured and recorded in the diary (including date, actual, 
clock time and plasma glucose value) at the following time points, always starting with 
measurement just before breakfast. 
Time-points for 7-point profile:
∀
Before breakfast
∀
90 min after the start of breakfast
∀
Before lunch
∀
90 min after the start of lunch
∀
Before dinner
∀
90 min after the start of dinner
∀
At bedtime
8.7
Assessments for safety
8.7.1
Adverse events
At all visits following screening investigator should ask subjects for any AEs. For more information 
on AEs refer to section 12.
8.7.2
Hypoglycaemic episodes
To avoid hypoglycaemic episodes subjects should be advised to avoid prolonged excessive fasting.  
Plasma glucose should always be measured and recorded when a hypoglycaemic episode is 
suspected. 
All plasma glucose values:
∀
equal or below 3.9 mmol/L (70 mg/dL)
or
∀
higher than 3.9 mmol/L (70 mg/dL) when they occur in conjunction with hypoglycaemic 
symptoms 
should be recorded by the subjects in the diaries. 
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These must be transcribed into the CRF throughout the trial from Visit 2 to Visit 26. 
The record should include the following information:
∀
The plasma glucose level before treating the episode (if available) 
∀
Date of hypoglycaemic episode
∀
Time of hypoglycaemic episode
∀
Whether the episode was symptomatic
∀
Whether the subject was able to treat him/herself
∀
Time of antidiabetic treatment administration prior to episode 
∀
Type of antidiabetic treatments taken within 24 hours prior to episode 
∀
Time of last main meal prior to episode
∀
Whether the episode occurred in relation to exercise
The answer to the question: “Was subject able to treat him/herself?” should be answered “No” if 
oral carbohydrates, glucagon or IV glucose had to be administered to the subject by another person 
because of severe central nervous system (CNS) dysfunction associated with the hypoglycaemic 
episode. Oral carbohydrates should not be given if the subject is unconscious.
A hypoglycaemic episode form must be filled in for each hypoglycaemic episode. If the 
hypoglycaemic episode fulfils the criteria for an SAE and/or a medical event of special interest 
(MESI) then an adverse event (AE) form and a safety information form must also be filled in.
8.7.2.1
ADA classification of hypoglycaemia 
According to the ADA the definition of a hypoglycaemic episode (Figure 8–1) is categorised as:
Severe hypoglycaemia: An episode requiring assistance of another person to actively administer 
carbohydrate, glucagon, or other resuscitative actions.
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).
Relative hypoglycaemia: An episode during which the person with diabetes reports any of the 
typical symptoms of hypoglycaemia, and interprets those as indicative of hypoglycaemia, but with a 
measured plasma glucose concentration > 3.9 mmol/L (70 mg/dL).
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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]).
Figure 8–1
ADA classification of hypoglycaemia
8.7.2.2
Additional definitions of hypoglycaemia
A hypoglycaemic episode will be defined as treatment emergent if the onset of the episode occurs 
after the first administration of IMP, and no later than one day after the last day on trial product 
(both inclusive).
Hypoglycaemic episodes will be defined as nocturnal if the time of onset is between 00:01 and 
05.59 inclusive.
In normal physiology, symptoms of hypoglycaemia occur below a blood glucose level of 
approximately 2.8 mmol/L (50 mg/dL) or plasma glucose level 3.1 mmol/L (56 mg/dL). Therefore, 
Novo Nordisk has used this cut-off point to define confirmed hypoglycaemia.
A confirmed hypoglycaemicepisode (referred to as minor hypoglycaemia) is defined as either:
∀
An episode with symptoms consistent with hypoglycaemia with confirmation by blood glucose 
< 2.8 mmol/L (50 mg/dL) or plasma glucose < 3.1 mmol/L (56 mg/dL), and which is handled 
by the subject him/herself,
Hypoglycaemia
Subject able
to treat it 
him/herself?
No
Yes
Symptoms?
No
Yes
Severe 
             hypoglycaemia
PG≤3.9 mmol/l                 Asymptomatic
     (70 mg/dl)                    hypoglycaemia
PG≤3.9 mmol/l                 Documented
     (70 mg/dl) 
symptomatic
  
hypoglycaemia
PG>3.9 mmol/l                 Relative 
     (70 mg/dl)                    hypoglycaemia
  
