Conditions: Diabetes Diabetes Mellitus, Type 2
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 635
Healthy volunteers: no

Brief summary:
This trial is conducted in Asia. The aim of the trial is to compare the efficacy and safety of liraglutide 1.8 mg/day to liraglutide 0.9 mg/day in Japanese subjects with type 2 diabetes mellitus.

Detailed description:

Arms:
arm 1: The total trial duration for the 1.8 mg/day treatment arm will be approximately 67 weeks, consisting of 2 weeks screening period, a 12 weeks run-in period, a 26-week main treatment period, a safety extension period of 26 weeks and a follow-up visit. arm 2: The total trial duration for the 0.9 mg/day treatment arm will be approximately 41 weeks, consisting of 2 weeks screening period, a 12 weeks run-in period, a 26-week treatment period, and a follow-up visit.

Interventions: intervention 1: liraglutide
Intervention descriptions: intervention 1: Injected subcutaneously s.c. (under the skin) once daily.

Protocol document:
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Link
Link
Link
Link
Link
Link
List of contents
Protocol ...............................................................................................................................................
Appendix A - Monitoring of Calcitonin ...........................................................................................
Appendix B - New York Heart Association Criteria for Functional Capacity.............................
Appendix C - Medical events of special interest, events with additional data collection and 
events requiring adjudication.....................................................................................................
Attachment I and II............................................................................................................................
Protocol amendment 1 .......................................................................................................................
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
Liraglutide
Trial ID: NN2211-4174
Clinical Trial Report
Appendix 16.1.1
10 April 2018
1.0
Final
16.1.1 Protocol and protocol amendments
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Protocol
CONFIDENTIAL
Date:
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Trial ID: NN2211-4174
Version:
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UTN: U1111-1164-5462
Status:
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Protocol
Trial ID: NN2211-4174
A trial comparing the efficacy and safety of liraglutide 1.8 mg/day to 
liraglutide 0.9 mg/day in Japanese subjects with type 2 diabetes 
mellitus
Trial phase: 3b
Protocol originator
, CMR Development Division, Novo Nordisk Pharma Ltd.
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
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Date:
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Trial ID: NN2211-4174
Version:
2.0
UTN: U1111-1164-5462
Status:
Final
     
Page:
2 of 103
Table of Contents
Page
Table of Contents..............................................................................................................................................2
Table of Figures................................................................................................................................................6
Table of Tables..................................................................................................................................................6
List of abbreviations.........................................................................................................................................7
1
Summary..................................................................................................................................................10
2
Flow chart ................................................................................................................................................13
3
Background information and rationale for the trial............................................................................17
3.1
Background information..............................................................................................................17
3.1.1
Type 2 diabetes..........................................................................................................17
3.1.2
Glucagon-like peptide-1 ............................................................................................17
3.1.3
Liraglutide..................................................................................................................18
3.2
Rationale for the trial...................................................................................................................19
4
Objectives and endpoints........................................................................................................................21
4.1
Objectives ....................................................................................................................................21
4.1.1
Primary objective.......................................................................................................21
4.1.2
Secondary objectives .................................................................................................21
4.2
Endpoints .....................................................................................................................................21
4.2.1
Primary endpoint........................................................................................................21
4.2.2
Secondary endpoints..................................................................................................21
4.2.2.1
Secondary efficacy endpoints..............................................................21
4.2.2.2
Secondary safety endpoints.................................................................22
5
Trial design ..............................................................................................................................................24
5.1
Type of trial .................................................................................................................................24
5.2
Rationale for trial design..............................................................................................................25
5.3
Treatment of subjects...................................................................................................................25
5.4
Treatment after discontinuation of trial product ..........................................................................27
5.5
Rationale for treatment ................................................................................................................27
6
Trial population.......................................................................................................................................28
6.1
Number of subjects......................................................................................................................28
6.2
Inclusion criteria ..........................................................................................................................28
6.3
Exclusion criteria.........................................................................................................................29
6.4
Randomisation criterion...............................................................................................................30
6.5
Withdrawal criteria ......................................................................................................................30
6.6
Subject replacement.....................................................................................................................31
6.7
Rationale for trial population.......................................................................................................32
7
Milestones.................................................................................................................................................33
8
Methods and assessments .......................................................................................................................34
8.1
Visit procedures...........................................................................................................................34
8.1.1
Informed Consent ......................................................................................................34
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Status:
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8.1.2
Screening (Visit 1).....................................................................................................34
8.1.2.1
Screening failures................................................................................35
8.1.3
Visits attended fasting................................................................................................35
8.1.4
Run-in visit (Visit 2)..................................................................................................35
8.1.4.1
Run-in failures.....................................................................................35
8.1.5
Randomisation ...........................................................................................................36
8.1.6
Visit............................................................................................................................36
8.1.7
End of treatment (EOT) visit and follow-up visit......................................................36
8.1.8
Withdrawal.................................................................................................................37
8.2
Subject related information..........................................................................................................37
8.2.1
Concomitant illness and medical history...................................................................37
8.2.2
Concomitant medication............................................................................................37
8.2.3
Demography...............................................................................................................38
8.2.4
Diagnosis of diabetes.................................................................................................38
8.2.5
Diabetes complications..............................................................................................38
8.2.6
Diabetes treatment history .........................................................................................38
8.2.7
Smoking status...........................................................................................................38
8.2.8
New York Heart Association classification...............................................................39
8.3
Assessments for efficacy..............................................................................................................39
8.3.1
Blood sample .............................................................................................................39
8.3.2
Self-measured blood glucose (SMBG)......................................................................39
8.3.3
Body measurement ....................................................................................................40
8.3.3.1
Height..................................................................................................40
8.3.3.2
Body weight ........................................................................................40
8.3.3.3
BMI .....................................................................................................41
8.3.3.4
Waist circumference............................................................................41
8.3.4
Blood pressure ...........................................................................................................41
8.4
Assessments for safety.................................................................................................................42
8.4.1
Adverse events (AEs) ................................................................................................42
8.4.1.1
Adverse Events requiring special forms in the eCRF .........................42
8.4.2
Blood samples............................................................................................................45
8.4.3
Electrocardiogram (ECG) – 12 lead ..........................................................................46
8.4.4
Eye Examination........................................................................................................47
8.4.5
Physical Examination ................................................................................................47
8.4.6
Hypoglycaemic episodes ...........................................................................................48
8.4.7
Pulse...........................................................................................................................49
8.4.8
Pregnancy test............................................................................................................49
8.4.9
Assessments in case of suspicion of acute pancreatitis..............................................50
8.5
Laboratory assessments ...............................................................................................................50
8.6
Other assessments........................................................................................................................51
8.6.1
Subject diary ..............................................................................................................51
8.7
Subject compliance......................................................................................................................52
9
Trial supplies ...........................................................................................................................................53
9.1
Trial products...............................................................................................................................53
9.2
Labelling......................................................................................................................................53
9.3
Storage .........................................................................................................................................53
9.4
Drug accountability and destruction............................................................................................54
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Protocol
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Date:
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Trial ID: NN2211-4174
Version:
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UTN: U1111-1164-5462
Status:
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9.5
Auxiliary supplies........................................................................................................................55
10 Interactive voice/web response system ..................................................................................................56
11 Randomisation procedure ......................................................................................................................57
12 Adverse events, and technical complaints and pregnancies................................................................58
12.1
Definitions ...................................................................................................................................58
12.2
Reporting of adverse events.........................................................................................................61
12.3
Follow-up of adverse events........................................................................................................63
12.4
Technical complaints and technical complaint samples ..............................................................64
12.4.1
Reporting of technical complaints .............................................................................64
12.4.2
Collection, storage and shipment of technical complaint samples ............................65
12.5
Pregnancies..................................................................................................................................65
12.6
Precautions and/or overdose ........................................................................................................67
12.7
Committees related to safety........................................................................................................67
12.7.1
Novo Nordisk safety committee ................................................................................67
12.7.2
Event adjudication committee (EAC)........................................................................67
13 Case report forms....................................................................................................................................69
13.1
Corrections to case report forms..................................................................................................69
13.2
Case report form flow..................................................................................................................69
13.3
Paper case report form flow.........................................................................................................70
14 Monitoring procedures ...........................................................................................................................71
15 Data management....................................................................................................................................73
16 Computerised systems.............................................................................................................................74
17 Statistical considerations ........................................................................................................................75
17.1
Sample size calculation................................................................................................................76
17.2
Definition of analysis sets............................................................................................................77
17.3
Primary endpoint..........................................................................................................................77
17.4
Secondary endpoints....................................................................................................................78
17.4.1
Secondary endpoints..................................................................................................78
17.4.1.1
Efficacy endpoints...............................................................................78
17.4.1.2
Safety endpoints..................................................................................81
18 Ethics........................................................................................................................................................87
18.1
Informed consent .........................................................................................................................88
18.2
Data handling...............................................................................................................................88
18.3
Information to subject during trial...............................................................................................88
18.4
Premature termination of the trial and/or trial site.......................................................................89
19 Protocol compliance................................................................................................................................90
20 Audits and inspections ............................................................................................................................91
21 Critical documents ..................................................................................................................................92
22 Responsibilities........................................................................................................................................93
23 Reports and publications........................................................................................................................94
23.1
Communication of results............................................................................................................94
CONFIDENTIAL


Protocol
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Date:
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Trial ID: NN2211-4174
Version:
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UTN: U1111-1164-5462
Status:
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23.1.1
Authorship .................................................................................................................95
23.1.2
Site-specific publication(s) by investigator(s) ...........................................................95
23.2
Investigator access to data and review of results.........................................................................96
24 Retention of clinical trial documentation..............................................................................................97
25 Institutional Review Boards and regulatory authorities .....................................................................98
26 Indemnity statement ...............................................................................................................................99
27 References..............................................................................................................................................100
Appendix A: Monitoring of calcitonin
Appendix B: New York Heart Association Criteria for Functional Capacity
Appendix C: Medical events of special interest and events requiring adjudication
Attachment I – List of key staff and relevant departments and suppliers
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
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Novo Nordisk
Trial ID: NN2211-4174
Version:
2.0
UTN: U1111-1164-5462
Status:
Final
     
Page:
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Table of Figures
Page
Figure 5–1
Trial design.............................................................................................................................24
Figure 12–1
Initial reporting of AEs...........................................................................................................63
Figure 17–1
Novo Nordisk classification of hypoglycaemia.....................................................................83
Figure 17–2
ADA classification of hypoglycaemia....................................................................................84
Table of Tables
Page
Table 2-1
Flow chart...............................................................................................................................13
Table 5-1
Liraglutide dose escalation in run-in period ...........................................................................26
Table 5-2
Liraglutide dose escalation in 1.8 mg/day treatment arm.......................................................26
Table 17-1
Powers for various combinations of SD and mean difference................................................77
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
25 March 2015
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Trial ID: NN2211-4174
Version:
2.0
UTN: U1111-1164-5462
Status:
Final
     
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List of abbreviations
ADA
American Diabetes Association
AE
adverse event
α-GI
alpha-glucosidase inhibitor
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AP
alkaline phosphatase
AST
aspartate aminotransferase
BG
blood glucose
BMI
body mass index
CCDS
Company Core Data Sheet 
CLAE
clinical laboratory adverse event
CRF
case report form
CRO
clinical research organisation
CT
computerised axial tomography
CTR
clinical trial report
CV
coefficient of variation
DFU
direction for use
DPP-4
dipeptidyl peptidase 4
DUN
dispensing unit number
EAC
Event adjudication committee
ECG
electrocardiogram
EDC
electronic data capture
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
ESC
European Society of Cardiology
ESH
European Society of Hypertension
EOT
end of treatment
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
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Trial ID: NN2211-4174
Version:
2.0
UTN: U1111-1164-5462
Status:
Final
     
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FAS
full analysis set
FDA
U.S. Food and Drug Administration
FDAAA
Food and Drug Administration Amendment Act
FPG
fasting plasma glucose
FSFV
first subject first visit
GCP
Good Clinical Practice
GLP-1
glucagon-like peptide-1
HbA1c
glycosylated haemoglobin
hCG
human chorionic gonadotropin
HDL
high density lipoprotein
HOMA-IR
homeostasis model assessment as an index of insulin 
resistance 
HOMA-B
homeotasis model assessment of beta-call function
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
ICMJE
International Committee of Medical Journal Editors
IMP
investigational medicinal product
IRB
institutional review board
ITT
Intention to treat
IV/WRS
interactive voice/web response system
J-PI
Japanese package insert
LDL
low density lipoprotein
LLOQ
lower limit of quantification
LOCF
last observation carried forward
LSFV
last subject first visit
LSLV
last subject last visit
LSMeans
Least Square Means
MedDRA
Medical Dictionary for Regulatory Activities
MEN 2
multiple endocrine neoplasia syndrome type2 
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
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Trial ID: NN2211-4174
Version:
2.0
UTN: U1111-1164-5462
Status:
Final
     
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MESI
medical event of special interest
MHLW
Ministry of Health, Labour and Welfare
MI
myocardial infarction
MMRM
mixed model for repeated measurement
MRI
magnetic resonance imaging
MTC
medullary thyroid carcinoma
NYHA
New York Heart Association
OAD
oral antidiabetic drug
PG
plasma glucose
PPG
postprandial glucose
SAE
serious adverse event
SAS
safety analysis set
s.c.
subcutaneous(ly)
SD
standard deviation
SDV
source data verification
SMBG
self-measured blood glucose
SU
sulfonylureas
SUSAR
suspected unexpected serious adverse reaction
T2DM
type 2 diabetes mellitus
TEAE
treatment emergent adverse event
TIA
transient ischemic attack
TMM
Trial Materials Manual
TSH
thyroid stimulating hormone
TZD
thiazolidinedione
UNR
upper normal range
UTN
Universal Trial Number
VLDL
very low density lipoprotein
CONFIDENTIAL


Protocol
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Date:
25 March 2015
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Trial ID: NN2211-4174
Version:
2.0
UTN: U1111-1164-5462
Status:
Final
     
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1
Summary
Objective(s) and endpoint(s):
Primary objective
To confirm the superiority of liraglutide 1.8 mg/day vs. liraglutide 0.9 mg/day in controlling 
glycaemia after 26 weeks of treatment in Japanese subjects with type 2 diabetes mellitus 
inadequately controlled with liraglutide 0.9 mg/day
Primary endpoint
Change from baseline in HbA1c after 26 weeks of treatment
Secondary objectives
To compare the overall efficacy and safety parameters of liraglutide 1.8 mg/day and liraglutide 0.9 
mg/day after 26 weeks of treatment
To evaluate the safety profile of liraglutide 1.8 mg/day over a period of 52 weeks and to monitor 
glycaemic control and other efficacy parameters over a period of 52 weeks
Key secondary endpoints
Key secondary efficacy endpoints
!
Responder for HbA1c after 26 weeks of treatment (Yes/No):
o
HbA1c < 7.0% (53 mmol/mol)
o
HbA1c ≤ 6.5% (48 mmol/mol)
!
Change from baseline in body weight after 26 weeks of treatment
Key secondary safety endpoints
!
Number of treatment emergent adverse events during 26 weeks of treatment 
!
Number of treatment emergent adverse events during 52 weeks of treatment 
Trial design:
This is a 26-week randomised, parallel, two-arm, open-label, multi-centre trial comparing the 
efficacy and safety of liraglutide 1.8 mg/day to liraglutide 0.9 mg/day in Japanese subjects with 
type 2 diabetes mellitus who are inadequately controlled on 1 oral anti-diabetic drug (OAD). 
Eligible subjects are presenting with an HbA1c level of 7.5-10.0 %. At Visit 2 the pre-trial OAD 
will be discontinued and liraglutide 0.9 mg/day will be initiated for a 12 week run-in period. 
CONFIDENTIAL


Protocol
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Trial ID: NN2211-4174
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Status:
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Subjects with an HbA1c ≥7.0% at the end of the run-in period will be randomised in a 1:1 manner; 
either continuing liraglutide 0.9 mg/day or dose escalation to liraglutide 1.8 mg/day. Only the 
liraglutide 1.8 mg/day treatment arm will be continued for a total of 52 weeks after randomisation 
for monitoring of long-term safety and glycaemic control over 52 weeks.
The total trial duration for the 1.8 mg/day treatment arm will be approximately 67 weeks, consisting 
of 2 weeks screening period, a 12 weeks run-in period, a 26-week main treatment period, a safety 
extension period of 26 weeks and a follow-up visit. The total trial duration for the 0.9 
mg/daytreatment arm will be approximately 41 weeks, consisting of 2 weeks screening period, a 12 
weeks run-in period, a 26-week treatment period, and a follow-up visit. 
Trial population:
Planned number of subjects to be included in the run-in period, starting liraglutide treatment: 1106
Planned number of subjects to be randomised: 470
Key inclusion criteria
!
Male or female Japanese subjects ≥20 years of age at the time of informed consent.
!
Type 2 diabetes subjects (diagnosed clinically) ≥ 6 months prior to screening.
!
HbA1c 7.5-10.0 % [58 mmol/mol-86 mmol/mol] (both inclusive).
!
Subjects on stable therapy with one OAD (stable therapy is defined as unchanged medication 
and unchanged dose) for ≥60 days before screening according to approved Japanese labelling.
Key exclusion criteria
!
Previous treatment with insulin (except for short-term treatment in connection with intercurrent 
illness including gestational diabetes).
!
Treatment with any medication for the indication of diabetes or obesity other than stated in the 
inclusion criteria in a period of 60 days before screening.
!
Screening calcitonin ≥50 ng/l.
!
History of pancreatitis (acute or chronic).
!
Personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine 
neoplasia type 2 (MEN 2).
!
Subjects presently classified as being in New York Heart Association (NYHA) Class IV.
!
Within the past 180 days any of the following: myocardial infarction, stroke or hospitalisation 
for unstable angina and/or transient ischemic attack.
!
Diagnosis of malignant neoplasms within the last 5 years (except basal and squamous cell skin 
cancer, polyps and in-situ carcinomas).
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Protocol
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Trial ID: NN2211-4174
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!
Any condition which, in the opinion of the investigator might jeopardise subject’s safety or 
compliance with the protocol.
Assessments:
Key efficacy assessments
!
HbA1c
!
Body weight
Key safety assessment
!
Adverse events
Trial product(s):
Liraglutide (Victoza®); 6.0 mg/mL, in a 3.0 mL pre-filled pen (FlexPen®), for subcutaneous (s.c.) 
injection. 
CONFIDENTIAL


Protocol
UTN: U1111-1164-5462
Date:
25 March 2015
Status:
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Novo Nordisk
Trial ID: NN2211-4174
     
Version:
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2
Flow chart
Table 2-1
Flow chart
Trial Periods
Scre
enin
g
Run-in
Rand
omis
ation
Main treatment
EOT
2614
FU14
Safety extension15
EOT
5215
FU15
Type of visit
(V: visit, P: phone contact)
V
V
P
P
V
V
V
V
P
P
V
V
V
V
V
V
P
V
V
V
V
V
V
P
Visit number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
Timing of visit
(Weeks)
-14
-12
-11
-10
-8
-4
-1
013
113
2
4
8
12
16
21
26
1w 
after 
EOT
30
34
38
42
46
52
1w 
after 
EOT
Visit window (Days)
0
±1
±1
±3
±3
±1
±1
±1
±1
±3
±5
±5
±5
±5
±4
+3
±7
±7
±7
±7
±7
±4
+3
SUBJECT RELATED
INFO/ASSESSMENTS
Informed consent
x
In/exclusion criteria
x
x1
Randomisation
x
Randomisation criterion
x 2
Withdrawal criteria8
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Concomitant illness
x
Concomitant medication
x
x12
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Demography
x
Medical history
x
NYHA classification
x
Smoking status
x
EFFICACY
Body weight
x
x
x
x
x
x
Waist circumference
x
x
x
x
x
x
Height
x
Blood pressure
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Glucose metabolism9
HbA1c
x
x
x
x
x
x
x
x
x
x
x
x


Protocol
UTN: U1111-1164-5462
Date:
25 March 2015
Status:
Final
Novo Nordisk
Trial ID: NN2211-4174
     
Version:
2.0
Page:
14 of 103
Trial Periods
Scre
enin
g
Run-in
Rand
omis
ation
Main treatment
EOT
2614
FU14
Safety extension15
EOT
5215
FU15
Type of visit
(V: visit, P: phone contact)
V
V
P
P
V
V
V
V
P
P
V
V
V
V
V
V
P
V
V
V
V
V
V
P
Visit number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
Timing of visit
(Weeks)
-14
-12
-11
-10
-8
-4
-1
013
113
2
4
8
12
16
21
26
1w 
after 
EOT
30
34
38
42
46
52
1w 
after 
EOT
Visit window (Days)
0
±1
±1
±3
±3
±1
±1
±1
±1
±3
±5
±5
±5
±5
±4
+3
±7
±7
±7
±7
±7
±4
+3
Fasting plasma glucose
x
x
x
x
x
x
x
x
x
x
x
x
Fasting glucagon
x
x
x
x
x
Fasting insulin
x
x
x
x
x
Fasting C-peptide
x
x
x
x
x
Pro-insulin
x
x
x
x
x
Lipids
x
x
x
x
x
x
Self-measured blood
glucose: 7-point profile3
x 
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
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
ECG
x4
x
x
x
Eye examination
x5
x
x
x
Physical examination
x
x
x
x
Pulse
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Biochemistry
x
x
x
x
x
x
Haematology
x
x
x
x
x
x
Calcitonin
x
x
x
x
x
x
Technical complaints
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Pregnancy test6
x
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
x
(x)
(x)
(x)
(x)
(x)
x
TRIAL MATERIAL
Dispensing visit
x
x
x
x
x
x
x
x
x
x10
x
x
x
x
x
Hand out directions for use
x
x
x
x
x
x
x
x
x
x10
x
x
x
x
x


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Trial Periods
Scre
enin
g
Run-in
Rand
omis
ation
Main treatment
EOT
2614
FU14
Safety extension15
EOT
5215
FU15
Type of visit
(V: visit, P: phone contact)
V
V
P
P
V
V
V
V
P
P
V
V
V
V
V
V
P
V
V
V
V
V
V
P
Visit number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
Timing of visit
(Weeks)
-14
-12
-11
-10
-8
-4
-1
013
113
2
4
8
12
16
21
26
1w 
after 
EOT
30
34
38
42
46
52
1w 
after 
EOT
Visit window (Days)
0
±1
±1
±3
±3
±1
±1
±1
±1
±3
±5
±5
±5
±5
±4
+3
±7
±7
±7
±7
±7
±4
+3
Dose escalation of trial 
product
x
x
x
x
x
x7
Drug accountability
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
IV/IWRS call
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
REMINDERS
End of trial form
x
x
x
Hand-out ID card
x
Attend visit fasting
x
x
x
x
x
x
x
x
x
x
x
x
Training in trial product 
and pen handling
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Hand out and instruct in 
diary11
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Hand out and instruct in 
BG meter use
x
End of treatment
x
x
x
Sign off Casebook
x
x
Flow chart explanatory descriptions
Footer
Description
1
All screening assessments must be completed prior to initiating run-in visit (V2) and all laboratory results at screening visit (V1) must be available and signed by investigator prior to V2
2
The HbA1c results at V7 must be available and signed by investigator prior to randomising the subject. Subjects will either be randomised and have the procedures done according to the flowchart, or 
be discontinued and have procedures for EOT performed.
3
7-point SMBG profile should be obtained on a normal day in the week prior to the scheduled visit (not anticipating unusual strenuous exercise). 
4
The ECG should be obtained at V1 or between V1 and V2. The result must be available prior to performing any procedures related to V2.


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5
Fundoscopy or fundus photography performed within 90 days prior to run-in visit (V2) is acceptable, and results should be available prior to V2.
6
For women of childbearing potential: A serum pregnancy test must be performed at V1, 16 and 23. Urine pregnancy test should be performed at site if a menstrual period is missed, or if pregnancy is 
suspected.
7
If subjects do not tolerate an increase in dose during dose escalation, the dose escalation period can be extended with 1 week at the discretion of the investigator.
8
Subjects meeting withdrawal criteria should attend EOT visit as soon after treatment discontinuation as possible.
9
Calculations will be performed on glucose metabolism parameters to assess beta-cell function and insulin resistance: HOMA-B and -IR, pro-insulin/insulin ratio.
10
This assessment only applies for subjects who will be randomised to 1.8 mg/day arm.
11
Diaries should be reviewed and data transcribed into the eCRF at every visit. At the phone visits the subject must confirm verbally the entries made and upon return to the site, the entries must be 
verified.
12
When initiating the run-in period pre-trial OAD must be terminated
13
For subjects not eligible for randomisation V8 will be an EOT and V9 will be conducted as follow-up visit 7-10 days after V8. For eligible subjects Visit 8 will be a randomisation visit and they will 
proceed to either 0.9mg or 1.8mg treatment arm and Visit 9 will be a normal phone contact.
14
EOT at week 26 and subsequent FU are only relevant for 0.9 mg/day treatment arm. 1.8 mg treatment arm will attend normal V16 at week 26 and won’t need to attend V17 at week 27.
15
All assessments from V18 to V24 are only relevant for 1.8 mg/day treatment arm.


