A Trial Comparing the Efficacy and Safety of Insulin Degludec/Liraglutide, Insulin Degludec, and Liraglutide in Chinese Subjects With Type 2 Diabetes Inadequately Controlled on Oral Antidiabetic Drugs (OADs)
Phase: PHASE3
Conditions: Diabetes, Diabetes Mellitus, Type 2
Sponsor: Novo Nordisk A/S

Cover Page for Protocol 
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT03172494 
Sponsor trial ID: 
NN9068-4148 
Official title of study: 
A trial comparing the efficacy and safety of insulin 
degludec/liraglutide, insulin degludec, and liraglutide in 
Chinese subjects with type 2 diabetes inadequately controlled 
on oral antidiabetic drugs (OADs). 
Document date: 
16 December 2019 
 

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List of contents
Protocol ...............................................................................................................................................
Appendix A .........................................................................................................................................
Appendix B..........................................................................................................................................
Appendix C .........................................................................................................................................
Appendix D .........................................................................................................................................
Attachment I and II............................................................................................................................
Protocol amendment 1 .......................................................................................................................
Protocol amendment 2 .......................................................................................................................
Protocol amendment 3 .......................................................................................................................
Protocol amendment 4 .......................................................................................................................
Protocol amendment 5 .......................................................................................................................
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
IDegLira
Trial ID: NN9068-4148
Clinical Trial Report
Appendix 16.1.1
16 December 2019
1.0
Final
16.1.1 Protocol and protocol amendments
CONFIDENTIAL
 
 
 
 
 
Redacted protocol 
Includes redaction of personal identifiable information only. 
 
 
 
. 
 
 

Protocol
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Trial ID: NN9068-4148
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Protocol
Trial ID: NN9068-4148
DUAL™ I - China
A trial comparing the efficacy and safety of insulin 
degludec/liraglutide, insulin degludec, and liraglutide in Chinese 
subjects with type 2 diabetes inadequately controlled on oral anti-
diabetic drugs (OADs)
Trial phase: 3a
Protocol originator
 
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.

Protocol
CONFIDENTIAL
Date:
07 October 2014
Novo Nordisk
Trial ID: NN9068-4148
Version:
2.0
UTN: U1111-1154-6671 
Status:
Final
     
Page:
2 of 84
Table of Contents   
Page
Table of Contents..............................................................................................................................................2
Table of Tables..................................................................................................................................................5
Table of Figures................................................................................................................................................5
List of abbreviations.........................................................................................................................................6
1
Summary....................................................................................................................................................9
2
Flow chart ................................................................................................................................................12
3
Background information and rationale for the trial............................................................................15
3.1
Background information..............................................................................................................15
3.2
Rationale for the trial...................................................................................................................15
4
Objectives and endpoints........................................................................................................................16
4.1
Objectives ....................................................................................................................................16
4.1.1
Primary objective.......................................................................................................16
4.1.2
Secondary objectives .................................................................................................16
4.2
Endpoints .....................................................................................................................................16
4.2.1
Primary endpoint........................................................................................................16
4.2.2
Secondary endpoints..................................................................................................16
4.2.2.1
Confirmatory secondary endpoints .....................................................16
4.2.2.2
Supportive secondary endpoints..........................................................17
5
Trial design ..............................................................................................................................................19
5.1
Type of trial .................................................................................................................................19
5.2
Rationale for trial design..............................................................................................................20
5.3
Treatment of subjects...................................................................................................................20
5.4
Treatment in the follow-up period...............................................................................................21
5.5
Treatment after end of trial ..........................................................................................................21
5.6
Rationale for treatment ................................................................................................................21
6
Trial population.......................................................................................................................................22
6.1
Number of subjects......................................................................................................................22
6.2
Inclusion criteria ..........................................................................................................................22
6.3
Exclusion criteria.........................................................................................................................23
6.4
Withdrawal criteria ......................................................................................................................24
6.5
Subject replacement.....................................................................................................................24
6.6
Rationale for trial population.......................................................................................................25
7
Milestones.................................................................................................................................................25
8
Methods and assessments .......................................................................................................................26
8.1
Visit procedures...........................................................................................................................26
8.1.1
Fasting requirement for blood sampling and body weight ........................................26
8.1.2
Screening (Visit 1).....................................................................................................26
8.1.3
Screening failures ......................................................................................................27
8.1.4
Randomisation (Visit 2).............................................................................................27
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8.1.5
Treatment period (Visits 2 to 28)...............................................................................28
8.1.6
Follow-up (Visit 29) ..................................................................................................28
8.1.7
Unscheduled visits.....................................................................................................28
8.1.8
Subject withdrawal ....................................................................................................29
8.2
Subject related information..........................................................................................................29
8.2.1
Demography...............................................................................................................29
8.2.2
Concomitant illness and medical history...................................................................29
8.2.3
Adverse events...........................................................................................................30
8.2.4
Diabetes complications and treatment history...........................................................30
8.2.5
Smoking habits ..........................................................................................................30
8.2.6
Concomitant medication............................................................................................30
8.2.7
Body measurements...................................................................................................30
8.2.8
Vital signs (blood pressure and pulse).......................................................................31
8.2.9
Physical examination.................................................................................................32
8.2.10
Eye examination ........................................................................................................32
8.2.11
ECG ...........................................................................................................................33
8.2.12
Self-measured plasma glucose...................................................................................33
8.2.13
Self-measured 9-point plasma glucose profile...........................................................33
8.2.14
Hypoglycaemic episodes ...........................................................................................34
8.3
Laboratory assessments ...............................................................................................................35
8.3.1
Blood and urine sampling (central laboratory analysis) ............................................35
8.3.2
Calcitonin sampling (central laboratory analysis) .....................................................36
8.3.3
Antibody sampling (special laboratory analysis).......................................................37
8.3.4
PK blood sampling (special laboratory analysis).......................................................37
8.4
Pancreatitis...................................................................................................................................38
8.5
Thyroid disease............................................................................................................................38
8.6
Subject diaries..............................................................................................................................38
8.7
Subject compliance......................................................................................................................39
9
Trial supplies ...........................................................................................................................................40
9.1
Trial products...............................................................................................................................40
9.2
Labelling......................................................................................................................................40
9.3
Storage .........................................................................................................................................41
9.4
Drug accountability and destruction............................................................................................42
9.5
Auxiliary supplies........................................................................................................................42
10 Interactive voice/web response system ..................................................................................................43
11 Randomisation procedure ......................................................................................................................43
12 Adverse events, MESIs, technical complaints and pregnancies..........................................................44
12.1
Definitions ...................................................................................................................................44
12.2
Reporting of adverse events.........................................................................................................47
12.3
Follow-up of adverse events........................................................................................................49
12.4
Technical complaints and technical complaint samples ..............................................................50
12.4.1
Reporting of technical complaints .............................................................................50
12.4.2
Collection, storage and shipment of technical complaint samples ............................51
12.5
Pregnancies in female subjects ....................................................................................................52
12.6
Precautions and/or overdose ........................................................................................................53
12.7
Committees related to safety........................................................................................................54
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Protocol
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Trial ID: NN9068-4148
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12.7.1
Novo Nordisk safety committee ................................................................................54
12.7.2
Calcitonin monitoring committee ..............................................................................54
12.7.3
Event adjudication committee....................................................................................54
13 Case report forms....................................................................................................................................55
13.1
Corrections to case report forms..................................................................................................55
13.2
Case report form flow..................................................................................................................56
14 Monitoring procedures ...........................................................................................................................57
14.1
Source data verification and source data requirements................................................................57
15 Data management....................................................................................................................................58
16 Computerised systems.............................................................................................................................58
17 Statistical considerations ........................................................................................................................59
17.1
Sample size calculation................................................................................................................60
17.2
Definition of analysis sets............................................................................................................61
17.3
Primary endpoint..........................................................................................................................62
17.3.1
Sensitivity analysis ....................................................................................................62
17.4
Secondary endpoints....................................................................................................................63
17.4.1
Confirmatory secondary endpoints............................................................................63
17.4.2
Supportive secondary endpoints ................................................................................64
17.4.2.1
Efficacy endpoints...............................................................................64
17.4.2.2
Safety endpoints..................................................................................66
17.5
Pharmacokinetic modelling .........................................................................................................72
18 Ethics........................................................................................................................................................74
18.1
Informed consent .........................................................................................................................74
18.2
Data handling...............................................................................................................................75
18.3
Information to subject during trial...............................................................................................75
18.4
Premature termination of the trial and/or trial site.......................................................................75
19 Protocol compliance................................................................................................................................76
20 Audits and inspections ............................................................................................................................76
21 Critical documents ..................................................................................................................................77
22 Responsibilities........................................................................................................................................78
22.1
Source data handling....................................................................................................................78
22.2
Delegation of responsibilities ......................................................................................................78
23 Reports and publications........................................................................................................................79
23.1
Communication of results............................................................................................................79
23.1.1
Authorship .................................................................................................................80
23.1.2
Site-specific publication(s) by investigator(s) ...........................................................80
23.2
Investigator access to data and review of results.........................................................................80
24 Retention of clinical trial documentation and human bio specimens.................................................81
24.1
Retention of clinical trial documentation.....................................................................................81
24.2
Retention of human bio specimens..............................................................................................81
25 Institutional Review Boards/Independent Ethics Committees and regulatory authorities..............82
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Protocol
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Trial ID: NN9068-4148
Version:
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Status:
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26 Indemnity statement ...............................................................................................................................82
27 References................................................................................................................................................83
Appendices and attachments to the protocol
Appendix A - Titration guideline
Appendix B - Medical events of special interest and events requiring adjudication 
Appendix C - New York Heart Association criteria for functional capacity in heart failure
Appendix D - Monitoring of calcitonin levels
Attachment I – List of key staff and relevant departments and vendors
Attachment II – Country list of key staff and relevant departments   
Table of Tables   
Page
Table 9–1
Trial products..........................................................................................................................40
Table 9–2
Storage conditions for trial products.......................................................................................41
Table of Figures   
Page
Figure 5–1
Trial Design ............................................................................................................................19
Figure 12–1
Initial reporting of AEs...........................................................................................................49
Figure 17–1
Novo Nordisk classification of hypoglycaemia......................................................................68
Figure 17–2
ADA classification of hypoglycaemia....................................................................................69
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Protocol
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Trial ID: NN9068-4148
Version:
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List of abbreviations
ADA
American Diabetes Association
AE
adverse event
AGI
α-glucosidase inhibitors
ALAT
alanine transaminase
ANCOVA
analysis of covariance
ASAT
aspartate aminotransferase 
BG
blood glucose
BMI
body mass index
CAS
completer analysis set
CFDA
China Food and Drug Administration
CRF
case report form
CTR
clinical trial report
DPP-4
dipeptidyl-peptidase-4 inhibitors
DUN
dispensing unit number
EASD
European Association for the Study of Diabetes
ECG
electrocardiogram
eCRF
electronic case report form
EMA
European Medicines Agency
EOT
end of treatment
FAS
full analysis set
FDA
Food and Drug Administration
FPG
fasting plasma glucose
GCP
good clinical practice
GLP-1
glucagon-like peptide-1
HbA1c
glycosylated haemoglobin
hCG
human chorionic gonadotrophin
HDL
high density lipoprotein
HOMA-β
homeostatic model assessment for β-cell function
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Protocol
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Date:
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Trial ID: NN9068-4148
Version:
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UTN: U1111-1154-6671 
Status:
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ICH
International Conference on Harmonisation
ICMJE
International Committee of Medical Journal Editors
IDeg
insulin degludec
IDeglira
insulin degludec/liraglutide
IEC
independent ethics committee
IMP
investigational medicinal product
IRB
Institutional Review Board
IV/WRS
interactive voice/web response system
LDL
low density lipoprotein
LOCF
last observation carried forward
MAP
modelling analysis plan
MESI
medical event of special interest
MEN2
multiple endocrine neoplasia type 2
MMRM
mixed model for repeated measurements
NYHA
New York Heart Association
OAD
oral anti-diabetic drug
OD
once daily
PK
pharmacokinetics
PP
per protocol
SAE
serious adverse event
SAS
safety analysis set
SIF
safety information form
SmPC
summary of product characteristics
SMPG
self-measured plasma glucose
SU
sulphonylureas
SUSAR
suspected unexpected serious adverse reaction
T2DM
type 2 diabetes mellitus
TEAE
treatment emergent adverse event
TTT
treat-to-target
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Trial ID: NN9068-4148
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TZD
thiazolidinedione
UNR
upper normal range
UTN
universal trial number
VLDL
very low density lipoprotein
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Trial ID: NN9068-4148
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1
Summary
Primary objective
To confirm the efficacy of insulin degludec/liraglutide in controlling glycaemia in Chinese subjects 
with type 2 diabetes mellitus inadequately controlled on oral anti-diabetic agents
Primary endpoint
Change from baseline in HbA1c after 26 weeks of treatment.