No measurement  
  Probable
  
symptomatic
  
hypoglycaemia
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or
∀
Any asymptomatic blood glucose value < 2.8 mmol/L (50 mg/dL) or plasma glucose value < 
3.1 mmol/L (56 mg/dL).
8.7.3
Electrocardiogram – 12 lead
A 12-lead ECG must be performed at Visits 1, 17 and 25 and interpreted locally by the investigator 
in relation to the trial. Investigators evaluation must be documented, signed and dated on the ECG 
print out. 
An ECG performed for any reason unrelated to this trial within 12 weeks prior to Visit 1 is 
acceptable provided no clinical symptoms suggestive of cardiac disease have occurred in the 
meantime. The investigator must still interpret, sign and date the ECG. If an ECG was performed 
before the informed consent and assent have been signed, it must be documented in the subject’s 
medical record that the reason for performance was not related to this trial.
Only applicable to Israel: Child assent form is not applicable.
An ECG performed 2 weeks before Visits 17 and 25 is acceptable as Visits 17 and 25 data 
respectively. 
8.7.4
Eye examination
A fundoscopy must be performed at Visits 1, 17 and 25 by the investigator or a local 
ophthalmologist according to local practice. Investigators evaluation must be documented in the 
subject’s medical records.
If a fundoscopy has been performed within 12 weeks prior to Visit 1 and if the results are available, 
the procedure does not need to be repeated. The investigator must still interpret, sign and date the 
fundoscopy results. If a fundoscopy was performed before the informed consent and assent have 
been signed, it must be documented in the subject’s medical record that the reason for performance 
was not related to this trial.
Only applicable to Israel: child assent form is not applicable.
A fundoscopy performed 2 weeks before Visits 17 and 25 is acceptable as Visits 17 and 25 data 
respectively. 
8.7.5
Physical examination
At Visits 1, 7, 13, 17 and 25 a physical examination must be performed 
Physical examination should include:
∀
Head, ears, eyes, nose, throat, neck
∀
Respiratory system
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∀
Cardiovascular system
∀
Gastrointestinal system including mouth
∀
Musculoskeletal system
∀
Central and peripheral nervous system
∀
Skin
∀
General appearance
∀
Lymph node palpation
∀
Thyroid gland
Any abnormalities found at Visit 1 should be recorded as a concomitant illness. Any clinically 
significant worsening from Visit 1 as well as any new clinically significant findings during the trial 
must be reported as an AE (see section 12).
8.7.6
Tanner staging
Pubertal status will be recorded in the CRF at Visits 7, 13, 17, 25, 27 and 28 for children and 
adolescents. Pubertal development will be assessed by the Tanner staging in accordance with 
stages I-V34. Assessment of testicular volume (by orchidometer) stages for boys will be included. 
The assessments must be conducted by personnel trained in pubertal assessments.
A Tanner staging assessment performed 2 weeks before Visits 7, 13, 17, 25, 27 and 28 is
acceptable as Visits 7, 13, 17, 25, 27 and 28 data assessment respectively. 
The Tanner staging assessment is no longer required to be performed, once the subject reaches the 
Tanner stage V, as judged by the investigator.
Evidence of accelerated pubertal development as judged by the investigator at Visit 1 should be 
recorded as concomitant illness. Acceleration of pubertal development after Visit 1 as judged by the 
investigator should be recorded as an AE
8.7.7
Bone age assessment
An x-ray of left hand and wrist will be performed at Visits 7 and 25 for all subjects for evaluation of 
bone age. In addition subjects treated with liraglutide for more than three months will have an x-ray 
performed at Visits 27 and 28. A repeat bone age assessment will not be performed at subsequent 
visits (25, 27 or 28) for subjects for whom the bone age assessment at Visit 7, or at a later visit, 
indicates that the epiphyses are fused. The x-rays will be analysed by a central reader for 
determination of bone age. Further requirements and details will be described in the x-ray site 
manual.
An x-ray performed within 2 weeks prior to Visit 7, 25, 27 and 28 is acceptable.
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8.7.8
Blood samples
Blood samples will be drawn at site at the specified time-points (section 2) and analysed at the 
central laboratory to determine levels of the following safety parameters:
∀
Haematology 
-
Haemoglobin
-
Haematocrit
-
Thrombocytes
-
Erythrocytes
-
Leucocytes
-
Differential count: 
o
Eosinophils
o
Neutrophils
o
Basophils
o
Lymphocytes 
o
Monocytes
∀
Biochemistry 
-
creatinine 
-
creatine kinase
-
urea
-
albumin
-
bilirubins (total)
-
ALAT 
-
ASAT 
-
Alkaline phosphatase
-
Sodium
-
Potassium
-
Calcium, total
-
Calcium, albumin corrected 
-
Amylase 
-
Lipase 
∀
Hormones 
-
Calcitonin (please refer to Appendix D for actions to be taken if calcitonin is > UNR)
-
Prolactin
-
FSH 
-
Estradiol
-
LH
-
Testosterone
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-
DHEAS
-
CEA
-
TSH
-
IGF-1
-
IGFBP-3
∀
Pregnancy test
Females of childbearing potential will have a serum pregnancy test (beta-human chorionic 
gonadotropin) performed at Visits 1, 7, 13, 17 and 25. In addition they will have a urine 
pregnancy test performed at Visit 7 prior to randomisation. During the rest of the trial a urine-
stick pregnancy test will be performed at the site if a menstrual period is missed. The 
investigator should comply with local laws with regard to pregnancy testing in minors during 
clinical trials.
Austria: A urine-stick pregnancy test will be performed at all visits to the clinic.
If a girl becomes of childbearing potential (has first menstrual period) during the trial a serum 
pregnancy test must be performed for that subject as soon as possible or at the latest at the next 
clinic visit. 
∀
Bone metabolism markers
-
Alkaline phosphatase
-
P1NP
-
NTX
-
CTX
∀
Insulin antibodies:
-
IA-2 
-
anti-GAD
∀
HIV 
∀
Hepatitis B and C
Liraglutide antibody samples
Blood samples for determination of anti-liraglutide antibodies will be drawn at Visits 7, 17 and 26.
Unblinded subjects who are not treated with liraglutide should not have a blood sample drawn for 
determination of anti-liraglutide antibodies. 
Samples will be analysed for anti-liraglutide antibody formation including cross reactivity to 
endogenous GLP-1. Samples from Visit 26 that are found to be positive for anti-liraglutide 
antibodies will be assessed for neutralising effect. 
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The blood samples collected for determination of anti-liraglutide antibodies will be stored until 
marketing authorisation for paediatric patient is given for liraglutide or as long as the local 
authorities permit the storage of blood samples, whichever comes first. 
The antibody samples will be analysed at a special laboratory (please refer to Attachment I for 
details). The results of the antibody samples will only be reported to the investigator upon request at 
the end of trial.
8.7.9
Urine samples
Urinalysis will be performed at Visits 7, 13, 17 and 25. For these visits the subjects should collect a 
morning urine sample on the day of the visit and bring the sample to the site. For information on 
collection, storage and transport to site, please refer to the laboratory manual. Urine samples will be 
analysed at the central laboratory to determine the levels of the following safety laboratory 
parameters:
Urinalysis
-
Micro albumin
-
Creatinine
-
Albumin:creatinine ratio (calculated)
-
Protein
-
Ketone
-
Glucose
-
pH
8.8
Other assessments
In addition to the assessments mentioned in sections 8.1- 8.7 the following should be performed:
∀
Diet and exercise counselling according to local standards (Visits 2, 5, 7, 8, 9, 11, 12, 13, 15, 17, 
18, 20, 22, 24 and 25). The counselling should be documented in the subject’s medical record 
∀
Dispense trial product (including IV/WRS session) (Visits 2, 5, 7, 11, 12, 13, 15, 17, 18, 20, 22 
and 24). Trial product must not be dispensed to any person not included in the trial. Trial 
products that have been stored improperly must not be dispensed to any subject before it has 
been re-evaluated and approved for further use by Novo Nordisk
∀
Instruct in the metformin titration to 2000 mg/day or MTD over 3 to 4 weeks at the discretion of 
the investigator and in metformin maintenance as applicable (titration at visits 2, 3, 4 and
maintenance at visit 5). Subjects already treated with metformin 2000 mg/day or more for at 
least 56 days prior to screening may have their BG meter, urine collection container and diary 
for Visit 7 provided at Visit 1 and advance directly to Visit 7 see section 5.3. Subjects who are 
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treated with basal insulin should in addition to the stable dose of metformin have a stable dose 
of basal insulin for at least 56 days to advance directly to Visit 7.
∀
Instruct in the use of the pen-injector for liraglutide administration (Visit 7), instructions should 
be repeated as needed
∀
Dose escalation of liraglutide at 0.6 mg increments in weekly intervals (Visits 7, 8, 9 and 10) 
based on the average of three FPG measurements taken on the three consecutive days preceding 
Visits 8, 9 and 10. The average FPG must be > 6.1 mmol/L (110 mg/dL) in order for the 
liraglutide dose to be escalated see section 5.3
∀
Obtain oral confirmation of compliance according to section 8.9 (Visits 3-25)
∀
Provide BG meter and instructions for use (Subjects already treated with a stable dose of with 
metformin 2000 mg/day or more for at least 56 days prior to screening may have their BG 
meter, for Visit 7 provided at Visit 1). Subjects who are treated with basal insulin should in 
addition to the stable dose of metformin have a stable dose of basal insulin for at least 56 days 
to advance directly to Visit 7)
∀
Provide urine collection containers for collection of urine (Visits 1, 5, 12, 15 and 24). Subjects 
already treated with a stable dose of with metformin 2000 mg/day or more for at least 56 days
prior to screening may have their urine collection container for Visit 7 provided at Visit 1 
∀
Provide diary and instruct in the use of the diary (Visits 1, 2, 5, 7, 8, 9, 11, 12, 13, 15, 17, 18, 
20, 22 and 24)
∀
Collect, review and transcribe data from diaries at Visits 2-25. At telephone contacts (TCs) 
information from the diary as reported by the subject and not the physical diary will be collected
∀
Perform drug accountability according to section 9.3 (Visits 5, 7, 11, 12, 13, 15, 17, 18, 20, 22, 
24 and 25)
∀
Complete relevant IV/WRS calls according to section 10 (Visits 1, 2, 5, 7, 9, 11, 12, 13, 15, 17, 
18, 20, 24 and 25)
∀
Review rescue (Visits 10-24) and withdrawal criteria (Visits 2-24) according to section 6.5 and
6.6.
8.8.1
Blood samples - pharmacokinetic
Blood samples for measuring the concentration of liraglutide in the blood will be drawn at Visits 8, 
9, 11, 13 and 17. Date, time and dose of liraglutide injections two days prior to Visits 8, 9, 11, 13 
and 17 should be recorded in the subject diary. Liraglutide injections should be withheld on the day 
of the visits until the blood sampling has been performed.
The PK samples will be analysed at a special laboratory (please refer to Attachment I for details). A 
detailed description of the assay and the results will be reported in a separate bioanalytical report. 
The results of the PK samples will only be reported to the investigator upon request.
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8.9
Subject compliance
At each visit the investigator will emphasise the necessity for the subject to adhere to trial 
procedures in order to encourage subject compliance. 
The investigator must assess the compliance of the subject at each visit based on a review of 
glycaemic control, adherence to the visit schedule and completion of the subject’s diary including 
previous day’s doses of metformin and liraglutide. At Visits 3-25 compliance must be assessed by 
oral confirmation from the subject and the subject’s LAR, the compliance assessment must be 
documented in subject’s medical record and transferred to the eCRF. 
In addition, subject compliance will be assessed by monitoring of drug accountability. The unused 
amount of IMP and NIMP will be assessed against the dispensed amount and, in case of 
discrepancies, the subject must be asked.
For metformin compliance is defined as taking between 80%-120% of the prescribed dose. There is 
no fixed compliance range for liraglutide. 
If a subject is discovered to be non-compliant, the investigator must inform the subject of the 
importance of taking IMP and NIMP as directed. Substantial failure to comply with the prescribed 
dose regimen should be discussed with Novo Nordisk and can lead to withdrawal.
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9
Trial supplies
Trial supplies comprise trial products and auxiliary supplies 
Trial products comprise IMPs, including liraglutide placebo and NIMP. 
Auxiliary supplies comprise supplies other than trial products, e.g. needles and blood glucose 
meters.
Procedures for supply, handling and storage of trial product will be described in the Trial Materials 
Manual (TMM) provided by Novo Nordisk. The TMM will be distributed to investigational sites. 
9.1
Trial products
The IMPs used in this trial are:
∀
liraglutide solution for s.c. injection (6.0 mg/mL)
∀
liraglutide placebo solution for s.c. injection 
Liraglutide and liraglutide placebo solutions for s.c. injection will be supplied by Novo Nordisk in a 
3 mL pre-filled pen injector. 
The administration of liraglutide and liraglutide placebo will be as outlined in section 5.3.2 . The 
liraglutide placebo and active drug are visually identical and identical with regards to smell.
The investigator will provide each subject with direction for use of the pre-filled pen injector at the 
dispensing visits. 
IMP dispensing units will be distributed to the sites according to enrolment. Please refer to the 
TMM provided by Novo Nordisk for further details.
9.1.1
Non-investigational medicinal product(s)
Metformin tablets (NIMP) will be purchased by Novo Nordisk and provided to sites for subject 
treatment during the trial. Metformin tablets will be provided in a metformin hydrochloride tablet 
form containing 500 mg. 
The investigator will provide each subject with verbal instruction in the use of metformin at the 
dispensing visits. 
NIMP dispensing units will be distributed to the sites according to enrolment. Please refer to the 
TMM provided by Novo Nordisk for further details. 
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Insulin (Concomitant and rescue treatment) is regarded as NIMPs and will not be supplied by Novo 
Nordisk.
9.2
Labelling
All trial products will be packed and labelled by Novo Nordisk and provided in non subject specific 
boxes.
Labelling of the IMPs will be in accordance with Annex 1335, local law and trial requirements. 
Labelling of the NIMP will be in accordance with local requirements.
Labelling will include the product related requirements and precautions. 
9.3
Storage, accountability and destruction
Storage
The investigator must ensure availability of proper storage conditions, and record and evaluate the 
temperature (at least once every working day). Storage facilities should be checked frequently. A 
log to document the temperature and the date of temperature must be kept. Trial products that have 
been stored improperly must not be dispensed to any subject before it has been re-evaluated and 
approved for further use by Novo Nordisk. The investigator must inform Novo Nordisk 
immediately if any trial product has been stored outside defined conditions (i.e. temperature 
ranges). The investigator’s first point of contact is the monitor. 
Liraglutide and liraglutide placebo
Storage condition for liraglutide and liraglutide placebo:
Not in use:
∀
Store in a refrigerator (+2ºC to +8ºC [+36ºF to +46ºF])
∀
Do not freeze
∀
Protect from light
∀
Store away from the freezer compartment
In use:
∀
After first use of the prefilled pen, the product can be stored for 1 month at room temperature 
(below +30°C/86ºF) or in a refrigerator (+2ºC to +8ºC [+36ºF to +46ºF])
!
US: 30 days at room temperature (+15°C to +30°C [+59ºF to +86ºF]) or in a refrigerator 
(+2ºC to +8ºC [+36ºF to +46ºF])
∀
Keep the pen cap on when the prefilled pen is not in use in order to protect from light
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∀
Store away from the freezer compartment
Metformin
Storage and handling of metformin must be in accordance with labelling.
Dispensing and return of medication
Trial products will be dispensed to each subject as required according to treatment group. The 
IV/WRS will allocate trial product dispensing unit numbers (DUN) to the appropriate subject at 
each dispensing visit. All DUNs must be dispensed to the appropriate subject.
Liraglutide and liraglutide placebo must not be used if it does not appear clear and colourless. 
Liraglutide, liraglutide placebo or metformin must not be dispensed to any person not participating 
in the trial.
Subjects must return the dispensed liraglutide, liraglutide placebo and metformin (used/ partly used 
and unused trial products including empty packaging material). Returned trial products (used/ partly 
used and unused trial products including empty packaging material) must be stored separately from 
non-allocated trial product(s).
Accountability and destruction 
The person delegated by the investigator must keep track of all received, used, partly used and 
unused trial products and if possible, all empty packaging, by using the drug accountability module 
in the IV/WRS. There should be performed full accountability for all IMPs (per pen) and NIMPs 
(per tablet).
Subjects are instructed to return all used, partly used and unused trial products including empty 
packaging material.
The investigator must keep all returned trial products until the monitor has performed drug 
accountability. Destruction of trial products will be done according to local procedures and after 
agreement with the monitor. Destruction of trial products must be documented.
9.4
Auxiliary supply
The following may be supplied by Novo Nordisk and in some countries bought locally:
∀
Needles, for pre-filled pen injector
∀
Blood glucose meters, incl. lancets, plasma calibrated test strips and control solutions
Further details will be described in the TMM.
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10 Interactive voice and web response system
A trial-specific IV/WRS will be set up which can be accessed at any time via the internet or 
telephone. Some sessions may only be available via the internet. Access to the IV/WRS must be 
restricted to and controlled by authorised persons. 
IV/WRS is used for: 
∀
Screening
∀
Screening failure (incl. run-in failure)
∀
Randomisation and stratification 
∀
Medication arrival
∀
Run-in dispensing
∀
Dispensing (incl. unblinding at Visit 17)
∀
Withdrawal
∀
Completion (treatment)
∀
Code break
∀
Drug accountability
∀
Data change
An IV/WRS user manual will be provided to each trial site.
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11 Randomisation and unblinding procedures 
At the randomisation visit (Visit 7) the subjects will be randomised to one of two parallel treatment 
groups:
∀
Liraglutide and metformin with or without basal insulin or
∀
Liraglutide placebo and metformin with or without basal insulin
The trial is a double-blind trial for the first 26 weeks. The randomisation will be carried out in a 1:1 
manner using IV/WRS.
Subjects will be stratified at randomisation by sex and according to their age at end of treatment (≤ 
14 and > 14 years of age) (see section 5.1 for definition of ≤14). Stratification will be controlled by 
the IV/WRS system. 
11.1
Breaking of blinded codes 
If the trial site needs to break the code, Novo Nordisk should, if possible, be contacted before the 
code is broken. The IV/WRS will notify Novo Nordisk (monitor and the Global Safety department) 
immediately after the code is broken.
The code for a particular subject may be broken in a medical emergency if knowing the actual 
treatment would influence the treatment of the subject. Whenever a code is broken the person 
breaking the code must print the Code Break Confirmation Notification generated by the IV/WRS, 
record the reason, and sign and date the document.
If the subject is withdrawn after the code has been broken, a withdrawal session should be 
completed in the IV/WRS.
When the code is broken, the treatment allocation will be accessible to the investigator and the 
Novo Nordisk Global Safety department. If IV/WRS is not accessible at the time of code break the 
IV/WRS vendor helpdesk should be contacted. Contact details are listed in attachment II. 
11.2
Unblinding procedure and laboratory access to blinded data
Subjects’ treatment will be blinded during the first 26 weeks of randomised treatment (Visit 7 to 
Visit 17). At Visit 17 a subject’s treatment allocation will be revealed via the IV/WRS.
The special laboratories analysing the samples for anti-liraglutide antibodies and concentration of 
liraglutide (PK) will be provided with a randomisation list. 
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12 Adverse events, and technical complaints and pregnancies
12.1
Definition of adverse events
An adverse event (AE) is any untoward medical occurrence in a subject administered a product, and 
which does not necessarily have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom or disease temporally associated with the use of a product, whether or not 
considered related to the product. 
Note: This includes events from the first trial related activity after the subject has signed the 
informed consent and until Visit 26 (for subjects treated with liraglutide for more than 3 months
until Visit 28).
AEs include:
∀
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 procedures (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 are AEs, but are reported on hypoglycaemic forms instead of on 
AE forms.
12.2
Definition of serious adverse events and non-serious adverse events 
An AE is either categorised as a serious AE (SAE) or a non-serious AE.
An 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
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∀
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 this definition.d
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 
∀
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 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.
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 dyscrasias or convulsions that do not result in hospitalisation, or development of drug 
dependency or drug abuse.
A non-serious AE is any AE which does not fulfil the definition of an SAE.
12.3
Definition of medical events of special interest 
A medical event of special interest (MESI) is an event which, in the evaluation of safety, has a 
special focus. A MESI should be reported according to the same reporting requirements and 
timelines as for SAEs (see section 12.5) irrespective of whether the MESI fulfils any SAE criterion.
The following are defined as MESIs in this trial (further defined in Appendix C):
1. Medication errors concerning trial products:
∀
Administration of wrong drug 
∀
Wrong route of administration, such as intramuscular instead of subcutaneous
∀
Administration of a high dose with the intention to cause harm (e.g. suicide attempt)
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∀
Administration of an accidental overdose:
o
An accidental overdose is defined as the subject having received dosing which 
exceeds the maximum intended dose 1.8 mg daily
2. Suspected transmission of an infectious agent via a trial product 
3. Altered renal function
4. Acute pancreatitis and the suspicion of acute pancreatitis
5. Elevated lipase or amylase >3x UNR 
6. Any confirmed episode of calcitonin value ≥20 ng/L (see Appendix D)
7. Neoplasm excluding thyroid neoplasm 
8. Thyroid disease including thyroid neoplasm 
9. Severe hypoglycaemia 
10. Immunogenicity (immune-complex disease and allergic reactions including allergic reactions 
at injection sites) 
11. AEs leading to withdrawal
12.4
Severity, relationship and outcome of adverse events
Severity assessment definitions:
∀
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.
The following terms and definitions are used when assessing the relationship between each AE and 
the relevant trial product(s): 
∀
Probable - Good reason and sufficient documentation to assume a causal relationship
∀
Possible - A causal relationship is conceivable and cannot be dismissed
∀
Unlikely - The event is most likely related to aetiology other than the trial product
Outcome categories and definitions
The following terms and definitions are used in assessing the final outcome of an AE:
∀
Recovered - 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 - This term is only applicable if the subject has completed the trial or has died from 
another AE. The condition is improving and the subject is expected to recover from the event.
∀
Recovered 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.
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∀
Not recovered - The condition of the subject has not improved and the symptoms are 
unchanged, or the outcome is not known at the time of reporting.
∀
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”, “recovering”, “recovered with sequelae” or “not recovered”. 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.
12.5
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 (Visit 26). The events must be recorded in the applicable forms 
in a timely manner. 
During each contact with the trial site staff (site visits and telephone contacts), the subject must be 
asked about AEs and technical complaints. This could be done by asking for example: “Have you 
experienced any problems since the last contact?”. Collection on technical complaints will start 
from the randomisation visit (Visit 7) which is the first visit where the subject will use liraglutide 
and the pen-injector.
At the follow-up Visits 27-28 the site will record reported AEs and SAE (based on the subject’s 
memory) and the associated concomitant medication. The SAE reporting must follow the timelines 
set for SAE reporting, please see below.
All AEs, either observed by the investigator or reported by the subject, must be reported by the 
investigator and evaluated. Novo Nordisk assessment of expectedness is performed according to the 
following reference documents: 
∀
Novo Nordisk IMPs (liraglutide): Current version of the company core data sheet (CCDS) or 
any updates hereof.
The investigator should report the diagnosis, if available. If no diagnosis is available, the 
investigator should record each sign and symptom as an individual AE.
All AEs, SAEs and MESIs must be recorded by the investigator on the AE form in the eCRF. A 
separate AE form should be used for each diagnosis or sign and symptom. For each SAE a safety 
information form (SIF) should be completed in addition to the AE form in the eCRF. If several 
symptoms or diagnoses occur as part of the same clinical picture, one SIF may be used to describe 
all the SAEs. 
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The SIF will be a paper based form. The completed form will be faxed or emailed to Novo Nordisk 
according to the below timelines. 
MESIs, regardless of seriousness, must be reported using the AE form and the SIF.
The investigator must ensure that the worst case severity and seriousness of an event is kept 
throughout the trial.
The reporting timelines for SAEs
∀
The investigator must enter the AE in the eCRF and tick the seriousness box within 24 hours of
obtaining knowledge of the SAE. If the SAE is fulfilling the MESI criteria also tick the MESI 
box.
∀
The paper-based SIF must be completed and forwarded to Novo Nordisk within 5 calendar 
days of obtaining knowledge of the SAE preferably electronically in PDF format or by fax. 
∀
The AE form in the eCRF must be signed within 7 calendar days from the date the information 
was entered in the eCRF.
The reporting timelines for non-serious AE fulfilling the MESI criteria
∀
The investigator must enter the AE in the eCRF, tick the MESI box and complete the paper-
based SIF within 14 calendar days of obtaining knowledge of the MESI.
If for some reason the eCRF is unavailable, the AE information should be reported to Novo Nordisk 
by fax, e-mail or courier within the same timelines.
Contact details (fax, e-mail and address) are provided in attachment II to the protocol.
All laboratory results outside of the pre-defined normal limits will automatically be reported to the 
investigator and Novo Nordisk and the laboratory results will be monitored by Novo Nordisk on a 
regular basis.
Novo Nordisk will notify the investigator of trial product-related suspected unexpected serious 
adverse reactions (SUSARs) in accordance with local requirements and ICH GCP33. In addition, the 
investigator will be informed of any trial-related SAEs that may warrant a change to any trial 
procedure.
Novo Nordisk must inform the Institutional Regional Boards/Independent Ethics Committees 