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3
Background information and rationale for the trial
The trial will be conducted in compliance with this protocol, International Conference on
Harmonisation (ICH) Good Clinical Practice (GCP)1 and applicable regulatory requirements, and in 
accordance with the Declaration of Helsinki2. 
In this document, the term investigator refers to the individual responsible for the overall conduct of 
the clinical trial at a trial site.
3.1
Background information
3.1.1
Type 2 diabetes
Type 2 diabetes mellitus (T2DM) is a progressive metabolic disease primarily characterised by 
abnormal glucose metabolism. The pathogenesis is not fully understood but seems to be 
heterogeneous, involving environmental, lifestyle, and genetic factors leading to chronic 
hyperglycaemia caused by peripheral tissue insulin resistance, impaired insulin secretion due to 
abnormal beta-cell function and abnormal glucose metabolism in the liver.3
Optimal glycaemic control is the treatment goal in subjects with T2DM, in order to prevent long-
term complications associated with chronic hyperglycaemia.4,5 Despite the availability of several 
OADs and insulin, a significant proportion of subjects with T2DM do not achieve the recommended 
blood glucose target levels.6,7,8,9,10
In addition to the need for new effective and safe glucose lowering agents, it is important to 
establish the benefits of the available marketed glucose lowering agents in order to optimise the 
individual treatment in the best possible way.
3.1.2
Glucagon-like peptide-1
Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted from the L-cells in the small 
intestine. An incretin hormone is a gut-derived peptide with important physiological function in 
augmenting post-prandial insulin secretion in response to ingestion of a meal. GLP-1 has a glucose-
dependent stimulatory effect on insulin- and inhibitory effect on glucagon secretion from the 
pancreatic islets (i.e., when plasma glucose levels are above normal).11,12,13 Both these effects are 
considered of importance for the glucose lowering effect of GLP-1.12 Physiologically GLP-1 has a 
pronounced inhibitory effect on gastric emptying.14 This effect seems to diminish upon chronic 
exposure to GLP-1.15,16 GLP-1 reduces appetite in lean and normal weight individuals, as well as in 
obese individuals,17,18,19 and has been shown to reduce body weight in people with T2DM and obese 
subjects without diabetes.20 The underlying mechanism mediating the weight-reducing effects of 
GLP-1 is most likely a combination of reduced appetite/increased satiety with a subsequent 
reduction in food intake. Patients with diabetes have a decreased incretin effect.21,22,23,24 However,
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the insulinotropic action of GLP-1 and thus the ability to lower blood glucose is preserved in 
subjects with T2DM when administered at supra-physiological levels.25
The mechanism of actions makes GLP-1 an attractive pharmacological tool for treatment of 
T2DM26,27,28 and a potential candidate for weight management.29
The very short elimination half-life (t½) of endogenous GLP-1 (t½ < 1.5 minutes after intravenous 
[i.v.] administration) due to rapid degradation by ubiquitous dipeptidyl peptidase 4 (DPP-4)30 makes 
native GLP-1 an unattractive treatment option. Clinical trials have revealed that 24-hour infusion of 
native GLP-1 would be necessary to achieve satisfactory glycaemic control.31 Therefore, to benefit 
from the potentials of GLP-1 in treatment of diabetes it has been necessary to develop GLP-1 
receptor agonists with longer half-life.
3.1.3
Liraglutide
Liraglutide is a once-daily human GLP-1 analogue, obtained by derivatising GLP-1 with a fatty
acid, providing a compound with kinetic properties suitable for once-daily injection.32 The
mechanism of protraction is believed to be self-association in the pharmaceutical solution, binding
to albumin and metabolic stability against DPP-4. This leads to delayed absorption from the s.c. 
injection site and decreased clearance. In vitro studies have shown that liraglutide is a full and 
potent agonist on the cloned human GLP-1 receptor.33,34 Animal studies have shown blood glucose 
lowering, stimulation of insulin secretion, decrease in plasma glucagon levels, inhibition of gastric 
emptying, inhibition of appetite, decreased body weight and an improved beta cell function.34
Liraglutide has been approved under the trade name Victoza® in more than 85 countries for the 
treatment of adults with T2DM, with a maximum maintenance dose of liraglutide of 1.8 mg/day. In 
Japan, Victoza® was approved by Ministry of Health, Labour and Welfare (MHLW) in 2010 with 
the indication as monotherapy and combination therapy with SU in subjects with T2DM. Thereafter, 
in Aug 2014, the indication of Victoza® has been broadened to treat T2DM without limitations [see 
Japanese Package Insert (J-PI) current version35 and its update] based on further trials. The 
currently approved maximum dose for liraglutide in Japan is 0.9 mg/day. 
The safe and efficacious use of liraglutide has been established through the clinical development of
liraglutide (the phase 3 global clinical programme) in which more than 4000 subjects were exposed 
to liraglutide. In Japanese population, four phase 3 trials in Japanese subjects including NN2211-
1700 (monotherapy), NN2211-1701 (add-on to SU) and NN2211-3924 (add-on to either glinide, 
metformin, α–GI or TZD) and NN2211-3925 (add-on to insulin) were conducted. These trials 
demonstrated the efficacy and safety of liraglutide 0.9 mg/day within these treatment scenarios. In 
addition, safety data for exposure to liraglutide at doses higher than 0.9 mg/day in Japanese subjects 
have been obtained from a phase 1 trial (NN2211-1694). In that trial, multiple escalating doses of 
liraglutide up to the dose levels of 15, 20 and 25 ∀g/kg were administered to healthy Japanese 
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subjects. When considering the higher dose levels of 20 and 25 ∀g/kg (each of which was tested in 
6 subjects), the mean absolute doses were 1.25 mg and 1.63 mg, respectively. There were no 
adverse events (AEs) reported in these subjects, and no adverse effects on laboratory parameters or 
physical examination were noted.
Liraglutide is generally well tolerated, and the AEs most frequently reported are from the 
gastrointestinal system (e.g., diarrhoea, nausea and vomiting, constipation, abdominal pain) and 
central and peripheral nervous system (e.g., dizziness and headache). These events were mostly 
mild-to-moderate in severity and typically resolved after the first 4–8 weeks. 
Cases of acute pancreatitis (including necrotising pancreatitis) presenting with persistent severe 
abdominal pain have been reported with liraglutide and other incretin based therapy in clinical trials 
and from marketed use.34,36,37 In the majority of cases there were confounding factors potentially
contributing to the diagnosis of pancreatitis. Continued safety surveillance obtained post-marketing 
has not altered the favourable risk-benefit ratio of liraglutide in this regard. The risk appears to be 
relatively small and adequately reflected in the labelling of Victoza®.
In two-year rodent carcinogenicity studies treatment with liraglutide was associated with thyroid C-
cell tumours as described below. Based on the extensive exposure to Victoza® in the post-marketing 
setting there is currently no indication of a causal relationship between treatment with Victoza® and 
the development of any cancer.
Liraglutide caused dose-dependent and treatment-duration-dependent thyroid C-cell tumours at 
clinically relevant exposures in both genders of rats and mice. It is unknown whether liraglutide 
causes thyroid C-cell tumours, including medullary thyroid carcinoma in humans, as human 
relevance has not been ruled out by clinical and non-clinical studies. Due to the findings in rodents, 
monitoring of serum calcitonin was performed during clinical trials. It is unknown whether 
monitoring of serum calcitonin will mitigate human risk of thyroid C-cell tumours.
For further information of liraglutide, please refer to investigator’s brochure34, Victoza® J-PI current 
version35 and their update.
For an assessment of benefits and risks of the trial, see section 18.
3.2
Rationale for the trial
The HbA1c lowering effect of liraglutide 0.9 mg/day in Japanese subjects with T2DM is well 
examined. The four completed phase 3 trials with liraglutide in Japanese subjects have tested 0.9 
mg/day liraglutide as monotherapy as well as in combination with OAD treatment or insulin. These 
trials demonstrated the efficacy and safety of liraglutide 0.9 mg/day within these treatment 
scenarios. Although a substantial proportion of subjects completing the trials (37% - 65%) met the 
HbA1c target of <7.0%, the fact that a proportion of subjects did not reach the target indicates that 
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there are Japanese subjects that may benefit from higher doses of liraglutide. Across trials, the 
subjects who did not reach the HbA1c target of <7.0% were characterised by mean end-of-trial 
fasting plasma glucose (FPG) levels above the Japan Diabetes Society target of good glycaemic 
control (< 130 mg/dL [< 7.2 mmol/L])38 and above the American Diabetes Association (ADA) 
target of 80–130 mg/dL (4.4–7.2 mmol/L)39.
The present trial will evaluate if Japanese subjects with T2DM who are not adequately controlled 
on liraglutide 0.9 mg/day may benefit from the dose of 1.8 mg/day approved outside of Japan. 
Treatment compliance generally decreases with increasing complexity of the treatment regimen40, 
which supports a dose increase of liraglutide if clinically indicated rather than additional anti-
diabetic medication.
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4
Objectives and endpoints
4.1
Objectives
4.1.1
Primary objective
To confirm the superiority of liraglutide 1.8 mg/day vs. liraglutide 0.9 mg/day in controlling 
glycaemia after 26 weeks of treatment in Japanese subjects with type 2 diabetes mellitus 
inadequately controlled with liraglutide 0.9 mg/day 
4.1.2
Secondary objectives
!
To compare the overall efficacy and safety parameters of liraglutide 1.8 mg/day and 
liraglutide 0.9 mg/day after 26 weeks of treatment.
!
To evaluate the safety profile of liraglutide 1.8 mg/day over a period of 52 weeks and to 
monitor glycaemic control and other efficacy parameters over a period of 52 weeks 
4.2
Endpoints
4.2.1
Primary endpoint
Change from baseline in HbA1c after 26 weeks of treatment
4.2.2
Secondary endpoints
4.2.2.1
Secondary efficacy endpoints
!
Responder for HbA1c after 26 weeks of treatment (Yes/No):
o
HbA1c < 7.0% (53 mmol/mol)*
o
HbA1c ≤ 6.5% (48 mmol/mol)*
o
HbA1c < 7.0% without weight gain
o
HbA1c < 7.0% without treatment emergent severe or blood glucose (BG) confirmed 
symptomatic hypoglycaemic episodes
!
Change from baseline after 26 weeks of treatment in:
o
Self-Measured Blood Glucose (SMBG) 7-point profile

7-point profile (individual points in the profile)
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Mean of 7-point profile

Mean of postprandial increments (from before meal to 90 min after for 
breakfast, lunch and dinner). The mean increment over all meals will be 
derived as the mean of all available meal increments.
o
Fasting plasma glucose (FPG)
o
Waist circumference
o
Body weight*
o
Body mass index (BMI)
o
Blood pressure (systolic and diastolic)
!
Fasting C-peptide, fasting insulin, fasting glucagon, proinsulin, proinsulin/insulin, HOMA-
B, HOMA-IR after 26 weeks of treatment 
!
Fasting lipid profile (total cholesterol, low density lipoprotein cholesterol [LDL cholesterol], 
high density lipoprotein cholesterol [HDL cholesterol], very low density lipoprotein 
cholesterol [VLDL cholesterol], triglycerides, and free fatty acids) after 26 weeks of 
treatment 
4.2.2.2
Secondary safety endpoints
!
Number of treatment emergent adverse events during 26 weeks of treatment*
!
Number of treatment emergent severe or BG confirmed symptomatic hypoglycaemic 
episodes during 26 weeks of treatment 
!
Number of treatment emergent nocturnal severe or BG confirmed symptomatic 
hypoglycaemic episodes during 26 weeks of treatment
!
Number of treatment emergent hypoglycaemic episodes according to ADA definition during 
26 weeks of treatment
!
Change from baseline after 26 weeks of treatment:
o
Clinical evaluations:

Physical examination

Eye examination
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Electrocardiogram (ECG)

Pulse
o
Laboratory assessments:

Biochemistry

Haematology

Calcitonin
The above mentioned primary endpoint, secondary efficacy endpoints and secondary safety 
endpoints will also be evaluated separately for 52 weeks of treatment.
* Key secondary endpoint prospectively selected for disclosure (e.g. clinicaltrials.gov and 
EudraCT)
Note; the following secondary safety endpoint for 52 weeks is also selected as key secondary 
endpoint and mentioned in section 1; number of treatment emergent adverse events during 52 weeks 
of treatment.
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5
Trial design
5.1
Type of trial
This is a 26-week randomised, parallel, two-arm, open-label, multi-centre trial comparing the 
efficacy and safety of liraglutide 1.8 mg/day to liraglutide 0.9 mg/day in Japanese subjects with 
T2DM. The liraglutide 1.8 mg/day treatment arm will be continued for a total of 52 weeks after 
randomisation for monitoring of safety and glycaemic control over 52 weeks.
Subjects on 1 OAD with an HbA1c level of 7.5-10.0%, both inclusive, will be eligible for the trial. 
At Visit 2 the pre-trial OAD will be discontinued and liraglutide 0.9 mg/day will be initiated for a 
12 week run-in period. Subjects with an HbA1c ≥7.0% at the end of run-in period will be 
randomised to the two treatment arms: continuing liraglutide 0.9 mg/day or dose escalation to 
liraglutide 1.8 mg/day, see Figure 5–1. Subjects not meeting the randomisation criterion of HbA1c
≥7.0% after run-in will not continue in the trial.
Figure 5–1
Trial design
Subjects will be randomised in a 1:1 manner, using a centralised allocation via an interactive 
voice/web response system (IV/WRS) to receive liraglutide 0.9 mg/day or dose escalation to 
liraglutide 1.8 mg/day.
Based on an anticipated screening failure rate and drop-out rate in the run-in period of both 15%, as 
well as an anticipated proportion of 50% of subjects meeting the randomisation criterion, 1301 
subjects will be screened.
The total trial duration for the 1.8 mg/day treatment arm will be approximately 67 weeks, consisting 
of 2 weeks screening period, a 12 weeks run-in period, a 26-week main treatment period, an 
extension period of 26 weeks and a follow-up visit. The total trial duration for the 0.9 mg/day 
treatment arm will be approximately 41 weeks, consisting of 2 weeks screening period, a 12 weeks 
run-in period, a 26-week treatment period, and a follow-up visit. 
EOT (Main treatment period)
EOT (Extension)
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5.2
Rationale for trial design
An open-label, randomised trial has been chosen due to the need for dose escalation in the 1.8 
mg/day treatment arm after randomisation and unchanged dose in the 0.9 mg/day treatment arm.
Blinding the trial by using a double dummy design would mean an unacceptable burden to the 
subjects and increase the trial design complexity, thereby increasing the risk of subjects 
withdrawing from the trial or being non-compliant. The double dummy design is therefore not 
considered acceptable for this trial. The primary endpoint HbA1c is a laboratory parameter and 
consequently the probability of assessment bias is limited. 
Duration of run-in period is considered adequate to obtain a stable effect of liraglutide 0.9 mg/day
on HbA1c (randomisation criterion).
Based on the data from the clinical development programme for liraglutide, the duration of 26 
weeks of treatment is considered adequate for obtaining meaningful information on efficacy and 
safety, in accordance with the trial objectives for the comparison between liraglutide 1.8 mg/day 
and liraglutide 0.9 mg/day.
The total duration of liraglutide 1.8 mg/day treatment (52 weeks) was chosen in order to investigate 
long-term safety of liraglutide 1.8 mg/day according to local requirement. 
5.3
Treatment of subjects
Subjects who enter the trial will discontinue pre-trial OAD and receive monotherapy with 
liraglutide. Liraglutide should be injected subcutaneously once daily in the thigh, upper arm or 
abdomen. Dosing can be done in the morning or the evening, but should be approximately at the 
same time of the day throughout the trial for the individual subject. Trial product will be provided in 
a prefilled device.
Antidiabetic drugs other than liraglutide are not to be used during the trial. 
During the run-in period liraglutide will be initiated with 0.3 mg/day and subsequent 0.3 mg weekly 
dose escalation to a maximum dose of 0.9 mg/day (see Table 5-1). 
Dose reduction to 0.6 mg/day of liraglutide due to AEs (for 7 days or less in total) is allowed at the 
investigator’s discretion during the run-in period. 
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Table 5-1
Liraglutide dose escalation in run-in period
1st week
2nd week
3rd week
Remaining run-in period
Liraglutide
0.3 mg/day
(50 μL=5 clicks)
0.6 mg/day
(100 μL=10 clicks)
0.9 mg/day
(150 μL=15 clicks)
0.9 mg/day
(150 μL=15 clicks)
After the 12 week run-in period subjects who are eligible for randomisation will be randomised to 
either continuation of liraglutide 0.9 mg/day or further dose escalation to liraglutide 1.8 mg/day. 
Subjects who are randomised to the liraglutide 0.9 mg/day treatment arm will continue their 
treatment unchanged for the 26-week treatment period. In the treatment period no dose reduction of 
the 0.9 mg/day dose is allowed except temporarily for safety reasons.
Subjects who are randomised to the liraglutide 1.8 mg/day treatment arm will have their dose 
escalated to 1.2 mg/day after randomisation and enter the dose escalation period of 2 weeks with 0.3 
mg weekly dose escalation to a maximum dose of 1.8 mg/day (see Table 5-2). If subjects do not 
tolerate an increase in dose during dose escalation, this dose escalation period can be extended, but 
should not extend 1 week (7 days) in total. During dose escalation period, tentative dose reduction 
will be allowed(1.8 mg/day to 1.5 mg/day or 1.5 mg/day to 1.2 mg/day, dose reduction to lower 
than 1.2 mg/day is not allowed)except temporarily for safety reasons, as long as the total 
recommended dose escalation period is within 4 weeks. All subjects in the 1.8 mg/day treatment 
arm must be at the target dose of 1.8 mg/day 28 days after randomisations at the latest. The 
Investigator must emphasise to subjects the necessity of reaching the target dose of 1.8 mg.
Table 5-2
Liraglutide dose escalation in 1.8 mg/day treatment arm
1st week
2nd week
3rd week
Remaining treatment 
period
Liraglutide
1.2 mg/day
(200 μL=20 clicks)
1.5 mg/day
(250 μL=25 clicks)
1.8 mg/day
(300 μL=30 clicks)
1.8 mg/day
(300 μL=30 clicks)
After the end of dose escalation, dose reduction in the 1.8 mg/day treatment arm to 1.5 mg or 1.2 
mg is allowed at the discretion of the investigator due to safety reasons, however, if possible this 
should not extend more than 7 days or less in total from end of dose escalation to end of treatment. 
The Investigator must emphasise to subjects the necessity of maintaining the target dose of 1.8 mg. 
If subjects do not tolerate the target dose they must be withdrawn from the trial due to safety 
concern, reporting the AE that led to the withdrawal..
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Subjects randomised to the liraglutide 1.8 mg/day treatment arm will after the 26-week main 
treatment period enter a 26-week extension period and continue treatment with liraglutide 1.8 
mg/day until 52 weeks post-randomisation.
5.4
Treatment after discontinuation of trial product
After the end of treatment (after 12 weeks of run-in period [for subjects who are ineligible for 
randomisation], 26 weeks of trial treatment period [for subjects in 0.9 mg/day treatment arm] or 52 
weeks of trial treatment period [for subjects in 1.8 mg/day treatment arm]) or at withdrawal, no trial 
products will be provided to the subjects.
At the end of treatment with trial product, the subject should be switched to a suitable marketed 
product at the discretion of the investigator.
5.5
Rationale for treatment
Liraglutide dose of 1.8 mg/day is the approved maximum maintenance dose for treatment of T2DM 
outside of Japan, and 0.9 mg/day is the currently approved maximum dose in Japan.
The dosage and administration of liraglutide 0.9 mg/day (in run-in period and treatment period in 
liraglutide 0.9 mg/day treatment arm) is set in accordance with the J-PI for Victoza®.
In liraglutide 1.8 mg/day treatment arm, in order to improve the tolerability of the 1.8 mg dose, a 
slow, stepwise dose escalation, i.e., 0.3 mg weekly dose escalation and allowance of 1 week 
extension of dose escalation period, is applied.
For the rationale for treatment duration, see section 5.2.
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6
Trial population
6.1
Number of subjects 
Number of subjects planned to be screened (i.e. documented informed consent): 1301 
Number of subjects planned to be included in the run-in period, starting liraglutide treatment: 1106
Number of subjects planned to be randomised: 470 (235 per arm)
Number of subjects expected to complete the 26 week main treatment period: 423 (withdrawal rate 
of 10%)
6.2
Inclusion criteria
For an eligible subject, all inclusion criteria must be answered “yes”. 
1. Informed consent obtained before any trial-related activities. Trial-related activities are any 
procedures that are carried out as part of the trial, including activities to determine suitability for 
the trial.
2. Male or female Japanese subjects ≥20 years of age at the time of informed consent.
3. Type 2 diabetes subjects (diagnosed clinically) ≥ 6 months prior to screening.
4. HbA1c 7.5-10.0 % [58 mmol/mol-86 mmol/mol] (both inclusive).
5. BMI ≥20 kg/m2.
6. Subjects on stable therapy with one OAD (stable therapy is defined as unchanged medication 
and unchanged dose) for ≥60 days before screening according to approved Japanese labelling.
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Rationale for the Inclusion Criteria: 
!
Criterion 1 is applied through an ethical consideration, in accordance with the GCP.1
!
Criterion 2 is applied to exclude minors through an ethical consideration. Subjects aged 65 year
or older are included in accordance with the ICH guideline: Studies in support of special
populations: Geriatrics.41
!
Criteria 3 and 4 are chosen according to the objective of the trial. Being diagnosed for 6 months
or more is included in order to ensure correct diagnosis and metabolic stabilisation. HbA1c
range (7.5-10.0 %) is chosen to include subjects whose glycaemic control is not adequate on 
OAD monotherapy and treatment with liraglutide is considered possible. The upper limit of 
HbA1c is chosen in order to exclude subjects with unacceptable glycaemic control who need a 
more intensive therapy. The lower limit of HbA1c is chosen as this trial includes a run-in period 
of treatment with liraglutide 0.9 mg/day to identify subjects who do not obtain adequate 
glycaemic control (HbA1c < 7.0%) on this dose level.
!
Criterion 5 is chosen in order to assure that subjects' BMI will not change to the low BMI 
category, since weight loss has been observed in global trials with liraglutide 1.8 mg/day.
!
Criterion 6 is applied since this trial per guideline should be a monotherapy trial and a minimum 
of treatment at entry is optimal for not risking excess hyperglycaemia. Sixty (60) days of pre-
trial OAD treatment are required to ensure that the subject's condition is stabilised.
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. Previous participation in this trial. Participation is defined as signed informed consent.
3. Female who is pregnant, breast-feeding or intend to become pregnant or of child-bearing 
potential not using adequate contraceptive methods (adequate contraceptive measures as 
required by local regulation or practice).
4. Receipt of any investigational medicinal product within 30 days prior to screening.
5. Previous treatment with insulin (except for short-term treatment in connection with intercurrent 
illness including gestational diabetes).
6. Treatment with any medication for the indication of diabetes or obesity other than stated in the 
inclusion criteria in a period of 60 days before screening.
7. Anticipated initiation or change in concomitant medications in excess of 14 days known to 
affect weight or glucose metabolism.
8. Impaired liver function, defined as alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) ≥2.5 times upper limit of normal.
9. Renal impairment eGFR <60ml/min as per CKD-EPI. 
10. Screening calcitonin ≥50 ng/l.
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11. History of pancreatitis (acute or chronic).
12. Personal or family history of MTC or MEN 2.
13. Subjects presently classified as being in NYHA Class IV (see Appendix B).
14. Within the past 180 days any of the following: myocardial infarction, stroke or hospitalisation 
for unstable angina and/or transient ischemic attack.
15. Inadequately treated hypertension, defined as Class 2 hypertension or higher 
(Systolic≥160mmHg or diastolic ≥100 mmHg), in accordance with National High Blood 
Pressure Education Program, 7th Joint National Committee and ESH/ESC 2013 guidelines.
16. Proliferative retinopathy or maculopathy requiring acute treatment as verified by fundoscopy or 
fundus photography performed within 90 days prior to run-in.
17. Diagnosis of malignant neoplasms within the last 5 years (except basal and squamous cell skin 
cancer, polyps and in-situ carcinomas).
18. Any condition which, in the opinion of the investigator might jeopardise subject’s safety or 
compliance with the protocol.
Rationale for the Exclusion Criteria: 
!
Criteria 1, 8-18 are chosen to ensure the safety of the subjects.
!
Criterion 2 is chosen in order to exclude subjects who were judged as ineligible more than once, 
since such subjects may be in an unstable condition and at risk for drop out.
!
Criterion 3 is chosen because the safety of liraglutide in pregnancy has not yet been established.
!
Criteria 4-7 are chosen to minimise factors that may influence the results.
6.4
Randomisation criterion
To be randomised, the randomisation criterion must be answered "yes".
1. HbA1c as assessed at the randomisation visit greater than or equal to 7.0% (based on the 
laboratory sample performed at Visit 7).
6.5
Withdrawal criteria
The subject may withdraw at will at any time. 
The subject may be withdrawn from the trial at the discretion of the investigator due to a safety 
concern.
Subjects not tolerating the target dose must be withdrawn from the trial due to safety concern, 
reporting the AE that led to the withdrawal.
The subject must be withdrawn from the trial if the following applies:
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1. Included in the trial in violation of the inclusion and/or exclusion criteria and/or randomised in 
violation of the randomisation criteria
2. Withdrawal of consent to proceed in the trial
3. Pregnancy
4. Intention of becoming pregnant
5. Use of any other antidiabetic medication during the trial
6. Any of the calcitonin samples analysed by the central laboratory are ≥ 50 ng/L (see Appendix 
A)
7. 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 (diagnosis is usually 
based on at least 2 of the following 3 criteria: characteristic abdominal pain, amylase and/or 
lipase > 3x upper normal range (UNR) or characteristic findings on ultrasound / computerised 
axial tomography [CT]/magnetic resonance imaging [MRI]), must be withdrawn from the trial
(see section 8.4.9).
8. Receipt of any investigational medicinal products after screening other than trial product
9. If the fasting SMBG values taken on three consecutive days or if any of the FPG samples 
analysed by the central laboratory exceeds the limit of:
!
15.0 mmol/L (270 mg/dl) during the first 6 weeks after initiation of run-in
!
13.3 mmol/L (240 mg/dl) from week 7 to week 12 after initiation of run-in
!
11.1 mmol/l (200 mg/dl ) after randomisation
given there is no intercurrent cause for the hyperglycaemia, action is to be taken by the 
investigator as soon as possible to obtain a confirmatory FPG . If there is no intercurrent cause 
for the hyperglycaemia, and FPG exceeds the limits stated above, the subject must be withdrawn.
Rationale for the Withdrawal Criteria
!
Criterion 1 is applied to withdraw the subjects enrolled or randomised in error.
!
Criterion 2 is applied since subjects can withdraw at will at any time.
!
Criterion 3 and 4 are applied because the safety of liraglutide in pregnancy has not yet been 
established.
!
Criterion 5 is applied to minimise any factors influencing the results of efficacy and safety in the 
trial.
!
Criteria 6-8 are applied for general safety concerns.
!
Criterion 9 is applied to withdraw subjects who have persistently unacceptable poor glycaemic 
control from the ethical and safety viewpoints.
6.6
Subject replacement
Subjects who are withdrawn will not be replaced.
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6.7
Rationale for trial population 
Japanese subjects with T2DM who are inadequately controlled on OAD monotherapy are eligible
for inclusion in the trial.
The trial is designed with a run-in phase to identify subjects inadequately controlled with the 
currently approved dose level for liraglutide in Japan.
Eligible subjects are presenting with an HbA1c level of 7.5-10.0 %.
The HbA1c range of 7.5-10.0 % is chosen to include a T2DM population on OAD monotherapy,
who are not optimally controlled on their current treatment and may benefit from treatment with 
liraglutide. The lower limit of the HbA1c range is set to 7.5% as this trial includes a run-in period of 
treatment with liraglutide 0.9 mg/day to identify subjects who do not obtain adequate glycaemic 
control (HbA1c < 7.0%) on this dose level. Subjects are thus required to have an HbA1c ≥ 7.0% at 
the end of run-in period (i.e. at randomisation). The efficacy of liraglutide 0.9 mg on glycaemic 
control was confirmed in the completed clinical trials (NN2211-1700, 1701, 3924 and 3925), and if 
the inclusion criterion included the HbA1c range 7.0 to 7.5% a significant proportion of subjects 
would have HbA1c below 7.0% after the run-in period and would not continue in the trial.
The randomisation criterion HbA1c ≥7.0% is chosen to randomise a T2DM population inadequately 
controlled on liraglutide 0.9 mg/day.
Subjects on OAD monotherapy are chosen since this trial per guideline should be a monotherapy 
trial and a minimum of treatment at entry is optimal for not risking excess hyperglycaemia.
As weight loss has been observed in global trials with liraglutide 1.8 mg a BMI ≥20 kg/m2 has been 
chosen in order to assure that subjects' BMI will not change to the low BMI category. 
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7
Milestones
Planned duration of recruitment period (FSFV – LSFV): 52 weeks (28-Jul-2015 to 26-Jul-2016)
Planned date for FSFV: 28-Jul-2015 
Expected/planned date for LSLV: 07-Nov-2017 
The end of the clinical trial is defined as LSLV.
Recruitment must be closed as soon as the planned number of subjects to be randomised is 
achieved.
The screening and randomisation rate will be followed closely via the interactive voice/web 
IV/WRS in order to estimate when to stop screening. All investigators will be notified immediately 
when the recruitment period ends, after which no further subjects may be screened and the IV/WRS 
will be closed for further screening. 
Trial registration:
Information of the trial will be disclosed at clinicaltrials.gov and novonordisk-trials.com and the
Clinical Trials Information/JapicCTI site (clinicaltrials.jp). According to the Novo Nordisk Code of 
Conduct for Clinical Trial Disclosure42, it will also be disclosed according to other applicable 
requirements such as those of the International Committee of Medical Journal Editors (ICMJE)43, 
the Food and Drug Administration Amendment Act (FDAAA)44, European Commission 
Requirements45,46 and other relevant recommendations or regulations. If a subject requests to be 
included in the trial via the Novo Nordisk e-mail contact at these web sites, Novo Nordisk may 
disclose the investigator’s contact details to the subject. As a result of increasing requirements for 
transparency, some countries require public disclosure of investigator names and their affiliations.
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8
Methods and assessments
8.1
Visit procedures
Throughout the trial, the investigator should ensure working in accordance with ICH GCP1 and 
local regulations. The investigator must ensure that trial procedures are performed as described in 
the protocol. Any discrepancies will result in protocol deviations and the investigator must take 
appropriate actions to avoid recurrence of the detected discrepancies. 
In addition, the investigator must keep a log of staff and a delegation of task (s) at site. Investigator 
must sign the log of staff and the delegation of task(s) at site at the time of delegation of tasks.
8.1.1
Informed Consent
Investigators must obtain informed consent for each subject before any trial related procedures. For 
information on informed consent procedure, please see section 18.1.
All subjects will be provided with a copy of their own signed and dated informed consent form.
The investigator must keep a subject screening log, a subject identification code list and a subject 
enrolment log. The subject screening log and subject enrolment log may be combined in one list. 
8.1.2
Screening (Visit 1)
For procedures and assessments performed at screening, please see flow chart (section 2).
Screening will take place within 2 weeks prior to run-in visit (Visit 2). 
At screening, subjects will be provided with a card stating that they are participating in a trial and 
giving contact address(es) and telephone number(s) of relevant trial site staff. Subjects should be 
instructed to return the card to the investigator at the last trial visit or to destroy the card after the 
last visit.
Each subject will be assigned a unique 6-digit subject number which will remain the same
throughout the trial. The first three digits in the subject number will consist of the site number and 
the last three digits of the subject number will indicate the individual number.
A screening session must be made in the IV/WRS. 
To minimise blood sampling from trial subjects, all efforts should be made to ensure that other 
screening parameters have been evaluated prior to blood sampling.
Subjects will continue on their current diabetes treatment until run-in visit (Visit 2) and they will 
not be supplied with any trial products until then.
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Once all data relating to Visit 1 have been obtained, these must be reviewed by the investigator to 
ensure that the subject is eligible to continue the trial prior to performing any procedures related to 
Visit 2.
8.1.2.1
Screening failures
For screening failures the screening failure form in the electronic case report form (eCRF) must be 
completed with the reason for not continuing in the trial. Serious adverse events from screening 
failures must be transcribed by the investigator into the eCRF. Follow-up of serious adverse events 
(SAEs) must be carried out according to section 12.2. Screening failures experiencing an AE that 
would qualify for adjudication (see section 12.7.2) will not be adjudicated as no trial product has 
been administered.
A screening failure session must be made in the IV/WRS. When all data has been monitored and all 
queries have been resolved, the case book must be signed. 
Re-sampling or re-screening is NOT allowed if the subject has failed one of the inclusion or 
exclusion criteria. 
8.1.3
Visits attended fasting
At the time points specified in the flowchart (section 2), subjects must attend the visits fasting. 
Fasting is defined as having consumed no food and drink except for water for the last 8 hours prior 
to visit. No diabetes treatment is allowed during fasting but other concomitant medication should be 
taken.
In case a subject attends a fasting visit in a non-fasting state, all non-fasting assessments should be 
performed and the subject should be asked to return to the site the day after in a fasting state to have 
fasting assessments done. If not possible the day after, re-scheduling should preferably be within the 
visit window for the relevant visit.
8.1.4
Run-in visit (Visit 2)
If the subject is found to be eligible after a review of the assessments and laboratory samples 
performed at screening (Visit 1), the subject will continue in the 12 week run-in period and receive 
trial products. No other anti-diabetic treatment is allowed during run-in period, therefore the subject 
will be instructed to discontinue pre-trial OAD on the day of Visit 2, i.e. last dose should be taken 
the day before Visit 2.
8.1.4.1
Run-in failures
If the Subject is not eligible to be randomised, i.e. has met one of the withdrawal criteria or not met 
the randomisation criterion, then the Subject will be considered a run-in failure. For run-in failures, 
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randomisation visit (Visit 8) will be End of treatment (EOT) and Visit 9 will be follow-up visit and 
this follow-up visit should be made 7-10 days after Visit 8 in contrast to the randomised subjects.
A run-in failure session must be made in the IV/WRS system and a run-in failure form must be 
completed in the eCRF together with the reason for not continuing in the trial. Subjects should be 
requested to return all used, partly used and unused trial product. 
Medical events of special interest (MESIs), serious adverse events (SAEs), adverse events (AEs) 
requiring special forms in the eCRF and non-SAEs from run-in failures must be transcribed by the 
Investigator into the eCRF. The last date of trial product must be captured. Follow-up of adverse 
events should be carried out according to section 12.3.
When data has been monitored and queries have been resolved the case book must be signed in the 
eCRF.
8.1.5
Randomisation
If the subject meets the randomisation criterion after a review of the laboratory sample performed 
at Visit 7, then the subject will be randomised into one of the 2 treatment groups by using IV/WRS
at randomisation visit (Visit 8), see section 10.
The subject will keep the same subject number as allocated at screening.
The subject must attend Visit 8 fasting. For definition of fasting please refer to section 8.1.3.
For randomisation visit procedures, please see flow chart (section 2).
8.1.6
Visit
For visit numbers, timing of visits, phone contacts and visit windows during the trial period, please 
refer to the flowchart (section 2).Visits can be re-scheduled within the allowed visit window.
It is the responsibility of the investigator to ensure that all site visits and phone contacts occur 
according to the flowchart in order to secure consistency in data over time it is encouraged that 
assessments are performed consistently (e.g. using the same type of equipment and trial site staff 
with alike qualifications) during the trial.
8.1.7
End of treatment (EOT) visit and follow-up visit
End of treatment at Visit 16 and subsequent follow-up visit (Visit 17) are only relevant for 0.9 
mg/day treatment arm. The subjects with 1.8 mg/day treatment arm will attend normal Visit 16 at 
week 26 and will not attend Visit 17.
For 1.8 mg/day treatment arm, EOT will be Visit 23 and follow-up visit will be Visit 24.
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8.1.8
Withdrawal
If a subject is withdrawn from the trial, the investigator must aim to undertake procedures similar to 
those for end of treatment visit (0.9 mg /day treatment arm: Visit 16, 1.8 mg/day treatment arm: 
Visit 23) as soon as possible after the last dose of trial product and the follow up visit (0.9 mg /day 
treatment arm: Visit 17, 1.8 mg/day treatment arm: Visit 24) should be performed 7-10 days after 
end of treatment visit. The subject should be requested to return all subject diaries and remainder of 
trial product to the site.
The end of trial form must be completed, and final drug accountability must be performed even if 
the subject is not able to come to the trial site. A withdrawal session must be made in the IV/WRS. 
When all data has been monitored and all queries have been resolved, the case book must be signed.
Although a subject is not obliged to give his/her reason(s) for withdrawing from a trial, the 
investigator must make a reasonable effort to ascertain the reason(s), while fully respecting the 
subject’s rights. Where the reasons are obtained, the primary reason for not completing the trial 
must be specified on the end-of-trial form in the eCRF.
8.2
Subject related information 
8.2.1
Concomitant illness and medical history
A concomitant illness is any illness that is present at the start of the trial or found as a result of a 
screening procedure which also includes assessments performed between Visit 1 and Visit 2 and at 
Visit 2. All concomitant illnesses should be reported including information on diabetes and diabetes 
complications.
Medical history is a medical event that the subject has experienced in the past. Only relevant 
medical history related to the evaluation of this trial should be reported at the investigator’s 
discretion.
The information collected for concomitant illness and medical history should include diagnosis, 
date of onset and date of resolution or continuation, as applicable.
Any change to a concomitant illness should be recorded in the eCRF during the trial. A clinically 
significant worsening of a concomitant illness must be reported as an AE. 
8.2.2
Concomitant medication
A concomitant medication is any medication, other than the trial product(s), which is taken during 
the trial, including the screening, run-in and follow-up periods.
Details of any concomitant medication must be recorded in the eCRF at the first visit.
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The information collected for each concomitant medication should include trade name or generic 
name, indication, start date and stop date or continuation and total daily dose (applicable only for 
antidiabetic medication).
Any changes in concomitant medication must be recorded at each visit as they occur, including 
antidiabetic treatment prescribed at the end of the trial. If a change is due to an AE, then this must 
be reported according to section 12. If the change influences the subject’s eligibility to continue in 
the trial, the monitor must be informed.
8.2.3
Demography
Demography will be recorded in the IV/WRS system at screening visit (Visit 1) and consists of:
!
Date of birth
!
Sex
In addition, the following should be captured in the eCRF:
!
Race (according to local regulation)
8.2.4
Diagnosis of diabetes
The date of diagnosis of type 2 diabetes should be recorded in the medical history/concomitant 
illness form at screening visit (Visit 1).
8.2.5
Diabetes complications
Diabetes complications should be recorded in the medical history/concomitant illness form at 
screening visit (Visit 1).
8.2.6
Diabetes treatment history
The details of pre-trial OAD should be recorded in concomitant medication form at screening visit
(Visit 1).
8.2.7
Smoking status
Details of smoking status must be recorded in the eCRF at the screening visit (Visit 1). Smoking is 
defined as smoking at least one cigarette, cigar or pipe daily. The collected information should 
include whether the subject is or has been a smoker or never has smoked. 
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8.2.8
New York Heart Association classification
The functional capacity of subjects with heart disease should be assessed according to the NYHA 
classification (please see Appendix B) and either class I, II, III, IV or ‘none’ should be captured in 
the eCRF. The assessment must be in accordance with relevant exclusion criterion.
8.3
Assessments for efficacy
8.3.1
Blood sample
Blood samples will be drawn according to flow chart (see section 2) and analysed at the central 
laboratory to determine levels of the following efficacy laboratory parameters:
Glucose metabolism:
!
HbA1c 
!
Fasting plasma glucose (FPG)
!
Fasting insulin
!
Fasting C-peptide
!
Fasting glucagon
!
Proinsulin
HOMA-B and –IR and proinsulin/insulin ratio will be calculated on glucose metabolism parameters 
to assess beta-cell function and insulin resistance.
Lipids (all fasting):
!
Total cholesterol
!
LDL-cholesterol
!
VLDL-cholesterol
!
HDL-cholesterol
!
Triglycerides
!
Free fatty acids
8.3.2
Self-measured blood glucose (SMBG)
At visit 1, subject will receive blood glucose (BG) meter to use for all SMBG measurements during 
the trial. Subject will receive written directions for use and demonstration on how to use the device 
including the performance of regular calibrations according to the manufacturer’s instructions. As 
necessary, sites should repeat the directions for use to the subject at subsequent visits. Subjects must 
be instructed to use the BG meter for all measurements of BG as defined in the protocol.
The blood glucose meters use test strips calibrated to plasma values. Therefore, all
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measurements performed with capillary blood are automatically calibrated to plasma
equivalent glucose values, which will be shown on the display.
The subject should be instructed how to record the results of the SMBG values in the provided 
diaries as agreed with the investigator. Subject should only record the SMBG values based on 
measurements obtained with the provided BG meter. The subjects must be instructed to contact the 
investigator in case of low or high SMBGs.
For all SMBG values that meet the definition of a hypoglycaemic episode (see section 8.4.6),
relevant information must be registered in the subject diary and a hypoglycaemic episode form must 
be completed in the eCRF.
7 point self-measured blood glucose profile
The subject will be instructed to perform a 7-point SMBG profile 5 times during the trial preferably 
within the week prior to site visit according to the flowchart (section 2) , on days where the subject 
does not anticipate unusual strenuous exercise.
The plasma glucose levels should be measured and recorded in the diary (including date, actual 
clock time,value) at the following time points always starting with the first.
!
Before breakfast  
!
90 min after start of breakfast 
!
Before lunch
!
90 minutes after start of lunch
!
Before dinner 
!
90 min after start of dinner 
!
At bedtime
8.3.3
Body measurement
8.3.3.1
Height
Height is measured without shoes in centimetres and recorded to nearest ½ cm. Height measured at 
Visit 1 will only be used for calculation of BMI.
8.3.3.2
Body weight
Body weight should be measured (kilogram [kg], with one decimal) without shoes and only wearing 
light clothing and recorded in the eCRF. 
Preferably the same set of scales should be used throughout the trial.
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8.3.3.3
BMI
BMI will be calculated at Visit 1 for assessment of eligibility (section 6.2) and at the other visits for 
efficacy assessment.
The BMI will be calculated by the eCRF once body weight at the visit specified in the flow chart 
(section 2) and height at Visit 1 are entered.
BMI will be calculated as follows:
BMI (kg/m2) = Body weight (kg)/(Height [m] × Height [m])
8.3.3.4
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 performed and recorded in the 
eCRF. The waist circumferences will be measured in cm using a non-stretchable measuring tape 
(measuring tapes will be provided to the sites by Novo Nordisk). It should be recorded to the 
nearest ½ cm using the same measuring tape throughout the trial
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 twists in the tape should 
be avoided. The subject should be asked to breathe normally and the measurement should be taken 
when the subject is breathing out gently. 
8.3.4
Blood pressure
Blood pressure (Systolic and diastolic blood pressure) will be measured at the visits specified in the 
flowchart (section 2).
Blood pressure must be measured after the subject has been resting for at least 5 minutes and by 
using the standard clinical practice at the site.
For blood pressure measurements at the screening visit (Visit 1), three measurements must be 
performed and all three values must be entered into the eCRF. The mean value will be calculated by 
the eCRF and must be in accordance with the relevant exclusion criterion. 
It is recommended to use the same arm and the same device and cuff as used at the first visit for the 
subsequent measurements. For the subsequent visits, only one measurement needs to be performed.
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If the investigator suspects white-coat hypertension at the screening visit (Visit 1), one re-
assessment of the systolic and diastolic blood pressure (as described above) is allowed and the mean 
of the three new measurements will be conclusive. These repeated measurements must be 
performed prior to any other study activities at the run-in visit to confirm eligibility.
8.4
Assessments for safety
8.4.1
Adverse events (AEs)
All AEs must be collected and reported according the procedure described in section 12.
8.4.1.1
Adverse Events requiring special forms in the eCRF 
For some AEs the Investigator must fill in special forms in the eCRF. The AEs that require special 
forms in the eCRF are:
!
Cardiovascular events
!
Pancreatitis
!
Neoplasm
!
Thyroid disease
In case any of these events fulfil the criteria for a SAE, please report accordingly. See section 12.1.
Certain events occurring in subjects eligible for the trial will be evaluated by an external and 
independent Clinical Safety Event Adjudication Committee in accordance with section 12.7.2.
Cardiovascular events
Cardiovascular events that are suspected as being related to: 
!
Acute coronary syndrome 
All types of myocardial infarction (MI) or hospitalisation for unstable angina, for further 
information see Appendix C. If an event of acute coronary syndrome (ranging from unstable angina 
pectoris to MI) is observed during the trial, this must be recorded as an AE and on a specific acute 
coronary syndrome form in the eCRF. The following information must be reported if available:
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o
Duration of symptoms
o
Changes in ECG
o
Collection of cardiac biomarkers
o
Cardiac imaging
o
Cardiac stress testing
o
Angiography
o
Use of thrombolytic drugs
o
Revascularisation procedures 
!
Cerebrovascular events, e.g. transient ischemic attack (TIA), stroke
If a cerebrovascular event is observed during the trial, this must be recorded as an AE and on a 
specific cerebrovascular event form in the eCRF. The following information must be reported if 
available: 
o
Type of event (e.g. TIA, Stroke)
o
Contributing condition
o
Neurologic signs and symptoms
o
History of neurologic disease
o
Imaging supporting the condition
o
Treatment given for the condition
!
Heart failure requiring hospitalisation
If an event of heart failure requiring hospitalisation (admission to an in-patient unit or a visit to an 
emergency department that results in at least a 24 hour stay) is observed during the trial, this must 
be recorded as an SAE and in addition on a specific cardiovascular event form in the eCRF. The 
following information must be reported if available: 
o
Signs and symptoms of heart failure
o
NYHA Class
o
Supportive imaging
o
Supportive laboratory measurements
o
Initiation or intensification of treatment for this condition
Pancreatitis
If an event of Pancreatitis is observed during the trial, this must be recorded as an AE and on a 
specific Pancreatitis event form in the eCRF. The following information must be reported if 
available: 
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!
Signs and symptoms of Pancreatitis
!
Specific laboratory test supporting a diagnosis of pancreatitis:
o
Amylase
o
Lipase
o
ALT and AST 
o
Bilirubin
o
Alkaline Phosphatase (AP)
!
Imaging performed and consistency with pancreatic disease
!
Complications to the event
!
Relevant risk factors for Pancreatic disease including:
o
History of gall-stones
o
History of pancreatitis
o
Family history of pancreatitis
o
Trauma
Thyroid disease
Subjects scheduled for thyroidectomy (partial or total) for any reason during the trial, must be 
instructed to inform the investigator prior to their operation. If an event of thyroid disease, including 
any thyroid neoplasms is observed during the trial, this must be recorded as an AE and on a specific 
thyroid disease event form in the eCRF. The following information must be reported if available: 
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!
History of thyroid disease
!
Signs and symptoms leading to investigations of thyroid disease
!
Specific laboratory tests describing thyroid function including:
o
Thyroid stimulating hormone (TSH)
o
Total and free T3 and T4 and Free Thyroid Index
o
Calcitonin
o
Thyroid Peroxidase antibodies
o
Thyroglobulin and Thyroglobulin antibody
o
TSH receptor antibody
!
Diagnostic imaging performed and any prior imaging supporting the disease history 
!
Pathologic examinations
!
Treatment given for the condition
!
Risk factors identified
!
Family history of Thyroid disease
Neoplasm
All events of neoplasm (excluding thyroid neoplasm, but including malignant neoplasm, in situ 
neoplasm and benign neoplasm) must be recorded as an AE and on a specific neoplasm event form 
in the eCRF. The following information must be reported if available: 
!
Type of neoplasm
!
Symptoms leading to identification of event
!
Diagnostic imaging
!
Pathological examination results
!
Treatment for the event
!
Participation in screening programs
!
Risk factors associated to the event
8.4.2
Blood samples
Blood samples must be drawn according to flow chart (section 2) and will be analysed at the central 
laboratory to determine levels of the following safety laboratory parameters:
!
Haematology:
o
Haemoglobin
o
Haematocrit
o
Thrombocytes
o
Erythrocytes
o
Leucocytes
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–
Differential count (eosinophils, neutrophils, basophils, monocytes and lymphocytes)
!
Biochemistry:
o
Creatinine
–
eGFR value will be calculated using the serum creatinine result and the CKD-EPI 
formula by the central laboratory.
o
Alanine aminotransferase (ALT)
o
Aspartate aminotransferase (AST)
o
Alkaline phosphatase
o
Sodium
o
Potassium
o
Albumin
o
Bilirubin (total)
o
Urea
o
Creatine kinase
o
Calcium total
o
Calcium (albumin corrected)
o
Lipase
o
Amylase
!
Calcitonin (please refer to the Appendix A for actions to be taken if calcitonin is ≥ 10 ng/L)
8.4.3
Electrocardiogram (ECG) – 12 lead
A 12-lead ECG must be performed and interpreted locally by the Investigator and to document this, 
the Investigator must sign and date the ECG print out and the interpretation must follow the 
categories:
!
Normal
!
Abnormal
o
Specify abnormality
o
Was the result clinically significant? (Yes/No)
A 12-lead ECG should be obtained at screening visit (Visit 1) or between Visit 1 and run-in visit 
(Visit 2). The result must be available prior to performing any procedures related to Visit 2.
Any abnormalities found up to Visit 2 should be recorded as a concomitant illness. Any new 
abnormal, clinically significant finding during the trial and any clinically significant worsening 
from ECG performed at baseline (up to Visit 2) must be reported as an AE (see section 12).
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8.4.4
Eye Examination
Fundoscopy/fundus photography must be performed at the visits specified in the flowchart (see 
section 2) by the Investigator or a local Ophthalmologist according to local practice. Dilation is not 
requirement. The result of the fundoscopy/fundus photography will be interpreted locally by the 
Investigator. To document this, the Investigator must sign and date the result page and the 
interpretation must follow the categories:
!
Normal
!
Abnormal
o
Specify abnormality
o
Was the result clinically significant? (Yes/No)
Any abnormalities found as a result of a screening procedure which also includes assessments 
performed between Visit 1 and Visit 2 should be recorded as a concomitant illness. Any new 
abnormal, clinically significant finding during the trial and any clinically significant worsening 
from Fundoscopy/fundus photography performed at baseline (up to Visit 2) must be reported as an 
AE (see section 12).
Fundoscopy/fundus photography performed within 90 days prior to run-in visit is acceptable. If a 
funduscopy/fundusphotography has been performed prior to the screening visit (Visit 1) the 
procedure does not need to be repeated, unless worsening of visual function since the last 
examination has been noted. The investigator must still interpret, sign and date the result page. If 
fundoscopy or fundus photography is performed before a subject has signed the informed consent
form, it must be documented in the medical record that the reason for performing the procedure was
not related to the present trial.
8.4.5
Physical Examination
A physical examination must be performed at the visits specified in the flowchart (section 2) and 
must include:
!
General appearance
!
Head, ears, eyes, nose, throat, neck
!
Thyroid gland
!
Respiratory system
!
Cardiovascular system
!
Gastrointestinal system (including mouth)
!
Musculoskeletal system
!
Central and peripheral nervous system
!
Skin
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!
Lymph node palpation
The interpretation must follow the categories:
!
Normal
!
Abnormal
o
Specify abnormality
o
Was the result clinically significant? (Yes/No)
Any clinically significant abnormalities found at the screening visit (Visit 1) should be recorded as 
concomitant illness. Any new abnormal, clinically significant finding during the trial and any 
clinically significant worsening from a physical examination performed at baseline (up to Visit 2)
must be reported as an AE (see section 12).
8.4.6
Hypoglycaemic episodes
Blood glucose should always be measured and recorded when a hypoglycaemic episode is 
suspected. 
All plasma glucose values:
!
≤ 3.9 mmol/L (70 mg/dL) or 
!
> 3.9 mmol/L (70 mg/dL) when they occur in conjunction with hypoglycaemic symptoms
should be recorded by the subject in the subject diary. These must be transcribed into the eCRF 
(hypoglycaemic episode form) throughout the trial from visit 1 to Visit 9 (for subjects who are not 
randomised)/Visit 17 (for 0.9 mg/day treatment arm)/Visit 24 (for 1.8 mg/day treatment arm) as 
according to the flowchart (section 2). 
The record should include the following information:
!
Date and time of hypoglycaemic episode 
!
The plasma glucose level before treating the episode (if available) 
!
Whether the episode was symptomatic 
!
Whether the subject was able to treat him/herself, if no: 
–
Who assisted in the treatment of the hypoglycaemic episode (ie family/friend/co-worker 
or similar, paramedic, doctor or other, please specify)
–
Where the treatment was administered (ie at home/at friends/at work or similar, in an 
ambulance, emergency room/hospital or other, please specify)
–
Type of treatment provided by other person (ie oral carbohydrates, glucagon, IV glucose 
or other, please specify)
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–
Were symptoms alleviated by the administration of treatment?
–
Factors contributing to the episode (ie physical activity, missed meal, diet changed, 
medication error (ie overdose, mix-up between products), other factors not listed, please 
specify or none)
–
Did the subject experience seizure?
–
Was the subject unconscious/comatose?
–
Did the subject experience any of the following symptoms?47
o
Autonomic: sweating, trembling, hunger or palpitations
o
Neuroglycopenic: confusion, drowsiness, speech difficulty, visual 
disturbances, odd behaviour, impaired balance or incoordination
o
General malaise: headache or malaise
–
Did the subject experience other symptoms? Please specify
–
Further description of the episode
!
Type, date and time of last trial product and other antidiabetic drug administration prior to 
episode 
!
Date and time of last main meal prior to episode
!
Whether the episode occurred in relation to physical activity
The answer to the question: "Was subject able to treat him/herself?" must be answered "No" for an 
episode requiring assistance of another person to actively administer carbohydrate, glucagon, or 
take other corrective actions. Plasma glucose concentrations may not be available during an event, 
but neurological recovery following the return of plasma glucose to normal is considered sufficient 
evidence that the event was induced by a low plasma glucose concentration48. 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 then an AE form and a safety information 
form must also be filled in, see section 12.
For all FPG values measured by central laboratory that meet the definition of a hypoglycaemic 
episode, a hypoglycaemic episode must be recorded in a hypoglycaemic episodes form. 
8.4.7
Pulse
Pulse (beats per minute) should be recorded in the eCRF at site visits after resting for 5 minutes in a 
sitting position.
8.4.8
Pregnancy test
Females of childbearing potential must have a blood pregnancy test (beta-human chorionic 
gonadotropin [beta-hCG]) performed according to section 2.
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Urine pregnancy tests will be performed at site during the trial for females of childbearing potential 
if a menstrual period is missed (unless this is a part of the mode of action of the contraceptive 
method) or if pregnancy is suspected.
If at the telephone contact, subject reports missing menstrual period, the subject will have to attend 
the site as soon as possible to have a urine-stick pregnancy test done.
Pregnancy test will not be required for women who have undergone a hysterectomy or tubal ligation, 
or for women above the age of 50, who have been without menses for at least 1 year. This must be 
documented in the subject’s medical record and eCRF.
8.4.9
Assessments in case of suspicion of acute pancreatitis
In case of acute, severe persistent abdominal pain leading to a suspicion of acute pancreatitis, the 
trial product should promptly be interrupted until pancreatitis is ruled out. Appropriate additional 
examinations must be performed, including local measurement of amylase and lipase. If acute 
pancreatitis is ruled out trial product should be re-initiated. If the discontinuation period is for three 
days and more, the trial product should be restarted with a dose of 0.3 mg/day, and dose escalation 
procedure described in section 5.3 should be followed.
Appropriate treatment and careful monitoring of the subject should be initiated if pancreatitis is 
confirmed (as a minimum 2 of 3): 
!
severe acute abdominal pain
!
amylase and/or lipase >3x upper normal range (UNR)
!
characteristic findings on relevant imaging (e.g. CT/MRI/ultrasound)
The event must be recorded as an AE and on a specific Pancreatitis event form in the eCRF and will 
undergo assessment by the Event adjudication committee (EAC) (see section 12.7.2).
8.5
Laboratory assessments
All laboratory samples will be analysed by a central laboratory contracted by Novo Nordisk. The 
central laboratory will provide all laboratory supplies for the sampling and transportation of all 
blood samples taken during the trial. The central laboratory may utilise Subcontractors.
A detailed description of the procedures for obtaining samples, handling, storage and shipment of 
the samples are specified in a trial-specific laboratory manual provided to the sites by the central 
laboratory. Information regarding laboratory materials such as tubes and labels are also described. 
Laboratory samples can be drawn 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)
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Samples will be coded in order to keep Subject’s identity anonymous.
Laboratory results will be made available by the central laboratory. Laboratory reports must be 
reviewed, dated and signed by the Investigator on the day of evaluation. It must be specified 
whether out of range results are clinically significant.
If any clinically significant abnormalities will be found as a result of screening procedures which 
also includes assessments performed between Visit 1 and Visit 2 and at Visit 2 then these must be 
recorded on the concomitant illness/medical history form in the eCRF. Any clinically significant 
deterioration of a pre-existing condition as well as any new clinically significant signs or symptoms 
should be reported as an AE in accordance with section 12.
The laboratory equipment may provide analyses not requested in the protocol but produced 
automatically in connection with the requested analyses according to specifications in the laboratory 
standard operating procedures. Such data will not be transferred to the trial database, but abnormal 
values will be reported to the investigator. The investigator must review all laboratory results for 
concomitant illnesses and AEs and report these according to this protocol.
8.6
Other assessments
8.6.1
Subject diary
The subjects must be provided with the subject diaries at the specified visits (section 2). The 
investigator and/or delegate or site staff should instruct subjects to record the following in the diary:
!
Date and value of all SMBG and also actual clock time of the 7-point SMBG measurements 
!
Date, dose and injection site for first dose of trial product
!
Dose of trial product one day prior to visit/phone contact during dose escalation
!
Date for last dose of trial product
!
Hypoglycaemic episodes
!
Medical problems
!
Changes in concomitant medication
The Investigator and/or delegate or site staff is allowed to record the following in the diary:
!
Prescribed doses of trial product
!
Time and date of next visit and/or phone contact
!
Subject ID and site contact details
It is the responsibility of the investigator to review the diary for possible AEs (see section 12), 
hypoglycaemic episodes (see section 8.4.6) and concomitant medication (see sections 8.2.2). 
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Review of the diaries must be documented either on the front page of the documents and/or in the 
Subject’s medical record. The investigator and/or delegate or site staff must transcribe data from the 
diary into the eCRF throughout the trial. If necessary, the investigator and/or delegate or site staff 
should convert the format of data used by the subject into the format used in the eCRF. The diaries 
dispensed to subjects at a previous visit should be collected at the following site visit.  
If clarification of entries or discrepancies in the diary is needed, the subject should be questioned 
and a conclusion made in the medical record. Care should be taken not to bias the subject.
8.7
Subject compliance
Throughout the trial, the investigator will remind the subjects to follow the trial procedures and 
requirements to ensure subject compliance. To ensure subject compliance, the investigator will at 
each visit assess the subject’s compliance by evaluating the glycaemic control, adherence to the 
visit schedule, drug accountability and completion of the subject’s diary. If a subject is found to be 
non-compliant, the investigator will remind the subject of the importance of following the 
instructions given including taking the trial products as prescribed and the 7-points SMBG profiles.
Treatment compliance will be assessed by monitoring of drug accountability. Prior to visits where 
drug accountability is performed the subject will be asked to return all used, partly used and unused 
investigational medicinal products (IMPs). The investigator must assess the amount of IMPs 
returned compared to what was dispensed at the last dispensing visit and, in case of discrepancies, 
question the subject.
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9
Trial supplies
Trial supplies comprise trial products and auxiliary supplies. Additional details regarding trial 
supplies can be found in the Trial Materials Manual (TMM). 
Trial products must not be dispensed to any person not included in the trial
Liraglutide must not be used, if it does not appear clear and colourless or almost colourless.
9.1
Trial products
The following trial products will be provided by Novo Nordisk A/S, Denmark:
Trial product
Strength
Dosage form
Route of 
administration
Delivery device
Liraglutide 6.0mg/mL
(Investigational 
medicinal products: 
[IMPs])
6.0 mg/mL
Solution for 
injection
Subcutaneous 
injection (s.c.)
3 mL FlexPen®
9.2
Labelling
The trial products will be labelled in accordance with Annex 1349, local regulations and trial 
requirements. Please refer to the TMM provided by Novo Nordisk for details regarding standard 
packages and handling of trial product.
Each trial site will be supplied with sufficient trial products for the trial on an on-going basis 
controlled by the IV/WRS. Dispensing unit numbers (DUNs) will be distributed to the trial sites 
according to enrolment and randomisation. 
The investigator must document that direction for use (DFU) is given to the subject orally and in 
writing at each dispensing visit.
9.3
Storage 
Liraglutide (both not in-use and in-use) must not be exposed to excessive heat or direct light.
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Srorage condition for Liraglutide: 
Trial product
Storage conditions
(not-in-use)
In-use conditions
In-use time*
Liraglutide 6.0mg/mL 
!
Store in a refrigerator  
between 2°C to 8°C 
!
Protect from light
!
Do not freeze
!
Store at room 
temperatures not above
30°C
!
Protect from light
!
Do not freeze
!
Use within 
30 days
*In-use time starts when first dose is taken or when carried as a spare.
The investigator, the head of the study site or the trial product storage manager (if assigned by the 
head of the study site) must ensure the availability of proper storage conditions, and also record and 
evaluate the temperature. A temperature log must be kept to document storage within the right 
temperature interval and storage facilities should be checked frequently.
The investigator, the head of the study site or the trial product storage manager (if assigned by the 
head of the study site) must inform Novo Nordisk immediately if any trial product has been stored 
outside specified conditions (e.g. outside temperature range) and register the product as out of 
temperature in the IV/WRS.
Trial product that has been stored improperly must not be dispensed to any subject and must be 
stored separately from other trial products but within allowed temperature range before it has been 
evaluated and approved for further use by Novo Nordisk. The investigator must take appropriate 
action to ensure correct storage.
9.4
Drug accountability and destruction
Drug accountability is the responsibility of the investigator and/or the head of the study site or the 
trial product storage manager if assigned by the head of the study site.
The trial product will be dispensed to each subject as required according to treatment group. The 
IV/WRS will allocate trial product DUN to the subject at each dispensing visit. The correct DUN 
must be dispensed to the subject.
The investigator, the head of the study site or the trial product storage manager (if assigned by the 
head of the study site) will perform drug accountability using the IV/WRS drug accountability 
module. Only dispensed DUNs returned by the subject (used/partly used or unused) are accounted 
for.
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Subjects are instructed to return all used, partly used and unused trial product including empty 
packaging material at each dispensing visit and at the end of treatment visit.
Returned trial product (used/partly used or unused including empty packaging material) can be 
stored at room temperature and must be stored separately from non-allocated trial product.
Destruction of trial products will be done according to local law after accountability is finalised at 
site and reconciled by monitor. Destruction of trial products must be documented.
9.5
Auxiliary supplies
The DFU will be supplied by Novo Nordisk A/S, Denmark and the following auxiliary supplies will 
be supplied by Novo Nordisk Pharma Ltd. in accordance with the TMM. The trial sites are allowed 
to purchase and supply themselves with auxiliary supplies, if possible.
!
Needles for the device
!
Blood glucose meters (BG meters) and BG meter auxiliaries
!
Glucose for treating a hypoglycaemia
!
Urine pregnancy test kit
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10
Interactive voice/web response system
A trial-specific IV/WRS will be set up which can be accessed at any time via the internet or 
telephone. Access to the IV/WRS must be restricted to and controlled by authorised persons. 
IV/WRS is used for: 
!
Screening
!
Screening failure
!
Run-in failure
!
Randomisation
!
Medication arrival
!
Run-in dispensing
!
Dispensing (including additional dispensing)
!
Withdrawal
!
Completion
!
Drug accountability
!
Data change
It is important that at all times during the trial only DUNs allocated by the IV/WRS are dispensed to 
the Subject. 
If a Subject requires additional trial product between dispensing visits, the site must perform an 
additional dispensing session in IV/WRS. 
IV/WRS user manuals will be provided to each trial site.
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11 Randomisation procedure
The trial is an open-labelled trial. A randomisation will be conducted at the randomisation visit 
(Visit 8). The subjects meeting randomisation criterion will be randomised at the ratio of 1:1 to
liraglutide 0.9 mg/day or dose escalation to liraglutide 1.8 mg/day.
Randomisation will be performed using the IV/WRS system (section 10).
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12 Adverse events, and technical complaints and pregnancies
12.1
Definitions
Adverse event 
An adverse event (AE) is any untoward medical occurrence in a subject administered a product, and 
which does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom or disease temporally associated with the use of a product, whether or not 
considered related to the product. 
An AE includes:
!
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 which also 
includes assessments performed between Visit 1 and Visit 2 and at Visit 2 (pre-existing 
conditions should be reported as medical history or concomitant illness).
!
Pre-planned procedures unless the condition for which the procedure was planned has worsened 
from the first trial related activity after the subject has signed the informed consent.
!
Non-serious hypoglycaemia is an AE, but is reported on a hypoglycaemic episode form instead 
of on an AE form, see section 8.4.6.
The following three definitions are used when assessing an AE:
!
Severity 
–
Mild - no or transient symptoms, no interference with the subject's daily activities.
–
Moderate - marked symptoms, moderate interference with the subject's daily activities.
–
Severe - considerable interference with the subject's daily activities; unacceptable.
!
Causality 
Relationship between an AE and the relevant trial product(s): 
–
Probable - Good reason and sufficient documentation to assume a causal relationship.
–
Possible - A causal relationship is conceivable and cannot be dismissed.
–
Unlikely - The event is most likely related to aetiology other than the trial product.
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!
Final outcome
–
Recovered/resolved - The subject has fully recovered, or by medical or surgical 
treatment the condition has returned to the level observed at the first trial-related activity 
after the subject signed the informed consent.
–
Recovering/resolving - The condition is improving and the subject is expected to 
recover from the event. This term is only applicable if the subject has completed the trial 
or has died from another AE.
–
Recovered/resolved with sequelae - The subject has recovered from the condition, but 
with lasting effect due to a disease, injury, treatment or procedure. If a sequela meets an 
SAE criterion, the AE must be reported as an SAE.
–
Not recovered/not resolved - The condition of the subject has not improved and the 
symptoms are unchanged, or the outcome is not known.
–
Fatal - This term is only applicable if the subject died from a condition related to the 
reported AE. Outcomes of other reported AEs in a subject before he/she died should be 
assessed as "recovered/resolved", "recovering/resolving", "recovered/resolved with 
sequelae" or "not recovered/not resolved". An AE with fatal outcome must be reported 
as an SAE.
–
Unknown - This term is only applicable if the subject is lost to follow-up.
Serious adverse event
A serious adverse event (SAE) is an experience that at any dose results in any of the following:
!
Death.
!
A life-threateninga experience.
!
In-patient hospitalisationb or prolongation of existing hospitalisation.
!
A persistent or significant disability or incapacityc.
!
A congenital anomaly or birth defect.
!
Important medical events that may not result in death, be life threateninga or require 
hospitalisationb may be considered an SAE when - based on appropriate medical judgement -
they may jeopardise the subject and may require medical or surgical intervention to prevent one 
of the outcomes listed in the definition of SAEd. 
Suspicion of transmission of infectious agents via the trial product must always be considered 
an SAE. 
a.
The term "life threatening" in the definition of SAE refers to an event in which the subject was 
at risk of death at the time of the event. It does not refer to an event which hypothetically might 
have caused death if it was more severe.
b. The term "hospitalisation" is used when a subject: 
–
Is admitted to a hospital or in-patient, irrespective of the duration of physical stay, or 
–
Stays at the hospital for treatment or observation for more than 24 hours
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Medical judgement must always be exercised, and when in doubt, the hospital contact should be 
regarded as a hospitalisation. Hospitalisations for administrative, trial related and social 
purposes do not constitute AEs and should therefore not be reported as AEs or SAEs. Hospital 
admissions for surgical procedures, planned before trial inclusion, are not considered AEs or 
SAEs.
c.
A substantial disruption of a subject's ability to conduct normal life functions (e.g. following the 
event or clinical investigation the subject has significant, persistent or permanent change, 
impairment, damage or disruption in his/her body function or structure, physical activity and/or 
quality of life).
d. For example intensive treatment in an emergency room or at home of allergic bronchospasm, 
blood dyscrasiasis or convulsions that do not result in hospitalisation, or development of drug 
dependency or drug abuse.
Non-serious adverse event
A non-serious AE is any AE which does not fulfil the definition of an SAE.
Medical event of special interest
A medical event of special interest (MESI) is an event which, in the evaluation of safety, has a 
special focus. A MESI is an AE (SAE or non-serious AE) which fulfils the below defined MESI 
criteria.
!
Medication errors concerning trial products:
–
Administration of wrong drug 
Note: Use of wrong DUN is not considered a medication error unless it results in 
administration of wrong drug.
–
Wrong route of administration, such as intramuscular instead of subcutaneous.
–
Administration of an overdose with the intention to cause harm (e.g. suicide attempt).
–
Accidental administration of a lower or higher dose than intended, however the 
administered dose must deviate from the intended dose to an extend where clinical 
consequences for the trial subject were likely to happen as judged by the investigator, 
although not necessarily did happen.
Adverse events with additional data collection 
AEs with additional data collection are AEs defined as critical for the evaluation of product safety. 
For these AEs the Investigator must fill in additional forms in the eCRF. The AEs that require 
additional forms in the eCRF are:
1. Acute coronary syndrome (MI or hospitalisation for unstable angina) 
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2. Cerebrovascular event (stroke or TIA)
3. Heart failure requiring hospital admission
4. Neoplasms
5. Pancreatitis 
6. Thyroid disorders 