Secondary objectives
!
To confirm superiority of insulin degludec/liraglutide vs. insulin degludec on the following:
o
Change from baseline in body weight after 26 weeks of treatment
o
Number of treatment emergent severe or blood glucose confirmed hypoglycaemic 
episodes during 26 weeks of treatment 
!
To compare general efficacy and safety of insulin degludec/liraglutide to insulin degludec and 
liraglutide after 26 weeks of treatment
!
To compare the pharmacokinetics of insulin degludec/liraglutide and its individual components 
at clinically relevant doses during 26 weeks of treatment
Confirmatory secondary endpoints
!
Change from baseline in body weight after 26 weeks of treatment
!
Number of treatment emergent severe or blood glucose confirmed hypoglycaemic episodes 
during 26 weeks of treatment.
Trial design
This is a 26 week, randomised, parallel three-arm, open-label, multi-centre, treat-to-target 
confirmatory trial in Chinese subjects with type 2 diabetes mellitus inadequately controlled with 
metformin ± one other oral anti-diabetic agent: α-glucosidase inhibitors, sulphonylureas, glinides 
and thiazolidinediones. 
Subjects will be randomised in a 2:1:1 manner to receive insulin degludec/liraglutide, insulin 
degludec or liraglutide all once daily in combination with metformin. Other pre-trial oral anti-
diabetic agent treatment will be discontinued at randomisation. 
The randomisation of subjects to treatment groups will be stratified by previous treatment with
metformin ± one other oral anti-diabetic agent. 
The total trial duration for the individual subject will be approximately 29 weeks. 
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Trial population
A total of 720 subjects will be randomised. 
Key inclusion criteria
!
Informed consent obtained before any trial-related activities. Trial-related activities are any 
procedures that are carried out as part of the trial, including activities to determine suitability for 
the trial
!
Type 2 diabetes mellitus (clinically diagnosed)
!
Male or female, age ≥ 18 years at the time of signing informed consent
!
HbA1c 7.0-10.0 % (both inclusive) by central laboratory analysis, with the aim of a median of 
8.3%. When approximately 50% of the randomised subjects have a HbA1c above 8.3%, the 
remaining subjects randomised must have a HbA1c below or equal to 8.3%; or when 
approximately 50% of the randomised subjects have a HbA1c below or equal to 8.3%, the 
remaining subjects randomised must have a HbA1c above 8.3%
!
Current treatment for at least 90 calendar days prior to screening with metformin ± one other 
OAD: α-glucosidase inhibitors, sulphonylureas, glinides or thiazolidinediones. For ≥60 
calendar days prior to screening subjects should be on a stable dose of: 
a.
Metformin (≥1500 mg or max tolerated dose) or
b. Metformin (≥1500 mg or max tolerated dose) and sulphonylureas (≥half of the max 
approved dose according to local label) or
c.
Metformin (≥1500 mg or max tolerated dose) and glinides (≥half of the max 
approved dose according to local label) or 
d. Metformin (≥1500 mg or max tolerated dose) and α-glucosidase inhibitors (≥half of 
the max approved dose according to local label) or
e. Metformin (≥1500 mg or max tolerated dose) and thiazolidinediones (≥half of the 
max approved dose according to local label)
Key exclusion criteria
!
Treatment with insulin (except for short-term treatment at the discretion of the investigator)
!
Treatment with glucagon-like-peptide-1 receptor agonists or dipeptidyl-peptidase-4 inhibitors 
within 90 days prior to screening
!
Impaired liver function, defined as alanine aminotransferase ≥ 2.5 times upper normal range
!
Impaired renal function defined as serum-creatinine ≥ 133 μmol/L for males and ≥ 125 μmol/L
for females, or as defined according to local contraindications for metformin
!
Screening calcitonin ≥ 50 ng/L
!
Personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 
2 (MEN2)
!
Cardiac disorder defined as: congestive heart failure (NYHA class III-IV), diagnosis of unstable 
angina pectoris, cerebral stroke and/or myocardial infarction within the last 12 months prior to 
screening and/or planned coronary, carotid or peripheral artery revascularisation procedures
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!
Severe uncontrolled treated or untreated hypertension (systolic blood pressure ≥ 180 mmHg or 
diastolic blood pressure ≥ 100 mmHg
!
Proliferative retinopathy or maculopathy (macular oedema), requiring acute treatment
!
History of pancreatitis (acute or chronic)
Key efficacy assessments
!
HbA1c
!
Weight
!
Fasting plasma glucose 
!
Insulin dose at end of treatment 
Key safety assessments 
!
Hypoglycaemic episodes
!
Adverse events
Key pharmacokinetic assessments
!
Serum concentrations of insulin degludec and plasma concentrations of liraglutide for 
population pharmacokinetics
Trial products
Trial products for subcutaneous injection in this trial are:
!
Insulin degludec/liraglutide 100 units/mL + 3.6 mg/mL, 3 mL pre-filled pen
!
Insulin degludec 100 Units/mL, 3 mL pre-filled pen
!
Liraglutide 6 mg/mL (Victoza®), 3 mL pre-filled pen
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Protocol
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Trial ID: NN9068-4148
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2
Flow chart
Screening (SC) 
Randomisation (R)
Site visit (V) 
Telephone contact (T) 
Follow-up visit (FU)
SC
R
V
V
T
V
T
V
T
V
T
V
T
V
T
V
FU
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 
25 
26 
27
28
29
Time of visit (week)
-21
0
1
2
3
4
5 
6 
7
8
9 
10 
11
12
13 
14 
15
16
17 
18 
19
20
21 
22 
23 
24 
25
26
27
Visit window (days)
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+3
Subject related information/assessments
Informed consent
X
In/exclusion criteria
X
X
Randomisation
X
Withdrawal criteria
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant illness/Medical 
history
X
Concomitant medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Smoking habits
X
X
Demography
X
Diagnosis of diabetes
X
Diabetes treatment history
X
Diabetes complications
X
Family history of diabetes
X
Body measurements
Height
X
Body weight
X
X
X
X
X
X
X
X
Waist circumference
X
X
X
BMI
X
X
EFFICACY
Glucose metabolism
HbA1c
X
X
X
X
X
X
X
X
Fasting plasma glucose
X
X
X
X
X
X
X
Fasting insulin
X
X
X
Fasting glucagon
X
X
X
Fasting C-peptide
X
X
X
PK Sampling2
X
X
X
X
X
X
X
X
X
Self-measured plasma glucose
1-point SMPG profile3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
9-point SMPG profile
X
X
X
SAFETY
Adverse events 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Technical complaints
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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Protocol
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Date:
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Trial ID: NN9068-4148
Version:
2.0
UTN: U1111-1154-6671 
Status:
Final
     
Page:
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Screening (SC) 
Randomisation (R)
Site visit (V) 
Telephone contact (T) 
Follow-up visit (FU)
SC
R
V
V
T
V
T
V
T
V
T
V
T
V
T
V
FU
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 
25 
26 
27
28
29
Time of visit (week)
-21
0
1
2
3
4
5 
6 
7
8
9 
10 
11
12
13 
14 
15
16
17 
18 
19
20
21 
22 
23 
24 
25
26
27
Visit window (days)
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+3
Hypoglycaemic episodes
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECG4
X
X
Eye examination5
X
X
Physical examination
X
X
Vital signs
X
X
X
X
Antibodies
X
X
X
X
Biochemistry
X
X
X
X
Haematology
X
X
X
X
Hormones, calcitonin
X
X
X
X
Lipids
X
X
X
Urine dipstick
X
X
X
Pregnancy test (blood sample)6
X
X
REMINDERS
Handout ID card
X
Handout and instruct in BG-meter
use
X
Attend visit fasting 
X
X
X
X
X
X
X
X7
IV/WRS call
X
X
X
X
X
X
X
X
Dispense trial product. Instruct 
and hand out Directions for Use.
X
X
X
X
X
X
Drug accountability
X
X
X
X
X
X
X
Handout and instruct in/collect 
diary
X
X
X
X
X
X
X
X
X
X
X
Collect first date and dose of trial 
product
X
Collect last date and dose of trial 
product
X
Confirmation of unchanged dose 
of metformin 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
For liraglutide arm:
Confirmation of unchanged dose 
of liraglutide8
X
X
X
X
X
X
X
X
X
X
X
End of trial and sign off on case 
book
X
1.