(IRBs/IECs) in accordance with local requirement and GCP, unless locally this is an obligation of 
the investigator, as for example in the US.
Novo Nordisk must always inform the regulatory authorities in accordance with local requirements 
and GCP.
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12.6
Follow-up of adverse events
All SAEs and MESIs must be followed up until the outcome of the event is “recovered”, “recovered 
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” or “not recovered”, when the subject has completed the follow up period. 
The follow-up period for this trial is one week (Visit 26). 
The follow-up information on SAEs should only include new (corrections or new or additional) 
information and should be reported within 24 hours of obtaining knowledge of the information. 
This is also the case for previously non-serious AEs which subsequently become SAEs. 
The follow-up information on MESIs should only include new (corrections or new or additional) 
information and must be reported within 14 calendar days of the investigators first knowledge of the 
information. This is also the case for previously reported non serious AEs which subsequently fulfil 
the MESI criteria.
Non-serious AEs must be followed until the outcome of the event is “recovering”, “recovered” or 
“recovered 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 or cancer or AEs ongoing at time of death (where death is due to another AE) may be 
closed with the outcome “recovering” or “not recovered”. 
Queries or follow-up requests from Novo Nordisk should be responded to within 13 calendar days. 
The investigator must forward follow-up information on SAEs within 24 hours and MESIs within 
14 days of obtaining the follow-up information by updating the AE form in the eCRF and/or 
completing a new SIF marked follow-up, and forward this to Novo Nordisk. If for any reason the 
eCRF is unavailable or, after access to edit the eCRF is revoked, the investigator must record any 
SAE and MESI follow-up information on the provided paper CRFs and/or SIF and send the 
information by fax, e-mail or courier to Novo Nordisk.
The investigator must record follow-up information on non-serious AEs by updating the AE form in 
the eCRF. If the eCRF is revoked after access to edit, the investigator must record any follow-up 
information on the provided paper CRFs. Information on AEs, SAEs and MESIs for Visit 27 and 28 
must be recorded on the provided paper CRFs.
12.7
Technical complaints and technical complaint samples
A technical complaint is any communication that alleges defects on trial supplies. The technical 
complaint may be associated with an AE, but does not concern the AE itself.
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Examples of technical complaints:
∀
The physical or chemical appearance of trial products (e.g. discoloration, particles or 
contamination)
∀
The packaging material (e.g., leakage, cracks, rubber membrane issues or errors in labelling 
text)
∀
Problems related to pen and needles (e.g., to the injection mechanism, needles, dose setting 
mechanism, push button or interface between the pen and the needle)
12.7.1
Reporting of technical complaints 
All technical complaints on any of the following products liraglutide or liraglutide placebo and 
metformin which occur from the time of first usage of trial supplies until the time of the last usage 
of trial supplies must be collected and reported to Novo Nordisk.
The investigator must assess whether the technical complaint is related to any AE(s), SAE(s) and/or 
MESI(s). 
Technical complaints must be reported on a separate technical complaint form and must be 
completed for each IMP (liraglutide and liraglutide placebo) Novo Nordisk provided NIMP 
(metformin) and for auxiliary supplies listed on the technical complaint form. If the technical 
complaint involves more than one batch number, a technical complaint form for each batch number 
must be completed. 
The investigator must complete and forward the technical complaint form by fax, e-mail or courier 
to Novo Nordisk, within the same timelines as for reporting AEs, SAEs and MESIs as follows:
∀
Technical complaint assessed as related to an SAE within 24 hours of the trial site obtaining 
knowledge of the complaint
∀
All other technical complaints within 5 calendar days
The technical complaint from will be a paper based form.
12.7.2
Collection, storage and shipment of technical complaint samples
The investigator must collect the technical complaint sample and notify the monitor within 
5 calendar days. The monitor must initiate the shipment to Novo Nordisk and ensure the sample is 
sent in accordance with local regulations and as soon as possible to Novo Nordisk complaint centre. 
A copy or a print of the technical complaint form should be sent with the sample.
The investigator should ensure that the technical complaint sample contains the batch number and, 
if available, the DUN.
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If the technical complaint sample is unobtainable, the investigator must specify on the technical 
complaint form why it is unobtainable. 
Storage and shipment of the technical complaint sample must be done in accordance with the 
conditions prescribed for the product (see section 9.3).
12.8
Pregnancies
Female subjects must be instructed to notify the investigator immediately if they become pregnant 
during the trial. Treatment in pregnant trial subjects must be stopped immediately. 
Only applicable to US: subjects must be instructed to notify the Investigator immediately if they or 
their partner become pregnant during the trial.
The investigator must report any pregnancy in subjects who received Novo Nordisk provided trial 
product. Only applicable to US: Pregnancies in partners of male subjects must be reported also 
(see section 12.8.1)
When an abnormality is reported in the foetus or newborn infant and information is needed from the 
male partner an informed consent must be obtained prior to this.
The investigator must report all information on pregnancies, including AEs in the subject, foetus, 
and newborn infant on the trial related pregnancy forms. Novo Nordisk will provide investigators 
with paper pregnancy forms. The pregnancy forms must be forwarded to Novo Nordisk preferably 
electronically in PDF format or by fax, see Attachment II.
The investigator must follow the pregnancy until the pregnancy outcome and the newborn infant(s) 
until the age of one month. The investigator must collect information on the pregnancy and 
pregnancy complications as well as the pregnancy outcome including the health of the newborn 
infant(s) on the pregnancy forms. 
The following must be collected: 
∀
Initial information within 14 calendar days of the investigator’s first knowledge of the 
pregnancy
∀
Information on the outcome of her pregnancy - including the health status of the newborn infant 
at the age of one month within 14 calendar days of the investigator’s knowledge of the 
pregnancy outcome
∀
All non-serious AEs in connection with the pregnancy and pregnancy outcome must be reported 
on the pregnancy forms within 14 calendar days of the investigator’s knowledge. It must be 
clear in the description if the event occurs in the subject, the foetus or the newborn infant.
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∀
All SAEs in connection with the pregnancy and pregnancy outcome must be reported on the 
pregnancy forms following the same timelines as required for other SAEs (see section 12.5).
It must be clear in the description if the event occurs in the subject foetus or the newborn infant.
!
The SAEs that must be reported include abnormal outcome - such as congenital anomalies, 
foetal death and termination of pregnancy (spontaneous or elective abortion), including any 
anomalies of the foetus observed at gross examination or during autopsy - as well as other 
pregnancy complications fulfilling the criteria of an SAE.
12.8.1
Pregnancies in partners of trial subjects (only applicable to US)
In case of an SAE (with a causal relationship evaluated as possible or probable by the
Investigator) in the fetus, newborn infant(s) or infant(s)/toddler(s) of a trial subject’s partner,
who is potentially exposed to the trial product via the trial subject, the pregnancy and the SAE
should be reported on the same forms and within the same timelines as for a subject in the trial.
Prior to obtaining any data on the pregnancy, “pregnant partner consent” must be completed by
the male subject’s partner.
12.9
Precautions and/or overdose
When initiating treatment with liraglutide, the subject may in some cases experience side effects. 
In the clinical trials of liraglutide, one subject with type 2 diabetes experienced a single overdose of
17.4 mg subcutaneous (10 times the maximal recommended maintenance dose of 1.8 mg). Effects 
of the overdose included severe nausea and vomiting. No hypoglycaemia was reported. The patient 
recovered without complications. 
For further details please refer to latest version of the IB for liraglutide15 or any updates thereof.
12.10
Committees related to safety
12.10.1
Novo Nordisk safety committee
Novo Nordisk will constitute an internal safety committee to perform ongoing safety surveillance. 
The safety committee will conduct ongoing monitoring of blinded safety data. The 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.
12.10.2
The external data monitoring committee
An external data monitoring committee (DMC) is established to independently review and evaluate 
accumulated unblinded safety data from the trial in order to protect the safety of the subjects and to 
evaluate the evolving risk-benefit if required.
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The DMC is composed of permanent members who are independent of Novo Nordisk and will 
cover relevant specialities (specialists in paediatrics and endocrinology) and they may request 
assistance from a number of additional ad hoc members, if needed.
The DMC is established as agreed with PDCO to review unblinded safety data after the first 12 
subjects have been randomised to liraglutide and undergone dose escalation starting with a 0.6 mg 
dose. The DMC will also monitor safety throughout the trial on an ongoing basis, and recommend 
to Novo Nordisk whether to continue, modify, or terminate the trial as necessary. The composition 
of the DMC, objectives of the surveillance, meeting frequency and type, data to be analysed at the 
meetings and responsibilities with regard to information (such as meeting minutes) will be 
described in a DMC charter.
Novo Nordisk Global Safety must be the only point of contact between the DMC and Novo 
Nordisk. Other departments can participate in DMC meetings if deemed relevant by Novo Nordisk 
Global Safety. The DMC recommendations should be addressed directly to Novo Nordisk Global 
Safety and the internal Novo Nordisk safety committee. It is the responsibility of the internal Novo 
Nordisk safety committee to take action for subject safety based on the DMC recommendations. 
DMC concerns relating to trial processes will be communicated to trial management via Novo 
Nordisk Global Safety.
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13 Case report forms 
Novo Nordisk will provide a system for the electronic case report forms (eCRF) and provide paper 
case report forms (CRF) to site. The electronic system and support services to the system will be 
supplied by a vendor. The subject visit data will be captured in the eCRFs for subject Visit 1-26. 
The follow-up data for Visit 27-28 will be captured on paper CRFs. 
The safety information forms which are used to capture information for SAEs and MESIs and the 
pregnancy forms (pregnancy A and pregnancy B) are paper based CRFs. The investigator must 
ensure that data are recorded in these forms as soon as possible and ensure that Novo Nordisk 
receives these forms within the required timeline (see section 12.5). 
Data entry for eCRFs
The investigator or delegated staff must ensure that all relevant questions are answered, and that no 
empty data field exists. If a test or an assessment has not been done and will not be available, or if 
the question is irrelevant (e.g. is not applicable), indicate this according to the data entry 
instructions.
Data entry for paper CRFs
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.
Signing the CRFs
The investigator must ensure that all information derived from source documentation is consistent 
with the source information. By electronically signing the case book the investigator confirms, that 
the information in the CRFs for the trial until Visit 26 including related forms, are completed and 
correct. Likewise by signing the affirmation statement for each of the Visits 27 and 28 the 
investigator confirms that the information in the CRFs for these visits including related forms are 
complete and correct.
13.1
Corrections to case report forms 
Correction procedure for eCRFs
Corrections to the CRF data may be made by the investigator or the investigator’s authorised staff. 
An audit trail will be maintained in the CRF application containing as a minimum: the old and the
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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 authorised staff after the date the investigator has 
signed the case book, the case book must be signed and dated again by the investigator.
Correction procedure for paper CRFs
Corrections to the data in CRFs may only be made by drawing a straight line through the incorrect 
data and then writing the correct entry next to the data that were crossed out. Each correction must 
be initialled, dated and explained (if necessary) by the investigator or the investigator’s authorised 
staff. If corrections are made by the investigator’s authorised staff after the date of the investigator’s 
signature on the affirmation statement, the affirmation statement must be signed and dated again by 
the investigator.
Corrections necessary after the CRFs have been removed from the investigator’s site must be 
documented on a data clarification form (DCF) or a monitor-initiated discrepancy form (MIDF). If 
the affirmation statement for the subject has not yet been signed, any corrections must be approved 
by the investigator or her/his authorised staff. If the affirmation statement for the subject has already 
been signed, the investigator must approve any correction.
13.2
Case report form flow 
The investigator must ensure that data are recorded in the eCRF as soon as possible after the visit, 
preferably within 3 business days. Once data have been entered, they will be available to Novo 
Nordisk for data verification and validation purposes.
At the end of the trial the investigator must ensure that all remaining data have been entered into the 
eCRF no later than business 3 days after the last subject’s last visit at the site in order to ensure the 
planned lock of the database.
Site specific eCRF data (in an electronic readable format) will be provided to the Investigator after 
the trial database is released, and access to update the trial data in electronic data capture (EDC) 
system has been removed. This data will be retained by the site.
When the final CTR is available the data will be archived by Novo Nordisk.
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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 paper or EDC source data verification, to 
monitor drug accountability and collect completed CRF pages. The visit intervals will depend on 
the outcome of the remote monitoring of the CRFs, the trial site's recruitment rate and the 
compliance of the trial site to the protocol and GCP, but will not exceed 8 weeks for sites with 
subjects between Visits 1 and 26 (inclusive). 
14.1
Source data verification
The monitor must be given direct access to source documents (original documents, data and 
records). Direct access includes permission to examine, analyse, verify and reproduce any record(s) 
and report(s) that are important to the evaluation of the trial. If the electronic medical record does 
not have a visible audit trail, the investigator must provide the monitor with signed and dated 
printouts. In addition the relevant trial site staff should be available for discussions at monitoring 
visits and between monitoring visits (e.g., by telephone). All data must be verifiable in source 
documentation other than the CRFs. 
For screening failures the monitor will ensure that relevant eCRF pages and other trial related forms 
containing data from screening failures are completed. For screening failures the following data 
should be source verified: informed consent, reason for screening failure and AEs if any.
The subject diaries will be collected at each subject visit to the clinic and must be kept as source 
data by the investigator. The diary will be source data verified by the monitor according to guidance 
for reduced source data verification (SDV) in the monitoring guideline. Considering the electronic 
source data environment, it is accepted that the earliest practically retainable record should be 
considered as the location of the source data. Therefore, transcription to the diary from the blood 
glucose meter is considered the source document for recordings of blood glucose.
For all data recorded in the CRFs the source document must be defined in a source document 
agreement at each site. The list must be detailed and there should only be one source defined at any 
time for any data element. 
The monitor must ensure that the CRFs and eCRFs are completed by site staff.
Monitors must review the medical records and other source data (e.g. the diaries) to ensure 
consistency and/or identify omissions compared to the CRF or eCRF. If discrepancies are found, the
investigator must be questioned about these.
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15 Data management
Data management is always the responsibility of Novo Nordisk. Data management may be 
delegated under an agreement of transfer of responsibilities to a data management unit within Novo 
Nordisk or an external 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. 
Laboratory data from central laboratories will be transferred electronically from the laboratory 
performing the analyses. In cases where laboratory data are transferred via non-secure electronic 
networks, data will be encrypted during transfer. The laboratory will provide all laboratory reports 
to the investigator for storage at the trial site.
The subject and any biological material obtained from the subject will be identified by subject ID 
and trial identification number. Appropriate measures such as encryption or leaving out certain 
identifiers will be enforced to protect the identity of subjects in all presentations and publications as 
required by local, regional and national requirements.
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16 Computerised systems
Novo Nordisk will capture and process clinical data using computerised systems that are described 
in Novo Nordisk Standard Operating Procedures (SOPs) 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. 
Novo Nordisk will collect information on the practical use of these systems within the conduct of 
this clinical trial. 
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17 Statistical considerations
General considerations
Novo Nordisk will be responsible for the statistical analysis and reporting. Analysis and reporting 
will be based on pooled data from all sites.
The statistical analyses will be performed with a significance level of 5% (two-sided tests).
For all endpoints analysed statistically, estimated mean treatment differences will be presented 
together with two-sided 95% confidence intervals and p-values.
Handling of missing data
If an assessment has been made both at screening and randomisation, and if not otherwise specified, 
the value from the randomisation visit will be used as the baseline value. If the value measured at 
the randomisation visit is missing and the assessment also has been made at screening, then the 
screening value will be used as the baseline value.
For efficacy variables missing values will be imputed as described in section 17.3 and 17.4.
Data collected after treatment discontinuation or initiation of rescue treatment (see section 5.3.5) 
will be considered missing in some of the efficacy analyses as described in section 17.3 and 17.4.
Data collected after treatment discontinuation will be data from withdrawals collected at either Visit 
17 or Visit 25 (see section 8.1.7) in case the measurement is within the visit window (± 5 days) of a 
planned visit.  
For safety variables missing values (including intermittent missing values) will be imputed using 
the last observation carried forward (LOCF) method on post-baseline measurements. All data for 
subjects receiving rescue treatment will be included.
Laboratory values below the lower limit of quantification (LLOQ) will be set to ½LLOQ.
17.1
Sample size calculation
The sample size has been determined in order to demonstrate superiority of liraglutide in 
combination with metformin with or without basal insulin treatment vs. liraglutide placebo with 
metformin with or without basal insulin treatment, with regards to change in HbA1C from baseline 
after 26 weeks, using a significance level of 5% and a two-sided test.
The sample size is based on calculations for the primary endpoint alone. Assumptions for the 
sample size calculations are as follows:
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Change in HbA1C: a mean difference of 0.9% of liraglutide in combination with metformin with or 
without basal insulin treatment vs. liraglutide placebo with metformin with or without basal insulin 
treatment; Standard deviation (SD) =1.2%.The change in mean difference was chosen based on the 
effect of liraglutide vs. placebo observed in the adult population (LEAD 1, 2, 4 and 5 trials)15 and a 
paediatric PK/PD trial which included HbA1c after 5 weeks of treatment as an exploratory endpoint 
(NN2211-1800)36.
The chosen withdrawal rates (see table 17.1) are based on the withdrawal rates seen in the LEAD 2 
trial15 where the withdrawal rate was approximately 40% for the placebo group and approximately 
20% for the active groups. A slightly higher withdrawal rate is assumed as the trial is performed in 
a paediatric population. Therefore, the withdrawal rate for the active group is assumed to be 22%.
The primary analysis will impute measurements for withdrawn placebo subjects based on placebo 
completers, and thus the sample size is not adjusted for placebo withdrawal rate.
Based on these assumptions, the sample size is set to 47 in each of the liraglutide and liraglutide 
placebo arms for the full analysis set (FAS) in order to achieve 80% power see Table 17–1. 
Assuming a screening failure rate of 65%, 269 subjects will need to be screened.
Table 17–1
Total sample size for a 1:1 randomisation
Difference to detect in subjects with week 26 data
Withdrawal 
rate
0.6%
0.7%
0.8%
0.9%
1.0%
20 Adjusted 
difference
0.48%
0.56%
0.64%
0.72%
0.80%
Sample 
size
200
148
114
90
74
22 Adjusted
difference
0.47%
0.55%
0.62%
0.70%
0.78%
Sample 
size
210
154
120
94
78
25 Adjusted 
difference
0.45%
0.53%
0.60%
0.68%
0.75%
Sample 
size
226
166
128
102
84
Power: 80%
Standard deviation of change in HbA1c (%) from baseline at week 26 assumed to be 1.2%
The withdrawn subjects treated with liraglutide are assumed to have an estimated change in HbA1c(%) of zero when compared to placebo.
Difference to detect: Minimum detectable difference between the changes in HbA1c from baseline to week 26, between two treatment arms
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17.2
Definition of analysis sets
Full analysis set (FAS): includes all randomised subjects receiving at least one dose of 
liraglutide/liraglutide placebo. In exceptional cases subjects or observations from the FAS may be 
eliminated. 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 FAS, and the reason for this, will be described in the CTR. The statistical evaluation 
of the FAS will follow the intention-to-treat principle and subjects will contribute to the evaluation 
“as randomised”. 
Safety Analysis Set: includes all subjects receiving at least one dose of the trial product. Subjects in 
the safety set will contribute to the evaluation “as treated”. 
Randomised subjects who are lost to follow up and where no exposure information of the 
investigational product or comparators is available after randomisation will be handled as 
unexposed.
17.3
Primary endpoint
The primary endpoint is the change from baseline to week 26 in HbA1c. The FAS will be used for 
this analysis. All available data will be used, including data collected after treatment discontinuation 
and rescue initiation. A pattern mixture model using multiple imputation will be used.
The null hypothesis is no difference between the changes from baseline in HbA1c (%) after 26 
weeks of randomised treatment with liraglutide + metformin with or without basal insulin and 
liraglutide placebo + metformin with or without basal insulin (H0: d=  liraglutide – placebo =0).
The alternative hypothesis is that there is a difference between the two treatment arms (HA: d≠0). 
Superiority of liraglutide over liraglutide placebo will be concluded if the 95% confidence interval 
for the treatment difference for change from baseline in HbA1c (%) after 26 weeks of randomised 
treatment lies entirely below 0%; implying that the two sided p-value is less than 5%.
The multiple imputation procedure will be as follows:
For subjects in the liraglutide arm who are missing their week 26 HbA1c measurement,
measurements will be imputed using the subjects’ baseline HbA1c under a regression model based
on the completers from the liraglutide placebo arm. Likewise, the same imputation model will be
used for subjects in the liraglutide placebo arm with missing week 26 data. Multiple imputation of
missing week 26 HbA1c data will be performed by utilizing the relationship between HbA1c
measured at baseline and weeks 10 and 14 with that measured at week 26 in placebo patients. 
The following four regression models will be built from the liraglutide placebo completers group
for this purpose:
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∀
Model 1: Only baseline covariates (baseline HbA1c, stratification group (gender*age group), 
concomitant diabetes treatment at baseline (diet and exercise alone vs. diet and exercise plus 
metformin and/or basal insulin))
∀
Model 2: Baseline covariates and week 10 HbA1c as covariates
∀
Model 3: Baseline covariates and week 14 HbA1c as covariates
∀
Model 4: Baseline covariates, week 10 HbA1c, and week 14 HbA1c as covariates
Missing week 26 data will be imputed by selecting a random observation from a normal distribution 
centered at the value predicted by the regression model and with variance analogous to predicting a 
new observation in regression analysis. For subjects on the placebo arm, the model used will be
dependent on the subjects’ available HbA1c data throughout the trial. For example, if a subject had
HbA1c measurements only at baseline and week 14, then model 3 would be used. For subjects on 
the liraglutide arm, the measurements will be imputed using only the subjects’ baseline HbA1c
(model 1).
The imputation procedure will be iterated 10,000 times, thus generating 10,000 complete data sets
including observed and imputed values.
For each of the imputed data sets the change in HbA1c from baseline to week 26 will be analysed
using an ANCOVA with treatment and stratification groups (gender*age group) as categorical fixed 
effects and baseline HbA1c as covariate. The results obtained from analysing the datasets will be 
combined using Rubin’s rule37 to draw inference.
The estimated treatment difference between liraglutide and liraglutide placebo together with two-
sided 95% CI and p-value for the test of no difference in effect will be presented.
Sensitivity analyses will be performed for the primary efficacy endpoint. They will include: 
∀
an analysis of covariance (ANCOVA) model with LOCF imputation for missing 
data. Data collected after treatment discontinuation or initiation of rescue 
medication will be handled as missing data. Effects in the model are treatment, 
stratification groups (gender*age group), and baseline HbA1c as a covariate.
∀
an ANCOVA model including data after treatment discontinuation or initiation of 
rescue treatment and LOCF imputation for missing data. Effects in the model are 
treatment, stratification groups (gender*age group), and baseline HbA1c as a 
covariate.
∀
multiple imputation of missing values in both treatment groups (data collected 
after treatment discontinuation or initiation of rescue treatment considered as 
missing) based on parameters estimated from the placebo group. The same model 
as for the primary analysis will be used.
∀
a RMA model using all data points for all visits, but excluding data collected after
treatment discontinuation or initiation of rescue medication. Fixed effects in the 
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model are treatment, stratification groups (gender*age group), and baseline HbA1c
as a covariate, all nested within visit.
∀
a RMA model as described above, but including age of the subjects at baseline as 