For detailed information on AEs with additional data collection, see section 8.4.1.1.
Along with fatal events, certain events of interest will be adjudicated by an external independent 
EAC as described in section 12.7.2.
For further information regarding definitions, rationales, and events that will be adjudicated, see 
Appendix C.
Technical complaint
A technical complaint is any written, electronic, or oral communication that alleges product 
(medicine or device) defects. The technical complaint may be associated with an AE, but does not 
concern the AE itself.
Examples of technical complaints:
!
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 devices (e.g. to the injection mechanism, dose setting mechanism, push 
button or interface between the pen and the needle)
12.2
Reporting of adverse events
All events meeting the definition of an AE must be collected and reported. This includes events 
from the first trial-related activity after the subject has signed the informed consent until the end of 
the post-treatment follow-up period (Run-in failure: Visit 9, 0.9 mg/day treatment arm: Visit 17, 1.8 
mg/day treatment arm: Visit 24). The events must be recorded in the applicable CRF forms in a 
timely manner, see timelines below and Figure 12–1. 
During each contact with the trial site staff, the subject must be asked about AEs, for example by 
asking: "Have you experienced any problems since the last contact?"
All AEs, either observed by the investigator or subject, must be reported by the investigator and 
evaluated. Novo Nordisk assessment of expectedness is performed according to the following 
reference documents: 
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!
Company Core Data Sheet for Victoza® 6.0 mg/mL, Current version and any updates hereof
All AEs must be recorded by the investigator on an AE form. The investigator should report the 
diagnosis, if available. If no diagnosis is available, the investigator should record each sign and 
symptom as individual AEs using separate AE forms.
For SAEs, a safety information form must be completed in addition to the AE form. If several 
symptoms or diagnoses occur as part of the same clinical picture, one safety information form can 
be used to describe all the SAEs. 
For AEs requiring additional information, a specific event form in addition to the AE form must be 
completed.
MESIs, regardless of seriousness, must be reported using the AE form and the safety information 
form and a MESI form. The MESI form is a form tailored to collect specific information related to 
the individual MESI.
The AE form for a non-serious AE not fulfilling the MESI criteria should be signed when the event 
is resolved or at the end of the trial.
Timelines for initial reporting of AEs:
The investigator must complete the following forms in the eCRF within the specified timelines:
!
SAEs: The AE form within 24 hours and the safety information form within 5 calendar days 
of the investigator's first knowledge of the SAE. Both forms must be signed within 7 calendar 
days from the date the information was entered in the eCRF. For SAEs with additional data 
collection: in addition also the specific event form within 14 calendar days of the investigator's 
first knowledge of the AE. 
!
SAEs fulfilling the MESI criteria: In addition to above, the MESI form within 14 calendar 
days of the investigator's first knowledge of the AE. 
!
Non-serious AE fulfilling the MESI criteria: The AE form, and safety information form and 
MESI form within 14 calendar days of the investigator's first knowledge of the event.
!
Non-serious AEs with additional data collection: The AE form and the specific event form 
within 14 calendar days of the investigator's first knowledge of the event.
!
Events for adjudication: Event Adjudication Document Collection Form must be populated 
within 14 calendar days. The investigator should provide the medical documentation within 4 
weeks of event identification
If the eCRF is unavailable, the concerned AE information must be reported on paper forms and sent 
to Novo Nordisk by fax, e-mail or courier within the same timelines as stated above. When the 
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eCRF becomes available again, the investigator must enter the information on the appropriate forms 
in the eCRF. 
Contact details (fax, telephone, e-mail and address) are provided in the investigator trial master file. 
An AE is 
observed and 
reported 
It is an SAE
complete:
!
AE form ≤ 24 hours
!
SIF ≤ 5 calendars days
It is a non-serious AE
complete:
!
AE form
Fulfilling 
seriousness 
criteria?
Additional 
data 
collection 
requeried?
Additional 
data collection 
required?
Complete ≤ 14 calendar 
days:
!
Specific event form
!
For medication Error 
(MESI): Medication 
Error form 
No additional forms to 
be completed
Complete ≤ 14 calendar 
days: 
!
Specific event form
!
For Medication Error 
(MESI):  SIF and 
Medication Error 
form
Yes
No
Yes
No
Yes
No
Is the AE 
category 
selected for 
adjudication?
Complete ≤ 14 
calendar days:
!
Adjudication 
form 
Yes
No additional forms 
to be completed
No
AE: Adverse Event
SIF: safety information form
All timelines are from the investigator’s
first knowledge of the event
Figure 12–1
Initial reporting of AEs
Reporting of trial product-related SUSARs by Novo Nordisk:
Novo Nordisk will notify the investigator of trial product-related suspected unexpected serious 
adverse reactions (SUSARs) in accordance with local requirements and GCP1. In addition, the 
investigator will be informed of any trial-related SAEs that may warrant a change in any trial 
procedure.
In accordance with regulatory requirements, Novo Nordisk will inform the regulatory authorities, 
including EMA, of trial product-related SUSARs. In addition, Novo Nordisk will inform the IRBs 
of trial product-related SUSARs in accordance with local requirement and GCP1, unless locally this 
is an obligation of the investigator.
12.3
Follow-up of adverse events
The investigator must record follow-up information by updating the forms in the eCRF. 
Follow up information must be reported to Novo Nordisk according to the following:
!
SAEs: All SAEs must be followed until the outcome of the event is “recovered/resolved”, 
“recovered/resolved with sequelae” or “fatal”, and until all queries have been resolved. Cases of 
chronic conditions, cancer or AEs ongoing at time of death (where death is due to another AE) 
may be closed with the outcome “recovering/resolving” or “not recovered/not resolved”. Cases 
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can be closed with the outcome of “recovering/resolving” when the subject has completed the 
follow-up period and is expected by the investigator to recover.
The SAE follow-up information should only include new (e.g. corrections or additional) 
information and must be reported within 24 hours of the investigator's first knowledge of the 
information. This is also the case for previously non-serious AEs which subsequently become 
SAEs. 
!
Non-serious AEs: Non-serious AEs must be followed until the outcome of the event is 
“recovering/resolving”, “recovered/resolved” or “recovered/resolved with sequelae” or until the 
end of the follow-up period stated in the protocol, whichever comes first, and until all queries 
related to these AEs have been resolved. Cases of chronic conditions, cancer or AEs ongoing at 
time of death (where death is due to another AE) may be closed with the outcome 
“recovering/resolving” or “not recovered/not resolved”. Cases can be closed with the outcome 
of “recovering/resolving” when the subject has completed the follow-up period and is expected 
by the investigator to recover.
!
Non-serious AE fulfilling the MESI criteria: Non-serious AE fulfilling the MESI criteria 
must be followed. Follow-up information on MESIs should only include new (e.g. corrections 
or additional) information and must be reported within 14 calendar days of the investigator’s 
first knowledge of the information. This is also the case for previously reported non-serious AEs 
which subsequently fulfil the MESI criteria. 
The investigator must ensure that the worst case severity and seriousness of an event is kept 
throughout the trial. A worsening of an unresolved AE must be reported as follow up with re-
assessment of severity and/or seriousness of the event.
Queries or follow-up requests from Novo Nordisk must be responded to within 14 calendar days
from the date of receipt of the request, unless otherwise specified in the follow-up request.
12.4
Technical complaints and technical complaint samples
12.4.1
Reporting of technical complaints 
All technical complaints on any of the following products: 
!
Liraglutide prefilled pen
!
Needles for prefilled pen
which occur from the time of first usage of the product until the time of the last usage of the product, 
must be collected and reported to Customer Complaint Center, Novo Nordisk.
Contact details (fax, e-mail and address) are provided in Attachment I to the protocol.
The investigator must assess whether the technical complaint is related to any AEs, SAEs, and/or 
MESI.
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Technical complaints must be reported on a separate technical complaint form. A technical 
complaint form for each batch, code or lot number or for each DUN must be completed.
The investigator must complete the technical complaint form in the eCRF within the following 
timelines of the trial site obtaining knowledge of the technical complaint:
!
Technical complaint assessed as related to an SAE within 24 hours
!
All other technical complaints within 5 calendar days
If the eCRF is unavailable or when reporting a technical complaint that is not subject related, the 
information must be provided on a paper form by fax, e-mail or courier to Customer Complaint 
Center, Novo Nordisk, within the same timelines as stated above. When the eCRF becomes 
available again, the investigator must enter the information on the technical complaint form in the 
eCRF.
12.4.2
Collection, storage and shipment of technical complaint samples
The investigator must collect the technical complaint sample and notify the monitor within 5 
calendar days of obtaining the sample at trial site. The monitor must coordinate the shipment to 
Customer Complaint Center, Novo Nordisk (the address is provided in Attachment I) and ensure 
that the sample is sent as soon as possible. A print or copy of the technical complaint form must be 
sent with the sample.
The investigator must ensure that the technical complaint sample contains the batch, code or lot 
number and, if available, the DUN.
If the technical complaint sample is unobtainable, the investigator must specify on the technical 
complaint form why it is unobtainable. 
Storage of the technical complaint sample must be done in accordance with the conditions 
prescribed for the product. The shipment of the technical complaint sample should be done in 
accordance with the same conditions as for storage (see section 9). 
12.5
Pregnancies
Female subjects must be instructed to notify the investigator immediately if they become pregnant 
during the trial. The investigator must report any pregnancy in subjects who have received trial 
product(s).
The investigator must follow the pregnancy until the pregnancy outcome and the newborn infant is 
one month of age.
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The investigator must report information about the pregnancy, pregnancy outcome, and health of 
the newborn infant(s), as well as AEs in connection with the pregnancy, and AEs in the foetus and 
newborn infant.
The following must be collected and reported by the investigator to Novo Nordisk electronically 
(e.g. in PDF format), or by fax or courier:
1. Reporting of pregnancy information
Information about the pregnancy and pregnancy outcome/health of the newborn infant(s) has to 
be reported on Maternal Form 1A and 1B, respectively. 
When the pregnancy outcome is abnormal (i.e. congenital anomalies, foetal death including
spontaneous abortion and/or any anomalies of the foetus observed at gross examination or 
during autopsy), and/or when a congenital anomaly is diagnosed within the first month, further 
information has to be reported for the female subject on Maternal Form 2. In addition, 
information from the male partner has to be reported on the Paternal Form, after an informed 
consent has been obtained from the male partner. 
Initial reporting and follow-up information must be reported within 14 calendar days of the 
investigator's first knowledge of initial or follow-up information. 
2. Reporting of AE information
The investigator has to report AEs in connection with the pregnancy as well as in the foetus and 
newborn infant(s). The SAEs that must be reported include abnormal outcome, such as foetal 
death (including spontaneous abortion), and congenital anomalies (including those observed at 
gross examination or during autopsy of the foetus), as well as other pregnancy complications 
fulfilling the criteria of an SAE.
Forms and timelines for reporting AEs:
Non-serious AEs: 
–
Paper AE form* within 14 calendar days of the investigator's first knowledge of the 
initial or follow-up information to the non-serious AE.
SAEs: 
–
Paper AE form* within 24 hours of the investigator's first knowledge of the SAE.
–
Paper safety information form within 5 calendar days of the investigator's first 
knowledge of the SAE.
–
SAE follow-up information to the AE form and/or safety information form within 24 
hours of the investigator's first knowledge of the follow-up information.
*
It must be clearly stated in the AE diagnosis field on the AE form if the event occurred in 
the subject, foetus or newborn infant.
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Any queries or follow-up requests from Novo Nordisk to non-serious AEs, SAEs and pregnancy 
forms must be responded to by the investigator within 14 calendar days from the date of receipt of 
the request, unless otherwise specified in the follow-up request.
12.6
Precautions and/or overdose
When initiating treatment with liraglutide, the subject may, in some cases, experience loss of 
fluids/dehydration, e.g., in cases of vomiting, nausea or diarrhoea sometimes with a decrease in 
kidney function. It is important to avoid dehydration by drinking enough fluids.
From clinical trials and marketed use overdoses of liraglutide have been reported up to 40 times the 
recommended maintenance dose (72 mg). Events reported included severe nausea and severe 
vomiting. None of the reports included severe hypoglycaemia. All patients recovered without 
complications. In the event of overdosage, appropriate supportive treatment should be initiated 
according to the patient’s clinical signs and symptoms.
12.7
Committees related to safety
12.7.1
Novo Nordisk safety committee
Novo Nordisk will constitute an internal liraglutide safety committee to perform ongoing safety 
surveillance. The liraglutide safety committee may recommend unblinding of any data for further 
analysis, and in this case an independent ad hoc group will be established in order to maintain the 
blinding of the trial personnel.
12.7.2
Event adjudication committee (EAC)
An independent external event adjudication committee (EAC) is established to perform qualitative 
or quantitative validation of selected AEs according to pre-defined diagnostic criteria. The 
validation is based on review of pre-defined clinical data related to the specific AE.
The events are reviewed by the EAC in an independent and a blinded manner.
The EAC is composed of permanent members covering required medical specialities. EAC 
members must disclose potential conflicts of interest and must be independent of Novo Nordisk. 
The role of the EAC is solely to adjudicate events in a blinded manner. The EAC will have no 
authorisations to impact on trial conduct, trial protocol or amendments.
The EAC works in accordance with written guidelines included in the EAC Charter describing in 
details the composition, tasks, responsibilities, and work processes of the committee.
The events will be adjudicated according to FDA requirements50.
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The EAC will review copies in English (translated if necessary) of medical documentation received 
in the adjudication packages (for example X-ray, ECGs, ultrasound images, discharge summaries, 
pathology reports, and death certificates). The investigator should provide medical documentation 
within 4 weeks of event identification. 
The supplier or EAC can evaluate an event not initially reported as a MESI for adjudication to be 
adjudicated. In this case the investigator must provide medical documentation as soon as possible, 
when receiving a request from Novo Nordisk or the Event Adjudication vendor. 
The assessments made by the EAC will be included in the CTR as well as assessments made by the 
investigator. However, the adjudication made by an EAC, given its independence and in-depth 
analysis of each event, will be attributed with greater importance of the two. The outcomes of 
adjudication will be kept in the clinical trial database.
The following AEs will be adjudicated in this trial (Please also see Appendix C):
!
Fatal events
!
Acute coronary syndrome (MI, hospitalisation for unstable angina)
!
Cerebrovascular event (stroke or TIA)
!
Heart failure requiring hospital admission
!
Pancreatitis
!
Neoplasms including thyroid neoplasm (all kinds of abnormal growth)
!
Thyroid disorders requiring thyroidectomy
Event adjudication will be performed for AEs in subjects eligible for the trial including AEs with an 
onset date during the screening or run-in period. Event adjudication will not be performed for AEs 
in screening failures. 
AEs for adjudication must be reported according to section 12.2. In addition the specific 
adjudication form should be completed within 14 calendar days of the investigator's first knowledge 
of the AE, and all relevant predefined documents provided according to instructions in the event 
adjudication site manual.
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13 Case report forms 
Novo Nordisk will provide a system for the eCRFs. This system and support services to the system 
will be provided by an external supplier.
Ensure that all relevant questions are answered, and that no empty data field exists. If a test or an 
assessment has not been done and will not be available, or if the question is irrelevant (e.g. is not 
applicable), indicate this according to the data entry instructions.
The following will be provided as paper CRFs:
!
Pregnancy forms
In addition paper AE forms, safety information forms and technical complaint forms will be 
provided. These must be used when access to the eCRF is revoked or if the eCRF is unavailable. 
On the paper CRF forms print legibly, using a ballpoint pen. Ensure that all questions are answered, 
and that no empty data blocks exist. Ensure that no information is recorded outside the data blocks. 
If a test/assessment has not been done and will not be available, indicate this by writing "ND" (not 
done) in the appropriate answer field in the CRF. If the question is irrelevant (e.g. is not applicable) 
indicate this by writing "NA" (not applicable) in the appropriate answer field. Further guidance can 
be obtained from the instructions in the CRF.
The investigator must ensure that all information is consistent with the source documentation. By 
electronically signing the case book in the eCRF, the investigator confirms that the information in 
the eCRF and related forms is complete and correct.
13.1
Corrections to case report forms 
Corrections to the CRF data may be made by the investigator or the investigator's delegated staff. 
An audit trail will be maintained in the eCRF application containing as a minimum: the old and the 
new data, identification of the person entering the data, date and time of the entry and reason for the 
correction.
If corrections are made by the investigator's delegated staff after the date the investigator has signed 
the case book, the case book must be signed and dated again by the investigator.
13.2
Case report form flow 
The investigator must ensure that data is recorded in the eCRF as soon as possible, preferably 
within 5 days after the visit. Once data has been entered, it will be available to Novo Nordisk for 
data verification and validation purposes.
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At the end of the trial the investigator must ensure that all remaining data have been entered into the 
eCRF no later than 3 days after LSLV 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 trial site before 
access to the eCRF is revoked. This data must be retained at the trial site. When the final CTR is 
available the data will be archived by Novo Nordisk.
13.3
Paper case report form flow
The pregnancy forms are paper based CRFs. Also, the technical complaint form, SIF and AE form 
will be provided in paper but are only to be used if for any reason the eCRF is unavailable. 
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).
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. Further guidance can 
be obtained from the instructions in the CRF. 
Corrections to the data in the 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.
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14 Monitoring procedures 
During the course of the trial, the monitor will visit the trial site to ensure that the protocol is 
adhered to, that all issues have been recorded, to perform source data verification and to monitor 
drug accountability. The first monitoring visit will be performed as soon as possible after FSFV at 
the trial site and no later than 4 weeks after. The monitoring visit intervals will depend on the 
outcome of the remote monitoring of the CRFs, the trial site's recruitment rate and the compliance 
of the trial site to the protocol and GCP1, but will not exceed 12 weeks.
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 eCRF (BMI is not source data 
verified as it is calculated in EDC).
For all data recorded the source document must be defined in a source document agreement at each 
trial site. There must only be one source defined at any time for any data element.
Considering the electronic source data environment, it is accepted that the earliest practically 
retainable record should be considered as the location of the source data and therefore the source 
document. The diary is considered source document for the SMBG values, dose of trial product one 
day prior to visit/phone contact during dose escalation, date, dose and injection site for first dose of 
trial product, date for last dose of trial product and hypoglycaemic episodes. 
Source data generated by the trial site can be corrected by another person than the person entering 
the source data if accepted by local regulations; any correction must be explained, signed and dated 
by the person making the correction.
The original diaries must not be removed from the trial site, unless they form part of the CRF and a 
copy is kept at the site.
The monitor will ensure that the CRFs are completed on an ongoing basis.
The following data will be source data verified for screening failures: 
!
Date for obtaining informed consent.
!
Reason for screening failure
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Monitors must review the subject's medical records and other source data (e.g. the diaries) to ensure 
consistency and/or identify omissions compared to the CRF. If discrepancies are found, the 
investigator must be questioned about these.
A follow-up letter (paper or electronic) will be sent to the investigator following each monitoring 
visit. This should address any action to be taken.
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15 Data management
Data management is the responsibility of Novo Nordisk. Data management may be delegated under 
an agreement of transfer of responsibilities to another data management unit within Novo Nordisk 
or an external Contract Research Organisation (CRO).
Appropriate measures, including encryption of data files containing person identifiable data, will be 
used to ensure confidentiality of subject data, when they are transmitted over open networks. 
Data from central laboratories will be transferred electronically from the laboratory performing the 
analyses. In cases where data is transferred via non-secure electronic networks, data will be 
encrypted during transfer.
The subject and any biological material obtained from the subject will be identified by subject 
number and trial ID. Appropriate measures such as encryption or leaving out certain identifiers will 
be enforced to protect the identity of subjects in all presentations and publications as required by 
local, regional and national requirements.
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16 Computerised systems
Novo Nordisk will capture and process clinical data using computerised systems that are described 
in Novo Nordisk Standard Operating Procedures and IT architecture documentation. The use and 
control of these systems are documented.
Investigators working on the trial may use their own electronic systems to capture source data. 
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17 Statistical considerations
Novo Nordisk will analyse and report data from all sites together.
All analyses of efficacy and safety endpoints will be based on the full analysis set (FAS).  All 
efficacy endpoints will be summarised using the FAS and safety endpoints will be summarised 
using the safety analysis set (SAS). 
The impact of protocol deviations and outliers may be investigated further in sensitivity analyses if 
deemed relevant.
Unless otherwise specified, all continuous measurements will be summarised descriptively at each 
visit by treatment using all observed data. Descriptive statistics will be presented based both on 
observed and last observation carried forward (LOCF) imputed data. Endpoints that are analysed 
untransformed and endpoints that are not formally analysed are summarised by the arithmetic mean, 
standard deviation (SD), median, and minimum and maximum value. Endpoints that are analysed 
log-transformed are supplemented with the geometric mean and coefficient of variation (CV).
For measurements over time, mean values will be plotted to explore the trajectory over time. LOCF 
imputed data will be used as the basis for plotting data, if not otherwise specified. For endpoints 
that are analysed log-transformed, the geometric mean values will be plotted.
An analysis of covariance (ANCOVA) model will be applied for the primary endpoint and 
continuous secondary endpoints after 26 weeks of treatment. The model includes treatment as fixed 
effect and the corresponding baseline value as covariate. In the following, this model will be 
referred to as the standard ANCOVA model.
Presentation of results from a statistical analysis will include the estimated mean treatment effects 
(Least Square Means [LSMeans]) for absolute values and change from baseline. In addition, 
estimated mean treatment difference (or ratio) will be presented together with the two-sided 95% 
confidence interval and corresponding two-sided p-value.
Handling of missing data
The expected percentage of missing data is around 10%. In accordance with industry guidance51
endpoints will be assessed at frequent visits and also on subjects who withdraw prematurely. This 
will facilitate an analysis in accordance with ITT principles. Also, the combined information on 
frequent outcomes and information on reason for drop-out is assumed to account for the missing 
data anticipated.
If not otherwise specified, the value from the randomisation visit (Visit 8) will be used as the 
baseline value. If the value measured at the randomisation visit is missing and the assessment has 
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also been made at an earlier visit, then the non-missing value obtained at the preceding visit closest 
to Visit 8 will be used as the baseline value.
Missing values (including intermittent missing values) will be imputed using the LOCF method. 
Subjects without data after randomisation will be included by carrying forward their baseline value. 
In this trial, sensitivity analyses will be made to examine the robustness of the LOCF method. 
17.1
Sample size calculation
The primary objective of this trial is to confirm superiority of liraglutide 1.8 mg/day vs. liraglutide 
0.9 mg/day in controlling glycaemia after 26 weeks of treatment in Japanese subjects with T2DM
inadequately controlled with liraglutide 0.9 mg/day.
Superiority in the primary endpoint for liraglutide 1.8 mg/day vs. liraglutide 0.9 mg/day will be 
considered confirmed if the upper bound of the two-sided 95% confidence interval for the estimated 
mean treatment difference in change from baseline in HbA1c is strictly below 0.0% or equivalently 
if the p-value for the two-sided test of
H0 D=0 against HA D≠0,
is less than 5% and D<0, where D is the true treatment difference. This is equivalent to using a one-
sided test of size 2.5%, which means that the type 1 error rate is controlled at 2.5%.
Based on experience from the NN2211-1842, NN2211-1700, NN2211-1701, NN2211-3924 and 
NN2211-3925 studies the following assumptions are made.
!
15% screening failure rate
!
15% drop-out rate in the run in period
!
50% chance that a subject at the end of the run-in will be randomised (i.e. HbA1c ≥7.0% at 
randomisation)
The sample size is determined using a t-statistic under the assumption of a two-sided test of size 5% 
and a standard deviation of SD=1.0%. From the above assumptions and based on a 1:1 
randomisation, a sample size of 235 subjects in each treatment arm; in total 470 subjects was 
chosen to obtain sufficient exposure to liraglutide 1.8 mg in the Japanese diabetes population as 
well as having a reasonable estimation of efficacy. With this sample size it would be possible to 
detect a 0.3% treatment difference with a power of at least 90%. In order to reach the required 
sample size 1,301 subjects should be screened and 1,106 subjects should enter the run-in period.
Considering 0% efficacy retention as the most conservative approach for the anticipated 10% of 
subjects discontinuing randomised treatment reduces the expected treatment difference to -0.27%, a 
total of 235 subjects per treatment arm will then yield a power of at least 83% (see Table 17-1).
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Table 17-1
Powers for various combinations of SD and mean difference
Mean difference (%) adjusted for subjects discontinuing randomised 
treatment (efficacy retention in % for subjects discontinuing randomised 
treatment)
SD (%)
-0.27 (0%)
-0.276 (20%)
-0.285 (50%)
-0.30 (100%)
0.9
90.1
91.3
92.9
95.0
1.0
83.2
84.7
86.9
90.1
1.1
75.7
77.5
80.0
83.9
17.2
Definition of analysis sets
The following analysis sets are defined in accordance with the ICH-E9 guidance.52
!
Full Analysis Set (FAS): includes all randomised subjects. In exceptional cases, subjects 
may be eliminated from the full analysis set. In such cases the elimination will be justified 
and documented. The statistical evaluation of the FAS will follow the intention-to-treat 
(ITT) principle and subjects will contribute to the evaluation “as randomised”
!
Safety Analysis Set (SAS): includes all subjects receiving at least one dose of randomised 
treatment. Subjects in the safety analysis 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.
Before data are released for statistical analysis, a review of all data will take place to identify 
protocol deviations that could potentially affect the results. Any decision to exclude any subject or 
observation from the statistical analysis is the joint responsibility of the members of the study group. 
The subjects or observations to be excluded, and the reasons for their exclusion must be 
documented and signed by those responsible before database lock. The subjects and observations 
excluded from analysis sets, and the reason for this, will be described in the clinical trial report.
17.3
Primary endpoint
The primary endpoint is the change from baseline in HbA1c after 26 weeks of treatment. 
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The change from baseline in HbA1c after 26 weeks of treatment will be analysed using an analysis 
of covariance (ANCOVA) model with treatment as a fixed effect and baseline HbA1c as a 
covariate.
Missing values after 26 weeks of treatment will be imputed applying last observation carried 
forward (LOCF) using HbA1c values at and after baseline.
Superiority of liraglutide 1.8 mg/day vs. liraglutide 0.9 mg/day will be considered as confirmed if 
the 95% confidence interval for the treatment difference (liraglutide 1.8 mg/day minus liraglutide 
0.9 mg/day) for change from baseline in HbA1c lies entirely below 0.0%; equivalent to a one-sided 
test with significance level of 2.5%. Conclusion of superiority will be based on FAS. 
Additionally, change from baseline in HbA1c after 52 weeks of treatment will be presented 
descriptively for the liraglutide 1.8 mg/day treatment arm.
Sensitivity analysis
Sensitivity analysis will be performed on FAS using the mixed model for repeated measurements 
(MMRM) method. All HbA1c values available post baseline at scheduled measurement times will 
be analysed in a linear mixed normal model using an unstructured residual covariance matrix for 
HbA1c measurements within the same subject. The model will include treatment and visit as fixed 
factors and baseline HbA1c as a covariate. Interactions between visit and treatment and between 
visit and baseline HbA1c will also be included in the model. The results of sensitivity analyses will 
be compared to the result of the standard ANCOVA method using LOCF for imputation of missing 
data.
17.4
Secondary endpoints
17.4.1
Secondary endpoints
17.4.1.1
Efficacy endpoints
Endpoints evaluated after 26 weeks of treatment
Responder for HbA1c
Two dichotomous endpoints (responder/non-responder) will be defined based on whether a subject 
has met a specific target level after 26 weeks of treatment:
!
HbA1c target < 7.0%53
!
HbA1c target ≤ 6.5%53, 54
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Analysis of each of the two responder endpoints will be based on a logistic regression model with 
treatment as factor and baseline HbA1c value as a covariate.
HbA1c responder endpoints without weight gain
Responder for HbA1c without weight gain after 26 weeks of treatment will be defined as HbA1c < 
7.0% after 26 weeks of treatment and change from baseline in body weight after 26 weeks of 
treatment below or equal to zero. Analysis will be based on a logistic regression model with 
treatment as factor and baseline HbA1c and baseline body weight values as covariates.
HbA1c responder endpoints without treatment emergent severe or blood glucose (BG) 
confirmed symptomatic hypoglycaemic episodes
Responder for HbA1c without hypoglycaemic episodes after 26 weeks of treatment will be defined 
as HbA1c < 7.0% after 26 weeks of treatment and without severe or BG confirmed symptomatic 
episodes during 26 weeks of treatment. Analysis will be based on a logistic regression model with 
treatment as factor and baseline HbA1c values as a covariate.
Fasting plasma glucose (FPG)
Change from baseline in FPG after 26 weeks of treatment will be analysed using the standard 
ANCOVA model.
Waist circumference
Change from baseline in waist circumference after 26 weeks of treatment will be analysed using the 
standard ANCOVA model.
Body weight 
Change from baseline in body weight after 26 weeks of treatment will be analysed using the 
standard ANCOVA model.
Body Mass Index (BMI) 
Change from baseline in BMI after 26 weeks of treatment will be analysed using the standard 
ANCOVA model.
Self measured blood glucose (SMBG) 7-point profile
Three endpoints from the 7 point SMBG profile will be defined: 
!
7-point profile (individual points in the profile)
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!
Mean of the 7-point profile, defined as the area under the profile (calculated using the 
trapezoidal method) divided by the measurement time
!
Mean of postprandial increments (from before meal to 90 min after for breakfast, lunch and 
dinner). The mean increment over all meals will be derived as the mean of all available 
meal increments.
A linear mixed effect model will be fitted to the 7-point SMBG profile data. The model will include 
treatment, time and interaction between treatment and time as fixed factors and subject as random 
effect . From the model mean profile by treatment and relevant treatment differences will be 
estimated and explored. 
Change from baseline after 26 weeks of treatment in mean of the 7-point profile and post-prandial 
increment endpoints will be analysed separately using the standard ANCOVA model.
Blood pressure (systolic and diastolic)
Systolic and diastolic blood pressure will be summarized descriptively.
Fasting C-peptide, fasting insulin, fasting glucagon, proinsulin, proinsulin/insulin, HOMA-B, 
HOMA-IR
In addition to fasting C-peptide, fasting insulin, fasting glucagon, and proinsulin, three derived 
parameters will be calculated; proinsulin/insulin ratio, beta-cell function (HOMA-B) and insulin 
resistance (HOMA-IR).
The calculation of the HOMA endpoints will be done as follows:
!
Beta-cell function (%) = 20·fasting insulin[μU/mL]/(FPG[mmol/L]-3.5)
!
Insulin resistance (%) = fasting insulin [μU/ml]·FPG [mmol/l]/ 22.5
These endpoints after 26 weeks of treatment will be analysed separately using the standard 
ANCOVA model. In these statistical analyses the endpoint will be log-transformed and so will the 
baseline covariate.
Fasting lipid profile 
Total cholesterol, low density lipoprotein cholesterol (LDL cholesterol), high density lipoprotein 
cholesterol (HDL cholesterol), very low density lipoprotein cholesterol (VLDL cholesterol), 
triglycerides, and free fatty acids after 26 weeks of treatment will be analysed separately using the 
standard ANCOVA model. In these statistical analyses the endpoint will be log-transformed and so 
will the baseline covariate.
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Endpoints evaluated after 52 weeks of treatment
All above listed efficacy endpoints will be summarised descriptively for the liraglutide 1.8 mg/day 
arm after 52 weeks of treatment. 
17.4.1.2
Safety endpoints
Adverse events
AEs will be coded using the most recent version of the Medical Dictionary for Regulatory 
Activities.
A treatment emergent adverse event (TEAE) is defined as an event that has onset date on or after 
the first day of IMP administration and no later than seven days after the last day on IMP. If the 
event has onset date before the first day of IMP administration and increases in severity during the 
treatment period and until 7 days after the last drug date, then this event should also be considered 
as a TEAE. Here the first day of IMP administration is defined as the first day of exposure to 
randomised treatment.
AEs will be summarised descriptively for each of the following periods separately:
!
The run-in period: AEs with an onset date on or after Visit 2 and before the first day of 
exposure to randomised treatment will be reported as part of the run-in period.
!
The 26 week treatment period: TEAEs with an onset date on or after the first day of 
exposure to randomised treatment and no later than seven days after Visit 16 (EOT26) will 
be reported as during 26 weeks of treatment.
!
The 52 week treatment period: For the liraglutide 1.8 mg/day arm all TEAEs will be 
reported as during 52 weeks of treatment.
For each of the above periods, AE data will be displayed 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 100 years of exposure (R).
Summaries of AEs and of serious AEs will be presented as an overview including all AEs, serious 
AEs, number of deaths, AEs by severity, AEs by relation to treatment and AEs of special interest 
including AEs leading to withdrawal for each period.
Furthermore separate summary tables for each period will be presented based on system organ class 
and preferred terms for: 
!
All AEs 
!
Serious AEs
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!
Possibly or probably related AEs
!
Severe, moderate and mild AEs
!
AEs reported by safety areas of interest
!
AEs with preferred term that are experienced by at least 5% of the subjects in any treatment 
arm or by at least 5% of all subjects
A listing for non-treatment emergent adverse events with onset date before Visit 2 will be presented. 
A listing will also be presented for non-treatment emergent adverse events collected after the 
treatment emergent period according to the definition of TEAE.
Classification of Hypoglycaemia:
Treatment emergent: hypoglycaemic episodes will be defined as treatment emergent if the onset of 
the episode occurs on or after the first day of IMP administration, and no later than 7 days after the 
last day on IMP. Here the first day of IMP administration is defined as the first day of exposure to 
randomised treatment.
Nocturnal hypoglycaemic episodes: are episodes occurring between 00:01 and 05.59 both inclusive.
Hypoglycaemic episodes are classified according to the Novo Nordisk classification of 
hypoglycaemia (see Figure 17–1) and the ADA classification of hypoglycaemia (see Figure 17–2).
Novo Nordisk classification of hypoglycaemia
In normal physiology, symptoms of hypoglycaemia occur below a plasma glucose level of 3.1 
mmol/L (56 mg/dL)55. Therefore, Novo Nordisk has included hypoglycaemia with plasma glucose 
levels below this cut-off point in the definition of blood glucose (BG) confirmed hypoglycaemia.
Novo Nordisk uses the following classification (see Figure 17–1) in addition to the ADA 
classification: 
!
Severe or BG confirmed symptomatic hypoglycaemia: An episode that is severe according to 
the ADA classification48 or BG confirmed by a plasma glucose value <3.1 mmol/L (56 mg/dL) 
with symptoms consistent with hypoglycaemia. 
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Figure 17–1
Novo Nordisk classification of hypoglycaemia
ADA classification48 of hypoglycaemia
! Severe hypoglycaemia: An episode requiring assistance of another person to actively administer 
carbohydrate, glucagon, or take other corrective actions. Plasma glucose concentrations may 
not be available during an event, but neurological recovery following the return of plasma 
glucose to normal is considered sufficient evidence that the event was induced by a low plasma 
glucose concentration.
! Asymptomatic hypoglycaemia: An episode not accompanied by typical symptoms of 
hypoglycaemia, but with a measured plasma glucose concentration ≤ 3.9 mmol/L (70 mg/dL).
! Documented symptomatic hypoglycaemia: An episode during which typical symptoms of 
hypoglycaemia are accompanied by a measured plasma glucose concentration ≤ 3.9 mmol/L 
(70 mg/dL).
! Pseudo-hypoglycaemia: An episode during which the person with diabetes reports any of the 
typical symptoms of hypoglycaemia with a measured plasma glucose concentration > 3.9 
mmol/L (70 mg/dL) but approaching that level.
! Probable symptomatic hypoglycaemia: An episode during which symptoms of hypoglycaemia 
are not accompanied by a plasma glucose determination but that was presumably caused by a 
plasma glucose concentration ≤ 3.9 mmol/L (70 mg/dL).
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Figure 17–2
ADA classification of hypoglycaemia 
Hypoglycaemic episodes will be summarised descriptively for each of the following periods 
separately:
!
The run-in period: hypoglycaemic episodes where the onset date of the episode occurs on or 
after Visit 2 and before the first day of exposure to randomised treatment will be reported as 
part of the run-in period.
!
The 26 week treatment period: treatment emergent hypoglycaemic episodes where the onset 
date of the episode occurs on or after the first day of exposure to randomised treatment and no 
later than seven days after Visit 16 (EOT26) will be reported as during 26 weeks of treatment. 
!
The 52 week treatment period: For the liraglutide 1.8 mg/day arm all treatment emergent 
hypoglycaemic episodes will be reported as during 52 weeks of treatment.
For each of the periods listed above, data on hypoglycaemic episodes are presented above 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 100 years (R). Separate summaries are 
made for severe or BG confirmed symptomatic hypoglycaemic episodes, nocturnal severe or BG 
confirmed symptomatic hypoglycaemic episodes and the ADA classification of hypoglycaemia.  
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The number of hypoglycaemic episodes during 26 weeks of treatment will be analysed separately 
for each endpoint using a negative binominal regression model with a log-link function and the 
logarithm of the time period in which a hypoglycaemic episode is considered to be part of the 26 
week treatment period as offset. The model will include treatment as factor. 
Pulse
Pulse will be summarized descriptively.
Clinical evaluations (physical examination, eye examination and ECG)
Eye examination (fundoscopy/fundus photography) and ECG findings will be summarised 
descriptively, including:
!
summaries for each visit
!
shift table from baseline to after 26 weeks of treatment and after 52 weeks of treatment
Any findings in the physical examination evaluation at screening will be presented as listings. Any 
clinically significant deterioration of a pre-existing condition after the screening visit, as well as any 
new clinically significant findings will be recorded as adverse events.
Laboratory assessments 
All laboratory parameters will be summarised descriptively.
The following tables will be presented based on both observed and LOCF imputed data:
!
Shift tables from baseline to after 26 weeks of treatment and after 52 weeks of treatment
!
Proportion of subjects with measurements outside reference range by treatment and week.
Laboratory values will be presented graphically as box plots by treatment and week.
For each laboratory parameter, individual values outside the reference ranges (abnormal values) 
will be listed.
For lipase and amylase the following rule will apply in the evaluation of the result:
!
If the amylase or lipase baseline (at screening) value is > 3xUNR this information is to be
recorded as medical history for that subject. 
The purpose of the calcitonin analysis is to evaluate longitudinal changes in calcitonin, with main 
focus on subjects who develop persistently high levels of calcitonin during the trial.
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Calcitonin will be displayed in terms of the number of subjects (N), the percentage of subjects (%) 
and the incidence rate per 100 years of exposure (R). The following criteria are defined for 
tabulations:
Persistent (all post baseline measurements)
!
From < UNR to persistently ≥ UNR
!
From < UNR to persistently ≥ 1.5 UNR
!
From < UNR to persistently ≥ 20 ng/L
!
From < UNR to persistently ≥ 50 ng/L
!
From < 20 ng/L to persistently ≥ 20 ng/L
!
From < 50 ng/L to persistently ≥ 50 ng/L
Incidental (at least one post baseline measurements)
!
From < UNR to ≥ UNR
!
From < UNR to ≥ 1.5 UNR
!
From < UNR to ≥ 20 ng/L
!
From < UNR to ≥ 50 ng/L
!
From < 20 ng/L to ≥ 20 ng/L
!
From < 50 ng/L to ≥ 50 ng/L
The distribution of all calcitonin measurements across treatment groups and time will be shown 
with histograms and corresponding cumulative plots for actual levels of calcitonin and change from 
baseline. The plots will be presented by treatment group (using EOT measurement - LOCF) and 
within treatment group by week. Plots will be done by gender.
Summaries tables of calcitonin continuous measurements, will include number and percentage of 
observations < and ≥ LLOQ, minimum, Q25, median, Q75 and maximum. Summaries will be 
presented for all subjects and by gender.
Longitudinal changes for subjects with calcitonin levels ≥ 20 ng/L will be plotted (longitudinal 
plots). The plots will be done by treatment and gender. They will be done for subjects in the 
persistent and incidental categories, separately.
A listing of subjects with at least one post baseline value ≥ 20 ng/l will be done. The listing will 
include age, gender, calcitonin measurements over time and AE history (including preferred term, 
onset and stop dates).
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18 Ethics
The trial will be conducted in compliance with ICH GCP1 and applicable regulatory requirements, 
and in accordance with the Declaration of Helsinki2.
All subjects will be included after a thorough evaluation in regards to inclusion/exclusion criteria 
defined in order to ensure that subjects are eligible for trial treatment. Liraglutide will be initiated 
liraglutide 0.9 mg/day treatment during the run-in period. Randomisation criterion has been defined 
in order to identify subjects inadequately controlled on liraglutide 0.9 mg/day. Furthermore 
withdrawal criteria have been defined to ensure that subjects are considered for discontinuation if
the subjects have unacceptable glycaemic control during trial participation.
Subjects will be treated within a regimen anticipated to be better than or equal to the treatment they 
receive at the time of entry into the trial. Subject will need to spend more time, as additional visits 
to the clinic are required and some of assessments performed during the trial are done outside 
normal practice.
Liraglutide have shown to be effective in lowering blood glucose levels. It can therefore be 
expected that the subjects entering the trial with insufficiently controlled blood glucose will 
experience an improved glucose control during the trial. Subjects may benefit from the effect of 
treatment on weight, previously demonstrated for liraglutide. Another potential benefit of 
participating in the trial is that the Investigator will obtain an additional knowledge of the subjects’ 
disease and will therefore be able to provide recommendations for the best treatment to be used 
following the trial participation.
The trial drugs 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 
participating in the trial. Furthermore, subjects 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 concluded that the potential benefits from participating in the trial outweigh the potential risks. 
The safety profile of liraglutide generated from the clinical and nonclinical development 
programme has not revealed any safety issues that would prohibit administration of liraglutide in 
accordance with the planned clinical trial. 
When treatment with trial product ends, the subject and investigator will decide on the best 
available treatment. Novo Nordisk will not offer investigational drugs after the end of trial
treatment.
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18.1
Informed consent
In seeking and documenting informed consent, the investigator must comply with applicable 
regulatory requirement(s) and adhere to ICH GCP1 and the requirements in the Declaration of 
Helsinki2.
Before any trial-related activity, the investigator must give the subject verbal and written 
information about the trial and the procedures involved in a form that the subject can read and 
understand. 
The subjects must be fully informed of their rights and responsibilities while participating in the 
trial as well as possible disadvantages of being treated with the trial products.
The investigator must ensure the subject ample time to come to a decision whether or not to 
participate in the trial. 
A voluntary, signed and personally dated informed consent must be obtained from the subject 
before any trial-related activity.
The responsibility for seeking informed consent must remain with the investigator, but the 
investigator may delegate the task to a medically qualified person, in accordance with local 
requirements. The written informed consent must be signed and personally dated by the person who 
seeks the informed consent before any trial-related activity.
If information becomes available that may be relevant to the subject’s willingness to continue 
participating in the trial, the investigator must inform the subject in a timely manner, and a revised 
written subject information must be provided and a new informed consent must be obtained.
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 and data collected at the end-of-trial visit will be retained by Novo 
Nordisk, entered into the database and used for the trial report. 
!
Safety events will be reported to Novo Nordisk and regulatory authorities according to 
local/national requirements.
If data is used, it will always be in accordance with local regulations and IRBs.
18.3
Information to subject during trial
All written information to subjects must be sent to IRB for approval/favourable opinion and to 
regulatory authorities for approval or notification according to local regulations.
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18.4
Premature termination of the trial and/or trial site
Novo Nordisk, the IRBs or a regulatory authority may decide to stop the trial, part of the trial or a 
trial site at any time, but agreement on procedures to be followed must be obtained.
If a trial is suspended or prematurely terminated, the investigator must inform the subjects promptly 
and ensure appropriate therapy and follow-up. The investigator and/or Novo Nordisk must also 
promptly inform the regulatory authorities and IRBs and provide a detailed written explanation. 
If, after the termination of the trial, the benefit-risk analysis changes, the new evaluation must be 
provided to the IRBs in case it has an impact on the planned follow-up of subjects who have 
participated in the trial. If it has an impact, the actions needed to inform and protect the subjects 
should be described.
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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.
Deviations must be documented and explained in a protocol deviation by stating the reason, date, 
and the action(s) taken. Some deviations, for which corrections are not possible, can be 
acknowledged and confirmed via edit checks in the eCRF or via listings from the clinical database. 
Documentation on protocol deviations must be kept in the investigator's trial master file and 
sponsor trial master file.
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Date:
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Trial ID: NN2211-4174
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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. Audits and inspections may take 
place during or after the trial. The investigator and the site staff as well as Novo Nordisk staff have 
an obligation to cooperate and assist in audits and inspections. This includes giving auditors and 
inspectors direct access to all source documents and other documents at the trial site relevant to the 
clinical trial. This includes permission to examine, analyse, verify and reproduce any record(s) and 
report(s) that are relevant to the evaluation of the trial.
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21
Critical documents
Before a trial 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 
!
Approval/favourable opinion from IRBs clearly identifying the documents reviewed as follows: 
protocol, any protocol amendments, subject information/informed consent form, any other 
written information to be provided to the subject and subject recruitment materials
!
List of IRB members and/or constitution (or a general assurance number/statement of 
compliance)
!
Curricula vitae of investigator and sub-investigator(s) (current, dated and signed - must include 
documented GCP training or a certificate)
!
Signed receipt of Investigator's Brochure 
!
Signed and dated Agreement on Protocol
!
Signed and dated agreement on protocol amendment, if applicable
!
Contract, signed and dated by the investigator and/or head of the investigator’s site and Novo 
Nordisk
!
Source document agreement
!
Central laboratory certification and normal ranges
!
Insurance statement, if applicable
!
Financial disclosure form from investigator and sub-investigator(s)
By signing the protocol, each investigator agrees to comply fully with ICH GCP1, applicable 
regulatory requirements and the Declaration of Helsinki2. 
By signing the protocol, each investigator also agrees to allow Novo Nordisk to make investigator's 
name and information about site name and address publically available if this is required by 
national or international regulations.
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22 Responsibilities
The investigator is accountable for the conduct of the trial at his/her site. If any tasks are delegated, 
the investigator must maintain a log of appropriately qualified persons to whom he/she has 
delegated specified trial-related duties. The investigator must ensure that there is adequate training 
for all staff participating in the conduct of the trial. It is the investigator's responsibility to supervise 
the conduct of the trial and to protect the rights, safety, and well-being of the subjects.
A qualified physician, who is an investigator or a sub-investigator for the trial, must be responsible 
for all trial-related medical decisions.
The investigator must ensure adequate supervision of the conduct of the trial at the trial site. 
The investigator will follow instructions from Novo Nordisk when processing data.
The investigator is responsible for filing essential documents (i.e. those documents which 
individually and collectively permit evaluation of the conduct of a trial and the quality of the data 
produced) in the investigator trial master file. The documents including the subject identification 
code list should be kept in a secure locked facility, so no unauthorized persons can get access to the 
data. 
The investigator will take all necessary technical and organisational safety measures to prevent 
accidental or wrongful destruction, loss or deterioration of data. The investigator will prevent any 
unauthorised access to data or any other processing of data against applicable law. The investigator 
must be able to provide the necessary information or otherwise demonstrate to Novo Nordisk that 
such technical and organisational safety measures have been taken.
During any period of unavailability, the investigator must delegate responsibility for medical care of 
subjects to a specific qualified physician who will be readily available to subjects during that time.
If the investigator is no longer able to fulfil the role as investigator (e.g. if he/she moves or retires), 
a new investigator will be appointed in consultation with Novo Nordisk. 
The investigator and other site personnel must have sufficient English skills according to their 
assigned task(s).
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23 Reports and publications
The information obtained during the conduct of this trial is considered confidential, and may be 
used by or on behalf of Novo Nordisk for regulatory purposes as well as for the general 
development of the trial product. All information supplied by Novo Nordisk in connection with this 
trial shall remain the sole property of Novo Nordisk and is to be considered confidential 
information. 
No confidential information shall be disclosed to others without prior written consent from Novo 
Nordisk. Such information shall not be used except in the performance of this trial. The information 
obtained during this trial may be made available to other physicians who are conducting other 
clinical trials with the trial product, if deemed necessary by Novo Nordisk. Provided that certain 
conditions are fulfilled, Novo Nordisk may grant access to information obtained during this trial to 
researchers who require access for research projects studying the same disease and/or trial product 
studied in this trial.
Novo Nordisk may publish on its clinical trials website a redacted clinical trial report for this trial.
One investigator will be appointed by Novo Nordisk to review and sign the clinical trial report 
(signatory investigator) on behalf of all participating investigators. The signatory investigator will 
be appointed based upon the criteria defined by the International Committee of Medical Journal 
Editors for research publications56. 
23.1
Communication of results
Novo Nordisk commits to communicating, and otherwise making available for public disclosure, 
results of trials regardless of outcome. Public disclosure includes publication of a paper in a 
scientific journal, abstract submission with a poster or oral presentation at a scientific meeting, or 
disclosure by other means.
The results of this trial will be subject to public disclosure on external web sites according to 
international and national regulations, as reflected in the Novo Nordisk Code of Conduct for 
Clinical Trial Disclosure42.
Novo Nordisk reserves the right to defer the release of data until specified milestones are reached, 
for example when the clinical trial report is available. This includes the right not to release the 
results of interim analyses, because the release of such information may influence the results of the 
entire trial.
At the end of the trial, one or more scientific publications may be prepared collaboratively by the 
investigator(s) and Novo Nordisk. Novo Nordisk reserves the right to postpone publication and/or 
communication for up to 60 days to protect intellectual property.
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In all cases the trial results will be reported in an objective, accurate, balanced and complete 
manner, with a discussion of the strengths and limitations. All authors will be given the relevant 
statistical tables, figures, and reports needed to evaluate the planned publication. In the event of any 
disagreement on the content of any publication, both the investigators' and Novo Nordisk opinions 
will be fairly and sufficiently represented in the publication.
Where required by the journal, the investigator from each trial site will be named in an 
acknowledgement or in the supplementary material, as specified by the journal. 
Novo Nordisk maintains the right to be informed of plans by any investigator to publish and to 
review any scientific paper, presentation, communication or other information concerning the 
investigation described in this protocol. Any such communication must be submitted in writing to 
Novo Nordisk before submission for comments. Comments will be given within four weeks from 
receipt of the planned communication.
23.1.1
Authorship
Authorship of publications should be in accordance with the Uniform Requirements of the 
International Committee of Medical Journal Editors56 (sometimes referred to as the Vancouver 
Criteria).
At the end of the trial, one or more publications (abstracts, posters, manuscripts) will be prepared 
for submission to scientific congresses and peer-reviewed journals in collaboration between 
Novo Nordisk and investigator(s) appointed by Novo Nordisk. These investigator(s) must meet the 
ICMJE authorship criteria to be named authors on publications.
23.1.2
Site-specific publication(s) by investigator(s)
For a multi-centre clinical trial, analyses based on single-site data usually have significant statistical 
limitations and frequently do not provide meaningful information for healthcare professionals or 
subjects, and therefore may not be supported by Novo Nordisk. It is a Novo Nordisk policy that 
such individual reports do not precede the primary manuscript and should always reference the 
primary manuscript of the trial.
Novo Nordisk reserves the right to prior review of such publications. Further to allow for the 
primary manuscript to be published as the first, Novo Nordisk asks for deferment of publication of 
individual site results until the primary manuscript is accepted for publication. As Novo Nordisk 
wants to live up to the industry publication policy, submission of a primary publication will take 
place no later than 18 months after trial completion. 
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23.2
Investigator access to data and review of results
As owner of the trial database, Novo Nordisk has the discretion to determine who will have access 
to the database. 
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24 Retention of clinical trial documentation
Subject's medical records must be kept for the maximum period permitted by the hospital, 
institution or private practice.
The investigator must agree to archive the documentation (this includes both electronic and paper-
based records) pertaining to the trial in an archive after completion or discontinuation of the trial if 
not otherwise notified. The investigator should not destroy any documents without prior permission 
from Novo Nordisk. If the investigator cannot archive the documents at the trial site, Novo Nordisk 
can refer the investigator to an independent archive provider that has a system in place to allow only 
the investigator to access the files.
The investigator must be able to access his/her trial documents without involving Novo Nordisk in 
any way. Site-specific CRFs and other subject data (in an electronic readable format or as paper 
copies or prints) will be provided to the investigator before access is revoked to the systems
supplied by Novo Nordisk. These data must be retained by the trial site. If the provided data (e.g. 
the CD-ROM) is not readable during the entire storage period, the investigator can request a new 
copy. A copy of all data will be stored by Novo Nordisk.
Novo Nordisk will maintain Novo Nordisk documentation pertaining to the trial for as long as the 
product is on the market plus 20 years. 
The files from the trial site/institution must be retained for 15 years after the completion of the trial, 
or longer if required by local regulations or Novo Nordisk. In any case trial files cannot be 
destroyed until the trial site/institution is notified by Novo Nordisk. The deletion process must 
ensure confidentiality of data and must be done in accordance with local regulatory requirements.
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25 Institutional Review Boards and regulatory authorities
IRB:
Written approval or favourable opinion must be obtained from IRB prior to commencement of the 
trial.
During the trial, the investigator or Novo Nordisk, as applicable, must promptly report the 
following to the IRB, in accordance with local requirements: updates to Investigator's Brochure, 
unexpected SAEs where a causal relationship cannot be ruled out, protocol amendments according 
to local requirements, deviations to the protocol implemented to eliminate immediate hazards to the 
subjects, new information that may affect adversely the safety of the subjects or the conduct of the 
trial (including new benefit-risk analysis in case it will have an impact on the planned follow-up of 
the subjects), annually written summaries of the trial status, and other documents as required by the 
local IRB.
The investigator must ensure submission of the clinical trial report synopsis to the IRB according to 
local regulatory requirements.
Protocol amendments must not be implemented before approval or favourable opinion according to 
local regulations, unless necessary to eliminate immediate hazards to the subjects.
The investigator must maintain an accurate and complete record of all submissions made to the 
IRB. The records must be filed in the investigator trial master file and copies must be sent to Novo 
Nordisk.
Regulatory Authorities:
Regulatory authorities will receive the clinical trial application, protocol amendments, reports on 
SAEs, and the clinical trial report according to national requirements.
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26 Indemnity statement
Novo Nordisk carries product liability for its products, and liability as assumed under the special 
laws, acts and/or guidelines for conducting clinical trials in any country, unless others have shown 
negligence.
Novo Nordisk assumes no liability in the event of negligence, or any other liability of the sites or 
investigators conducting the trial, or by persons for whom the said site or investigator are 
responsible.
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27 References
                                                