Screening must take place within 14 calendar days prior to randomisation.
2.
For source data to be recorded in subject’s diary prior to every PK sampling visit, please see section 8.3.4.
3.
For IDeglira and IDeg arm: Daily pre-breakfast SMPG, last dose prior to titration and dose to be taken after titration must be recorded.       
For liraglutide arm: Pre-breakfast SMPG on 3 consecutive days prior to each visit/telephone contact must be recorded.
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4.
ECG obtained within 14 calendar days prior to Visit 2 as part of routine practice may replace the screening assessment, if results are available 
for evaluation at Visit 2. See section 8.2.11.
5.
Eye examination obtained within 90 calendar days prior to Visit 2 as part of routine practise may replace the screening assessment if results are 
available for evaluation at Visit 2. See section 8.2.10.
6.
For females of childbearing potential a urine pregnancy test should be performed at site if pregnancy is suspected or a menstrual period is 
missed. If the subject reports missing menstrual period at a telephone contact the subject must attend the site for an unscheduled visit as soon as 
possible for a urine pregnancy test. If positive, a confirmatory serum hCG test should be sent to the central laboratory.
7.
Please see section 8.1.6 for special fasting requirement at Visit 29.
8.
Subjects are to confirm unchanged dose of liraglutide once they have reached a dose of 1.8 mg.
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3
Background information and rationale for the trial
The trial will be conducted in compliance with this protocol, ICH GCP1and 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
Type 2 diabetes mellitus (T2DM) is a progressive disorder characterised by insulin resistance and 
impaired insulin secretion. A number of landmark studies have demonstrated the importance of 
maintaining good glycaemic control to reduce the risk of long-term complications associated with 
diabetes3,4. Given the progressive nature of T2DM, current anti-diabetic therapies with one or two 
oral anti-diabetic drugs (OADs) often fail to provide sustained glycaemic control. The current 
treatment cascade by the Chinese Diabetes Society, American Diabetes Association (ADA) and 
European Association for the Study of Diabetes (EASD) consensus follows a stepwise approach 
comprising lifestyle changes with pharmacological intervention. Metformin is recommended as 
initial pharmacological therapy, followed by combination therapy with other OADs, glucagon-like 
peptide 1 (GLP-1) receptor agonists or insulin as the disease progresses5,6. The successful outcome 
of recent global trials combining basal insulin and GLP-1 receptor agonist treatment as separate 
injections has led to the inclusion of this treatment combination in the most recent ADA/EASD 
position statement on management of hyperglycaemia in T2DM5.
3.2
Rationale for the trial
Insulin degludec/liraglutide (IDegLira) is a combination drug containing the long acting basal 
insulin analogue, insulin degludec (IDeg) and the GLP-1 analogue, liraglutide intended for once 
daily (OD) use in a single injection in subjects with T2DM. IDegLira was developed to take 
advantage of the combined effects of a basal insulin and GLP-1 analogue on glycaemic control 
through the actions on fasting glucose mediated by IDeg and liraglutide, and on postprandial 
glycaemic control mediated by liraglutide. The global clinical development programme for 
IDegLira has confirmed that the modes of action of IDeg and liraglutide result in clinically 
important improvements in glycaemic control with low risk of hypoglycaemia and weight gain in 
patients with T2DM7. In addition, the convenience of administering both components in a single 
daily injection, using a titration scheme similar to that used for basal insulin products, is expected to 
facilitate treatment compliance for patients.  
This protocol describes a clinical trial with the aim to confirm the safety and efficacy of OD
treatment with IDegLira compared to each of the monocomponents. The trial will be used for 
registration of IDegLira in China. For detailed information on IDeglira, IDeg or liraglutide, please 
see Investigator’s Brochure, any updates hereof, and/or SmPCs/ local labelling, as applicable.
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4
Objectives and endpoints
4.1
Objectives
4.1.1
Primary objective
To confirm the efficacy of IDegLira in controlling glycaemia in Chinese subjects with T2DM
inadequately controlled on oral anti-diabetic agents
This is done by comparing the difference in change from baseline in HbA1c after 26 weeks of 
treatment to a superiority margin of 0.0% for IDegLira vs. liraglutide and to a non-inferiority 
margin of 0.4% for IDegLira vs. IDeg.
4.1.2
Secondary objectives
!
To confirm superiority of IDegLira vs. IDeg on the following:
o
Change from baseline in body weight after 26 weeks of treatment
o
Number of treatment emergent severe or blood glucose confirmed hypoglycaemic 
episodes during 26 weeks of treatment 
!
To compare general efficacy and safety of IDegLira to IDeg and liraglutide after 26 weeks of 
treatment
!
To compare the pharmacokinetics of IDegLira and its individual components at clinically 
relevant doses during 26 weeks of treatment
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
Confirmatory secondary endpoints
The below endpoints will be tested with the aim to confirm superiority of IDegLira vs. IDeg:
!
Change from baseline in body weight after 26 weeks of treatment
!
Number of treatment emergent severe or blood glucose (BG) confirmed hypoglycaemic 
episodes during 26 weeks of treatment
To protect the type 1 error rate when testing the confirmatory endpoints, a closed test procedure will 
be used. 
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4.2.2.2
Supportive secondary endpoints
Efficacy endpoints
!
Insulin dose after 26 weeks of treatment
!
Responder for HbA1c after 26 weeks of treatment (Yes/No)
-
HbA1c < 7.0% 
-
HbA1c ≤ 6.5%  
-
HbA1c < 7.0% and change from baseline in body weight below or equal to zero
-
HbA1c ≤ 6.5% and change from baseline in body weight below or equal to zero
-
HbA1c < 7.0% without severe or BG confirmed hypoglycaemic episodes during the last 
12 weeks of treatment
-
HbA1c ≤ 6.5% without severe or BG confirmed hypoglycaemic episodes during the last 
12 weeks of treatment
-
HbA1c < 7.0% and change from baseline in body weight below or equal to zero and 
without severe or BG confirmed hypoglycaemic episodes during the last 12 weeks of 
treatment
-
HbA1c ≤ 6.5% and change from baseline in body weight below or equal to zero and 
without severe or BG confirmed hypoglycaemic episodes during the last 12 weeks of 
treatment 
!
Change from baseline after 26 weeks of treatment in:
-
Fasting plasma glucose (FPG)
-
Waist circumference 
-
9-point profile
-
Mean of the 9-point profile
-
Mean post prandial increment (from before meal to 90 min after breakfast, lunch and 
dinner). The mean increment over all meals will be derived as the mean of all available 
meal increments
!
Fasting C-peptide, fasting insulin, and fasting glucagon after 26 weeks of treatment
!
Beta-cell function, quantified by homeostatic model assessment (HOMA-β) after 26 weeks of 
treatment
!
Fasting lipid profile after 26 weeks of treatment
Safety endpoints
!
Number of treatment emergent adverse events (TEAEs) during 26 weeks of treatment
!
Number of treatment emergent nocturnal severe or BG confirmed hypoglycaemic episodes 
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
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!
Number of treatment emergent hypoglycaemic episodes according to ADA definition during 26 
weeks of treatment
!
Change from baseline in clinical evaluations after 26 weeks of treatment
-
Physical examination
-
Fundoscopy or fundusphotography
-
Electrocardiogram (ECG)
-
Pulse
-
Blood pressure
!
Change from baseline in laboratory assessments during 26 weeks of treatment 
-
Biochemistry 
-
Haematology 
-
Calcitonin
!
Urinalysis (dipstick for erythrocytes, protein, glucose and ketones)
!
Antibodies towards trial product
Pharmacokinetic (PK) endpoint
!
Serum concentrations of IDeg and plasma concentrations of liraglutide to be evaluated in a 
population PK analysis
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5
Trial design
5.1
Type of trial
This is a 26 week, randomised, parallel three-arm, open-label, multi-centre, treat-to-target (TTT)
confirmatory trial in Chinese subjects with T2DM inadequately controlled with metformin ± one 
other OAD: α-glucosidase inhibitors (AGI), sulphonylureas (SU), glinides and thiazolidinediones 
(TZD). Inadequately controlled diabetes will be defined as a HbA1c level of 7.0-10% (both 
inclusive).
Subjects will be randomised in a 2:1:1 manner to receive IDegLira, IDeg or liraglutide all once 
daily (OD) in combination with metformin. Other pre-trial OAD treatment will be discontinued at 
randomisation. The randomisation of subjects to treatment groups will be stratified by previous 
treatment with metformin ± one other OAD. 
The duration of the trial from screening (Visit 1) to follow-up (Visit 29) will be approximately 29
weeks with treatment duration of 26 weeks. At the screening visit, eligibility of the subjects is
determined followed by randomisation (Visit 2). One week after end of treatment (Visit 28), the 
follow-up (Visit 29) will be conducted. 
The trial design is summarised schematically below.
Figure 5–1
Trial Design
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5.2
Rationale for trial design
Based on prior experience from IDegLira trials, the treatment duration of 26 weeks is sufficient to 
reach a stable HbA1c level, and to obtain sufficient data for efficacy and safety evaluation. The 
parallel design has been chosen instead of a cross-over design to avoid the risk of carry-over effect 
and to keep the treatment period as short as possible. 
An open label design has been chosen due to two different regimens; fixed dose treatment of 
liraglutide with a maximal recommended dose of 1.8 mg/mL per day and treat-to-target for the IDeg 
and IDegLira arms. For the IDegLira treatment arm the maximal dose is 50 dose-steps per day since 
this will contain the liraglutide component maximal recommended dose of 1.8 mg/mL per day.
Blinding of the trial by use of double dummy design would mean an unacceptable number of 
injections, increase the complexity and thereby introduce an increased risk of non-compliance or 
withdrawal. 
To obtain improved HbA1c results the TTT approach has been chosen in order to ensure optimal 
treatment with frequent visits and titration of IDeg and IDegLira based on pre-breakfast self-
measured plasma glucose (SMPG) values. 