covariate, as well as concomitant diabetes treatment at baseline and region (North 
America, Asia including Russia, Europe including Israel, South America including 
Mexico).
17.4
Secondary endpoints
17.4.1
Confirmatory secondary endpoint
All confirmatory secondary endpoints will be presented and analysed using FAS, unless otherwise 
specified.
Change from baseline in FPG after 26 weeks of treatment
The change from baseline in FPG after 26 weeks of treatment will be analysed with the same 
method as the primary efficacy endpoint. Baseline FPG will be included in the analyses instead of
baseline HbA1c.
HbA1c < 7.0% after 26 weeks of treatment (yes/no)
This dichotomous endpoint will be analysed by a logistic regression model. Effects in the model are 
treatment, stratification groups (gender*age group), and baseline HbA1c as a covariate. The results 
will include the 95% confidence interval for the odds ratio (liraglutide over liraglutide placebo) and 
the p-value for test of no difference between the groups as part of the presentation.
Missing data at week 26 will be imputed from the multiple imputation procedure for the primary 
endpoint.
Change from baseline in BMI SDS after 26 weeks of treatment
The change from baseline in BMI SDS after 26 weeks of treatment will be analysed with the same 
method as the primary efficacy endpoint. Baseline BMI SDS will be included in the analyses 
instead of baseline HbA1c,
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Version:
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Hierarchical testing
The primary endpoint and confirmatory secondary endpoints will be analysed in a hierarchical 
manner in the following order:
∀
Primary efficacy endpoint
∀
Change from baseline in FPG after 26 weeks of treatment 
∀
HbA1c < 7.0% after 26 weeks of treatment (yes/no)
∀
Change from baseline in BMI SDS after 26 weeks of treatment
In order to be able to conclude significance for an endpoint in the hierarchical list above, the test for 
that endpoint and the tests for the endpoints higher up in the hierarchy must all be concluded 
significant with a difference in favour of the liraglutide group.
The hierarchically testing is chosen to maintain the family wise type I error of 5%.
17.4.2
Supportive secondary endpoints
All supportive endpoints will be presented and analysed using FAS.
The following dichotomous endpoints are defined:
At 26 and 52 weeks of treatment unless otherwise stated:
HbA1c <7.0% (yes/no) at 52 weeks
HbA1c #6.5% (yes/no)
HbA1c <7.0% without severe or minor hypoglycaemic episodes (yes/no)
HbA1c <7.5% (yes/no)
The dichotomous endpoints will be analysed by a logistic regression model. Effects in the model are 
treatment, stratification groups (gender*age group), and baseline HbA1c as a covariate. The results 
will include the 95% confidence interval for the odds ratio (liraglutide over liraglutide placebo) and 
the p-value for test of no difference between the groups as part of the presentation.
Missing data at week 26 will be imputed from the RMA of the primary endpoint.
The following continuous endpoints are defined:
∀
Change from baseline at 26 and 52 weeks of treatment unless otherwise stated:
∀
HbA1c at 52 weeks
∀
FPG at 52 weeks
∀
7-point SMPG 
-
mean 7-point SMPG, defined as the area under the profile (calculated using the trapezoidal 
method) divided by the measurement time
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Date:
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Version:
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Status:
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-
post-prandial increments after breakfast, lunch and dinner respectively (from before meal to 
90 min after breakfast, lunch and dinner respectively)
∀
Fasting insulin, fasting pro-insulin, pro-insulin to insulin ratio, fasting glucagon, 
fasting C-peptide, and homeostasis model assessment (HOMA-B and HOMA-IR). 
If there is evidence for a skewed distribution of an endpoint, the values will be 
logarithmic transformed, and the actual values will be modelled instead of change 
from baseline.
∀
Fasting lipid profile (cholesterol, LDL cholesterol, VLDL cholesterol, HDL 
cholesterol, triglycerides and free fatty acids. If there is evidence for a skewed 
distribution of an endpoint, the values will be logarithmic transformed, and the 
actual values will be modelled instead of change from baseline.
∀
Body weight 
∀
Waist circumference
∀
BMI
∀
BMI SDS at 52 weeks
∀
BMI percentile (age and gender adjusted) 
∀
Systolic and diastolic blood pressure
∀
Basal insulin dose
These continuous endpoints will be analysed with a similar method as the primary endpoint, except 
for change in basal insulin dose that will be presented only by descriptive statistics.
17.4.3
Safety endpoints
All safety endpoints will be presented using the safety analysis set. Unless otherwise specified 
safety endpoints will be presented only by descriptive statistics. 
Change from baseline at 26 and 52 weeks of treatment unless otherwise stated
∀
Clinical evaluations (physical examination including fundoscopy [fundoscopy at 26 and 52 
weeks])
∀
ECG with rhythm strip (at 26 and 52 weeks)
∀
Laboratory tests: 
∀
Haematology (haemoglobin, haematocrit, thrombocytes, erythrocytes, leucocytes 
and differential count (eosinophils, neutrophils, basophils, lymphocytes and 
monocytes) 
∀
Biochemistry (creatinine, creatine kinase, urea, albumin, bilirubins (total), ALAT, 
ASAT, sodium, potassium, alkaline phosphatase, calcium, calcium (albumin 
corrected), amylase and lipase)
∀
Hormones (calcitonin, prolactin, FSH, estradiol, LH, testosterone, DHEAS, CEA 
and TSH, IGF-1, IGFBP-3
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∀
First morning urinalysis (Micro albumin, creatinine, albumin:creatinine ratio 
calculated, protein, ketone, glucose, pH)
∀
Biochemical parameters of bone metabolism: Alkaline Phosphatase, NTX, CPX, 
P1NP
∀
Formation of anti-liraglutide antibodies (at 26 and 53 weeks) 
∀
Pulse
∀
Pubertal assessment/ progression (Tanner staging) , DHEAS, LH, FSH, estradiol in females 
and testosterone in males
∀
Height SDS versus baseline at 26 and 52 weeks
∀
Bone age assessment (x-ray of left hand and wrist) at 52 weeks
In addition the following will be assessed at 26, and 52 weeks:
∀
Assessment of compliance (questioning of subjects and subjects legally acceptable 
representative) 
∀
Growth velocity in cm/year and height velocity SDS (if subject is still growing). A 
growth velocity < 1.0 cm/year is defined as no longer growing.
∀
Hypoglycaemic episodes
∀
AEs and serious adverse events (SAEs)
Pulse
Pulse will be analysed with a similar method as for the primary endpoint.
Hypoglycaemic episodes
Hypoglycaemic episodes are recorded by subjects in their trial diaries throughout the trial. The 
information collected includes PG before treating the episode and whether the subject was able to 
treat him/herself. This information is used by Novo Nordisk to classify an episode according to the 
ADA definition (severe, documented symptomatic, asymptomatic, probable symptomatic and 
relative) and the additional minor category. A hypoglycaemic episode is defined as treatment 
emergent if the onset of the episode is on or after the first day of exposure to randomised treatment 
and no later than one day after the last day on randomised treatment. All hypoglycaemic episodes 
will be summarised by treatment and severity
Adverse events 
All AEs will be coded using the most recent version of the Medical Dictionary for regulatory 
Activities (MedDRA) coding. A treatment emergent adverse event is defined as an event that has 
onset date (or increase in severity) on or after the first day of exposure to randomised treatment and 
no later than seven days after the last day of randomised treatment.
Safety follow-up at 1 and 2 years after trial drug cessation at week 52 (only applicable for 
subjects on active liraglutide treatment for more than 3 months) 
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Version:
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∀
AEs and SAEs
∀
Growth velocity in cm/year (if subject is still growing)
∀
Height velocity SDS (if subject is still growing)
Change in:
∀
Height SDS  
∀
Pubertal assessment/progression by Tanner staging
∀
Bone age assessment (x-ray of left hand and wrist)
17.5
PK modelling
The objective for this population PK analysis is to investigate potential covariates for liraglutide 
plasma exposure in children and adolescents with type 2 diabetes and compare it to adults. Blood 
samples for liraglutide PK drawn at site visits (Visits 8, 9, 11, 13 and 17) will be included in the 
analysis. The exact dosing time and dose for the 2 last liraglutide doses prior to the PK sample will 
be recorded in the subject diary, as well as the metformin dosing regimen used prior to the visit. The 
time of blood sampling (time of day not pre-specified) relative to the last time of dosing will be 
used in the analysis. Relevant adult data from previous studies will be included in the analysis to 
allow for a comparison with adults. 
The population PK analysis will be performed by Novo Nordisk. The pre-specified analysis will 
explore the effect of covariates on liraglutide exposure. A compartmental model with first-order 
absorption in the central compartment and first-order elimination will be used. The absorption rate 
constant (Ka) will be estimated if feasible. If this is not feasible, Ka will be set to the value 
estimated previously in adult subjects with type 2 diabetes. Two other parameters will be estimated: 
apparent clearance (CL/F) and apparent volume of distribution (Vd/F).
The influence of covariates on exposure relative to a typical subject will be summarized in a forest 
plot showing the estimated mean (90% confidence interval) effect and comparing it with the 
bioequivalence criterion of 80-125% for PK relevance. 
The population PK analysis will be described in greater detail in the modelling analysis plan (MAP) 
and reported separately from the CTR.
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Version:
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18 Ethics
The trial will be conducted in compliance with ICH GCP33 and applicable regulatory requirements, 
and in accordance with the Declaration of Helsinki38. 
Subjects will only be included after a thorough evaluation of the inclusion, exclusion and 
randomisation criteria. The trial has been designed to provide a treatment which is assumed to 
adequately control the subject’s blood glucose. This is expected to be achieved by treating all 
randomised subjects with metformin in addition to randomised treatment. In addition subjects 
treated with basal insulin may continue their basal insulin treatment. Furthermore subjects may have 
addition of rescue treatment if needed.
Rescue and withdrawal criteria are defined to ensure that subjects are considered for rescue 
treatment or withdrawal if the level of glycaemic control exceeds acceptable limits during both the 
blinded and un-blinded periods.
Subjects treated with basal insulin at screening should reduce their insulin dose by 20% at 
randomisation to limit the potential risk of hypoglycaemic episodes induced by the combined 
therapy of basal insulin and liraglutide. Once reaching the maximum dose of liraglutide/liraglutide 
placebo basal insulin treatment can be titrated up to no higher than pre-trial dose levels to ensure 
that treatment in the placebo arm is comparable to the pre-randomisation treatment.
Throughout the trial, subjects will be in regular contact (by telephone or visits) with the investigator 
or designated persons. Blood sampling and contacts with the clinic are considered an inconvenience 
for the children and adolescents participating in the trial. On the other hand, the intensified 
treatment may help to improve glycaemic control.
During the trial (incl. 2 year’s follow-up period) up to 4 x-rays of left hand and wrist will be 
performed. When performing the x-rays the subject will be exposed to x-ray radiation. The amount 
of x-ray radiation when performing the x-rays is comparable to the amount of background radiation 
received from the surroundings in the United States during a period of approximately 3 days. This 
means that the risk of cancer will increase with 0.000125% for the x-rays performed. 
Currently liraglutide does not have regulatory approval for treatment of paediatric subjects. 
However liraglutide has been approved by the authorities for use in adults in more than 60 countries 
including the US, China and the EU.
The trial product may be associated with AEs, but relevant precautions have been implemented in 
the design and planned conduct of the trial in order to minimise the risks and inconveniences of trial 
participation. These precautions include providing thorough information regarding the correct 
administration of the trial drugs and gradual dose adjustment. Furthermore, subjects and subjects’ 
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LAR are fully informed about possible AEs and inconveniences and will be instructed to contact the 
investigator in case of any concerns regarding the trial participation.
It is assumed that the risks and benefits associated with liraglutide treatment will be the same for the 
paediatric population as for the adult populations (see section 3.1.3) with the exception of any 
unforeseen effects on growth and pubertal development. 
When treatment with trial products ends, the subject and investigator will decide on the best 
available treatment for the subject. Novo Nordisk will not offer investigational drug(s) after the end 
of trial.
Subjects participating in the trial and their parents may be reimbursed for documented reasonable 
travelling expenses and loss of income, as according to local law. All agreements on compensation 
should be approved by the IRB/Ethical committee. 
18.1
Informed consent 
In seeking and documenting informed consent, the investigator must comply with applicable 
regulatory requirement(s) and adhere to ICH GCP33 and the requirements in the Declaration of 
Helsinki38. 
Before any trial-related activity, the investigator must give the subject and subject’s LAR oral and 
written information about the trial in a form that the subject and the subject’s LAR can read and 
understand. This process may include the use of an impartial witness where required. 
The investigator must ensure the subject and the subject’s LAR 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 the subject’s LAR agree to have the subject participating.
A voluntary, signed and personally dated informed consent and assent form will be obtained from 
the subject’s LAR and the subject respectively before any trial-related activity is performed. 
The responsibility for seeking informed consent and assent must remain with the investigator, but 
the task may be delegated by the investigator to a medically qualified person, in accordance with 
local requirements. The written informed consent and assent must be signed and personally dated 
by the person who seeks the consent and assent. 
The informed consent may be signed up to 30 days before Visit 1, unless a modification to the 
informed consent is approved during that period of time.
If information becomes available that may be relevant to the subject’s or subject’s LAR’s 
willingness to continue participating in the trial, the investigator must inform the subject and the 
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subject’s LAR in a timely manner, and a revised written informed consent and assent must be 
obtained.
Local laws and requirements may differ from the procedures described above and must be followed.
Only applicable to Israel: child assent form is not applicable.
18.2
Data handling
If the subject is withdrawn from the trial or lost to follow up, then the subject’s data will be handled 
as follows:
∀
Data already collected will be retained by Novo Nordisk, entered into the database and used for 
the trial report
∀
Safety events will be reported to the Novo Nordisk and regulatory authorities according to 
local/national requirements
If data are used, it will always be in accordance with local law and IRBs/IECs.
18.3
Premature termination of the trial and/or trial site
Novo Nordisk, the investigator, the IRBs/IECs or a regulatory authority may decide to stop the trial, 
part of the trial or a trial site at any time, but agreement on procedures to be followed must be 
obtained.
If a trial is suspended or prematurely terminated, the investigator must inform the subjects promptly 
and ensure appropriate therapy and follow-up. The investigator and/or Novo Nordisk should also 
promptly inform the IRBs/IECs and provide a detailed written explanation. The relevant regulatory 
authorities should be informed.
If, after the termination of the trial, the risk/benefit analysis changes, the new evaluation should be 
provided to the IRBs/IECs in case it has an impact on the planned follow-up of subjects who have 
participated in the trial. If it does have an impact, the actions needed to inform and protect the 
subjects should be described.
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19 Protocol compliance
Deviations from the protocol should be avoided.
If deviations do occur, the investigator must inform the monitor and the implications of the 
deviation must be reviewed and discussed.
Investigator must document and explain protocol deviations by stating the reason, date, and the 
action(s) taken. Some deviations, for which corrections are not possible, can be acknowledged and 
confirmed via edit checks in the eCRF or via listings from the clinical database.
Documentation on all protocol deviations must be kept in the investigator’s trial file and Novo 
Nordisk trial master file.
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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 and after the trial. The investigator and the site staff as well as Novo Nordisk staff 
have an obligation to cooperate and assist in such audits and inspections. This includes giving 
auditors and inspectors direct access to all source documents and other documents at the 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.
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21 Critical documents
Before a site is allowed to start screening subjects, the following documents must be available to 
Novo Nordisk:
∀
Regulatory approval and/or acknowledgement of notification as required 
∀
Curricula vitae of investigator and sub-investigator(s) and other relevant staff (current, dated 
and signed and/or supported by an official regulatory document. Must include documented GCP 
training or a certificate)
∀
Signed receipt of IB and summary of product characteristics 
∀
Signed and dated agreement on the final protocol
∀
Signed and dated agreement on any substantial protocol amendment, if applicable
∀
Approval/favourable opinion from IRBs/IECs clearly identifying the documents reviewed as 
follows: protocol, any substantial 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
∀
Financial agreement(s)
∀
Source document agreement
∀
Central laboratory certification and normal ranges
∀
Insurance statement, if applicable
∀
Signed and dated investigator Agreement
∀
Financial disclosure form for all investigators
For US: verification under disclosures per Code of Federal regulation (CFR) of Financial Conflict 
of Interest.
For US sites: FDA form 1572 must be completed and signed for each investigator.
FDA form 1572:
For US sites:
∀
Intended for US sites
∀
Conducted under the investigational new drug application (IND)
∀
All US investigators , as described above, will sign FDA form 1572
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
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Novo Nordisk will analyse and report data from all sites together.
As documented in writing by protocol signature, each investigator agrees to comply fully with ICH 
standards of current GCP, applicable regulatory requirements and the declaration of Helsinki. 
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22 Responsibilities
All staff (Novo Nordisk, site, laboratory, CRO etc) will conduct the trial in compliance with ICH 
GCP33, applicable regulatory requirements and the Declaration of Helsinki38.
The investigator is accountable for the conduct of the trial at his/her site. If any tasks are delegated, 
the investigator should maintain a list of appropriately qualified persons to whom he/she has 
delegated specified significant trial-related duties. The investigator should ensure that there is 
adequate training for all staff participating in the conduct of the trial. It is the investigator’s 
responsibility to supervise the conduct of the trial and to protect the rights, safety, and well-being of 
the subjects.
A qualified physician, who is an investigator or a sub-investigator for the trial, must be responsible 
for all trial-related medical decisions.
The investigator must ensure adequate supervision of the conduct of the trial at the trial site. 
The investigator will follow instructions from Novo Nordisk when processing data.
The investigator is responsible for filing essential documents (i.e. those documents which 
individually and collectively permit evaluation of the conduct of a trial and the quality of the data 
produced) in the investigator’s trial file. The documents should be kept in a secure locked facility, 
so no unauthorized persons can get access to the data. The subject ID list should be kept securely 
and separate from the personal 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 should delegate responsibility for medical care 
of subjects to a specific qualified physician who will be readily available to subjects during that 
time.
If the investigator is no longer able to fulfil the role of investigator (e.g. if he/she retires), a new 
investigator will be appointed in consultation with Novo Nordisk. 
The investigator and site personal must have sufficient English skills according to their assigned 
task(s).
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23 Reports and publications
The information obtained during the conduct of this trial is considered confidential, and may be 
used by Novo Nordisk for regulatory purposes and 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.
Novo Nordisk will be responsible for preparation of the CTR. The CTR will be reviewed and 
signed by one or more investigator(s) (signatory investigator) appointed by Novo Nordisk based on 
their experience in clinical research and input during the analysis phase. 
23.1
Communication of results
No permission to publish shall be granted to any clinical research organisation involved in the trial.
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.
Novo Nordisk reserves the right to defer the release of data until specified milestones are reached, 
for example when the CTR is available. This includes the right not to release the results of interim 
analyses, because the release of such information may invalidate the results of the entire trial.
At the end of the trial, one or more public disclosures 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.
The results of this trial will be subject to public disclosure on external web sites according to 
international regulations, as reflected in the Novo Nordisk Code of Conduct for Clinical Trial 
Disclosure.
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 support 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.
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In a multi-centre trial based on the collaboration of all trial sites, any publication of results in a 
journal article must acknowledge all trial sites. Where required by the journal, the principal 
investigator from each site will be named in the acknowledgement. 
23.1.1
Authorship
Authorship of publications should be in accordance with the Uniform Requirements of the ICMJE 
(sometimes referred to as the Vancouver Criteria39).
The investigator(s) offered authorship will be asked to comment and approve the publication. No 
permission to publish will be granted to any CRO involved in the trial described in this protocol. 
The authorship of publications of all trial results will be determined by the Publication group.
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 and to ask for deferment of 
publication of individual site results until after the primary manuscript is accepted for publication.
23.2
Investigator access to data and review of results
As owner of the trial database, Novo Nordisk has the discretion to determine who will have access 
to the database. 
Individual investigators will have their own research participants' data, and will be provided with 
the randomisation code after results are available.
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24 Retention of clinical trial documentation
Subject 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 site. If the Novo 
Nordisk provided data (e.g. the CD-ROM) is not readable during the entire storage period, the 
investigator can request a new copy, as a copy of all data will be stored by Novo Nordisk.
Novo Nordisk will maintain Novo Nordisk documentation pertaining to the trial for as long as the 
product is on the market plus 20 years. 
The files from the investigator site/institution must be retained for 15 years after the completion of 
the trial, or longer if required by national regulations. The deletion process must ensure 
confidentiality of data and must be done in accordance with local requirements.
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25 Institutional review boards/independent ethics committees and 
regulatory authorities
Written approval or favourable opinion must be obtained from IRB/IEC prior to commencement of 
the trial.
During the trial, the investigator or sponsor, as applicable, must promptly report the following to the 
IRB/IEC, in accordance with local requirements: updates to IB, unexpected SAEs where a causal 
relationship cannot be ruled out, substantial protocol amendments, non-substantial 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 risk/benefit 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.
Substantial protocol amendments must not be implemented before approval or favourable opinion, 
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 should be filed in the investigator’s trial file and copies must be sent to Novo 
Nordisk.
Regulatory Authorities
Regulatory authorities will receive the clinical trial application (CTA), substantial/non-substantial 
protocol amendments, reports on SAEs, and the CTR according to national requirements.
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03 April 2017
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Trial ID: NN2211-3659
Version:
7.0
UTN:U1111-1121-8743
Status:
Final
EudraCT No.:2011-002605-29
Page:
109 of 113
26 Indemnity statement
Novo Nordisk carries product liability for its products, and liability is 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 by the clinics or 
doctors conducting experiments, or by persons for whom the said clinic or doctors are responsible.
Novo Nordisk accepts liability in accordance with:
Austria: Arzneimittelgesetz (BGBI. Nr. 185/1983) last amended with BGBl Nr. 63/2009 
Belgium: Law concerning experiments on the human person of 07 May 2004.
France: The French Public Health Code article L 1121-10 (law n° 2004-806 of 9 August 2004 art. 
88 I, IX Journal Officiel of 11 August 2004. "The sponsor is responsible for identification of the 
harmful consequences of the biomedical research for the person lending himself thereto and for 
indemnification of his beneficiaries, except in case of proof, incumbent on it, that the prejudice is 
not attributable to his fault of or the fault of any intervening party, without the sponsor's being 
entitled to call on acts by a third party or the voluntary withdrawal of the person who had initially 
consented to cooperating in the research.
Germany: The German drug law dated August 24, 1976 last amended by Article 1 of the ordinance 
of July 19, 2011.
Netherlands: Wetgeving betreffende geneesmiddelen; geneesmiddelenwet 1 juli 2007 (Medicines 
Law, 1 July 2007). De Wet Medisch-wetenschappelijk Onderzoek met mensen (WMO), 1 maart 
2006 (Medical Research Involving Human Subjects Act, 1 March 2006). Besluit van 23 juni 2003, 
houdende regels inzake de verplichte verzekering bij medischwetenschappelijk onderzoek met 
mensen (Decree of 23 June 2003, containing rules for compulsory insurance in medical research 
involving human subjects (Medical Research (Human Subjects) Compulsory Insurance Decree).
Poland: Pharmaceutical Law of 6 September 2001 (Journal of Laws 08.45.271, as amended) –
definitions + Chapter 2a, Law of 5 December 1996 on the profession of doctor and dentist doctor 
(Journal of Laws 08.136.857, as amended) – Chapter 4, Law of 27 July 2001 on the Office for 
Registration of Medicinal Products, Medical Devices, and Biocides (Journal of Laws 01.126.1379) 
– lists competences of the President of the Office and the Office
Russia: Federal law “On Medical Products” #86-FZ dated 22 June 1998 (last amendments dated 30 
December 2008. Federal Law of 12 April 2010 No. 61-FZ "On Medicinal Drugs' Cerculation"
CONFIDENTIAL