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World Medical Association. Declaration of Helsinki. Ethical Principles for Medical Research 
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DeFronzo RA. Pathogenesis of type 2 diabetes mellitus. Med Clin North Am 2004; 88:787-
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Nauck MA. Incretin based therapies for type 2 diabetes mellitus: properties, functions, and 
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Holst JJ. Enteroglucagon. Annu Rev Physiol 1997; 59:257-271.
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Larsen J, Hylleberg B, Ng K, Damsbo P. Glucagon-like peptide-1 infusion must be maintained 
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Jin J, Sklar GE, Min SO, V, Chuen LS. Factors affecting therapeutic compliance: A review 
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of good clinical practice in the conduct of clinical trials on medicinal products for human use, 
article 11. Official Journal of the European Communities. May 2001.
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The European Parliament and the Council of the European Council: Regulation (EC) No 
726/2004 of the European Parliament and of the Council of 31 March 2004 laying down 
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and veterinary use and establishing a European Medicines Agency, article 57. Official Journal 
of the European Communities. April 2001.
47
McAulay V, Deary IJ, Frier BM. Symptoms of hypoglycaemia in people with
diabetes. Diabetic Medicine 2001; 18:690-705.
48
Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L et al: Hypoglycemia and 
Diabetes: A Report of a Workgroup of the American Diabetes Association and The 
EndocrineSociety. Diabetes Care 2013; 36:1384-1395.
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European Commission; The Rules Governing Medicinal Products in the European Union, 
Volume 4, Annex 13, Investigational Medicinal Products. Brussels, February 2010.
50
Food and Drug Administration. Guidedance for Industry. Diabetes Mellitus – Evaluating 
Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. 1-Dec-2008.
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Guidance (draft) for Industry Diabetes Mellitus: Developing Drugs and Therapeutic Biologics
for Treatment and Prevention. Food and Drug Administration, February 2008.
52
International Conference on Harmonisation. ICH Harmonised Tripartite Guideline. Statistical
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principles for clinical trials E9. International Conference on Harmonisation E9 Expert
Working Group. 5-Feb-1998.
53
American Diabetes Association. Classification and Diagnosis of Diabetes. Diabetes Care. 
2015;38(Suppl. 1):S8-S16
54
Garber AJ, Abrahamson MJ, Barzilay JI, Blonde L, Bloomgarden ZT, Bush MA, et al. AACE 
comprehensive diabetes management algorithm 2013. Endocrine Practice: Official Journal of 
the American College of Endocrinology and the American Association of Clinical 
Endocrinologists. 2013;19(2):327-36
55
Schwartz NS, Clutter WE, Shah SD, Cryer PE. Glycemic thresholds for activation of glucose 
counterregulatory systems are higher than the threshold for symptoms. J Clin Invest 1987; 
79(3):777-781.
56
International Committee of Medical Journal Editors. Recommendations for the Conduct, 
Reporting, Editing and Publication of Scholarly Work in Medical Journals; current version 
available at www.icmje.org.
CONFIDENTIAL