5.3
Treatment of subjects
Subjects treated with metformin ± one other OAD (AGI, SU, glinides or TZD) in accordance with 
the inclusion criterion are eligible for the trial. At randomisation subjects will have to discontinue 
all OADs except for metformin, leaving this at pre-trial dose in combination with one of the 
treatments for subcutaneous injection described below:
1. IDegLira added to current metformin therapy. Start dose will be 10 dose steps (10 U of IDeg 
and 0.36 mg of liraglutide) and will be titrated according to the Titration Guideline (appendix 
A) aiming for a FPG target of 4.0-5.0 mmol/L
2. IDeg added to current metformin therapy. Start dose will be 10 U and will be titrated according 
to the Titration Guideline aiming for a FPG target of 4.0-5.0 mmol/L
3. Liraglutide added to current metformin therapy. Start dose will be 0.6 mg and subsequent 0.6 
mg weekly dose escalation to the target dose of 1.8 mg. If subjects are not able to tolerate the 
dose escalation as described above, the visit window may be used to prolong exposure time for 
a given dose. Liraglutide dose of 1.8 mg/day will be continued for the remaining part of the trial 
and at each site visit/telephone contact subjects must be asked to confirm their dose
The Titration Guideline contains more detailed guidance on switching from pre-trial treatment to 
trial products, timing of injection, and titration of these.
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5.4
Treatment in the follow-up period
After 26 weeks of trial product exposure, a 1-week interval between the end of treatment (Visit 28) 
and the follow-up (Visit 29) is necessary to allow for trial product washout. Subjects must at the 
investigator’s discretion be switched to a suitable marketed product excluding insulin detemir
(Levemir®), IDeg, or any GLP-1 receptor agonists as these may interfere with antibody 
measurements performed at Visit 29. 
5.5
Treatment after end of trial
When completing the trial subjects should be switched to a suitable marketed product at the 
discretion of the investigator.
5.6
Rationale for treatment
Enrolment of insulin-naïve subjects with T2DM, inadequately controlled on 1-2 OADs, has been 
chosen to demonstrate the efficacy and safety of IDegLira, when added to metformin. 
The rationale for including subjects with pre-trial treatment metformin ± one other OAD is to 
mimic common practice of diabetes treatment in subjects with T2DM failing on 1-2 OADs and will 
prevent undue heterogeneity of the treatment arms due to diverse treatment. The daily dose of
metformin (∀1500 mg or max tolerated dose) is close to the maximum recommended dose as per 
local labelling for the treatment of type 2 diabetes.
When glycaemic control is not achieved or sustained on this background, the addition of another 
OAD, or initiation of GLP-1 receptor agonists, basal insulin or IDegLira can be considered. 
The expected outcome after 26 weeks of treatment with IDegLira compared to IDeg is similar 
change in HbA1c, less weight gain, lower post-prandial glucose levels, and a lower rate of 
hypoglycaemic events. In comparison with liraglutide a greater decrease in HbA1c, a lower FPG
level and fewer gastro intestinal AEs are anticipated for IDegLira. For more detailed information on 
IDegLira, please see Investigator’s Brochure7 or any updates hereof.
IDeg and liraglutide have been included as comparators in order to comply with regulatory 
requirements to assess the risk benefit profile of the combination product as compared to the 
individual components.
Apart from metformin, other OADs are primarily excluded at randomisation because they are not 
approved for use combined with liraglutide and metformin by the CFDA and are also not supported 
by the China clinical programme for liraglutide in terms of safety (and efficacy).
Metformin treatment will be in accordance with locally approved label. 
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6
Trial population
6.1
Number of subjects 
Countries planned to participate: China
Number of subjects planned to be screened: 1200
Number of subjects planned to be randomised: 720
Number of subjects expected to complete the trial: 612
A screening failure rate of 40% and a withdrawal rate of 15% are anticipated.
6.2
Inclusion criteria
For an eligible subject, all inclusion criteria must be answered "yes".
1. Informed consent obtained before any trial-related activities. Trial-related activities are any 
procedures that are carried out as part of the trial, including activities to determine suitability for 
the trial
2. Male or female, age ≥ 18 years at the time of signing informed consent
3. Type 2 diabetes mellitus (clinically diagnosed)
4. HbA1c 7.0-10.0 % (both inclusive) by central laboratory analysis, with the aim of a median of 
8.3%. When approximately 50% of the randomised subjects have a HbA1c above 8.3%, the 
remaining subjects randomised must have a HbA1c below or equal to 8.3%; or when 
approximately 50% of the randomised subjects have a HbA1c below or equal to 8.3%, the 
remaining subjects randomised must have a HbA1c above 8.3%
5. Current treatment for at least 90 calendar days prior to screening with metformin ± one other 
OAD: AGI, SU, glinides or TZD. For ≥60 calendar days prior to screening subjects should be 
on a stable dose of: 
a.
Metformin (≥1500 mg or max tolerated dose) or
b. Metformin (≥1500 mg or max tolerated dose) and SU (≥half of the max approved 
dose according to local label) or
c.
Metformin (≥1500 mg or max tolerated dose) and glinides (≥half of the max 
approved dose according to local label) or 
d. Metformin (≥1500 mg or max tolerated dose) and AGI (≥half of the max approved 
dose according to local label) or
e. Metformin (≥1500 mg or max tolerated dose) and TZD (≥half of the max approved 
dose according to local label)
6. Body mass index (BMI) ≤40 kg/m2
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7. Able and willing to adhere to the protocol including performing self-monitoring of plasma 
glucose profiles, keeping a trial diary and using a pre-filled pen device
6.3
Exclusion criteria
For an eligible subject, all exclusion criteria must be answered "no".
1. Known or suspected hypersensitivity to trial product(s) or related products
2. Previous participation in this trial. Participation is defined as informed consent
3. Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing 
potential and not using adequate contraceptive methods (sterilisation, intrauterine device (IUD), 
oral contraceptives or barrier methods)
4. Receipt of any investigational medicinal product within 30 calendar days prior to Visit 1
5. Current use of any antidiabetic drug (except for metformin, AGI, SU, glinides or TZD) or 
anticipated change in concomitant medication, that in the investigator’s opinion could interfere 
with glucose level (e.g. systemic corticosteroids)
6. Use of non-herbal Chinese medicine or other non-herbal local medicine with 
unknown/unspecified content within 90 calendar days prior to screening. Herbal traditional 
Chinese medicine or other local herbal medicines may, at the investigator’s discretion, be 
continued throughout the trial 
7. Treatment with insulin (except for short-term treatment at the discretion of the investigator)
8. Treatment with GLP-1 receptor agonists or DPP-4 inhibitors within 90 calendar days prior to 
screening
9. Impaired liver function, defined as alanine aminotransferase (ALAT) ≥ 2.5 times upper normal 
range (UNR)
10. Impaired renal function defined as serum-creatinine ≥ 133 μmol/L for males and ≥ 125 μmol/L
for females, or as defined according to local contraindications for metformin
11. Screening calcitonin ≥ 50 ng/L
12. Personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine 
neoplasia type 2 (MEN2)
13. Cardiac disorder defined as: congestive heart failure (NYHA class III-IV), diagnosis of unstable 
angina pectoris, cerebral stroke and/or myocardial infarction within the last 12 months prior to 
screening and/or planned coronary, carotid or peripheral artery revascularisation procedures
14. Severe uncontrolled treated or untreated hypertension (systolic blood pressure ≥ 180 mm Hg or 
diastolic blood pressure ≥ 100 mm Hg
15. Proliferative retinopathy or maculopathy (macular oedema), requiring acute treatment
16. Subject with a clinically significant, active (during the past 12 months) disease of the 
gastrointestinal, pulmonary, neurological, genitourinary or haematological system (except for 
conditions associated with T2DM) that in the opinion of the investigator may confound the 
results of the trial or pose additional risk in administering trial drug
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17. Mental incapacity, unwillingness or language barrier precluding adequate understanding of the 
trial procedure or cooperation with the trial site personnel
18. Known or suspected abuse of alcohol or narcotics
19. History of pancreatitis (acute or chronic)
20. Suffer from a life threatening disease including malignant neoplasms and medical malignant 
neoplasms within the last 5 years (except basal and squamous cell skin cancer)
6.4
Withdrawal criteria
The subject may withdraw at will at any time without explanation.
The subject may be withdrawn from the trial at the discretion of the investigator due to a safety 
concern or if judged non-compliant with trial procedures
A subject must be withdrawn if the following applies:
1. Inclusion in the trial in violation of the inclusion and/or exclusion criteria
2. Pregnancy 
3. Intention of becoming pregnant
4. Initiation of any systemic treatment with products which in the investigator’s opinion could 
interfere with glucose metabolism (e.g. systemic corticosteroids)
5. If all pre-breakfast SMPG values taken on three consecutive days or if any FPG samples 
analysed by the central laboratory exceeds the limit of:
-
15.0 mmol/L after baseline to week 6 
-
13.3 mmol/L from week 6 to week 12 
-
11.1 mmol/L from week 12 to last week prior to end of treatment 
-
and given there is no intercurrent cause for the hyperglycaemia, a confirmatory FPG 
must be performed  at the next scheduled visit, or if deemed necessary by the 
investigator at an unscheduled visit. If the confirmatory FPG exceeds the limits stated 
above, the subject must be withdrawn
6. 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 who are diagnosed with acute pancreatitis with minimum 2 of 3 
characteristics: abdominal pain, amylase and/or lipase > 3x UNR or characteristic findings on 
computer axial tomography (CT)/magnetic resonance imaging (MRI) must be withdrawn from 
the trial
6.5
Subject replacement
Subjects who are withdrawn will not be replaced.
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6.6
Rationale for trial population
The rationale for this specific trial population is to ensure inclusion of subjects resembling the target 
population in common practice. The HbA1c range is chosen to include subjects for whom diabetes is 
not optimally controlled on their current treatment and hence would benefit from an intensified 
treatment regimen. 
A BMI limit of ≤40 kg/m2 is chosen to include as broad a population as possible while excluding 
morbidly obese individuals who are extremely insulin resistant. 
Only serious concomitant conditions i.e. NYHA class III-IV (see appendix C), history of recent 
serious cardiac event, neoplastic disease, renal or hepatic impairment, major surgery etc.), which 
could interfere with trial schedule/procedures, preclude subjects from entering into the trial.
7
Milestones
Planned duration of recruitment period (First Subject First Visit - Last Subject First Visit): 54
weeks. End of trial is defined as Last Subject Last Visit.
Recruitment will be performed according to an agreement made up-front with the individual 
investigational site. The screening will be monitored closely during the entire recruitment period. In 
order to secure recruitment timelines, the agreed distribution of subjects between sites may be 
changed. The screening and randomisation rate will be followed closely in order to estimate when 
to stop screening. Please see section 11 for randomisation procedure.
Trial registration:
Information of the trial will be disclosed at clinicaltrials.gov, chinadrugtrials.org.cn and 
novonordisk-trials.com. According to the Novo Nordisk Code of Conduct for Clinical Trial 
Disclosure, it will also be disclosed according to other requirements such as those of the 
International Committee of Medical Journal Editors (ICMJE)8, the Food and Drug Administration 
Amendment Act (FDAAA)9, European Commission Regulation for European Drug Regulatory 
Authorities Clinical Trials (EudraCT)10and 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
Timing of site visits, telephone contacts, their windows and assessments to be performed are 
specified in the flow chart in section 2. In the following section instructions on how to perform and 
record results of all assessments are described in more detail.