Protocol
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Trial ID: NN2211-3659
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UTN:U1111-1121-8743
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Spain: Royal decree 223/2004, of 6th February, establishing the requisites concerning clinical 
trials.
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Date:
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Novo Nordisk
Trial ID: NN2211-3659
Version:
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UTN:U1111-1121-8743
Status:
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EudraCT No.:2011-002605-29
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27 References
1.
Group TS, Zeitler P, Epstein L, Grey M, Hirst K, Kaufman F, et al. Treatment options for 
type 2 diabetes in adolescents and youth: a study of the comparative efficacy of metformin 
alone or in combination with rosiglitazone or lifestyle intervention in adolescents with type 
2 diabetes. Pediatr Diabetes. 2007;8(2):74-87.
2.
Jones KL, Arslanian S, Peterokova VA, Park JS, Tomlinson MJ. Effect of metformin in 
pediatric patients with type 2 diabetes: a randomized controlled trial. Diabetes Care. 
2002;25(1):89-94.
3.
Silverstein JH, Rosenbloom AL. Treatment of type 2 diabetes mellitus in children and 
adolescents. J Pediatr Endocrinol Metab. 2000;13 Suppl 6:1403-9.
4.
Rosenbloom AL, Silverstein JH, Amemiya S, Zeitler P, Klingensmith GJ, International 
Society for Pediatric, et al. ISPAD Clinical Practice Consensus Guidelines 2006-2007. Type 
2 diabetes mellitus in the child and adolescent. Pediatr Diabetes. 2008;9(5):512-26.
5.
Nauck MA, Heimesaat MM, Orskov C, Holst JJ, Ebert R, Creutzfeldt W. Preserved incretin 
activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric 
inhibitory polypeptide in patients with type-2 diabetes mellitus. Journal of clinical 
investigation. 1993;91(1):301-7.
6.
Williams B, Werner J, Holst JJ, Orskov C, Creutzfeldt W, Nauck MA. Gastric emptying, 
glucose responses, and insulin secretion after a liquid test meal: effects of exogenous 
glucagon-like peptide-1 (GLP-1)-(7-36) amide in type 2 (noninsulin-dependent) diabetic 
patients. J Clin Endocrinol Metab. 1996;81(1):327-32.
7.
Qualmann C, Nauck MA, Holst JJ, Orskov C, Creutzfeldt W. Insulinotropic Actions of 
Intravenous Glucagon-Like Peptide-1 (Glp-1) [7-36-Amide] in the Fasting State in Healthy-
Subjects. Acta Diabetologica. 1995;32(1):13-6.
8.
Nathan DM, Schreiber E, Fogel H, Mojsov S, Habener JF. Insulinotropic action of 
glucagonlike peptide-I-(7-37) in diabetic and nondiabetic subjects. Diabetes Care. 
1992;15(2):270-6.
9.
Kreymann B, Williams G, Ghatei MA, Bloom SR. Glucagon-like peptide-1 7-36: a 
physiological incretin in man. Lancet. 1987;2(8571):1300-4.
10.
Rachman J, Barrow BA, Levy JC, Turner RC. Near-normalisation of diurnal glucose 
concentrations by continuous administration of glucagon-like peptide-1 (GLP-1) in subjects 
with NIDDM. Diabetologia. 1997;40(2):205-11.
11.
Nauck MA, Wollschlager D, Werner J, Holst JJ, Orskov C, Creutzfeldt W, et al. Effects of 
subcutaneous glucagon-like peptide 1 (GLP-1 [7-36 amide]) in patients with NIDDM. 
Diabetologia. 1996;39(12):1546-53.
12.
Hansen L, Deacon CF, Orskov C, Holst JJ. Glucagon-like peptide-1-(7-36)amide is 
transformed to glucagon-like peptide-1-(9-36)amide by dipeptidyl peptidase IV in the 
capillaries supplying the L cells of the porcine intestine. Endocrinology. 1999;140(11):5356-
63.
13.
Larsen J, Hylleberg B, Ng K, Damsbo P. Glucagon-like peptide-1 infusion must be 
maintained for 24 h/day to obtain acceptable glycemia in type 2 diabetic patients who are 
poorly controlled on sulphonylurea treatment. Diabetes Care. 2001;24(8):1416-21.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
03 April 2017
Novo Nordisk
Trial ID: NN2211-3659
Version:
7.0
UTN:U1111-1121-8743
Status:
Final
EudraCT No.:2011-002605-29
Page:
112 of 113
14.
Knudsen LB, Nielsen PF, Huusfeldt PO, Johansen NL, Madsen K, Pedersen FZ, et al. Potent 
derivatives of glucagon-like peptide-1 with pharmacokinetic properties suitable for once 
daily administration. J Med Chem. 2000;43(9):1664-9.
15.
Investigators Brochure Liraglutide (NN2211), Edition 13. 10/11/2011 2011.
16.
Lind M, Jendle J, Torffvit O, Lager I. Glucagon-like peptide 1 (GLP-1) analogue combined 
with insulin reduces HbA1c and weight with low risk of hypoglycemia and high treatment 
satisfaction. Prim Care Diabetes. 2012;6(1):41-6.
17.
Levin P, Wei W, Wang L, Pan C, Douglas D, Baser O. Combination therapy with insulin 
glargine and exenatide: real-world outcomes in patients with type 2 diabetes. Curr Med Res 
Opin. 2012;28(3):439-46.
18.
Levin PA, Mersey JH, Zhou S, Bromberger LA. Clinical Outcomes Using Long-Term 
Combination Therapy With Insulin Glargine and Exenatide In Patients With Type 2 
Diabetes. Endocr Pract. 2011;8:1-28.
19.
Buse JB, Bergenstal RM, Glass LC, Heilmann CR, Lewis MS, Kwan AY, et al. Use of 
twice-daily exenatide in Basal insulin-treated patients with type 2 diabetes: a randomized, 
controlled trial. Ann Intern Med. 2011;154(2):103-12.
20.
Arnolds S, Dellweg S, Clair J, Dain MP, Nauck MA, Rave K, et al. Further improvement in 
postprandial glucose control with addition of exenatide or sitagliptin to combination therapy 
with insulin glargine and metformin: a proof-of-concept study. Diabetes Care. 
2010;33(7):1509-15.
21.
Texas Diabetes Council's Medical Professionals Advisory Subcommittee. Insulin Algorithm 
for Type 2 Diabetes Mellitus in Children and Adults. 2010.
22.
DeVries JH, Bain SC, Rodbard HW, Seufert J, D'Alessio D, Thomsen AB, et al. Sequential 
intensification of metformin treatment in type 2 diabetes with liraglutide followed by 
randomized addition of basal insulin prompted by A1C targets. Diabetes Care. 
2012;35(7):1446-54.
23.
Group TS, Zeitler P, Hirst K, Pyle L, Linder B, Copeland K, et al. A clinical trial to 
maintain glycemic control in youth with type 2 diabetes. N Engl J Med. 2012;366(24):2247-
56.
24.
Type 2 diabetes in children and adolescents. American Diabetes Association. Diabetes Care. 
2000;23(3):381-9.
25.
Tamborlane WV, Sikes KA. Insulin therapy in children and adolescents. Endocrinol Metab 
Clin North Am. 2012;41(1):145-60.
26.
Dabelea D. Incidence of diabetes in youth in the United States (vol 297, pg 2716, 2007). 
Jama-Journal of the American Medical Association. 2007;298(6):627-.
27.
Copeland KC, Silverstein J, Moore KR, Prazar GE, Raymer T, Shiffman RN, et al. 
Management of newly diagnosed type 2 Diabetes Mellitus (T2DM) in children and 
adolescents. Pediatrics. 2013;131(2):364-82.
28.
Gungor N, Hannon T, Libman I, Bacha F, Arslanian S. Type 2 diabetes mellitus in youth: 
the complete picture to date. Pediatr Clin North Am. 2005;52(6):1579-609.
29.
Schober E, Rami B, Grabert M, Thon A, Kapellen T, Reinehr T, et al. Phenotypical aspects 
of maturity-onset diabetes of the young (MODY diabetes) in comparison with Type 2 
diabetes mellitus (T2DM) in children and adolescents: experience from a large multicentre 
database. Diabet Med. 2009;26(5):466-73.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
03 April 2017
Novo Nordisk
Trial ID: NN2211-3659
Version:
7.0
UTN:U1111-1121-8743
Status:
Final
EudraCT No.:2011-002605-29
Page:
113 of 113
30.
De Angelis C, Drazen JM, Frizelle FA, Haug C, Hoey J, Horton R, et al. Clinical trial 
registration: a statement from the International Committee of Medical Journal Editors. N 
Engl J Med. 2004;351(12):1250-1.
31.
U.S. Department of Health and Human Services, Food and Drug Administration. Food and 
Drug Administration Amendments Act of 2007.
32.
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International Conference of Harmonisation. ICH Harmonised Tripartite Guideline E6(R1): 
Guideline for Good Clinical Practice. 10 Jun 1996.
34.
Tanner JM. Normal growth and techniques of growth assessment. Clin Endocrinol Metab. 
1986;15(3):411-51.
35.
European Commission. The Rules Governing Medicinal Products in the European Union, 
Volume 4, Annex 13, Investigational Medicinal Products. Brussels. July 2003.
36.
Klein DJ, Battelino T, Chatterjee DJ, Jacobsen LV, Hale PM, Arslanian S, et al. 
Liraglutide's safety, tolerability, pharmacokinetics, and pharmacodynamics in pediatric type 
2 diabetes: a randomized, double-blind, placebo-controlled trial. Diabetes Technol Ther. 
2014;16(10):679-87.
37.
Little RJA, Rubin DB. Statistical analysis with missing data: New York: John Wiley & 
Sons. 1987.
38.
World Medical Association. Declaration of Helsinki - Ethical Principles for Medical 
Research Involving Human Subjects. Last amended by the 59th WMA General Assembly, 
Seoul, Republic of Korea. October 2008.
39.
International Committee of Medicinal Journal Editors. Uniform Requirements for 
Manuscripts submitted to Biomedical Journals.: N Engl J Med; 1997 1997. p. 309-15.
CONFIDENTIAL