Protocol - Appendix A
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Appendix A
Monitoring of Calcitonin
Trial ID: NN2211-4174
A trial comparing the efficacy and safety of liraglutide 1.8 
mg/day to liraglutide 0.9 mg/day in Japanese subjects with 
type 2 diabetes mellitus
Trial Phase: 3b
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties
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This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol - Appendix A
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1
Background
Treatment with GLP-1 receptor agonists has shown to be associated with thyroid C-cell changes in 
rodents but not in non-human primates. The human relevance of this finding is unknown. However, 
based on the findings in rodents, monitoring of serum calcitonin (a sensitive biomarker for C-cell 
activation) is currently being performed in clinical trials with liraglutide.
While there is general agreement on the clinical interpretation of substantially elevated calcitonin 
levels (greater than 100 ng/L) as likely indicative of C-cell neoplasia, the interpretation of values 
between upper normal range (5.0 and 8.4 ng/L for women and men, respectively) and 100 ng/L can 
become challenging. 
There are several known confounding factors affecting calcitonin levels, namely renal dysfunction, 
smoking, autoimmune thyroiditis and several drug classes (e.g. proton pump inhibitors, beta-
blockers, H2-blockers and glucocorticoids). Physiology of C-cell activation in various clinical 
conditions and in different patient populations (i.e. with various co-morbidities) is poorly 
understood. There may be various clinical conditions not identified so far which mildly or 
moderately affect calcitonin secretion by C-cells.
CONFIDENTIAL


Protocol - Appendix A
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2
Calcitonin and C-cell abnormalities - evaluation and follow-up
Subjects with a personal or family history of medullar thyroid cancer (MTC) or multiple endocrine 
neoplasia syndrome type 2 (MEN 2) or with a screening calcitonin ≥ 50 ng/L will be excluded from 
the trial. 
A blood sample will be drawn at pre-specified trial visits for measurement of calcitonin. In case a 
subject has an increased calcitonin value ≥ 10 ng/L the algorithm outlined below should be 
followed. The algorithm applies for all calcitonin values including screening values.
The summary for the rationale for the use of specific calcitonin values to trigger medical evaluation 
and an overview of the algorithm is provided below:
2.1
Calcitonin ≥ 100 ng/L  
The subject (even if a screen failure) should immediately be referred to a thyroid specialist for 
further evaluation and the trial treatment should be discontinued. 
The subject can remain in the trial, however, all drugs suspected to relate to this condition should be 
discontinued until appropriate treatment has been initiated. If it is a screening value the subject 
cannot be entered into run-in period. 
These values were found in 0.15% of a population with thyroid nodular disease published by 
Costante et al1 and in one subject (on active comparator) in the liraglutide development program. 
For a calcitonin value of ≥100 ng/L, the subject should be assumed to have significant C-cell 
disease and a high likelihood of having medullary carcinoma of the thyroid. Diagnostic evaluation 
should consist of thyroid ultrasound, fine needle aspiration of any nodules >1 cm and potentially 
surgery with neck dissection. Family history of MTC or MEN2 should be evoked and a RET proto-
oncogene analysis should be performed. 
2.2
Calcitonin ≥ 50 and < 100 ng/L 
The subject (even if a screen failure) should be referred to a thyroid specialist for further evaluation 
and the trial treatment should be discontinued. 
The subject can remain in the trial however, all drugs suspected to relate to this condition should be 
discontinued until appropriate treatment has been initiated. If it is a screening value the subject 
cannot be entered into run-in period.
These values were found in 0.14% of the population with thyroid nodular disease published by 
Costante et al. Diagnostic evaluation will likely include ultrasound examination and if available and 
if there is no contraindication, subjects should undergo a pentagastrin stimulation test. Subjects with 
CONFIDENTIAL


Protocol - Appendix A
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positive pentagastrin stimulation tests will be considered to undergo surgery. In the US and other 
countries where pentagastrin is not available, thyroid ultrasound and fine needle aspiration biopsy 
may add important clinical information informing the need for surgery. 
2.3
Calcitonin ≥ 20 and <50 ng/L
The subject can continue in the trial. Repeat testing of calcitonin at next protocol scheduled 
calcitonin visit. If the subject is a screen failure or if the value is the last one taken in the trial, the 
subject should be referred to a thyroid specialist for further evaluation.
These values are expected to be found in up to 1% of subjects. Based on data from Costante et al1, 
the predictive value of calcitonin levels ≥ 20 and < 50 ng/L for clinically significant C-cell disease 
begins to fall. However, up to 25% of these subjects had a positive pentagastrin stimulation test. 
The likelihood of having a medullary carcinoma >1 cm with calcitonin in this range is extremely 
low. 
2.4
Calcitonin ≥ 10 and < 20 ng/L
The subject can continue in the trial. Repeat testing of calcitonin at next protocol scheduled 
calcitonin visit. If the subject is a screen failure or if the value is the last one taken in the trial, the 
subject should be referred to a thyroid specialist for further evaluation. 
Costante et al1 had 216 (3.7%) patients in this category. One patient out of the 216 had a subsequent 
basal (unstimulated) calcitonin of 33 ng/L, and had C-cell hyperplasia at surgery, a lesion of 
unknown clinical significance. Two other studies used a cutoff of CT > 10 ng/L to screen for C-cell 
disease, but they do not provide sufficient information on patients with basal CT >10 and <20 ng/L 
to allow conclusions.2,3
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Protocol - Appendix A
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3
References
                                                
1 Costante G, Meringolo D, Durante C, Bianchi D, Nocera M, Tumino S et al. Predictive value of serum calcitonin 
levels for preoperative diagnosis of medullary thyroid carcinoma in a cohort of 5817 consecutive patients with thyroid 
nodules. Journal of Clinical Endocrinology and Metabolism 2007; 92(2):450-455.
2 Scheuba C, Kaserer K, Moritz A, Drosten R, Vierhapper H, Bieglmayer C et al. Sporadic hypercalcitoninemia: 
clinical and therapeutic consequences. Endocrine-Related Cancer 2009; 16(1):243-253.
3 Verga U, Ferrero S, Vicentini L, Brambilla T, Cirello V, Muzza M et al. Histopathological and molecular studies in 
patients with goiter and hypercalcitoninemia: reactive or neoplastic C-cell hyperplasia? Endocr Relat Cancer 2007; 
14(2):393-403.
CONFIDENTIAL


Protocol - Appendix B
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Date:
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Trial ID: NN2211-4174
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Appendix B
New York Heart Association Criteria for Functional Capacity
Trial ID: NN2211-4174
A trial comparing the efficacy and safety of liraglutide 1.8 
mg/day to liraglutide 0.9 mg/day in Japanese subjects with 
type 2 diabetes mellitus
Trial Phase: 3b
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol - Appendix B
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1
Criteria for Functional Capacity
Functional Capacity１
Objective Assessment
Class I. Patients with cardiac disease but without resulting limitation of physical 
activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, 
or anginal pain.
A.
No objective evidence of 
cardiovascular disease.
Class II. Patients with cardiac disease resulting in slight limitation of physical 
activity. They are comfortable at rest. Ordinary physical activity results in fatigue, 
palpitation, dyspnea, or anginal pain.
B.
Objective evidence of 
minimal cardiovascular 
disease.
Class III. Patients with cardiac disease resulting in marked limitation of physical 
activity. They are comfortable at rest. Less than ordinary activity causes fatigue, 
palpitation, dyspnea, or anginal pain.
C.
Objective evidence of 
moderately severe 
cardiovascular disease.
Class IV. Patients with cardiac disease resulting in inability to carry on any physical 
activity without discomfort. Symptoms of heart failure or the anginal syndrome may 
be present even at rest. If any physical activity is undertaken, discomfort is increased.
D.
Objective evidence of 
severe cardiovascular 
disease.
CONFIDENTIAL


Protocol - Appendix B
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Date:
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Trial ID: NN2211-4174
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2
Reference
                                                
１The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for 
Diagnosis of Diseases of the Heart and Great Vessels. 9th ed. Boston, Mass: Little, Brown & Co; 
1994:253-256.
CONFIDENTIAL


Protocol - Appendix C
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Date:
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Trial ID: NN2211-4174
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Appendix C
Medical events of special interest, events with additional data 
collection and events requiring adjudication
Trial ID: NN2211-4174
A trial comparing the efficacy and safety of liraglutide 1.8 
mg/day to liraglutide 0.9 mg/day in Japanese subjects with 
type 2 diabetes mellitus
Trial Phase: 3b
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol - Appendix C
UTN: U1111-1164-5462 
Date:
25 March 2015
Status:
Final
Novo Nordisk
Trial ID: NN2211-4174
     
Version:
2.0
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1
Events with additional data collection and events requiring adjudication
Events with additional data 
collection and/or events 
requiring adjudication
Definitions
Rationale
Event Adjudication 
Committee
Fatal events
All fatal events should be reported  including all-cause mortality: 
!
Cardiovascular death 
!
Non-cardiovascular death
!
Undetermined cause of death
An FDA guidance document１
requests that Sponsors demonstrate 
the cardiovascular safety profile of 
any new therapy for type 2 diabetes in 
order to ensure, that the new therapy 
does not increase the cardiovascular 
risk to an unacceptable extent.
All events will be 
adjudicated.
Acute coronary syndrome
(myocardial infarction (MI)
or hospitalisation for unstable 
angina
All types of myocardial infarction (MI) must be reported:
!
Spontaneous MI (including re-infarction and MI associated with stent 
thrombosis)
!
Percutaneous coronary intervention (PCI) related MI
!
Coronary artery bypass graft surgery (CABG) related MI 
!
Silent MI
All events with symptoms of unstable angina requiring hospitalization must 
be reported.
An FDA guidance document１
requests that Sponsors demonstrate 
the cardiovascular safety profile of 
any new therapy for type 2 diabetes in 
order to ensure, that the new therapy 
does not increase the cardiovascular 
risk to an unacceptable extent.
All events will be 
adjudicated.
Cerebrovascular event; 
stroke or transient ischemic 
attack
Stroke (ischemic, haemorrhagic or undetermined) is defined as an acute 
episode of neurological dysfunction, caused by focal or global brain, spinal 
cord, or retinal vascular injury.
Transient Ischemic Attack (TIA) is defined as a transient (<24 hours) 
episode of neurological dysfunction caused by focal brain, spinal cord, or 
retinal ischemia, without acute infarction.
An FDA guidance document１
requests that Sponsors demonstrate 
the cardiovascular safety profile of 
any new therapy for type 2 diabetes in 
order to ensure, that the new therapy 
does not increase the cardiovascular 
risk to an unacceptable extent.
All events will be 
adjudicated.