The investigator must keep a subject screening log, a subject identification code list and a subject 
enrolment log. The screening log and enrolment log may be combined into one list. 
8.1.1
Fasting requirement for blood sampling and body weight
As outlined in the flow chart subjects must attend most of the site visits fasting, i.e. at least eight 
hours without food and drink intake, except for water. Trial products and metformin should be 
withheld on the day of the site visit until blood sampling and body weight assessment (if applicable) 
have been performed. Any other prescribed medication should be taken as usual. If the subjects 
attend the visit in a non-fasting state the blood sampling should be rescheduled as per section 8.1.7.
Please see section 8.1.6  for special requirement in relation to fasting and administration of insulin 
prior to the follow-up Visit 29.
8.1.2
Screening (Visit 1)
Must take place within 14 calendar days prior to randomisation.
Before screening, the trial site staff must provide the subjects with oral and written information 
about the trial. See section 18.1 for instructions on informed consent. Ensure subject has signed the 
informed consent before any trial related procedures can take place.
At screening, subjects will be assigned a unique number. This will remain the same throughout the 
trial. The number will be registered in an interactive voice/web response system (IV/WRS) which 
will be used for screening, randomisation and allocation of trial product to each subject throughout 
the trial (see section 9.4 and 10 for use of the IV/WRS). Subject numbers will automatically be 
transferred into an electronic case report form (eCRF) system used by the investigator or other
relevant trial site staff for transcription of source data throughout the trial. See section 13 for more 
information on the eCRF.
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.
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All inclusion/exclusion criteria must be reviewed and if any of the criteria cannot be assessed e.g. 
criteria related to results from blood sampling performed at screening or if a valid eye examination 
is missing, the investigator must ensure these are obtained for assessment of eligibility prior to 
being able to randomise the subject at Visit 2. If the subject is ineligible, please see section 8.1.3 for
how to screen fail subjects.
Eligible subjects should be instructed to continue on their current OAD treatment until Visit 2.
Subjects will be provided with diaries for completion of source data in between site visits. Please 
see section 8.6 for source data to be recorded in the diaries and how review is to be done by the 
investigator.
Subjects will be provided with a BG-meter for use throughout the trial. Please see section 8.2.12 for 
instructions.
8.1.3
Screening failures
For screening failures the screening failure form must be completed with the reason for not 
continuing in the trial. The date of informed consent must be transcribed into the eCRF. Only 
serious adverse events (SAEs) from screening failures must be transcribed into the eCRF. Follow-
up of SAEs must be carried out according to section 12.3.
Screening failures experiencing an AE that would otherwise quality for adjudication (see section 
12.7.3) will not be adjudicated as no trial product has been administered. 
A screening failure session must be made in the IV/WRS.
When data has been source data verified and all queries have been resolved, the case book must be 
signed by the investigator in the eCRF.
Re-sampling or re-screening is not allowed if the subject has failed one of the inclusion or exclusion 
criteria related to laboratory parameters.
8.1.4
Randomisation (Visit 2)
All inclusion/exclusion criteria and results from assessments at the screening visit including blood 
sampling, ECG and eye examination results must be available and reviewed by the investigator 
prior to randomisation to ensure subject remains eligible.
To be randomised, subjects must discontinue any OAD treatment except for metformin. Subjects 
will then be randomised to receive IDegLira, IDeg or liraglutide all in combination with metformin. 
Please see the Titration Guideline for initiation of randomised treatment. Also start doses and 
titration of IDegLira and IDeg can be found here. Please see section 5.3 for start dose and escalation 
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of liraglutide. Subjects must be trained in correct use of the pens, and directions for use of the pens 
must be provided in writing to randomised subjects. This must be documented in subjects’ records. 
At Visit 2, prior to leaving the site, subjects should demonstrate to the investigator, that they are 
able to use the pens correctly". The training can be repeated if deemed necessary.
The dose of metformin should remain unchanged throughout the trial. See section 8.2.6.
8.1.5
Treatment period (Visits 2 to 28)
During the treatment period the investigator should ensure that subjects comply with the scheduled 
site visits and telephone contacts and that they record the required source data in the diaries prior to 
every site visit/telephone contact.
If needed a telephone contact may be changed into a site visit. It is the responsibility of the 
investigator to ensure the contact regardless of the format takes place.
At the end of treatment (Visit 28) subjects will be switched from trial product to an appropriate anti-
diabetic treatment at the discretion of the investigator. However, IDeg, insulin detemir (Levemir®) 
or any GLP-1 receptor agonists are not allowed, since they may interfere with antibodies measured
at follow-up (Visit 29). 
8.1.6
Follow-up (Visit 29)
The follow-up visit should be undertaken no earlier than 7 calendar days after Visit 28. Subjects 
must attend this visit having fasted for 2 hours (i.e. no food or drink except water) prior to the blood 
sampling for antibody analysis. Subjects on any type of insulin must not have administered this 
within 12 hours of the blood sampling.
At completion of this visit subjects may again be switched to another suitable marketed product at 
the investigator’s discretion.
8.1.7
Unscheduled visits 
Unscheduled visits can be performed at any time at the discretion of the investigator. An 
unscheduled visit should be performed, if:
!
An AE occurs that needs further attention
!
Additional laboratory sample is needed due to a medical event of special interest (MESI)
!
A confirmatory pregnancy test is needed
!
A confirmatory FPG test for withdrawal criteria #5 is required
!
A blood re-sampling related to a specific visit (if not possible to reschedule blood sampling 
within the visit window)
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For all of the above an unscheduled visit form must be completed in the eCRF, indicating the reason 
for the visit. 
An unscheduled visit form should not be completed, if the subject attends the clinic for a blood re-
sampling within the visit window. Instead a requisition form must be completed with the visit 
number the re-sampling refers to and data must be entered into the eCRF for the corresponding 
visit. Also, additional trial product dispensing does not require the use of the unscheduled visit 
form. Here an additional dispensing session should be made in the IV/WRS.
8.1.8
Subject withdrawal 
If a subject is withdrawn from the trial, the investigator must aim to undertake procedures similar to 
those described for Visits 28 and 29 as soon as possible. The end-of-trial form must be completed, 
and final drug accountability must be performed even if the subject is not able to come to the trial 
site. A withdrawal session must be made in the IV/WRS. The case book must be signed.
Although a subject is not obliged to give his/her reason(s) for withdrawing from a trial, the 
investigator must make a reasonable effort to ascertain the reason(s), while fully respecting the 
subject's rights. Where the reasons are obtained, the primary reason for not completing the trial
must be specified on the end-of-trial form in the eCRF. 
8.2
Subject related information 
8.2.1
Demography 
This is an account of date of birth, sex, race and ethnicity.  
8.2.2
Concomitant illness and medical history
A concomitant illness is any illness that is present at the start of the trial (i.e. at the screening visit). 
Concomitant illness includes any pre-planned procedures/surgeries and any intermittent illness (e.g. 
allergy to food, medication, pollen or others) that is not apparent at the time of screening. 
T2DM should not be recorded as concomitant illness.
Medical history is a medical event that the subject has experienced in the past.
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 during the trial. A clinically significant 
worsening of a concomitant illness must be reported as an AE.
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8.2.3
Adverse events
Adverse events (AEs) will be recorded throughout the trial in accordance with the procedure 
described in section 12.
8.2.4
Diabetes complications and treatment history
The date of diagnosis of T2DM, current diabetes complications, diabetes treatment history, and
family history of diabetes must as a minimum be recorded in the eCRF at screening.
8.2.5
Smoking habits
Details of smoking habit or history must be recorded at Visit 1 and Visit 28. Smoking is defined as 
smoking at least one cigarette, cigar or pipe daily. The collected information should include whether 
or not the subject smokes or has smoked. If the subject smokes or has smoked, record 
approximately when the subject started smoking, and if applicable, when the subject stopped 
smoking.
8.2.6
Concomitant medication
A concomitant medication is any medication including traditional herbal Chinese medicine and 
other local herbal medicine, other than the trial product(s), which is taken during the trial, from 
Visit 1 to Visit 28.
The information collected for each concomitant medication includes trade name or generic name, 
indication, start date and stop date or continuation.
Details of any concomitant medication must be recorded at the first visit. Changes in concomitant 
medication must be recorded at each visit as they occur. 
At each contact with site the subject should confirm that their metformin treatment is unchanged. In 
case of safety concern the dose may be reduced at the discretion of the investigator. The reason, 
date and duration of the change should be documented and transcribed into the eCRF. 
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.
8.2.7
Body measurements
Height
Height is measured without shoes in centimetres (cm) and recorded to nearest cm.
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Body weight
Body weight should be recorded in kilograms (kg) with one decimal, measured without shoes and 
only wearing light clothing. Subject should be fasting except for body weight assessed at Visit 1. 
The same scale should be used throughout the trial, if possible. 
Body Mass Index 
BMI will be automatically calculated in the eCRF once height and body weight have been entered. 
At the screening visit the BMI must be in accordance with the relevant inclusion criterion, see 
section 6.2. 
Waist circumference
The waist circumference is defined as the minimal abdominal circumferences located midway 
between the lower rib margin and the iliac crest.
The waist circumferences will be measured to the nearest 0.5 cm using a non-stretchable measuring 
tape (provided by Novo Nordisk). Three consecutive measurements should be performed and 
recorded in the eCRF.
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. 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.
8.2.8
Vital signs (blood pressure and pulse)
Diastolic blood pressure, systolic blood pressure and pulse (beats per minute) should be assessed 
while the subject is in a sitting position. Measurements should be performed after 5 minutes of rest. 
Blood pressure must be measured three times at a visit and all three values should be recorded. The 
mean value will be calculated by the eCRF and must be in accordance with the relevant exclusion 
criterion, see section 6.3.
If the investigator suspects white coat hypertension at the screening visit and/or randomisation visit, 
one re-assessment of the systolic and diastolic blood pressure (as described above) is allowed.
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8.2.9
Physical examination
A physical examination 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
!
Lymph node palpation
The investigator must interpret whether results are normal or abnormal and if abnormal whether this 
is clinically significant or not. Results must be transcribed into the eCRF.
8.2.10
Eye examination
Eye examination (fundoscopy or fundusphotography) must be performed by the investigator, a local 
ophthalmologist or an optometrist according to local practice. 