SAP_001.pdf: 
Cover Page for Statistical Analysis Plan  
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT01541215 
Sponsor trial ID: 
NN2211-3659 
Official title of study: 
Efficacy and safety of liraglutide in combination with 
metformin versus metformin monotherapy on glycaemic 
control in children and adolescents with type 2 diabetes 
A 26-week double-blind, randomised, parallel group, placebo 
controlled multi-centre trial followed by a 26-week open-label 
extension 
Document date: 
25 June 2018 
 


Liraglutide
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Trial ID: NN2211-3659
Version:
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EurdraCT No.: 2011-002605-29
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Statistical Analysis Plan 
Trial ID: NN2211-3659
Efficacy and Safety of liraglutide in combination with 
metformin monotherapy on glycaemic control in children and 
adolescents with type 2 diabetes
A 26-week double-blind, randomised, parallel group, placebo controlled 
multi-centre trial followed by a 26-week open-label extension
Trial Phase: 3a
Author 
, 
2129 Biostatistics GLP-1 Diabetes
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.
Redacted VWDWLVWLFDODQDO\VLVSODQ 
Includes redaction of personal identifiable information only. 
. 


Liraglutide
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Trial ID: NN2211-3659
Version:
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Table of Contents   
Page
Table of Contents........................................................................................................................................2
List of Abbreviations ..................................................................................................................................3
1
Introduction .........................................................................................................................................5
1.1
Trial information.......................................................................................................................5
1.2
Scope of the Statistical Analysis Plan........................................................................................7
2
Endpoints .............................................................................................................................................8
2.1
Primary endpoint.......................................................................................................................8
2.2
Secondary endpoints .................................................................................................................8
2.2.1
Confirmatory secondary endpoints to be assessed at 26 weeks of treatment ..............8
2.2.2
Supportive secondary efficacy endpoints to be assessed at 26 and 52 weeks of 
treatment unless otherwise stated .............................................................................8
2.2.3
Secondary safety endpoints ......................................................................................9
3
Statistical considerations ...................................................................................................................12
3.1
Evaluability of subjects for analysis.........................................................................................12
3.2
Handling of missing data.........................................................................................................12
3.3
General considerations ............................................................................................................13
3.4
Sample size calculation ...........................................................................................................13
3.5
Primary endpoint.....................................................................................................................13
3.6
Secondary endpoints ...............................................................................................................15
3.6.1
Confirmatory secondary endpoints.........................................................................15
3.6.2
Supportive secondary endpoints .............................................................................17
3.6.3
Safety endpoints ....................................................................................................19
3.6.4
Safety follow-up at 1 and 2 years after trial drug cessation at week 52 (only 
applicable for subjects on active liraglutide treatment for more than 3 months).......21
3.7
Exploratory analyses ...............................................................................................................22
3.8
Interim analysis.......................................................................................................................22
3.9
Sequential safety analysis/safety monitoring............................................................................22
3.10
Explorative statistical analysis for pharmacogenetics and biomarkers ......................................22
3.11
PK data...................................................................................................................................22
4
Changes to the statistical analyses planned in the protocol..............................................................23
4.1
Sensitivity analysis for the primary endpoint on all randomised subjects..................................23
4.2
Handling of missing data.........................................................................................................23
4.3
Definition of fixed effects........................................................................................................23
4.4
Supportive secondary endpoints ..............................................................................................23
4.5
Statistical analyses of the confirmatory and supportive secondary endpoints............................24
4.6
Exploratory analyses ...............................................................................................................24
4.7
Miscellaneous .........................................................................................................................24
5
References ..........................................................................................................................................25
CONFIDENTIAL


Liraglutide
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Date:
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Trial ID: NN2211-3659
Version:
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Statistical Analysis Plan 
Status:
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EurdraCT No.: 2011-002605-29
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List of Abbreviations
ADA
American Diabetes Association
AE
adverse event
ALAT
alanine aminotransferase
ANCOVA
analysis of covariance
ASAT
aspartate aminotransferase
BMI
body mass index
CEA
carcinoembryonic antigen
CTR
clinical trial report
DHEAS
dehydroepiandrosterone sulfate
ECG
electrocardiogram
FAS
full analysis set
FPG
fasting plasma glucose
FSH
follicle stimulating hormone
HbA1C
glycosylated haemoglobin A1c
HDL
high density lipoprotein
HOMA
homeostasis model assessment
ID
identification 
IGF-1
insulin-growth factor-1
IGFBP-3
insulin-growth factor-binding protein-3
LDL
low density lipoprotein
LH
luteinizing hormone
LLOQ
lower limit of quantification
CONFIDENTIAL


Liraglutide
CONFIDENTIAL
Date:
25 June 2018
Novo Nordisk
Trial ID: NN2211-3659
Version:
2.0
Statistical Analysis Plan 
Status:
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EurdraCT No.: 2011-002605-29
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LOCF
last observation carried forward
LSMean
least square mean
MAP
modelling analysis plan
MedDRA
Medical Dictionary for Regulatory Activities
N
number of subjects 
NTX
N-telopeptide
PG
plasma glucose
PK
pharmacokinetics
SAE
serious adverse event
SAP
statistical analysis plan
SDS
standard deviation score 
SMPG
self-measured plasma glucose
SPS
Statistical Programming Specification
TSH
thyroid stimulating hormone
VLDV
very low density lipoprotein 
CONFIDENTIAL


Liraglutide
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Date:
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Trial ID: NN2211-3659
Version:
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Statistical Analysis Plan 
Status:
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EurdraCT No.: 2011-002605-29
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1
Introduction
1.1
Trial information
Trial design
This is a multi-centre, 26-week randomised double-blind, parallel-group, placebo-controlled clinical 
trial followed by a 26-week open-label extension in subject’ aged 10–17 years with type 2 diabetes. 
After being titrated to 2000 mg of metformin or maximum tolerated dose (MTD) (metformin dose 
must be ≥1000 mg and ≤2000 mg) subjects will be randomised 1:1 to receive liraglutide (1.8 mg or 
MTD) or liraglutide placebo. Subjects treated with basal insulin will continue treatment with basal 
insulin.
Subjects already treated with 2000 mg or more of metformin and with a stable dose for at least 56 
days prior to Visit 1 may advance directly to randomisation (Visit 7) when eligibility according to 
the inclusion and exclusion criteria has been confirmed. Subjects who are treated with basal insulin 
should in addition to the stable dose of metformin have a stable dose of basal insulin for at least 56 
days in order to advance directly to Visit 7.
After 26 weeks of blinded treatment, the treatment allocation will be unblinded. Subjects treated 
with liraglutide will continue their trial medication until end of treatment. Subjects treated with 
liraglutide placebo will discontinue their liraglutide placebo treatment. Rescue treatment will be 
allowed for subjects in both treatment groups experiencing confirmed hyperglycaemia. Subjects on 
rescue medication will stay in the trial.
Subjects treated with liraglutide for more than 3 months will complete 1 and 2 year follow-up visits.
Figure 1 Overview of Trial Design
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Trial ID: NN2211-3659
Version:
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Primary objective
To confirm the superiority of liraglutide at the maximum tolerated dose (0.6 mg, 1.2 mg or 1.8 mg) 
versus placebo when added to metformin with or without basal insulin in controlling glycaemia in 
children and adolescent (ages 10–17 years) with type 2 diabetes.
Secondary objectives
To assess and compare the effect of liraglutide versus placebo in combination with metformin with 
or without basal insulin treatment on:
!
Parameters of glycaemic control
!
Parameters of beta-cell function
!
Parameters of body composition
!
Vital signs
!
Growth velocity (if subject is still growing)
!
Safety and tolerability
!
Growth and pubertal development at 1 and 2 year follow up after trial drug cessation at 
week 52 (only applicable for subjects on active liraglutide treatment for more than 3 
months)
Number of subjects to be investigated
It is planned to randomise 94 subjects in this trial.
Please refer to the protocol for further details.
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Liraglutide
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Trial ID: NN2211-3659
Version:
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1.2
Scope of the Statistical Analysis Plan
The planned analyses for trial NN2211-3659 “Efficacy and safety of liraglutide in combination with 
metformin monotherapy on glycaemic control in children and adolescents with type 2 diabetes. A 
26-week double-blind, randomised, parallel group, placebo controlled multi-centre trial followed by 
a 26-week open-label extension” are described in the trial protocol, version 7.0. 
The Statistical Analysis Plan (SAP) version 1 was finalised before the protocol version 7.0. The 
update to protocol version 7.0 included a major revision of the statistical analysis for the primary 
endpoint as requested by the FDA. 
The description of the analyses in this SAP, version 2.0, is according to that in the protocol version
7.0 and includes additional details and clarifications on the planned statistical analyses. The SAP 
version 1.0 can be disregarded.
This SAP is finalised prior to database lock of the main period of the trial and release of the 
randomisation code. The 1- and 2-year follow-up after the 52 weeks of treatment is not part of the 
database lock of the main period.
CONFIDENTIAL


Liraglutide
CONFIDENTIAL
Date:
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Novo Nordisk
Trial ID: NN2211-3659
Version:
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Statistical Analysis Plan 
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EurdraCT No.: 2011-002605-29
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2
Endpoints
2.1
Primary endpoint
Change in HbA1c from baseline to week 26*
2.2
Secondary endpoints
2.2.1
Confirmatory secondary endpoints to be assessed at 26 weeks of treatment
!
Change from baseline in FPG*
!
HbA1c <7.0% (yes/no)*
!
Change from baseline in BMI standard deviation score (SDS)*
2.2.2
Supportive secondary efficacy endpoints to be assessed at 26 and 52 weeks of 
treatment unless otherwise stated
!
HbA1c <7.0% (yes/no) at 52 weeks*
!
HbA1c ∀6.5% (yes/no)*
!
HbA1c <7.0% without severe or minor hypoglycaemic episodes (yes/no)*
!
HbA1c<7.5% (yes/no)*
!
7-point self-measured plasma glucose (SMPG)
!
Basal insulin dose
Change from baseline at 26 and 52 weeks of treatment unless otherwise stated:
!
HbA1c at 52 weeks*
!
FPG at 52 weeks*
!
Mean 7-point SMPG*
!
Post-prandial increments*
!
Body weight*
!
Waist circumference
CONFIDENTIAL