Protocol - Appendix C
UTN: U1111-1164-5462 
Date:
25 March 2015
Status:
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Heart failure requiring 
hospital admission
Clinical manifestations of a new episode or worsening of existing heart 
failure.
An FDA guidance document１
requests that Sponsors demonstrate 
the cardiovascular safety profile of 
any new therapy for type 2 diabetes in 
order to ensure, that the new therapy 
does not increase the cardiovascular 
risk to an unacceptable extent.
All cases of heart 
failure requiring 
hospitalisation, 
defined as an 
admission to an 
impatient unit or a 
visit to an 
emergency 
department that 
results in a least a 
24 hours stay, will 
be adjudicated.
Pancreatitis
Two of the following three diagnostic criteria fulfilling the diagnosis of 
acute pancreatitis: 
!
Severe acute upper abdominal pain 
!
Elevated blood levels of pancreatic enzymes (lipase, amylase) > 
3xUNR
!
Characteristic imaging finding (ultrasound, computerised axial 
tomography (CT), magnetic resonance imaging (MRI)) 
Chronic pancreatitis will be defined by characteristic imaging finding 
(ultrasound, CT, MRI) with abnormal pancreatic function tests or 
characteristic histological findings.
Treatment with GLP-1 receptor 
agonists has been associated with 
acute pancreatitis. Pancreatitis 
(including necrotising pancreatitis) is 
an identified risk according to the 
Company Core Data Sheet (CCDS)
for liraglutide. Novo Nordisk 
therefore monitors these events 
closely.
All events will be 
adjudicated.
Neoplasm
All types of neoplasms (i.e. all new growth incl. polyps, warts etc.) must be 
reported including:
!
Malign neoplasm
!
In situ neoplasm
!
Benign neoplasm
!
Neoplasms of uncertain or unknown behaviour
(Please note: for operational reasons thyroid neoplasms will be reported as
Neoplasm is an event we follow 
closely for GLP-1 analogues due to 
non-clinical findings in rats and mice 
treated with GLP-1 agonists.
All neoplasm 
events, irrespective 
of malignancy 
stage, will be 
adjudicated.


Protocol - Appendix C
UTN: U1111-1164-5462 
Date:
25 March 2015
Status:
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Trial ID: NN2211-4174
     
Version:
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thyroid disease and should not be reported as a Neoplasm)
Thyroid disease
All disorders of thyroid gland (incl. thyroid neoplasms) must be reported.
Please refer to the protocol for further details on the assessments.
Thyroid C-cells carcinogenicity has 
been reported in rats and mice treated 
with GLP-1 receptor agonists in non-
clinical studies
All thyroid 
neoplasms will be 
adjudicated.
Thyroid disease
requiring 
thyroidectomy will 
be adjudicated.


Protocol - Appendix C
UTN: U1111-1164-5462 
Date:
25 March 2015
Status:
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Version:
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2
Medical Events of Special Interest (MESI)
Medical Events of Special 
Interest 
Definitions
Rationale
Event Adjudication 
Committee
Medication errors concerning 
trial products
!
Administration of wrong drug or use of wrong device
Note: Use of wrong DUN is not considered a medication error unless it 
results in administration of wrong drug.
!
Wrong route of administration, such as intramuscular instead of 
subcutaneous
!
Administration of an over dose with the intention to cause harm ( e.g., 
suicide attempt
!
Accidental administration of a lower or higher dose than intended.
Standard MESI in all Novo Nordisk 
clinical trials.
Medication errors are captured to 
collect information which may be 
used to improve the design, name or 
packaging of the product and/or 
information which may have an 
impact on product labelling (for 
example information about substantial 
overdoses)
No adjudication


Protocol - Appendix C
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3
Reference
                                                
１Hicks KA, Hung HMJ, Mahaffey KW, Mehran R, Nissen SE, Strockbridge NL et al. 
Standardized Definitions for Cardiovascular and Stroke End Point Events in Clinical Trials 
(DRAFT). 20 Aug 2014.
CONFIDENTIAL


Global and country key Novo Nordisk staff
Attachments I and II (if applicable) to the protocol are located in the Trial Master File.
Content: Global key staff and Country key staff
CONFIDENTIAL
Date:
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Version:
Status:
Liraglutide
Trial ID: NN2211-4174
Clinical Trial Report
Appendix 16.1.1
10 April 2018
1.0
Final
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Protocol Amendment
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Protocol Amendment
no 1
to Protocol, final version 2.0
dated 25-Mar-2015
Trial ID:NN2211-4174
A trial comparing the efficacy and safety of liraglutide 1.8 
mg/day to liraglutide 0.9 mg/day in Japanese subjects with 
type 2 diabetes mellitus
Trial phase: 3b
Applicable to Japan
Amendment originator:
, CMR Development Division, Novo Nordisk Pharma Ltd.
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
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parties.


Protocol Amendment
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Table of Contents   
Page
Table of Contents..............................................................................................................................................2
Table of Figures................................................................................................................................................2
1
Introduction including rationale for the protocol amendment.............................................................3
2
Changes......................................................................................................................................................4
2.1
Section 1 Summary........................................................................................................................4
2.2
Section 2 Flowchart .......................................................................................................................4
2.3
Section 6.3 Exclusion criteria ........................................................................................................4
2.4
Section 6.5 Withdrawal criteria .....................................................................................................4
2.5
Section 8.4.4 Eye Examination......................................................................................................5
2.6
Protocol Appendix A .....................................................................................................................5
Table of Figures   
Page
Figure 2-1
Flow of calcitonin monitoring ..................................................................................................6
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Protocol Amendment
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1
Introduction including rationale for the protocol amendment
The purpose of this amendment is to update an exclusion criterion and further correct minor 
inconsistencies and errors. Exclusion criterion no. 5 will be updated to specify how previous insulin 
treatment should be handled when subject eligibility is assessed. A timeframe will be added to the 
current text in order to make the criterion more clear for the sites. This will not have any impact on 
already included subjects.
The following changes are implemented as well:
!
Allowance of a time interval for the conduct of fundoscopy or fundus photography at visit 8, 16 
and 23. This is intended to give operational flexibility to perform the fundoscopy or fundus 
photography.
!
Withdrawal criteria no. 9 is updated since previous protocol didn’t provide the detailed process
if the fasting SMBG values taken on three consecutive days or if any of the FPG samples
analysed by the central laboratory exceeds the limit given there is no intercurrent cause for the 
hyperglycaemia.
!
Appendix A is updated to correct some inconsistencies with withdrawal criteria no.6 and to 
update algorithm of calcitonin monitoring to comply with revised company standards.
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
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Protocol Amendment
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2
Changes
2.1
Section 1
Summary
Key exclusion criteria
!
Previous treatment with insulin (except for short-term treatment in connection with intercurrent 
illness including gestational diabetes). Treatment with insulin within 12 weeks prior to 
screening.
2.2
Section 2
Flowchart
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
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
ECG
x4
x
x
x
Eye 
examination5
x5
x
x
x
Flow chart explanatory descriptions
Footnote No. 5: Fundoscopy or fundus photography performed within 90 days prior to run-in visit 
(V2) is acceptable, and results should be available prior to V2. Eye examination obtained within 7
days prior to V8 and 28 days prior to V16 and 23 are acceptable.
2.3
Section 6.3
Exclusion criteria
5. Previous treatment with insulin (except for short-term treatment in connection with intercurrent 
illness including gestational diabetes). Treatment with insulin within 12 weeks prior to screening.
2.4
Section 6.5
Withdrawal criteria
9. If the fasting SMBG values taken on three consecutive days or if any of the FPG samples
analysed by the central laboratory exceeds the limit of:
!
15.0 mmol/L (270 mg/dL) during the first 6 weeks after initiation of run-in
!
13.3 mmol/L (240 mg/dL) from week 7 to week 12 after initiation of run-in
!
11.1 mmol/L (200 mg/dL) after randomisation
given there is no intercurrent cause for the hyperglycaemia, action is to be taken by the investigator 
as soon as possible to obtain a confirmatory FPG the subject should be called in as soon as possible 
for a confirmatory FPG sample to be analysed by central laboratory. The next scheduled site visit 
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Protocol Amendment
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should not be awaited. If there is no intercurrent cause for the hyperglycaemia, and FPG exceeds 
the limits stated above, the subject must be withdrawn.
2.5
Section 8.4.4
Eye Examination
…Fundoscopy/fundus photography performed within 90 days prior to run-in visit is acceptable. If a
funduscopy/fundusphotography has been performed prior to the screening visit (Visit 1) the
procedure does not need to be repeated, unless worsening of visual function since the last
examination has been noted. The investigator must still interpret, sign and date the result page. If
fundoscopy or fundus photography is performed before a subject has signed the informed consent
form, it must be documented in the medical record that the reason for performing the procedure was
not related to the present trial.
Eye examination obtained within 7 days prior to V8 and 28 days prior to V16 and V23 are
acceptable.
2.6
Protocol Appendix A
Section 1
Background
…While there is general agreement on the clinical interpretation of substantially elevated calcitonin
levels (greater than 100 ng/L) as likely indicative of C-cell neoplasia, the interpretation of values
between upper normal range (5.0 and 8.4 ng/L for women and men, respectively) and 100 ng/L can
become challenging is less clear with regards to indication of disease.
There are several known confounding factors affecting calcitonin levels, namely e.g.:
!
renal dysfunction,
!
smoking,
!
autoimmune thyroiditis and 
!
several drug classes (e.g. proton pump inhibitors, betablockers, H2-blockers and 
glucocorticoids).
Physiology of C-cell activation in various clinical conditions and in different patient populations (i.e. 
with various co-morbidities) is poorly understood. There may be various clinical conditions not 
identified so far which mildly or moderately affect calcitonin secretion by C-cells.
Section 2
Calcitonin and C-cell abnormalities – evaluation and follow-up monitoring
Subjects with a personal or family history of medullar thyroid cancer (MTC) or multiple endocrine
neoplasia syndrome type 2 (MEN 2) or with a screening calcitonin ≥ 50 ng/L will be excluded from
the trial.
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Protocol Amendment
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A blood sample will be drawn at pre-specified trial visits for measurement of calcitonin. Subjects
with a calcitonin value ≥ 50 ng/L at screening cannot be entered into run-in period according to 
protocol section 6.3 and further if the calcitonin value is measured to be ≥ 50 ng/L after run-in visit 
(Visit2), the subjects must be withdrawn according to section 6.5 in the protocol.
In case a subject has an increased calcitonin value ≥ 10 ng/L the algorithm outlined in Figure 2-1
and described below should be followed. The algorithm applies for all calcitonin values including 
screening values.
The summary for the rationale for the use of specific calcitonin values to trigger medical evaluation
and an overview of the algorithm is provided below:
Figure 2-1
Flow of calcitonin monitoring
Section 2.1
Calcitonin ≥ 100 ng/L
Action: The subject (even if a screen failure) must immediately be referred to a thyroid specialist 
for further evaluation and the trial treatment should be discontinued the subject must be withdrawn 
from the trial. 
The subject can remain in the trial, however, allAll medicationsdrugs suspected to relate to this 
condition should be discontinued until appropriate treatment has been initiated. If it is a screening 
value the subject cannot be entered into run-in period.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
10 September 2015
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Trial ID: NN2211-4174
Version:
1.0
UTN: 1111-1164-5462
Status:
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Background: These values were found in 9 (0.15%) of a population of 5817 patients with thyroid 
nodular disease published by Costante et al1 and in one subject (on active comparator) in the 
liraglutide development program. For a calcitonin value of ≥100 ng/L, the subject should be 
assumed to have significant C-cell disease and a high likelihood of having medullary carcinoma of 
the thyroid. All of these patients were diagnosed with MTC resulting in a positive predictive value 
of 100%.
Diagnostic evaluation should consist of include: 
!
thyroid ultrasound,
!
fine needle aspiration of any nodules >1 cm and 
!
potentially surgery with neck dissection.
In case a subject is diagnosed with MTC, it is common clinical practice to explore the Ffamily 
history of MTC or MEN2 should be evoked and perform a genetic test for a RET proto-oncogene
analysis should be performed mutation.
Section 2.2
Calcitonin ≥ 50 and < 100 ng/L
Action: The subject (even if a screen failure) should be referred to a thyroid specialist for further 
evaluation and the trial treatment should be discontinued the subject must be withdrawn from the 
trial.
The subject can remain in the trial however, Aall drugs medications suspected to relate to this 
condition should be discontinued until appropriate treatment has been initiated. If it is a screening 
value the subject cannot be entered into run-in period.
Background: These values were found in 8 (0.14%) of the population of 5817 patients with thyroid 
nodular disease published by Costante et al1. Two of these subjects were diagnosed with MTC and 
two were diagnosed with C-cell hyperplasia, resulting in a positive predictive value of a C-cell 
anomaly of 50%.
Diagnostic evaluation will likely should include:
!
thyroid ultrasound examination and
!
if available and if there is no contraindication, subjects should undergo a pentagastrin
stimulation test. Subjects with positive pentagastrin stimulation tests will should be
considered to undergo surgery. 
!
In the US and other countries whereIf pentagastrin is not available, thyroid ultrasound and 
fine needle aspiration biopsy may add important clinical information informing the need 
for surgery.
CONFIDENTIAL


Protocol Amendment
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Date:
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Section 2.3
Calcitonin ≥ 20 and <50 ng/L
The subject can continue in the trial. Repeat testing of calcitonin at next protocol scheduled
calcitonin visit. If the subject is a screen failure or if the value is the last one taken in the trial, the
subject should be referred to a thyroid specialist for further evaluation.
These values are expected to be found in up to 1% of subjects. Based on data from Costante et al1,
the predictive value of calcitonin levels ≥ 20 and < 50 ng/L for clinically significant C-cell disease
begins to fall. However, up to 25% of these subjects had a positive pentagastrin stimulation test.
The likelihood of having a medullary carcinoma >1 cm with calcitonin in this range is extremely
low.
Section 2.4
Calcitonin ≥ 10 and < 20 ng/L
The subject can continue in the trial. Repeat testing of calcitonin at next protocol scheduled
calcitonin visit. If the subject is a screen failure or if the value is the last one taken in the trial, the
subject should be referred to a thyroid specialist for further evaluation.
Costante et al1 had 216 (3.7%) patients in this category. One patient out of the 216 had a subsequent
basal (unstimulated) calcitonin of 33 ng/L, and had C-cell hyperplasia at surgery, a lesion of
unknown clinical significance. Two other studies used a cutoff of CT > 10 ng/L to screen for C-cell
disease, but they do not provide sufficient information on patients with basal CT >10 and <20 ng/L
to allow conclusions.2,3
Section 2.3
Calcitonin ≥ 10 and <50 ng/L
Action: The subject can continue in the trial on trial product. Continue sampling of calcitonin 
according to the protocol. If the subject is a screen failure or if the value is from the last sample 
taken in the trial, the subject should be referred to a thyroid specialist for further evaluation.
Background: Calcitonin values from 20-50 ng/L were found in up to 1% of subjects of the 
population of 5817 patients with thyroid nodular disease1. The predictive value of a C-cell anomaly 
for this calcitonin level was 8.3%. However, the likelihood of having a medullary carcinoma >1 cm 
with calcitonin in this range is extremely low.
For calcitonin values 10-20 ng/L Costante et al1 identified 216 (3.7%) patients. One patient out of 
the 216 had a subsequent basal (unstimulated) calcitonin of 33 ng/L, and had C-cell hyperplasia at 
surgery. Two other studies used a cut-off of CT > 10 ng/L to screen for C-cell disease, but they do 
not provide sufficient information on patients with basal CT >10 and <20 ng/L to allow 
conclusions2,3.
CONFIDENTIAL

SAP_001.pdf: 
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Link
List of contents
Statistical analysis plan......................................................................................................................
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
Liraglutide
Trial ID: NN2211-4174
Clinical Trial Report
Appendix 16.1.9
10 April 2018
1.0
Final
16.1.9 Documentation of statistical methods
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
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Trial ID: NN2211-4174
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Statistical Analysis Plan
Trial ID: NN2211-4174
A trial comparing the efficacy and safety of liraglutide 1.8 
mg/day to liraglutide 0.9 mg/day in Japanese subjects with type 2 
diabetes
Author:
Clinical Statistics Group
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. 
. 


Statistical Analysis Plan
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Date:
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Trial ID: NN2211-4174
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Table of contents   
Page
Table of contents.........................................................................................................................................2
List of abbreviations ...................................................................................................................................3
1
Introduction .........................................................................................................................................4
1.1
Trial information.......................................................................................................................4
1.2
Scope of the statistical analysis plan..........................................................................................4
2
Endpoints .............................................................................................................................................4
2.1
Primary endpoint.......................................................................................................................4
2.2
Secondary endpoints .................................................................................................................4
2.2.1
Secondary efficacy endpoints...................................................................................4
2.2.2
Secondary safety endpoints ......................................................................................5
3
Statistical considerations .....................................................................................................................6
3.1
Sample size calculation .............................................................................................................9
3.2
Definition of analysis sets..........................................................................................................9
3.3
Primary endpoint.......................................................................................................................9
3.4
Secondary endpoints ...............................................................................................................10
3.4.1
Efficacy endpoints .................................................................................................10
3.4.2
Safety endpoints ....................................................................................................13
4
Changes to the statistical analyses planned in the protocol..............................................................19
5
References ..........................................................................................................................................22
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
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Trial ID: NN2211-4174
Version:
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List of abbreviations
AE
adverse event
ANCOVA
analysis of covariance
BMI
body mass index
CI
confidence interval
CTR
clinical trial report
CV
coefficient of variation 
FAS
full analysis set
FPG
fasting plasma glucose
HOMA-IR
homeostasis model assessment as an index of insulin resistance
HOMA-B
homeostasis model assessment of beta-call function
ITT
intention-to-treat
LLOQ
lower limit of quantification
LOCF
last observation carried forward
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
mixed model for repeated measurements
SAP
statistical analysis plan
SAS
safety analysis set
SD
standard deviation
SMBG
self-measured blood glucose
T2DM
type 2 diabetes mellitus
TEAE
treatment emergent adverse event
UNR
upper normal range
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
26 November 2017
Novo Nordisk
Trial ID: NN2211-4174
Version:
2.0
UTN: U1111-1164-5462
Status:
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1
Introduction
1.1
Trial information
This is a 26-week randomised, parallel, two-arm, open-label, multi-centre trial comparing the 
efficacy and safety of liraglutide 1.8 mg/day to liraglutide 0.9 mg/day in Japanese subjects with 
T2DM. The liraglutide 1.8 mg/day treatment arm will be continued for a total of 52 weeks after 
randomisation for monitoring of safety and glycaemic control over 52 weeks. Refer to the protocol 
for further details.
1.2
Scope of the statistical analysis plan
This Statistical Analysis Plan (SAP) is based on the statistical analyses of NN2211-4174 as planned 
in the trial protocol. 
Changes to the statistical methods proposed in this SAP and the reason for the change must be 
reported in the clinical trial report (CTR).
This SAP is based on the protocol version 3.0 (Dated 10 September 2015).
2
Endpoints
2.1
Primary endpoint
Change from baseline in HbA1c after 26 weeks of treatment
2.2
Secondary endpoints
2.2.1
Secondary efficacy endpoints
!
Responder for HbA1c after 26 weeks of treatment (Yes/No):
o
HbA1c < 7.0% (53 mmol/mol)*
o
HbA1c ≤ 6.5% (48 mmol/mol)*
o
HbA1c < 7.0% without weight gain*
o
HbA1c < 7.0% without treatment emergent severe or blood glucose (BG) confirmed 
symptomatic hypoglycaemic episodes*
!
Change from baseline after 26 weeks of treatment in:
o
Self-Measured Blood Glucose (SMBG) 7-point profile
CONFIDENTIAL


Statistical Analysis Plan
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Date:
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Trial ID: NN2211-4174
Version:
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Status:
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7-point profile (individual points in the profile)*

Mean of 7-point profile*

Mean of postprandial increments (from before meal to 90 min after for 
breakfast, lunch and dinner). The mean increment over all meals will be 
derived as the mean of all available meal increments.*
o
Fasting plasma glucose (FPG)*
o
Waist circumference*
o
Body weight*
o
Body mass index (BMI)*
o
Blood pressure (systolic and diastolic)*
!
Fasting C-peptide, fasting insulin, fasting glucagon, proinsulin, proinsulin/insulin, HOMA-
B, HOMA-IR after 26 weeks of treatment*
!
Fasting lipid profile (total cholesterol, low density lipoprotein cholesterol [LDL cholesterol], 
high density lipoprotein cholesterol [HDL cholesterol], very low density lipoprotein 
cholesterol [VLDL cholesterol], triglycerides, and free fatty acids) after 26 weeks of 
treatment*
2.2.2
Secondary safety endpoints
!
Number of treatment emergent adverse events during 26 weeks of treatment*
!
Number of treatment emergent severe or BG confirmed symptomatic hypoglycaemic 
episodes during 26 weeks of treatment*
!
Number of treatment emergent nocturnal severe or BG confirmed symptomatic 
hypoglycaemic episodes during 26 weeks of treatment*
!
Number of treatment emergent hypoglycaemic episodes according to ADA definition 
during 26 weeks of treatment*
!
Change from baseline after 26 weeks of treatment:
o
Clinical evaluations:

Physical examination
CONFIDENTIAL


Statistical Analysis Plan
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Trial ID: NN2211-4174
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Eye examination

Electrocardiogram (ECG)

Pulse*
o
Laboratory assessments:

Biochemistry

Haematology

Calcitonin
The above mentioned primary endpoint, secondary efficacy endpoints and secondary safety 
endpoints will also be evaluated separately for 52 weeks of treatment.
* Key secondary endpoint prospectively selected for disclosure (e.g. clinicaltrials.gov and 
EudraCT)
Please note that following endpoints are also selected for disclosure.
!
Change from baseline in HbA1c after 52 weeks of treatment
!
Responder for HbA1c after 52 weeks of treatment (Yes/No):
o
HbA1c < 7.0% (53 mmol/mol)
!
Change from baseline in body weight after 52 weeks of treatment
!
Number of treatment emergent adverse events during 52 weeks of treatment
3
Statistical considerations
Novo Nordisk will analyse and report data from all sites together.
All analyses of efficacy and safety endpoints will be based on the full analysis set (FAS). All 
efficacy endpoints will be summarised using the FAS and safety endpoints will be summarised 
using the safety analysis set (SAS). 
The impact of protocol deviations and outliers may be investigated further in sensitivity analyses if 
deemed relevant.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
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Trial ID: NN2211-4174
Version:
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UTN: U1111-1164-5462
Status:
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Unless otherwise specified, all continuous measurements will be summarised descriptively at each 
visit by treatment using all observed data. Descriptive statistics will be presented based both on 
observed and last observation carried forward (LOCF) imputed data. Endpoints that are analysed 
untransformed and endpoints that are not formally analysed are summarised by the arithmetic mean, 
standard deviation (SD), median, and minimum and maximum value. Endpoints that are analysed 
log-transformed are supplemented with the geometric mean and coefficient of variation (CV). CV is 
calculated as () −1 where  is the SD of log-transformed values.
Unless otherwise specified, laboratory values below the lower limit of quantification (LLOQ) will 
be set to ½ LLOQ.
For measurements over time, mean values will be plotted to explore the trajectory over time. LOCF 
imputed data will be used as the basis for plotting data, if not otherwise specified. For endpoints 
that are analysed log-transformed, the geometric mean values will be plotted.
An analysis of covariance (ANCOVA) model will be applied for the primary endpoint and 
continuous secondary endpoints after 26 weeks of treatment. The model includes treatment as a 
fixed effect and the corresponding baseline value as a covariate. In the following, this model will be 
referred to as the standard ANCOVA model.
Presentation of results from a statistical analysis will include the estimated mean treatment effects 
(Least Square Means [LSMeans]) for absolute values and change from baseline. In addition, 
estimated mean treatment difference (or ratio) will be presented together with the two-sided 95% 
confidence interval and corresponding two-sided p-value. The “obsmargins” option will be used in 
the “LSMEANS TREATMENT”.i
Handling of missing data
The expected percentage of missing data is around 10%. In accordance with industry guidanceii
endpoints will be assessed at frequent visits and also on subjects who withdraw prematurely. This 
will facilitate an analysis in accordance with ITT principles. Also, the combined information on 
frequent outcomes and information on reason for drop-out is assumed to account for the missing 
data anticipated.
If not otherwise specified, the value from the randomisation visit (Visit 8) will be used as the 
baseline value. If the value measured at the randomisation visit is missing and the assessment has 
also been made at an earlier visit, then the non-missing value obtained at the preceding visit closest 
to Visit 8 will be used as the baseline value.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
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Trial ID: NN2211-4174
Version:
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Status:
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Missing values (including intermittent missing values) will be imputed using the LOCF method. 
Subjects without data after randomisation will be included by carrying forward their baseline value. 
In this trial, sensitivity analyses will be made to examine the robustness of the LOCF method.
Handling of laboratory measurements
A laboratory measurement in which the central laboratory could not guarantee a reliability of data, 
e.g. measurements with a comment like ”Only for reference because of xxxx”, will not be used for 
the summary and statistical analysis.
For laboratory parameters which is required to be measured in a fasting status (fasting plasma 
glucose, fasting insulin, fasting C-peptide, fasting glucagon, proinsulin and all lipids), the 
measurements in a non-fasting status will not be used for the summary and statistical analysis.
Handling of retest data
If more than one measurement exists at a visit after exclusion of non-fasting values for the fasting 
parameters or non-reliable laboratory data, the first one is chosen.
Visit reallocation
The following basic ideas are followed:
1) Visit reallocation is not applicable for assessments performed before date of first dosing of the 
randomised treatment.
2) Visit reallocation is only applicable for non-missing assessments. Hence, if an assessment is 
missing or treated as missing it cannot be reallocated to a different visit.
3) Any scheduled measurement (observed or missing), except the end of trial visit for the 
premature discontinuation (EOTpd), cannot be relocated to another visit.
4) Observed unscheduled measurements can only substitute preceding and adjacent scheduled 
assessments if these latter measurements were planned to be sampled in fasting conditions but 
were in fact sampled in non-fasting conditions.
Notice that such a non-fasting record which should have been fasting may or may not be 
actually missing. Regardless, the non-fasting record will be treated as missing.
5) Observed scheduled measurements from EOTpd should replace
a.
the adjacent earlier scheduled assessments from the preceding visit, in case this assessment 
is missing
b.
the later adjacent scheduled missing assessment from the succeeding visit in case the 
adjacent earlier scheduled assessment from the preceding visit is not missing.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
26 November 2017
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Trial ID: NN2211-4174
Version:
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UTN: U1111-1164-5462
Status:
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3.1
Sample size calculation
Sample size calculations are described in the protocol section 17.1 and will not further be described 
here.
3.2
Definition of analysis sets
The following analysis sets are defined in accordance with the ICH-E9 guidance.iii
!
Full Analysis Set (FAS): includes all randomised subjects. The statistical evaluation of the 
FAS will follow the intention-to-treat (ITT) principle and subjects will contribute to the 
evaluation “as randomised”.
!
Safety Analysis Set (SAS): includes all subjects receiving at least one dose of liraglutide. 
Subjects in the safety analysis set will contribute to the evaluation “as treated”.
Subjects who are lost to follow up and where no exposure information of liraglutide is available will 
be handled as unexposed.
3.3
Primary endpoint
The primary endpoint is the change from baseline in HbA1c after 26 weeks of treatment.
The change from baseline in HbA1c after 26 weeks of treatment will be analysed using an analysis 
of covariance (ANCOVA) model with treatment as a fixed effect and baseline HbA1c as a covariate.
Missing values after 26 weeks of treatment will be imputed applying last observation carried 
forward (LOCF) using HbA1c values at and after baseline.
Superiority of liraglutide 1.8 mg/day vs. liraglutide 0.9 mg/day will be considered as confirmed if 
the 95% confidence interval for the treatment difference (liraglutide 1.8 mg/day minus liraglutide 
0.9 mg/day) for change from baseline in HbA1c lies entirely below 0.0%; equivalent to a one-sided 
test with significance level of 2.5%. Conclusion of superiority will be based on FAS. 
Additionally, change from baseline in HbA1c after 52 weeks of treatment will be presented 
descriptively for the liraglutide 1.8 mg/day treatment arm.
Sensitivity analysis
Sensitivity analysis will be performed on FAS using the mixed model for repeated measurements 
(MMRM) method. All HbA1c values available post baseline at scheduled measurement times will 
be analysed in a linear mixed normal model using an unstructured residual covariance matrix for 
HbA1c measurements within the same subject. The model will include treatment and visit as fixed 
factors and baseline HbA1c as a covariate. Interactions between visit and treatment and between 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
26 November 2017
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Trial ID: NN2211-4174
Version:
2.0
UTN: U1111-1164-5462
Status:
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visit and baseline HbA1c will also be included in the model. The results of sensitivity analyses will 
be compared to the result of the standard ANCOVA method using LOCF for imputation of missing 
data.
Further, a pattern mixture model approach using multiple imputation and mimicking an ITT 
scenario will be applied. Imputation in both arms will be based on liraglutide 0.9 mg/day values. 
The imputations will be done as follows:
!
In the first step, for each subject with a non-monotone missing data pattern, missing values 
at visits prior to the last non-missing value for that subject are imputed using a Markov 
Chain Monte Carlo (MCMC) method (with seed of 20170427), in order to obtain a 
monotone missing data pattern. This imputation is done for each treatment group separately 
and 1000 copies of the dataset will be generated.
!
In the second step, for each of the 1000 copies of the dataset, an analysis of variance model 
with baseline HbA1c as a covariate is fitted to the change in HbA1c from baseline to 4 
weeks (Visit 11) for liraglutide 0.9 mg/day only. The estimated parameter and their 
variance from this model are used to impute missing values at 4 weeks for subjects in both 
the liraglutide 0.9 mg/day and liraglutide 1.8 mg/day groups, based on HbA1c at baseline.
!
In the third step, for each of the 1000 copies of the dataset, missing HbA1c values at 8 
weeks (Visit 12) are imputed in the same way as for 4 weeks. Now the imputations are 
based on an analysis of variance model with the HbA1c values at baseline and 4 weeks as 
covariates, fitted to liraglutide 0.9 mg/day group.
!
This stepwise procedure is then repeated sequentially over the available planned visits, 
adding one visit in each step until 26 weeks (Visit 16). In this stepwise procedure, seed of 
19671230 will be used.
!
For each of the complete data sets, the change from baseline to 26 weeks is analysed using 
an analysis of covariance model with treatment as a fixed effect and baseline HbA1c value 
as a covariate.
The estimates and standard deviations for the 1000 data sets are pooled to one estimate and 
associated standard deviation using Rubin’s ruleiv. From these pooled estimates the confidence 
interval for the treatment differences and the associated p-value are calculated.
3.4
Secondary endpoints
3.4.1
Efficacy endpoints
Endpoints evaluated after 26 weeks of treatment
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
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Trial ID: NN2211-4174
Version:
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Status:
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In the statistical analysis for the responder endpoints, the endpoint derived from imputed HbA1c 
and/or body weight by LOCF will be used.
Responder for HbA1c
Two dichotomous endpoints (responder/non-responder) will be defined based on whether a subject 
has met a specific target level after 26 weeks of treatment:
!
HbA1c target < 7.0%v
!
HbA1c target ≤ 6.5%vi, vii
Analysis of each of the two responder endpoints will be based on a logistic regression model with 
treatment as factor and baseline HbA1c value as a covariate.
HbA1c responder endpoints without weight gain
Responder for HbA1c without weight gain after 26 weeks of treatment will be defined as HbA1c < 
7.0% after 26 weeks of treatment and change from baseline in body weight after 26 weeks of 
treatment below or equal to zero. Analysis will be based on a logistic regression model with 
treatment as factor and baseline HbA1c and baseline body weight values as covariates.
HbA1c responder endpoints without treatment emergent severe or blood glucose (BG) 
confirmed symptomatic hypoglycaemic episodes
Responder for HbA1c without hypoglycaemic episodes after 26 weeks of treatment will be defined 
as HbA1c < 7.0% after 26 weeks of treatment and without severe or BG confirmed symptomatic 
episodes during 26 weeks of treatment. Analysis will be based on a logistic regression model with 
treatment as factor and baseline HbA1c values as a covariate.
Fasting plasma glucose (FPG)
Change from baseline in FPG after 26 weeks of treatment will be analysed using the standard 
ANCOVA model.
Waist circumference
Change from baseline in waist circumference after 26 weeks of treatment will be analysed using the 
standard ANCOVA model.
Body weight 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
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Trial ID: NN2211-4174
Version:
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Change from baseline in body weight after 26 weeks of treatment will be analysed using the 
standard ANCOVA model.
Body Mass Index (BMI) 
Change from baseline in BMI after 26 weeks of treatment will be analysed using the standard 
ANCOVA model.
Self measured blood glucose (SMBG) 7-point profile
Three endpoints from the 7 point SMBG profile will be defined: 
!
7-point profile (individual points in the profile)
!
Mean of the 7-point profile, defined as the area under the profile (calculated using the 
trapezoidal method) divided by the measurement time. The area under the profile will be 
calculated for profiles which have at least one valid measurement. If a profile has only one 
valid measurement (e.g. 170 mg/dL before lunch), the value (i.e. 170 mg/dL) is set to the 
mean of 7-point profile.
!
Mean of postprandial increments (from before meal to 90 min after for breakfast, lunch and 
dinner). The mean increment over all meals will be derived as the mean of all available 
meal increments. In case of only one valid increment (eg. 50 mg/dL for breakfast), the 
increment (i.e. 50 mg/dL) is set to the mean of postprandial increments.
A linear mixed effect model will be fitted to the 7-point SMBG profile data. The model will include 
treatment, time and interaction between treatment and time as fixed factors and subject as random 
effect. From the model mean profile by treatment and relevant treatment differences will be 
estimated and explored. 
Change from baseline after 26 weeks of treatment in mean of the 7-point profile and post-prandial 
increment endpoints will be analysed separately using the standard ANCOVA model.
Blood pressure (systolic and diastolic)
Change from baseline in systolic blood pressure and diastolic blood pressure after 26 weeks of 
treatment will be analysed separately using the standard ANCOVA model.
Fasting C-peptide, fasting insulin, fasting glucagon, proinsulin, proinsulin/insulin, HOMA-B, 
HOMA-IR
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
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Trial ID: NN2211-4174
Version:
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Status:
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In addition to fasting C-peptide, fasting insulin, fasting glucagon, and proinsulin, three derived 
parameters will be calculated; proinsulin/insulin ratio, beta-cell function (HOMA-B) and insulin 
resistance (HOMA-IR).
The calculation of the HOMA endpoints will be done as follows:
!
Beta-cell function (%) = 20·fasting insulin[μU/mL]/(FPG[mmol/L]-3.5)
!
Insulin resistance (%) = fasting insulin [μU/ml]·FPG [mmol/l]/ 22.5
These endpoints after 26 weeks of treatment will be analysed separately using the standard 
ANCOVA model. In these statistical analyses the endpoint will be log-transformed and so will the 
baseline covariate.
Fasting lipid profile 
Total cholesterol, low density lipoprotein cholesterol (LDL cholesterol), high density lipoprotein 
cholesterol (HDL cholesterol), very low density lipoprotein cholesterol (VLDL cholesterol), 
triglycerides, and free fatty acids after 26 weeks of treatment will be analysed separately by using 
the standard ANCOVA model. In these statistical analyses the endpoint will be log-transformed and 
so will the baseline covariate.
Endpoints evaluated after 52 weeks of treatment
All above listed efficacy endpoints will be summarised descriptively for the liraglutide 1.8 mg/day 
arm after 52 weeks of treatment. 
3.4.2
Safety endpoints
Adverse events
AEs will be coded using the most recent version of the Medical Dictionary for Regulatory 
Activities.
A treatment emergent adverse event (TEAE) is defined as an event that has onset date on or after 
the first day of IMP administration and no later than seven days after the last day on IMP. If the 
event has onset date before the first day of IMP administration and increases in severity during the 
treatment period and until 7 days after the last drug date, then this event should also be considered 
as a TEAE. Here the first day of IMP administration is defined as the first day of exposure to 
liraglutide.
AEs will be summarised descriptively for each of the following periods separately:
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
26 November 2017
Novo Nordisk
Trial ID: NN2211-4174
Version:
2.0
UTN: U1111-1164-5462
Status:
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!
The run-in period: TEAEs with an onset date on or after the first day of exposure to 
liraglutide and before the date of randomisation will be reported as part of the run-in period.
For the run-in failure subjects, AEs with an onset date on or after the first day of exposure 
to liraglutide and no later than seven days after the last day of liraglutide treatment will be 
reported as part of the run-in period.
!
The 26 week treatment period: TEAEs with an onset date on or after the date of 
randomisation and no later than seven days after Visit 16 (EOT26) will be reported as 
during 26 weeks of treatment. For subjects in the liraglutide 0.9 mg arm as well as for 
subjects in both arms who withdrew from the trial during 26 weeks of treatment, TEAEs 
with an onset date on or after the date of randomisation and no later than seven days after 
the last day of liraglutide treatment will be reported as part of 26 weeks of treatment.
!
The 52 week treatment period: For the liraglutide 1.8 mg arm all TEAEs with an onset date 
on or after the date of randomisation will be reported as during 52 weeks of treatment.
For each of the above periods, AE data will be displayed 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 100 years of exposure (R).
Summaries of AEs and of serious AEs will be presented as an overview including all AEs, serious 
AEs, number of deaths, AEs by severity, AEs by relation to treatment and AEs of special interest 
including AEs leading to withdrawal for each period.
Furthermore separate summary tables for each period will be presented based on system organ class 
and preferred terms for: 
!
All AEs 
!
Serious AEs
!
Possibly or probably related AEs
!
Severe, moderate and mild AEs
!
AEs reported by safety areas of interest
!
AEs with preferred term that are experienced by at least 5% of the subjects in any treatment 
arm or by at least 5% of all subjects
A listing for non-treatment emergent adverse events with onset date before the first day of exposure 
to liraglutide will be presented. A listing will also be presented for non-treatment emergent adverse 
events collected after the treatment emergent period according to the definition of TEAE.
Classification of Hypoglycaemia:
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
26 November 2017
Novo Nordisk
Trial ID: NN2211-4174
Version:
2.0
UTN: U1111-1164-5462
Status:
Final
     
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Treatment emergent: hypoglycaemic episodes will be defined as treatment emergent if the onset of 
the episode occurs on or after the first day of IMP administration, and no later than 7 days after the 
last day on IMP. Here the first day of IMP administration is defined as the first day of exposure to 
liraglutide.
Nocturnal hypoglycaemic episodes: are episodes occurring between 00:01 and 05.59 both inclusive.
Hypoglycaemic episodes are classified according to the Novo Nordisk classification of 
hypoglycaemia (see Figure 3-1) and the ADA classification of hypoglycaemia (see Figure 3-2).
Novo Nordisk classification of hypoglycaemia
In normal physiology, symptoms of hypoglycaemia occur below a plasma glucose level of 3.1 
mmol/L (56 mg/dL)viii. Therefore, Novo Nordisk has included hypoglycaemia with plasma glucose 
levels below this cut-off point in the definition of blood glucose (BG) confirmed hypoglycaemia.
Novo Nordisk uses the following classification (see Figure 3-1) in addition to the ADA 
classification: 
Severe or BG confirmed symptomatic hypoglycaemia: An episode that is severe according to the 
ADA classificationix or BG confirmed by a plasma glucose value <3.1 mmol/L (56 mg/dL) with
symptoms consistent with hypoglycaemia. 
Figure 3-1
Novo Nordisk classification of hypoglycaemia
ADA classificationix of hypoglycaemia
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
26 November 2017
Novo Nordisk
Trial ID: NN2211-4174
Version:
2.0
UTN: U1111-1164-5462
Status:
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Severe hypoglycaemia: An episode requiring assistance of another person to actively 
administer carbohydrate, glucagon, or take other corrective actions. Plasma glucose 
concentrations may not be available during an event, but neurological recovery following 
the return of plasma glucose to normal is considered sufficient evidence that the event was 
induced by a low plasma glucose concentration.
!
Asymptomatic hypoglycaemia: An episode not accompanied by typical symptoms of 
hypoglycaemia, but with a measured plasma glucose concentration ≤ 3.9 mmol/L (70 
mg/dL).
!
Documented symptomatic hypoglycaemia: An episode during which typical symptoms of 
hypoglycaemia are accompanied by a measured plasma glucose concentration ≤ 3.9 
mmol/L (70 mg/dL).
!
Pseudo-hypoglycaemia: An episode during which the person with diabetes reports any of 
the typical symptoms of hypoglycaemia with a measured plasma glucose concentration > 
3.9 mmol/L (70 mg/dL) but approaching that level.
!
Probable symptomatic hypoglycaemia: An episode during which symptoms of 
hypoglycaemia are not accompanied by a plasma glucose determination but that was 
presumably caused by a plasma glucose concentration ≤ 3.9 mmol/L (70 mg/dL).
Figure 3-2
ADA classification of hypoglycaemia
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
26 November 2017
Novo Nordisk
Trial ID: NN2211-4174
Version:
2.0
UTN: U1111-1164-5462
Status:
Final
     
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Hypoglycaemic episodes will be summarised descriptively for each of the following periods 
separately:
!
The run-in period: Treatment emergent hypoglycaemic episodes where the onset date of the 
episode occurs on or after the first day of exposure to liraglutide and before the date of 
randomisation will be reported as part of the run-in period. For the run-in failure subjects, 
hypoglycaemic episodes where the onset date of the episode occurs on or after the first day 
of exposure to liraglutide and no later than seven days after the last day of liraglutide 
treatment will be reported as part of the run-in period.
!
The 26 week treatment period: Treatment emergent hypoglycaemic episodes where the 
onset date of the episode occurs on or after the date of randomisation and no later than 
seven days after Visit 16 (EOT26) will be reported as during 26 weeks of treatment. For 
subjects in the liraglutide 0.9 mg arm as well as for subjects in both arms who withdrew 
from the trial during 26 weeks of treatment, treatment emergent hypoglycaemic episodes 
with an onset date on or after the date of randomisation and no later than seven days after 
the last day of liraglutide treatment will be reported as part of 26 weeks of treatment.
!
The 52 week treatment period: For the liraglutide 1.8 mg arm all treatment emergent 
hypoglycaemic episodes with an onset date on or after the date of randomisation will be 
reported as during 52 weeks of treatment.
For each of the periods listed above, data on hypoglycaemic episodes are presented above 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 100 years (R). Separate summaries are 
made for severe or BG confirmed symptomatic hypoglycaemic episodes, nocturnal severe or BG 
confirmed symptomatic hypoglycaemic episodes and the ADA classification of hypoglycaemia.
The number of hypoglycaemic episodes during 26 weeks of treatment will be analysed separately 
for each endpoint listed above using a negative binominal regression model with a log -link function 
and the logarithm of the time period in which a hypoglycaemic episode is considered to be part of 
the 26 week treatment period as offset. The model will include treatment as factor. For each 
endpoint, the analysis will be performed only if the number of episodes observed is adequate for 
convergence of the model fit.
Pulse
Pulse will be summarized descriptively.
Clinical evaluations (physical examination, eye examination and ECG)
Eye examination (fundoscopy/fundus photography) and ECG findings will be summarised 
descriptively, including:
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Statistical Analysis Plan
CONFIDENTIAL
Date:
26 November 2017
Novo Nordisk
Trial ID: NN2211-4174
Version:
2.0
UTN: U1111-1164-5462
Status:
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!
summaries for each visit
!
shift table from baseline to after 26 weeks of treatment and after 52 weeks of treatment
Any findings in the physical examination evaluation at screening will be presented as listings. Any 
clinically significant deterioration of a pre-existing condition after the screening visit, as well as any 
new clinically significant findings will be recorded as adverse events.
Laboratory assessments 
All laboratory parameters will be summarised descriptively.
The following tables will be presented based on both observed and LOCF imputed data:
!
Shift tables from baseline to after 26 weeks of treatment and after 52 weeks of treatment
!
Proportion of subjects with measurements outside reference range by treatment and week.
Laboratory values will be presented graphically as box plots by treatment and week.
For each laboratory parameter, individual values outside the reference ranges (abnormal values) 
will be listed.
For lipase and amylase the following rule will apply in the evaluation of the result:
!
If the amylase or lipase baseline (at screening) value is > 3xUNR this information is to be 
recorded as medical history for that subject. 
The purpose of the calcitonin analysis is to evaluate longitudinal changes in calcitonin, with main 
focus on subjects who develop persistently high levels of calcitonin during the trial.
Calcitonin will be displayed in terms of the number of subjects (N), the percentage of subjects (%) 
and the incidence rate per 100 years of exposure (R). The following criteria are defined for 
tabulations:
Persistent (all post baseline measurements)
!
From < UNR to persistently ≥ UNR
!
From < UNR to persistently ≥ 1.5 UNR
!
From < UNR to persistently ≥ 20 ng/L
!
From < UNR to persistently ≥ 50 ng/L
!
From < 20 ng/L to persistently ≥ 20 ng/L
!
From < 50 ng/L to persistently ≥ 50 ng/L
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
26 November 2017
Novo Nordisk
Trial ID: NN2211-4174
Version:
2.0
UTN: U1111-1164-5462
Status:
Final
     
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Incidental (at least one post baseline measurements)
!
From < UNR to ≥ UNR
!
From < UNR to ≥ 1.5 UNR
!
From < UNR to ≥ 20 ng/L
!
From < UNR to ≥ 50 ng/L
!
From < 20 ng/L to ≥ 20 ng/L
!
From < 50 ng/L to ≥ 50 ng/L
The distribution of all calcitonin measurements across treatment groups and time will be shown 
with histograms and corresponding cumulative plots for actual levels of calcitonin and change from 
baseline. The plots will be presented by treatment group (using EOT measurement - LOCF) and 
within treatment group by week. Plots will be done by gender.
Summaries tables of calcitonin continuous measurements, will include number and percentage of 
observations < and ≥ LLOQ, minimum, Q25, median, Q75 and maximum. Summaries will be 
presented for all subjects and by gender.
Longitudinal changes for subjects with calcitonin levels ≥ 20 ng/L will be plotted (longitudinal 
plots). The plots will be done by treatment and gender. They will be done for subjects in the 
persistent and incidental categories, separately.
A listing of subjects with at least one post baseline value ≥ 20 ng/L will be done. The listing will 
include age, gender, calcitonin measurements over time and AE history (including preferred term, 
onset and stop dates).
4
Changes to the statistical analyses planned in the protocol
The following changes from the protocol are implemented in this SAP.
Full analysis set
In the protocol, it was stated that “In exceptional cases, subjects may be eliminated from the full 
analysis set. In such cases the elimination will be justified and documented.”. Since it is technically 
difficult to keep the statisticians and programmers blinded before database lock in this trial design, 
it is deleted in order to minimise the potential bias by excluding the subjects based on the 
knowledge of randomised treatment for each subject.
Data handling
The possible data handlings are described in order to minimise the potential bias and the following 
text in section 17.2 in the protocol section was deleted.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
26 November 2017
Novo Nordisk
Trial ID: NN2211-4174
Version:
2.0
UTN: U1111-1164-5462
Status:
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Before data are released for statistical analysis, a review of all data will take place to identify 
protocol deviations that could potentially affect the results. Any decision to exclude any subject or 
observation from the statistical analysis is the joint responsibility of the members of the study group. 
The subjects or observations to be excluded, and the reasons for their exclusion must be 
documented and signed by those responsible before database lock. The subjects and observations 
excluded from analysis sets, and the reason for this, will be described in the clinical trial report.
The following changes from SAP version 1 are implemented in SAP version 2.
Endpoints section is created according to the protocol and endpoints selected for disclosure are 
updated.
Sensitivity analysis
As a sensitivity analysis for the primary endpoint, a pattern mixture model approach using multiple 
imputation is added.
Blood pressure (systolic and diastolic)
Statistical analysis is added for change from baseline in systolic blood pressure and diastolic blood 
pressure after 26 weeks of treatment as well as other efficacy secondary endpoints.
Safety analysis set
In the protocol, it was stated that the Safety Analysis Set “includes all subjects receiving at least one 
dose of randomised treatment”. In order to clarify that all adverse events occurring after initiation of 
treatment with liraglutide (including during the run-in phase) will be reported appropriately, this has 
been updated to state “includes all subjects receiving at least one dose of liraglutide”. Deletions are 
strikethrough and new text is in bold.
!
Safety Analysis Set (SAS): includes all subjects receiving at least one dose of randomised 
treatmentliraglutide. Subjects in the safety analysis set will contribute to the evaluation “as 
treated”.
Randomised sSubjects who are lost to follow up and where no exposure information of the 
investigational product or comparatorsliraglutide is available after randomisation will be 
handled as unexposed.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
26 November 2017
Novo Nordisk
Trial ID: NN2211-4174
Version:
2.0
UTN: U1111-1164-5462
Status:
Final
     
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Adverse events
In order to ensure proper alignment with the updated SAS definition, the definition of treatment 
emergent and the specification of AEs included in summary tables in each period are updated as 
follows. Deletions are strikethrough and new text is in bold.
A treatment emergent adverse event (TEAE) is defined as an event that has onset date on or after 
the first day of IMP administration and no later than seven days after the last day on IMP. If the 
event has onset date before the first day of IMP administration and increases in severity during the 
treatment period and until 7 days after the last drug date, then this event should also be considered 
as a TEAE. Here the first day of IMP administration is defined as the first day of exposure to 
randomised treatmentliraglutide.
AEs will be summarised descriptively for each of the following periods separately:
!
The run-in period: TEAEs with an onset date on or after Visit 2the first day of exposure to 
liraglutide and before the first day of exposure to randomised treatmentthe date of 
randomisation will be reported as part of the run-in period. For the run-in failure 
subjects, TEAEs with an onset date on or after the first day of exposure to liraglutide 
and no later than seven days after the last day of liraglutide treatment will be reported 
as part of the run-in period.
!
The 26 week treatment period: TEAEs with an onset date on or after the first day of 
exposure to randomised treatmentthe date of randomisation and no later than seven days 
after Visit 16 (EOT26) will be reported as during 26 weeks of treatment. For subjects in 
the liraglutide 0.9 mg arm as well as for subjects in both arm who withdrew from the 
trial during 26 weeks of treatment, TEAEs with an onset date on or after the date of 
randomisation and no later than seven days after the last day of liraglutide treatment 
will be reported as part of 26 weeks of treatment.
!
The 52 week treatment period: For the liraglutide 1.8 mg/day arm all TEAEs with an onset 
date on or after the date of randomisation will be reported as during 52 weeks of 
treatment.
A listing for non-treatment emergent adverse events with onset date before Visit2the first day of 
exposure to liraglutide will be presented. A listing will also be presented for non-treatment 
emergent adverse events collected after the treatment emergent period according to the definition of 
TEAE.
Hypoglycaemic episodes
In order to ensure proper alignment with the updated SAS definition, the definition of treatment 
emergent and the specification of hypoglycaemic episodes included in summary tables in each 
period are updated as follows. Deletions are strikethrough and new text is in bold.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
26 November 2017
Novo Nordisk
Trial ID: NN2211-4174
Version:
2.0
UTN: U1111-1164-5462
Status:
Final
     
Page:
22 of 23
Treatment emergent: hypoglycaemic episodes will be defined as treatment emergent if the onset of 
the episode occurs on or after the first day of IMP administration, and no later than 7 days after the 
last day on IMP. Here the first day of IMP administration is defined as the first day of exposure to 
randomised treatmentliraglutide.
Hypoglycaemic episodes will be summarised descriptively for each of the following periods 
separately:
!
The run-in period: Treatment emergent hypoglycaemic episodes where the onset date of 
the episode occurs on or after Visit 2the first day of exposure to liraglutide and before the 
first day of exposure to randomised treatmentthe date of randomisation will be reported as 
part of the run-in period. For the run-in failure subjects, hypoglycaemic episodes where 
the onset date of the episode occurs on or after the first day of exposure to liraglutide
and no later than seven days after the last day of liraglutide treatment will be reported 
as part of the run-in period.
!
The 26 week treatment period: Treatment emergent hypoglycaemic episodes where the 
onset date of the episode occurs on or after the first day of exposure to randomised 
treatmentthe date of randomisation and no later than seven days after Visit 16 (EOT26) 
will be reported as during 26 weeks of treatment. For subjects in the liraglutide 0.9 mg 
arm as well as for subjects in both arms who withdrew from the trial during 26 weeks
of treatment, treatment emergent hypoglycaemic episodes with an onset date on or 
after the date of randomisation and no later than seven days after the last day of 
liraglutide treatment will be reported as part of 26 weeks of treatment.
!
The 52 week treatment period: For the liraglutide 1.8 mg/day arm all treatment emergent 
hypoglycaemic episodes with an onset date on or after the date of randomisation will be 
reported as during 52 weeks of treatment.
For statistical analyses of hypoglycaemic episodes, it is described additionally in text that “For each 
endpoint, the analysis will be performed only if the number of episodes observed is adequate for 
convergence of the model fit.”.
5
References
                                               
i SAS/STAT(R) 9.2 User's Guide, Second Edition
ii Guidance (draft) for Industry Diabetes Mellitus: Developing Drugs and Therapeutic Biologics for 
Treatment and Prevention. Food and Drug Administration, February 2008.
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Statistical Analysis Plan
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Date:
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Trial ID: NN2211-4174
Version:
2.0
UTN: U1111-1164-5462
Status:
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iii International Conference on Harmonisation. ICH Harmonised Tripartite Guideline. Statistical 
principles for clinical trials E9. International Conference on Harmonisation E9 Expert Working 
Group. 5-Feb-1998.
iv Little RJA, Rubin DB. Statistical analysis with missing data: New York: John Wiley & Sons. 
1987.
v American Diabetes Association. Classification and Diagnosis of Diabetes. Diabetes Care. 
2015;38(Suppl. 1):S8-S16
vi European Commission; The Rules Governing Medicinal Products in the European Union, 
Volume 4, Annex 13, Investigational Medicinal Products. Brussels, February 2010.
vii Garber AJ, Abrahamson MJ, Barzilay JI, Blonde L, Bloomgarden ZT, Bush MA, et al. AACE 
comprehensive diabetes management algorithm 2013. Endocrine Practice: Official Journal of the 
American College of Endocrinology and the American Association of Clinical Endocrinologists. 
2013;19(2):327-36
viii Schwartz NS, Clutter WE, Shah SD, Cryer PE. Glycemic thresholds for activation of glucose 
counterregulatory systems are higher than the threshold for symptoms. J Clin Invest 1987; 
79(3):777-781.
ix Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L et al: Hypoglycemia and 
Diabetes: A Report of a Workgroup of the American Diabetes Association and The 
EndocrineSociety. Diabetes Care 2013; 36:1384-1395.
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