If an eye examination has been performed within 90 calendar days prior to Visit 2, the procedure 
does not need to be repeated, if the results are available for evaluation at Visit 2 and no worsening 
of visual function since the examination has occurred. If the eye examination is performed before 
the subject consented to participate in the trial, it must also be stated in the subject’s medical 
records that this procedure was not performed in relation to the trial. 
If an eye examination has been performed within 14 calendar days prior to Visit 28, the procedure 
does not need to be repeated, if the results are available for evaluation at Visit 28 and no worsening 
of visual function since the examination has occurred. 
The investigator must interpret whether results are normal or abnormal and if abnormal whether this 
is clinically significant or not. The investigator must sign and date all eye examination results to 
verify that data has been reviewed, and results must be transcribed into the eCRF.
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8.2.11
ECG
A 12-lead ECG must be performed as part of screening procedures and results must be available for 
evaluation at Visit 2 prior to randomisation.
An ECG obtained within 14 calendar days prior to Visit 2 as part of routine practice may replace the 
screening assessment, if results are available for evaluation at Visit 2. If the ECG is performed 
before the subject consented to participate in the trial, it must also be stated in the subject´s medical 
records that this procedure was not performed in relation to the trial. 
An ECG performed within 14 calendar days prior to Visit 28 is acceptable, if the results are 
available for evaluation at Visit 28.
The investigator must interpret whether results are normal or abnormal and if abnormal whether this 
is clinically significant or not. The investigator must sign and date the ECG to verify that data has 
been reviewed, and results must be transcribed into the eCRF.
8.2.12
Self-measured plasma glucose
At the screening visit, subjects should be supplied with a BG-meter which must be used for all 
measurements during the trial. Subjects should be supplied with oral and written directions for use 
of the device including the performance of regular calibrations according to the manufacturer’s 
instructions. Trial site staff should, as necessary, repeat the directions for use to subjects at 
subsequent visits. 
The BG-meter uses test strips calibrated to plasma values. Therefore, all measurements performed 
with capillary blood are automatically calibrated to plasma equivalent glucose values, which will be 
shown on the display and hence recorded in the eCRF as SMPG values.
Subjects should be instructed in how to record the SMPG values in the provided diaries and should 
only record the values based on measurements obtained with the provided BG-meter. See section 
8.6 for source data to be recorded in subject diaries for each treatment arm.
For telephone contacts the investigator or delegated site staff must transcribe the data used for 
titration into the eCRF during/after the telephone contact. Please see the titration guideline.
8.2.13
Self-measured 9-point plasma glucose profile
Subjects will be instructed to perform measurements and record the SMPG values for a 9-point 
profile within one week prior to Visits 2, 14 and 28 on days where subjects do not anticipate 
unusual strenuous exercise. Anti-diabetic medication should be withheld until after the pre-
breakfast measurement.
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SMPG values should be recorded in the diary (including date and actual clock time for the 
measurement) at the following time points, always starting with the measurement before breakfast: 
!
Before breakfast
!
90 min after the start of breakfast
!
Before lunch
!
90 min after the start of lunch
!
Before dinner
!
90 min after the start of dinner
!
At bedtime
!
At 4 am 
!
Before breakfast the following day
8.2.14
Hypoglycaemic episodes
Plasma glucose should always be measured and recorded when a hypoglycaemic episode is 
suspected. 
All plasma glucose values:
!
≤ 3.9 mmol/L or 
!
> 3.9 mmol/L when they occur in conjunction with hypoglycaemic symptoms, 
should be recorded by the subject.These must be transcribed into the eCRF on the hypoglycaemic 
episode form throughout the trial from Visit 2 to Visit 29.
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 
!
Date, time and dose of last trial product (OR other anti-diabetic treatment) administration prior 
to episode 
!
Type of last trial product (OR other anti-diabetic treatment) prior to episode 
!
Date and time of last main meal prior to episode 
!
Whether the episode occurred in relation to physical activity
!
Any sign of fever or other disease 
!
Whether the subject was asleep when the episode occurred
!
Whether the symptoms of the episode woke up the subject
The answer to the question: "Was subject able to treat him/herself?" must be answered "No" for an 
episode requiring assistance of another person to actively administer carbohydrate, glucagon, or 
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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 concentration11.
If the question "Was subject able to treat him/herself?" is answered "No", the following information 
should be recorded and transcribed into the eCRF:
!
Who assisted in the treatment of the hypoglycaemic episode (i.e. family/friend/co-worker or 
similar, paramedic, doctor or other, please specify)
!
Where the treatment was administered (i.e. at home/at friends/at work or similar, in an 
ambulance, emergency room/hospital or other, please specify)
!
Type of treatment provided by other person (i.e. oral carbohydrates, glucagon, IV glucose or 
other, please specify)
!
Were symptoms alleviated by the administration of treatment?
!
Factors contributing to the episode (i.e. physical activity, missed meal, diet changed, medication 
error (i.e. overdose, mix-up between products), miscalculation of dose, 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?12
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 
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.
8.3
Laboratory assessments
The laboratory analyses will be performed by a central laboratory unless otherwise specified in this 
section. Descriptions of assay methods, laboratory supplies and procedures for obtaining samples, 
handling, labelling and storage of samples along with information regarding who will perform the 
assessments, will be described in a trial-specific laboratory manual, provided by the central 
laboratory. For laboratory details, see Attachment I.
8.3.1
Blood and urine sampling (central laboratory analysis)
The investigator must review all laboratory results, specify on the laboratory report whether any 
values out of range are non-clinically significant or clinically significant, and report concomitant 
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illnesses and AEs according to section 12. Laboratory reports must be signed and dated by the 
investigator on the day of evaluation. The signed laboratory report must be retained at the 
investigator’s site as source documentation. 
Laboratory equipment used may provide analyses not requested in the protocol but produced 
automatically in connection with the requested analyses according to specifications in the laboratory 
standard operating procedures. Such data will not be transferred to the trial database, but abnormal 
values must be reported to the investigator. Laboratory results will be sent by the central laboratory 
to the investigator on an ongoing basis. 
Blood samples analysed by the central laboratory will be destroyed on an ongoing basis. 
Blood sampling performed on subjects throughout the trial will determine levels of the following 
efficacy and safety parameters: 
Efficacy parameters
Glucose metabolism: HbA1c, FPG, Fasting insulin, Fasting glucagon, Fasting C-peptide and 
calculation of HOMA-β (see section 17.4.2.1 for calculation)
Safety parameters
Haematology: Erythrocytes, Haematocrit, Haemoglobin, Leucocytes, Thrombocytes and 
Differential count (eosinophils, neutrophils, basophils, monocytes, and lymphocytes)
Biochemistry: Amylase, Lipase, Aspartate aminotransferase (ASAT/SGOT), Alanine 
aminotransferase (ALAT/SPGT), Alkaline phosphatase, Albumin, Bilirubins (total), Creatinine, 
Potassium, Sodium, Total protein, Urea, Creatine kinase, Calcium and Albumin corrected calcium
Lipids: Cholesterol, HDL cholesterol, LDL cholesterol, Triglycerides, VLDL cholesterol and Free 
fatty acids
Hormones: Calcitonin
Pregnancy test: Serum/plasma hCG
Urine samples: Erythrocytes, Protein, Glucose and Ketones by dipstick. 
8.3.2
Calcitonin sampling (central laboratory analysis)
Blood samples for the measurement of calcitonin concentration will be drawn as per flow chart (see 
section 2). Calcitonin values ≥20 ng/L will be submitted to an independent calcitonin monitoring 
committee of thyroid experts. The committee will provide guidance to the investigator with regards 
to treatment and further investigations. If a subject is screen failed for other reasons than calcitonin 
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exclusion criterion # 11 (calcitonin ≥ 50 ng/L), but has a value of calcitonin ≥10 ng/L, it is 
recommended that they are referred to a thyroid expert for further evaluation. For details see 
appendix D.
8.3.3
Antibody sampling (special laboratory analysis)
Blood samples will be drawn as per flow chart for determination of serum antibodies to IDeg
(including cross reacting antibodies to human insulin) and to liraglutide, dependent on treatment 
arm. Positive anti-liraglutide antibody samples will be further characterised for cross reactivity to 
native GLP-1. 
Visit 29 samples positive for anti-liraglutide antibodies will in addition be analysed for in vitro
neutralising effect in a cell based assay.
Blood sampling for antibody assessment should be performed prior to administering trial product.
Antibody results will not be provided to the investigator as these are not used for clinical evaluation 
during the trial. Instead they will be included in an analytical report after end of trial and retained at 
Novo Nordisk.
Please see section 24.2 for information on storage of antibody samples.
8.3.4
PK blood sampling (special laboratory analysis)
Blood samples for PK will be drawn as per flow chart. Blood sample(s) will be drawn once per 
subject per visit (no PK-profiling required). Samples will be analysed for serum concentrations of 
IDeg and/or plasma concentrations of liraglutide dependent of treatment arm.
The investigator must record the exact time for blood sampling in the eCRF. Blood samples for 
serum IDeg and plasma liraglutide levels will be collected, treated and shipped according to the 
description in a laboratory manual provided by the relevant laboratory.
Subjects must be instructed to write in their diary:
!
Date, dose, injection site and exact clock time for injection from the previous three days of 
dosing and on the day of the visit, if a dose is taken before blood sampling
It is important to explain to the subjects the necessity of accurate diary recording as the investigator 
must transcribe all data into the eCRF subsequently to ensure accurate PK calculation.
The population PK analysis is outlined in section 17.5
The bio-analysis of IDeg and liraglutide will be done at a special laboratory (see attachment I), 
using a specific validated ELISA assay for each component developed by Novo Nordisk. Validation 
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documentation must be provided and a bio-analytical report must be available. PK results will not 
be provided to the investigator as these are not used for clinical evaluation during the trial. Instead 
they will be included in a bio-analytical report that will be available at data base lock and retained at 
Novo Nordisk.
PK samples will be destroyed no later than at the completion of the clinical trial report (CTR).
Destruction of PK samples must only occur with permission from Novo Nordisk.
8.4
Pancreatitis
Confirmed cases of pancreatitis should be followed up with investigations of other potential causes 
(tests such as gallbladder ultrasound, triglycerides, liver enzymes, detailed history of concomitant 
medications or alcohol).
8.5
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.
8.6
Subject diaries
At each site visit subjects will be provided with a new diary for recording of source data until next 
site visit. Here the diary must be collected and retained at the site as source data in accordance with 
section 14. From handout at a site visit a diary will hence contain source data from e.g. several 
telephone contacts prior to being returned at an upcoming visit.