Liraglutide
CONFIDENTIAL
Date:
25 June 2018
Novo Nordisk
Trial ID: NN2211-3659
Version:
2.0
Statistical Analysis Plan 
Status:
Final
EurdraCT No.: 2011-002605-29
Page:
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!
Body mass index (BMI)
!
BMI SDS at 52 weeks*
!
BMI percentile (age and gender adjusted) 
!
Systolic and diastolic blood pressure*
Ratio to baseline at 26 and 52 weeks of treatment unless otherwise stated:
!
Fasting insulin, fasting pro-insulin, pro-insulin to insulin ratio, fasting glucagon, fasting C-
peptide, and homeostasis model assessment (HOMA-B and HOMA-IR)*
!
Fasting lipid profile (cholesterol, low density lipoprotein (LDL), very low density 
lipoprotein (VLDL), high density lipoprotein (HDL), triglycerides and free fatty acids*
2.2.3
Secondary safety endpoints
Change from baseline at 26 and 52 weeks of treatment unless otherwise stated
!
Clinical evaluations (physical examination including fundoscopy [fundoscopy at 26 and 52 
weeks])
!
Electrocardiography (ECG) with rhythm strip (at 26 and 52 weeks)
!
Pulse*
!
Laboratory tests:
#
Haematology (haemoglobin, haematocrit, thrombocytes, erythrocytes, leucocytes and 
differential count (eosinophils, neutrophils, basophils, lymphocytes and monocytes) 
#
Biochemistry (creatinine, creatine kinase, urea, albumin, bilirubins (total), alanine 
aminotransferase (ALAT), aspartate aminotransferase (ASAT), alkaline phosphatase, 
sodium, potassium, calcium, calcium (albumin corrected), amylase and lipase) 
#
Hormones (calcitonin, prolactin, follicle stimulating hormone (FSH), estradiol, 
luteinizing hormone (LH), testosterone, dehydroepiandrosterone sulfate (DHEAS), 
carcinoembryonic antigen (CEA) and thyroid stimulating hormone (TSH), insulin-like 
growth factor 1 (IGF-1), insulin–like growth factor binding protein 3 (IGFBP-3)
#
First morning urinalysis (micro albumin, creatinine, albumin:creatinine ratio calculated, 
protein, ketone, glucose, pH)
CONFIDENTIAL


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Date:
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Novo Nordisk
Trial ID: NN2211-3659
Version:
2.0
Statistical Analysis Plan 
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EurdraCT No.: 2011-002605-29
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#
Biochemical parameters of bone metabolism: Alkaline Phosphatase, N-telopeptide 
(NTX), C-telopeptide (CTX), serum type 1 procollagen (P1NP)
#
Formation of anti liraglutide antibodies (at 26 and 53 weeks) 
!
Height SDS* 
!
Bone age assessment (x-ray of left hand and wrist) at 52 weeks* 
!
Pubertal assessment/ progression (Tanner staging)* 
In addition the following will be assessed at 26 and 52 weeks:
!
Assessment of compliance (questioning of subjects and subjects legally acceptable 
representative) 
!
Growth (height) velocity in cm/year and height velocity SDS (if subject is still growing). A 
growth velocity < 1.0 cm/year is defined as no longer growing.*
!
Hypoglycaemic episodes*
!
AEs and serious adverse events (SAEs)*
Safety follow-up at 1 and 2 years after trial drug cessation at week 52 (only applicable for 
subjects on active liraglutide treatment for more than 3 months) 
!
AEs and SAEs* 
!
Growth (height) velocity in cm/year (if subject is still growing)*
!
Height velocity SDS (if subject is still growing)
Change in: 
!
Height SDS
!
Pubertal assessment/progression (Tanner staging)*
CONFIDENTIAL


Liraglutide
CONFIDENTIAL
Date:
25 June 2018
Novo Nordisk
Trial ID: NN2211-3659
Version:
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Statistical Analysis Plan 
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!
Bone Age assessment (x-ray of left hand and wrist)*
* Key secondary endpoint prospectively selected for disclosure (e.g. clinicaltrials.gov and 
EudraCT)
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3
Statistical considerations
3.1
Evaluability of subjects for analysis
Full analysis set (FAS): includes all randomised subjects receiving at least one dose of 
liraglutide/liraglutide placebo. The statistical evaluation of the FAS will follow the intention-to-treat 
principle and subjects will contribute to the evaluation “as randomised”. 
In exceptional cases subjects or observations from the FAS may be eliminated. 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 FAS, and the 
reason for this, will be described in the CTR.
Safety Analysis Set: includes all subjects receiving at least one dose of liraglutide/liraglutide 
placebo. Subjects in the safety set will contribute to the evaluation “as treated”.
Randomised subjects who are lost to follow up and where no exposure information of the 
investigational product or comparators is available after randomisation will be handled as 
unexposed.
3.2
Handling of missing data
If an assessment has been made both at screening and randomisation, and if not otherwise specified, 
the value from the randomisation visit will be used as the baseline value. If the value measured at 
the randomisation visit is missing and the assessment also has been made at screening, then the 
screening value will be used as the baseline value.
For efficacy variables missing values will be imputed as described in protocol section 17.3 and 17.4
(section 3.5 and 3.6 in this SAP).
Data collected after treatment discontinuation or initiation of rescue treatment (see protocol section 
5.3.5) will be considered missing in some of the efficacy analyses as described in protocol section 
17.3 and 17.4 (section 3.5 and 3.6 in this SAP). Data collected after treatment discontinuation will 
be data from withdrawals collected at either Visit 17 or Visit 25 (see protocol section 8.1.7) in case 
the measurement is within the visit window (± 5 days) of a planned visit.
For safety variables missing values will not be imputed, except for ‘pulse’ which will be imputed as 
described for the secondary efficacy endpoints (section 3.6). 
For subjects who received rescue medication, all data collected after initiation of rescue medication 
will be included.
Laboratory values below the lower limit of quantification (LLOQ) will be set to ½LLOQ.
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3.3
General considerations
Novo Nordisk will be responsible for the statistical analysis and reporting. Analysis and reporting 
will be based on pooled data from all sites.
The statistical analyses will be performed with a significance level of 5% (two-sided tests).
For all endpoints analysed statistically, estimated mean treatment differences will be presented 
together with two-sided 95% confidence intervals and p-values.
The fixed effects in the models described in the following sections are defined as:
!
‘age group’ is ‘10-14’ and ‘>14 years’ at end of trial, where age at end of trial is calculated 
as age at baseline + 1 year.
!
‘concomitant diabetes treatment at baseline’ is determined by the prescribed insulin dose at 
baseline. The fixed effect will be ‘Y’ for all subjects with a prescribed insulin dose above 
zero at baseline, and ‘N’ otherwise.
!
‘region’ is defined as ‘Asia’, ‘Europe’, ‘North America’, ‘South America’ and ‘Rest of the 
world’. A list of the countries in each region can be found in the NN2211 project statistical 
programming specification (4).
3.4
Sample size calculation
Please refer to the protocol.
3.5
Primary endpoint
The primary endpoint is change from baseline to week 26 in HbA1c. The FAS will be used for this 
analysis. All available data will be used, including data collected after treatment discontinuation and 
rescue initiation. A pattern mixture model using multiple imputation will be used.
The null hypothesis is no difference between the changes from baseline in HbA1c (%) after 26 
weeks of randomised treatment with liraglutide + metformin with or without basal insulin and 
liraglutide placebo + metformin with or without basal insulin (H0: d= liraglutide – placebo =0). The 
alternative hypothesis is that there is a difference between the two treatment arms (HA: d≠0). 
Superiority of liraglutide over liraglutide placebo will be concluded if the 95% confidence interval 
for the treatment difference for change from baseline in HbA1c (%) after 26 weeks of randomised 
treatment lies entirely below 0%; implying that the two sided p-value is less than 5%.
The multiple imputation procedure will be as follows:
For subjects in the liraglutide arm who are missing their week 26 HbA1c measurement, 
measurements will be imputed using the subjects’ baseline HbA1c under a regression model based 
on the completers from the liraglutide placebo arm. Likewise, the same imputation model will be 
used for subjects in the liraglutide placebo arm with missing week 26 data. Multiple imputation of 
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Trial ID: NN2211-3659
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missing week 26 HbA1c data will be performed by utilizing the relationship between HbA1c
measured at baseline and weeks 10 and 14 with that measured at week 26 in placebo patients. 
The following four regression models will be built from the liraglutide placebo completers group 
for this purpose:
!
Model 1: Only baseline covariates (baseline HbA1c, stratification group (gender*age group), 
concomitant diabetes treatment at baseline )
!
Model 2: Baseline covariates and week 10 HbA1c as covariates
!
Model 3: Baseline covariates and week 14 HbA1c as covariates
!
Model 4: Baseline covariates, week 10 HbA1c, and week 14 HbA1c as covariates
Missing week 26 data will be imputed by selecting a random observation from a normal distribution 
centered at the value predicted by the regression model and with variance analogous to predicting a 
new observation in regression analysis. For subjects on the placebo arm, the model used will be 
dependent on the subjects’ available HbA1c data throughout the trial. For example, if a subject had 
HbA1c measurements only at baseline and week 14, then model 3 would be used. For subjects on 
the liraglutide arm, the measurements will be imputed using only the subjects’ baseline HbA1c
(model 1).
The imputation procedure will be iterated 10,000 times, thus generating 10,000 complete data sets 
including observed and imputed values.
For each of the imputed data sets the change in HbA1c from baseline to week 26 will be analysed 
using an ANCOVA with treatment and stratification groups (gender*age group) as categorical fixed 
effects and baseline HbA1c as covariate. The results obtained from analysing the datasets will be 
combined using Rubin’s rule (1) to draw inference.
The estimated treatment difference between liraglutide and liraglutide placebo together with two-
sided 95% CI and p-value for the test of no difference in effect will be presented.
Sensitivity analyses will be performed for the primary endpoint. They will include:
1. an analysis of covariance (ANCOVA) model with LOCF imputation for missing data. Data 
collected after treatment discontinuation or initiation of rescue medication will be handled as 
missing data. Effects in the model are treatment, stratification groups (gender*age group), 
and baseline HbA1c as a covariate. The LOCF will be performed using data collected at time 
points in the treatment period (on treatment) and before initiation of rescue medication, or 
data at baseline if there is no data on treatment without rescue medication post baseline.
2. an ANCOVA model including data after treatment discontinuation or initiation of rescue 
treatment and LOCF imputation for missing data. Effects in the model are treatment, 
stratification groups (gender*age group), and baseline HbA1c as a covariate. The LOCF will 
be performed using baseline data, if this is the only available data, and otherwise data 
collected at time points during the trial.
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3. multiple imputation of missing values in both treatment groups (data collected after 
treatment discontinuation or initiation of rescue treatment considered as missing) based on 
parameters estimated from the placebo group. The same model as for the primary analysis 
will be used.
4. a repeated measurement analysis (MMRM) model using all data points for all visits, but 
excluding data collected after treatment discontinuation or initiation of rescue medication. 
Fixed factors in the model are treatment, stratification groups (gender*age group), and 
baseline HbA1c included as a covariate, all nested within visit. If possible an unstructured 
covariance matrix will be used.
5. an MMRM model as described above, but including age of the subjects at baseline as 
covariate, as well as concomitant diabetes treatment at baseline and region. All will be 
nested within visit.
6. multiple imputation of missing values in both treatment groups based on parameters 
estimated from the placebo group (the same model as for the primary analysis) based on all 
randomised subjects
The HbA1c over time (at randomisation, week 10, 14, 26 and 52) will be presented in figures as:
-
mean (SE) from the primary analysis multiple imputation, combined using Rubin’s rule, at 
week 26 and 52
-
Least square mean (SE) estimated from the MMRM model (no. 4 above) at week 10, 14, 26 
and 52. The mean values of the covariate effects will be used for computation of the least 
square means.
The change in HbA1c over time will in addition be summarised by age group and concomitant 
diabetes treatment at baseline (see section 3.3 for the definitions of age group and concomitant 
diabetes treatment at baseline). The summary of change in HbA1c over time will also be shown in 
plots as mean (SE) both grouped by treatment alone, age group by treatment and subjects having a 
run-in period by treatment
3.6
Secondary endpoints
3.6.1
Confirmatory secondary endpoints
All confirmatory secondary endpoints will be presented and analysed using FAS, unless otherwise 
specified.
The primary analysis for the confirmatory secondary endpoints is the pattern mixture model using 
multiple imputation and using all available data, including data collected after treatment 
discontinuation and initiation of rescue medication. The model is described in detail in the primary 
analysis for the primary endpoint, except that the baseline value of the analysed endpoint will be 
included instead of the baseline HbA1c. value For the dichotomous endpoint (HbA1c<7.0%), a 
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Trial ID: NN2211-3659
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logistic regression model will be used with missing values imputed from the pattern mixture model
of change from baseline in HbA1c
In addition, the confirmatory secondary endpoints will be analysed by an MMRM model using all 
data points for all visits, but excluding data collected after treatment discontinuation or initiation of 
rescue medication. Fixed factors in the model are treatment and stratification groups (gender*age 
group),with baseline value of the analysed endpoint included as covariate., Both fixed factors and 
the covariate will be nested within visit (sensitivity analysis no. 4 for the primary endpoint). For 
measurements within a subject an unstructured covariance will be used. For the dichotomous 
endpoint (HbA1c<7.0%), a logistic regression model will be used with missing values imputed from 
the corresponding MMRM model of change from baseline in HbA1c. 
The continues confirmatory endpoints will be presented as described for the primary analysis.
Change from baseline in FPG after 26 weeks of treatment
The change from baseline in FPG after 26 weeks of treatment will be analysed with the same 
method as the primary efficacy endpoint (as described above). Baseline FPG will be included in the 
analyses instead of baseline HbA1c. 
HbA1c < 7.0% after 26 weeks of treatment (yes/no)
This dichotomous endpoint will be analysed by a logistic regression model. Effects in the model are 
treatment, stratification groups (gender*age group), and baseline HbA1c as a covariate. The results 
will include the 95% confidence interval for the odds ratio (liraglutide over liraglutide placebo) and 
the p-value for test of no difference between the groups as part of the presentation.
Missing data for HbA1c at week 26 will be imputed from the multiple imputation procedure of the 
primary endpoint (as described above).
Change from baseline in BMI SDS after 26 weeks of treatment
The change from baseline in BMI SDS after 26 weeks of treatment will be analysed with the same 
method as the primary efficacy endpoint (as described above). Baseline BMI SDS will be included 
in the analyses instead of baseline HbA1c.
BMI SDS will be calculated using the following formula:
 =
	