Subjects are required to record the below source data in their diaries at the timing specified in the 
flow chart in section 2.
!
For all subjects:
o
Date and dose of first trial product
o
Date and dose of last trial product
o
Prior to PK sampling visits: See section 8.3.4 for source data to be recorded
o
9-point profile SMPG values, see section 8.2.13 for source data to be recorded
!
Any AEs, hypoglycaemic episodes and changes in concomitant medication since last site 
visit/telephone contact
!
For subjects on IDeg or IDegLira: 
o
Daily pre-breakfast SMPG values
o
Last trial product dose prior to each titration day
o
Trial product dose to be taken after each titration day
!
For subjects on liraglutide: 
o
Pre-breakfast SMPG values on 3 consecutive days prior to every site visit/telephone 
contact 
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Based on the SMPG values, the investigator/subject will assess whether the trial product dose needs 
adjustment according to the Titration Guideline. 
The diary must be reviewed by the investigator to ensure that AEs, including any overall change in 
health and concomitant medication, are reported. The review of the diary must be documented 
either on the front page of the diary and/or in the subject’s medical records.
The investigator or delegated staff must transcribe data from the diary into the eCRF after each site 
visit/telephone contact according to timelines in section 13.2. 
If clarification of entries or discrepancies in the diaries is needed, the subject should be questioned 
and a conclusion made in the subject’s medical record. Care must 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. 
The investigator should assess the compliance of the subject based on a review of glycaemic 
control, adherence to the visit schedule, completion of the subject’s diary including the 9-point 
profiles. The doses of metformin and the trial product should be assessed at each site visit e.g. by 
reviewing the subject’s diary and by performing drug accountability (see section 9.4). 
If a subject is discovered to be non-compliant, the investigator must inform the subject of the 
importance of taking trial product and metformin as directed. Substantial failure to comply with the 
prescribed trial product dose regimen will lead to withdrawal.
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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. 
Trial product must not be dispensed to any person not included in the trial. 
Trial product must not be used, if it does not appear clear and colourless. 
9.1
Trial products
The trial products listed in the table below are considered Investigational Medicinal Products 
(IMPs) and will be provided by Novo Nordisk A/S, Denmark:
Table 9–1
Trial products
Trial product (IMP)
Strength
Dosage form
Route of 
administration
Insulin 
degludec/liraglutide 
100 units/mL + 3.6 
mg/mL
Solution for 3 mL pre-
filled pen
Subcutaneous 
injection
Insulin degludec 
100 Units/mL
Liraglutide (Victoza#) 
6 mg/mL
Metformin is a Non-Investigational Medicinal Product. It is not considered a trial product and will 
not be provided by Novo Nordisk.
9.2
Labelling
Labelling of the trial products will be in accordance with Annex 1313, local regulations and trial 
requirements.
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Each investigator site will be supplied with sufficient trial products for the trial on an on-going basis 
controlled by the IV/WRS. The investigator must document that direction for use is given to the 
subject orally and/or in writing at each dispensing visit.
9.3
Storage 
The trial products must be stored according to the instructions in the table below.
Table 9–2
Storage conditions for trial products
Insulin degludec/liraglutide
Storage conditions (not-in-use)
In-use conditions
In-use time*
Store in refrigerator (2°C to 8°C)
Do not freeze
Protect from light
Store below 30∃C 
Protect from light
Use within 3 weeks
Insulin degludec 
Storage conditions (not-in-use)
In-use conditions
In-use time*
Store in refrigerator (2°C to 8°C) 
Do not freeze
Protect from light
Do not refrigerate.
Do not store above 30∃C 
Protect from light
Use within 8 weeks
Liraglutide (Victoza#) 
Storage conditions (not-in-use)
In-use conditions
In-use time*
Store in refrigerator (2°C to 8°C) 
Keep away from the cooling element
Do not freeze 
Protect from light
Store in refrigerator (2°C to 8°C) or
Store below 30∃C 
Keep the cap on the pen in order to 
protect from light
Do not freeze
Use within one 
month
* In-use time starts when first dose is taken.
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The investigator must ensure the availability of proper storage conditions, record and evaluate the 
temperature. The investigator must inform Novo Nordisk immediately if any trial product has been 
stored outside specified conditions (e.g. outside temperature range).
Trial product that has been stored improperly must not be dispensed to any subject before it has 
been re-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.
For each subject the IV/WRS allocates trial product by assigning dispensing unit numbers (DUN) 
where each DUN represents a box with a defined number of trial product to be handed out to the 
subject at a dispensing visit.
The investigator or delegated person is responsible for ensuring:
!
The correct DUN is dispensed to the subject
!
The dispense date for any dispensed DUN is confirmed in the IV/WRS drug accountability 
module after each dispensing
!
Subjects are instructed to return all used, partly used and unused trial products including empty 
packaging material at each dispensing visit
!
Drug accountability is performed using the IV/WRS drug accountability module. Only 
dispensed DUNs returned by the subject (used/ partly used or unused) are accounted for
!
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
Returned trial product destruction will be done according to local procedures after accountability is 
finalised and verified by the monitor. Destruction of trial products must be documented.
9.5
Auxiliary supplies
The following will be provided by Novo Nordisk:
!
Directions for Use of pens
!
Needles for pens
!
BG-meters and BG-meter auxiliaries
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10
Interactive voice/web response system
A trial-specific IV/WRS will be set up and 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. 
The IV/WRS is used for tracking of subjects throughout the trial i.e. screening, randomisation and 
allocation of trial products according to treatment arm. This is to ensure all subjects receive the 
correct trial product and a sufficient amount according to their dose regimen until end of treatment. 
If a subject withdraws early from the trial, this will also have to be entered into the IV/WRS in 
order to stop trial product allocation to this patient. More specifically the IV/WRS must be used for 
the below tasks in the trial:
!
Screening
!
Screening failure
!
Randomisation
!
Medication arrival
!
Dispensing of trial product
!
Withdrawal
!
Completion
!
Drug accountability
!
Data change
IV/WRS user manuals will be provided to each trial site.
11 Randomisation procedure
Subject will be randomised in a 2:1:1 manner to receive IDegLira, IDeg or liraglutide.
When randomising subjects the IV/WRS is also used to ensure a trial population with a mean HbA1c
level of 8.3%. When the number of subjects with a HbA1c below or equal to 8.3% reach 50% of the 
required number of subjects to be randomised, it will only be possible to randomise subjects with a
HbA1c above 8.3%. Subjects will be stratified with respect to their previous OAD treatment 
(metformin ± one other OAD). Stratification with regards to previous OAD treatment is done to 
ensure an equal proportion of subjects previously on mono therapy and combination therapy in each 
of the three arms. 
The distribution of subjects having a HbA1c above or below 8.3% will be followed closely and 
investigators will be notified in due time before randomisation is closed. Subjects eligible for 
randomisation will be randomised if closing occurs while they are in the screening period.
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12 Adverse events, MESIs, technical complaints and pregnancies
12.1
Definitions
Adverse event (AE)
An 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: 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 or baseline 
measurements for lipids (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 8.2.14
The following three definitions are used when assessing severity of an AE:
!
Mild - no or transient symptoms, no interference with the subject's daily activities.
!
Moderate - marked symptoms, moderate interference with the subject's daily activities.
!
Severe - considerable interference with the subject's daily activities; unacceptable.
The following terms are used when assessing the causality 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 of an AE
!
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 (SAE)
A 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 (MESI)
A MESI is an event which, in the evaluation of safety, has a special focus. A MESI is an AE (SAE 
or non-serious AE) which fulfils one or more of the below defined MESI criteria.
1. Acute coronary syndrome (myocardial infarction or hospitalisation for unstable angina)
2. Cerebrovascular event (transient ischemic attack or stroke) 
3. Heart failure requiring hospital admission
4. Revascularisation procedure
5. Pancreatitis or clinical suspicion of pancreatitis
6. Neoplasm
7. Thyroid disease
8. Medication errors concerning trial products:
!
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. That is a dose that is 
20 % lower or higher than  the intended dose; 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.
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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 (screening) until 
Visit 29 which is the end of the post-treatment follow-up period (7 days after end of treatment). 
Exceptions:
!
Non serious events of hypoglycaemic episodes should not be reported before any trial drug is 
given e.g. prior to the randomisation visit
!
Non-serious AEs should not be collected and reported for screening failures
The events must be recorded in the applicable CRF forms in a timely manner, see timelines below.
During each contact with the trial site staff, the subject must be asked about AEs and technical 
complaints, for example by asking: "Have you experienced any problems since the last contact?"
All AEs, 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: 
IDegLira: NN9068 Investigator’s Brochure edition 6.0 or any updates hereof
IDeg: NN1250 CCDS version 5.0 or any updates hereof
Liraglutide: NN2211 CCDS version 14.0 or any updates hereof
All AEs must be recorded by the investigator on an AE form. The investigator should report the 
diagnosis, if available. If no diagnosis is available, the investigator should record each sign and 
symptom as individual AEs using separate AE forms.  
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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. 
MESIs, regardless of seriousness, must be reported using both 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.
Any event confirmed or suspected to be a MESI must be reported as such. In case the sponsor 
identifies potentially missed MESIs through predefined review of available data, the investigator 
will be asked to reconsider if the event is a MESI.
The AE form for a non-serious AE 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
!
SAEs fulfilling the MESI criteria and/or result in fatal outcome: In addition to above, the 
MESI form and/or the fatal follow up 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
!
Events fulfilling the adjudication criteria: Complete the event adjudication collection form 
within 14 calendar days of the investigator's first knowledge of the event
Please see figure Figure 12–1  for timelines. Please see section 12.7.3 for MESIs to be adjudicated. 
If the eCRF is unavailable, the concerned AE information must be reported on paper forms and sent 
to Novo Nordisk by fax, e-mail or courier within the same timelines as stated above. When the 
eCRF becomes available again, the investigator must re-enter the information on the appropriate 
forms in the eCRF. 
Contact details (fax, telephone, e-mail and address) are provided in the investigators trial file. 
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Yes
Yes
No
Fulfilling 
seriousness 
criteria?
Fulfilling MESI 
criteria?
Fatal outcome
or fulfilling 
MESI criteria?
No
Yes
No
Fulfilling 
Adjudication 
criteria?
No
Yes
Complete ≤ 14 calendar 
days:
! MESI and/or
! Fatal FU form
Complete ≤ 14 calendar 
days:
! SIF
! MESI form 
Complete ≤ 14 calendars 
days:
!
Event adjudication 
document collection 
form
An AE is 
observed and 
reported
No additional forms 
to be completed
No additional forms 
to be completed
No additional forms 
to be completed
Complete:
!