−1
 ∗
where L,M and S are median (M), skewness (L) and variation coefficient (S) of children’s BMI 
provided for each sex and age . For each subject a standard deviation score Z (SDS) will be 
calculated based on age and sex referring to the values L, M and S. The method is described in the 
WHO Multicentre Growth Reference (3) Values for M, L and S by age and sex is also found in the 
WHO reference. For Z (SDS) scores below -3 and above 3 the score will be adjusted as described in 
the WHO instruction.
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Trial ID: NN2211-3659
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Hierarchical testing
The primary endpoint and confirmatory secondary endpoints will be analysed in a hierarchical 
manner in the following order:
1. Primary efficacy endpoint
2. Change from baseline in FPG after 26 weeks of treatment
3. HbA1c < 7.0% after 26 weeks of treatment (yes/no)
4. Change from baseline in BMI SDS after 26 weeks of treatment
In order to be able to conclude significance for an endpoint in the hierarchical list above, the test for 
that endpoint and the tests for the endpoints higher up in the hierarchy must all be concluded 
significant with a difference in favour of the liraglutide group.
The hierarchical testing is chosen to maintain the family wise type I error of 5%.
3.6.2
Supportive secondary endpoints
All supportive endpoints will be presented and analysed using FAS.
The supportive secondary endpoints will be analysed using the models as described for the 
confirmatory secondary analyses (see section 3.6.1).
In the analyses at week 52 the pattern mixture model is extended with the following models:
!
Model 5: Baseline covariates and week 26 data of the endpoint as covariates
!
Model 6: Baseline covariates and week 10, and week 26 data of the endpoint as covariates
!
Model 7: Baseline covariates, week 14 and week 26 data of the endpoint as covariates
!
Model 8: Baseline covariates, week 10, week 14 and week 26 data of the endpoint as 
covariates
Data at baseline, week 10, 14, 26 and 52 will be used in the pattern mixture model.
In the MMRM analysis for the supportive secondary endpoints data points at all visits , but 
excluding data collected after treatment discontinuation or initiation of rescue medication will be 
used.
The following dichotomous endpoints are defined:
At 26 and 52 weeks of treatment unless otherwise stated:
HbA1c <7.0% (yes/no) at 52 weeks
HbA1c ≤6.5% (yes/no)
HbA1c <7.0% without severe or minor hypoglycaemic episodes (yes/no)
HbA1c <7.5% (yes/no) 
The dichotomous endpoints will be analysed by a logistic regression model. Effects in the model are 
treatment, stratification groups (gender*age group), and baseline HbA1c as a covariate. The results 
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Trial ID: NN2211-3659
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will include the 95% confidence interval for the odds ratio (liraglutide over liraglutide placebo) and 
the p-value for test of no difference between the groups as part of the presentation.
Missing data at week 26 and week 52 will be imputed
!
using the multiple imputation procedure as described above 
!
and in addition using imputations from the MMRM sensitivity analysis no. 4 of the primary 
endpoint.
The following continuous endpoints are defined:
Change from baseline at 26 and 52 weeks of treatment unless otherwise stated:
!
HbA1c at 52 weeks
!
FPG at 52 weeks
!
7-point SMPG
- mean 7-point SMPG, defined as the area under the profile (calculated using the trapezoidal 
method) divided by the measurement time
- post-prandial increments after breakfast, lunch and dinner  (from before meal to 90 min 
after breakfast, lunch and dinner)
- mean post-prandial increment for all meals (breakfast, lunch, and dinner)
!
Fasting insulin, fasting pro-insulin, pro-insulin to insulin ratio, fasting glucagon, fasting 
C-peptide, and homeostasis model assessment (HOMA-B and HOMA-IR). The values will 
be logarithmically transformed before analysis, and the actual values will be modelled 
instead of change from baseline.
!
Fasting lipid profile (total cholesterol, LDL cholesterol, VLDL cholesterol, 
HDL cholesterol, triglycerides and free fatty acids. The values will be logarithmically
transformed before analysis, and the actual values will be modelled instead of change from 
baseline.
!
Body weight
!
Waist circumference
!
BMI
!
BMI SDS at 52 weeks
!
BMI percentile (age and gender adjusted)
!
Systolic and diastolic blood pressure
Throughout the trial:
!
Basal insulin dose
For calculation of BMI SDS please refer to section 3.6.1 above.
BMI percentile (age and gender adjusted) is the result of the cumulative normal distribution 
function based on the respective Z-value (SDS value).
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Trial ID: NN2211-3659
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The continuous endpoints described above will be analysed with a similar method as for the 
primary endpoint (detailed above), except for change in basal insulin dose that will only be 
presented by descriptive statistics. The BMI percentile will also only be summarised (descriptive 
statistics) as it is uniquely determined from the BMI SDS. The post prandial increments after 
breakfast, lunch, and dinner will also only be presented by descriptive statistics, whereas the mean 
post-prandial increment will be analysed as the other endpoints. 
If data has been log transformed, the ratio to baseline and treatment ratio will be considered instead 
of the change from baseline and treatment difference.
3.6.3
Safety endpoints
All safety endpoints will be presented using the safety analysis set. Unless otherwise specified 
safety endpoints will be presented only by descriptive statistics.
Change from baseline at 26 and 52 weeks of treatment unless otherwise stated
!
Clinical evaluations (physical examination including fundoscopy [fundoscopy at 26 and 52 
weeks])
!
ECG with rhythm strip (at 26 and 52 weeks)
!
Laboratory tests:
o
Haematology (haemoglobin, haematocrit, thrombocytes, erythrocytes, leucocytes and 
differential count (eosinophils, neutrophils, basophils, lymphocytes and monocytes)
Biochemistry (creatinine, creatine kinase, urea, albumin, bilirubin (total), ALAT, ASAT, 
sodium, potassium, alkaline phosphatase, calcium, calcium (albumin corrected), amylase 
and lipase)
o
Hormones (calcitonin, prolactin, FSH, estradiol, LH, testosterone, DHEAS, CEA and 
TSH, IGF-1, IGFBP-3
o
First morning urinalysis (Micro albumin, creatinine, albumin:creatinine ratio calculated, 
protein, ketone, glucose, pH)
o
Biochemical parameters of bone metabolism: Alkaline Phosphatase, NTX, CPX, P1NP
o
Formation of anti-liraglutide antibodies (at 26 and 53 weeks)
!
Pulse
!
Pubertal assessment/ progression (Tanner staging), DHEAS, LH, FSH, estradiol in females and
testosterone in males
!
Height SDS versus baseline at 26 and 52 weeks
!
Bone age assessment (x-ray of left hand and wrist) at 52 weeks
In addition the following will be assessed at 26, and 52 weeks:
!
Assessment of compliance (questioning of subjects and subjects legally acceptable
representative)
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!
Growth (height) velocity in cm/year and height (growth) velocity SDS  (if subject is still 
growing). A growth (height) velocity < 1.0 cm/year is defined as no longer growing.
Collected throughout the trial:
!
Hypoglycaemic episodes (see details below)
!
AEs and serious adverse events (SAEs) (see details below)
Pulse
Pulse will be analysed with a similar method as for the primary analysis for the primary endpoint
(as described for the secondary confirmatory and supportive efficacy endpoints).
Height SDS
Height SDS will be calculated using the same formula as described for BMI SDS (see section 3.6.1) 
The values for M, S and L are downloaded from 
http://www.who.int/growthref/hfa_boys_perc_WHO2007_exp.txt and 
http://www.who.int/growthref/hfa_girls_perc_WHO2007_exp.txt on 2nd February, 2018)
Height velocity
Growth (height) velocity is the change in height per year and is measured in cm/year (height 
velocity is the same as growth velocity). 
The height velocity is calculated as the difference between current height and baseline divided by 
time duration in days between those measurement time points and multiplied by 365 days.
Height velocity SDS
Height velocity SDS will be calculated using the same formula as described for BMI SDS (see 
section 3.6.1) The reference values for M, S and L are downloaded from
https://academic.oup.com/jcem/article/99/6/2104/2537746. Height velocity SDS at week 26 will
only be used to find extreme outliers as it is not recommended to calculate this value based on 
height change over less than one year.
Hypoglycaemic episodes
Hypoglycaemic episodes are recorded by subjects in their trial diaries throughout the trial. The 
information collected includes plasma glucose (PG) before treating the episode and whether the 
subject was able to treat him/herself. This information is used by Novo Nordisk to classify an 
episode according to the ADA definition (severe, documented symptomatic, asymptomatic, 
probable symptomatic and relative) and the additional minor category as defined by Novo Nordisk
(also named as BG confirmed). A hypoglycaemic episode is defined as treatment emergent if the 
onset of the episode is on or after the first day of exposure to randomised treatment and no later 
than one day after the last day on randomised treatment. All hypoglycaemic episodes will be 
summarised by treatment and severity.
Nocturnal hypoglycaemic episodes, defined as episodes with time of onset between 00:01 and 
05:59, will also be summarised by severity. In addition the hypoglycaemic episodes will be 
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summarised by events occurring at periods in the trial when the subjects are on basal insulin and/or 
bolus insulin, and at periods without insulin.
The hypoglycaemic episodes will be summarised for the blinded period of the trial (up to week 26) 
and for the total exposure period.
Adverse events
All AEs will be coded using the most recent version of the Medical Dictionary for Regulatory 
Activities (MedDRA). A treatment emergent adverse event (TEAE) is defined as an event that has 
onset date (or increase in severity) on or after the first day of exposure to randomised treatment and 
no later than seven days after the last day of randomised treatment. In the open period of the trial 
the randomised treatment for placebo is metformin alone.
The TEAEs will be summarised by treatment for all TEAEs by system organ class, preferred term, 
seriousness, severity, outcome and relation to trial product. TEAEs are summarised descriptively in 
terms of the number of subjects with at least one event (N), the percentage of subjects with at least 
one event (%), the number of events (E) and the event rate per 1000 years (R). 
The most frequent TEAEs will be defined as preferred terms that are experienced by at least 5% of 
the subjects in any of the treatment arms. The most frequent TEAEs will be summarised and 
presented in a plot with number of subjects with an event and rate of events (number per 1000 years 
of exposure).
The TEAEs will be summarised for the blinded period of the trial (up to week 26) and for the total 
exposure period.
Non-treatment emergent AEs will be presented in listings.
Medical events of special interest (MESI) will be summarised separately.
MedDRA search terms have been defined to find AEs of special interest in the following categories: 
Cardiac events, Pancreatitis, Medication error, Neoplasm, Thyroid disease, Altered renal function, 
Injection site reactions, Overdose, Gallstone, Cardiac arrhythmia, Hyperglycaemia, Allergic 
reaction, Elevated amylase, Elevated calcitonin, Suspected transmission of infectious agents, Rare 
adverse events, Depression adverse events, Device issue events and Immune adverse events. These 
MedDRA search terms are defined prior to DBL (5). The AEs of special interest will be listed by 
category.
3.6.4
Safety follow-up at 1 and 2 years after trial drug cessation at week 52 (only 
applicable for subjects on active liraglutide treatment for more than 3 months)
!
AEs and SAEs
!
Growth (height) velocity in cm/year (if subject is still growing)
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!
Height velocity SDS (height velocity is the same as growth velocity) (if subject is still 
growing)
Change in:
!
Height SDS
!
Pubertal assessment/progression by Tanner staging
!
Bone age assessment (x-ray of left hand and wrist)
For calculation of height SDS please refer to section 3.6.2.
3.7
Exploratory analyses
To evaluate the influence of intake of insulin on the treatment effect on change in HbA1c at week 26 
and 52 a repeated measurement analysis (MMRM) model including treatment interaction with 
insulin at baseline will be performed. All data points for all visits, but excluding data collected after 
treatment discontinuation or initiation of rescue medication, will be used. Fixed effects in the model 
are treatment, stratification groups (gender*age group), diabetes medication at baseline and 
treatment by diabetes medication at baseline interaction. The baseline HbA1c will be included as a 
covariate. All factors and covariates will be nested within visit. If possible, an unstructured 
covariance matrix will be used.
3.8
Interim analysis
NA
3.9
Sequential safety analysis/safety monitoring
An external data monitoring committee (DMC) was established to independently review and 
evaluate accumulated unblinded safety data from the trial in order to protect the safety of the 
subjects and to evaluate the evolving risk-benefit if required. See protocol for details.
Novo Nordisk constituted an internal safety committee to perform ongoing safety surveillance. The 
safety committee conducted ongoing monitoring of blinded safety data. The safety committee could 
recommend unblinding of any data for further analysis, and in this case an independent ad hoc 
group would be established in order to maintain the blinding of the trial personnel.
3.10
Explorative statistical analysis for pharmacogenetics and biomarkers
NA
3.11
PK data
The liraglutide concentrations will be listed.
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4
Changes to the statistical analyses planned in the protocol
This statistical analysis plan follows the protocol with the following clarifications:
4.1
Sensitivity analysis for the primary endpoint on all randomised subjects
The primary analysis is based on FAS which includes all randomised subjects receiving at least one 
dose of liraglutide/liraglutide placebo. Due to an FDA request to change in the primary analysis, the 
primary estimand is the “treatment policy” estimand, and therefore it is appropriate to add a 
sensitivity analysis of the primary endpoint including all randomised subjects.
4.2
Handling of missing data
For safety variables it was stated in the protocol that missing values (including intermittent missing 
values) would be imputed using the last observation carried forward (LOCF) on post-baseline 
measurements. The analyses on safety parameters will be performed using a pattern mixture model 
with multiple imputation and missing values will therefore not be imputed using the LOCF method.
4.3
Definition of fixed effects
The fixed effect ‘region’ was not specified in the protocol, but in a sensitivity analysis the regions
were described as: North America, Asia including Russia, Europe including Israel, South America 
including Mexico. To align with other NN2211 trials, the regions are defined as has been done 
overall for the NN2211 project. The only difference from the description in the protocol is that 
Russia is not assigned to region Asia, but is assigned to region Europe.
The fixed effect ‘concomitant diabetes treatment at baseline’ was described as ‘diet and exercise 
alone vs. diet and exercise plus metformin and/or basal insulin’. As all subjects were to take 
metformin at baseline the definition is updated to with/without basal insulin at baseline (see section 
3.3)
4.4
Supportive secondary endpoints
The mean post prandial increment is added as an endpoint, as this endpoint has been presented in 
other trials in project NN2211. The mean post-prandial increment will be analysed as the other 
supportive secondary endpoints. The post prandial increments after breakfast, lunch and dinner will 
only be presented by descriptive statistics, whereas in the protocol they were planned to be 
analysed.
The BMI percentile will also only be summarised, as it is closely related to the BMI SDS.
CONFIDENTIAL


Liraglutide
CONFIDENTIAL
Date:
25 June 2018
Novo Nordisk
Trial ID: NN2211-3659
Version:
2.0
Statistical Analysis Plan 
Status:
Final
EurdraCT No.: 2011-002605-29
Page:
24 of 25
4.5
Statistical analyses of the confirmatory and supportive secondary endpoints
In the protocol it is stated the confirmatory and supportive secondary endpoints ‘will be analysed 
with the same method as the primary efficacy endpoint’. It has been clarified that the endpoints 
analysed with the same method as the primary efficacy endpoint will be analysed using the primary 
analysis for the primary endpoint (the pattern mixture model) and, in addition, using the MMRM
sensitivity analysis described as no. 4 for the primary analysis (see section 3.5). These analyses 
have been described in detail in sections 3.6.1 and 3.6.2. 
4.6
Exploratory analyses
To evaluate the influence of intake of insulin on the treatment effect on change in HbA1c at week 
26 and 52 an exploratory analysis including treatment and diabetes medication at baseline 
interaction has been added.
4.7
Miscellaneous
Some wordings have been updated without changing the content, these are not mentioned here. In 
addition, details have been added with regards to how data will be summarised and presented which 
are also not mentioned here.
CONFIDENTIAL


Liraglutide
CONFIDENTIAL
Date:
25 June 2018
Novo Nordisk
Trial ID: NN2211-3659
Version:
2.0
Statistical Analysis Plan 
Status:
Final
EurdraCT No.: 2011-002605-29
Page:
25 of 25
5
References
1. Rubin, D. B. (1987), Multiple Imputation for Nonresponse in Surveys, New York: John Wiley 
& Sons
2. Ratitch, B., O’Kelly (2011), M. Implementation of Pattern-Mixture Models Using Standard 
SAS/STAT Procedures, PharmaSUG2011 - Paper SP04
3. WHO Multicentre Growth Reference Study Group. WHO Child Growth Standards: 
Length/height-for-age, weight-for-age, weight-for-length, weight-for-height and body mass 
index-for-age: Methods and development. Geneva: World Health Organization, 2006 (312 
pages) (http://www.who.int/childgrowth/standards/technical_report/en/)
4. nn2211-phase3b-4-project-statistical-programming-specification, Version 1.0 (Novo Docs ID 
004154390)
5. SAS dataset with MedDRA search terms for AEs of special interest (3659_meddra, Novo Docs 
ID 004247169)
CONFIDENTIAL