AE Form ≤ 24 hours
!
SIF ≤ 5 calendars 
days
Complete:
!
AE Form
Figure 12–1
Initial reporting of AEs
Reporting of trial product-related SUSARs by the sponsor:
Novo Nordisk will notify the investigator of trial product-related suspected unexpected serious 
adverse reactions (SUSARs) in accordance with local requirements and ICH GCP1. In addition, the 
investigator will be informed of any trial-related SAEs that may warrant a change in any trial 
procedure.
In accordance with regulatory requirements, Novo Nordisk will inform the regulatory authorities, 
including EMA, of trial product-related SUSARs. In addition, Novo Nordisk will inform the 
IRBs/IECs of trial product-related SUSARs in accordance with local requirement and ICH GCP1
unless locally this is an obligation of the investigator.
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:
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!
SAEs: All SAEs must be followed until the outcome of the event is "recovered/resolved", 
"recovered/resolved with sequelae" or "fatal", and until all queries have been resolved. Cases of 
chronic conditions, cancer or AEs ongoing at time of death (where death is due to another AE) 
may be closed with the outcome "recovering/resolving" or "not recovered/not resolved". Cases 
can be closed with the outcome of "recovering/resolving" when the subject has completed the 
follow-up period and is expected by the investigator to recover
The SAE follow-up information should only include new (e.g. corrections or additional) 
information and must be reported within 24 hours of the investigator's first knowledge of the 
information. This is also the case for previously non-serious AEs which subsequently become 
SAEs
!
Non-serious AEs: Non-serious AEs must be followed until the outcome of the event is 
"recovering/resolving", "recovered/resolved" or "recovered/resolved with sequelae" or until the 
end of the follow-up period stated in the protocol, whichever comes first, and until all queries 
related to these AEs have been resolved. Cases of chronic conditions, cancer or AEs ongoing at 
time of death (where death is due to another AE) may be closed with the outcome 
"recovering/resolving" or "not recovered/not resolved". Cases can be closed with the outcome 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: 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: 
!
Insulin degludec/liraglutide 100 units/mL + 3.6 mg/mL(IDegLira), 3 mL pre-filled pen.
!
Insulin degludec 100 Units/mL (IDeg), 3 mL pre-filled pen
!
Liraglutide 6 mg/mL (Victoza®), 3 mL pre-filled pen
!
Novo Nordisk needles for pre-filled pens,
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which occur from the time of first usage of the product until the time of the last usage of the 
product, must be collected and reported to Customer Complaint Center, Novo Nordisk.
Contact details (fax, e-mail and address) are provided in Attachment I to the protocol.
The investigator must assess whether the technical complaint is related to any AEs, SAEs, and/or
MESI.
Technical complaints must be reported on a separate technical complaint form for each product 
listed. If the technical complaint involves more than one batch or lot number or more than one 
DUN, a technical complaint form for each batch 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.
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 of the technical complaint form must be sent with 
the sample.
The investigator must ensure that the technical complaint sample contains the batch 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 9.3). 
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12.5
Pregnancies in female subjects
Female subjects must be instructed to notify the investigator immediately if they become pregnant 
during the trial. The investigator must report any pregnancy in subjects who have received trial 
products.
The investigator must follow the pregnancy until the pregnancy outcome and the newborn infant is 
one month of age.
The investigator must report information about the pregnancy, pregnancy outcome, and health of 
the newborn infant(s), as well as AEs in connection with the pregnancy, and AEs in the foetus and 
newborn infant.
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 related to pregnancy:
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
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SAEs: 
!
Paper AE form* within 24 hours of the investigator's first knowledge of the SAE
!
Paper safety information form within 5 calendar days of the investigator's first knowledge of 
the SAE
!
SAE follow-up information to the AE form and/or safety information form within 24 hours of 
the investigator's first knowledge of the follow-up information
*
It must be clearly stated in the AE diagnosis field on the AE form if the event occurred in the 
subject, foetus or newborn infant.
Any queries or follow-up requests from Novo Nordisk to non-serious AEs, SAEs and pregnancy 
forms must be responded to by the investigator within 14 calendar days from the date of receipt of 
the request, unless otherwise specified in the follow-up request.
12.6
Precautions and/or overdose
During treatment with insulin there is a risk of hypoglycaemia. Symptoms of hypoglycaemia 
usually occur suddenly and may include cold sweat, nervousness or tremor, anxious feelings, 
unusual tiredness, confusion, difficulty in concentrating, excessive hunger, temporary vision 
changes, headache, nausea and palpitation. Severe hypoglycaemia may lead to unconsciousness.
Hypoglycaemic episodes should be treated according to best practise at the discretion of the 
investigator. Attention should be given to the fact that the action profile of the insulin component in 
IDegLira and IDeg is long-acting and the prolonged effect may delay recovery from a 
hypoglycaemic episode.
Asymptomatic hypoglycaemia and symptoms of minor hypoglycaemia should be treated by 
ingestion of carbohydrate (for example juice). Severe hypoglycaemia resulting in loss of 
consciousness should be treated with parenteral glucose, glucagon or dextrose at the investigator’s 
discretion.
From clinical trials and marketed use of Liraglutide overdoses up to 40 times the recommended 
maintenance dose (72 mg) have been reported. Events reported included severe nausea and severe 
vomiting. None of the reports included severe hypoglycaemia. All patients recovered without 
complications.
When initiating treatment with IDegLira or Liraglutide, the subject may in some cases experience 
loss of fluids/dehydration, due to vomiting, nausea or diarrhoea. It is important to avoid dehydration
by drinking plenty of fluids. 
For further information on IDeglira, IDeg or liraglutide, please see Investigator’s Brochure, any 
updates hereof, and/or SmPCs/ local labelling, as applicable.
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12.7
Committees related to safety
12.7.1
Novo Nordisk safety committee
Novo Nordisk will constitute an internal IDegLira/NN9068 safety committee to perform ongoing 
safety surveillance. The safety committee will be informed about the results of on-going safety 
surveillance activities for the individual mono components IDeg and liraglutide, respectively.
12.7.2
Calcitonin monitoring committee
An independent committee of thyroid experts is established to perform calcitonin monitoring of all 
calcitonin values ≥20 ng/L in subjects throughout the trial (except for screening failures). The
committee will provide recommendations to investigators with regards to further investigation and 
treatment of the individual subject. The committee will be blinded to trial treatment. 
For further instructions on calcitonin monitoring, see appendix D.
12.7.3
Event adjudication committee
An external event adjudication committee 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 source data related to the specific AE. The events are reviewed by the 
event adjudication committee in an independent and blinded manner.
The following AEs will be adjudicated in this trial:
!
Death
!
Acute coronary syndrome (myocardial infarction or hospitalisation for unstable angina)
!
Cerebrovascular event (transient ischemic attack or stroke) 
!
Heart failure requiring hospital admission
!
Coronary revascularisation
!
Pancreatitis or clinical suspicion of pancreatitis
!
Neoplasm
!
Thyroid disorders requiring thyroidectomy 
AEs for adjudication must be reported according to section 12.2. In addition the specific event 
adjudication document collection form has to be completed and relevant pre-defined documents 
provided within 14 calendar days of the investigator's first knowledge of the AE, according to 
instructions in the event adjudication site manual. The investigator should provide the medical 
documentation within 4 weeks of event identification.
Event adjudication will not be performed for AEs in screening failures. For further information 
regarding definitions, rationales, and events that will be adjudicated, see appendix B.
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13 Case report forms 
Novo Nordisk will provide a system for the eCRF. This system and support services to the system 
will be supplied by a vendor.
When entering data into the eCRF, trial site staff must ensure that all relevant questions are 
answered, and that no empty data field exists. If a test or an assessment has not been done and will 
not be available, or if the question is irrelevant (e.g. is not applicable), indicate this according to the 
data entry guidelines.
The following will be provided as paper CRFs only:
!
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.
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 eCRF data may be made by the investigator or the investigator's authorised 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 authorised staff after the date the investigator has 
signed the case book, the case book must be signed and dated again by the investigator.
Corrections to the data on paper 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 was crossed out. Each 
correction must be initialled, dated and explained (if necessary). If corrections are made by the 
investigator's authorised staff after the date of the investigator's signature on the affirmation 
statement, the affirmation statement must be signed and dated again by the investigator.
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Corrections necessary after the CRFs have been removed from the trial site must be documented on 
a data clarification form or a monitor-initiated discrepancy form. If the affirmation statement for the 
subject has not yet been signed, any corrections must be approved by the investigator or her/his 
authorised staff. If the affirmation statement for the subject has already been signed, the investigator 
must approve any correction.
13.2
Case report form flow 
The investigator must ensure that data is recorded in the eCRF as soon as possible, preferably 
within 5 days after a site visit/telephone contact. The SMPG values and corresponding insulin 
doses for titration purpose must preferably be entered within 24 hours after the site visit/telephone
contact on week days throughout the trial. 
Once data has been entered, it will be available to Novo Nordisk for data verification and validation 
purposes. Queries will be generated in the eCRF, and the investigator should solve these queries on 
an ongoing basis throughout the trial.
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.
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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 no later than 6 weeks after FPFV. 
The monitoring visit intervals will depend on the outcome of the remote monitoring of the eCRF, 
the trial site's recruitment rate and the compliance of the trial site to the protocol and ICH GCP1, but 
will not exceed 8 weeks.
14.1
Source data verification and source data requirements
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).
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 and/or relevant trial site staff should be available for discussion at/between monitoring 
visits.
All data must be verifiable in source documentation other than the CRF. This must be defined in a 
source document agreement at each trial site. There must only be one source defined at any time for 
any data element.
The monitor will collect CRF pages and other trial related forms containing data from screening 
failures. Source data verification requirements for screening failures are described in section 8.1.3.
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.
For SMPG values it is accepted that the earliest practically retainable record should be considered 
source data. Therefore, the data recorded by the BG-meter and transcribed into the diary by the 
subject will be considered source data. The diary will be considered the source document with 
respect to:
!
Date and fasting SMPG values
!
Date, time and dose of trial product
!
Date and time for hypoglycaemic episodes
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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.
A follow-up letter (paper or electronic) will be sent to the investigator following each monitoring 
visit addressing any action to be taken.
15 Data management
Data management is the responsibility of Novo Nordisk. 
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 to Novo Nordisk from the 
laboratory performing the analyses. Data from special laboratories may be transferred to Novo 
Nordisk via the central laboratory. In cases where data is transferred via non-secure electronic 
networks, data will be encrypted during transfer. Laboratory reports will be provided directly to the 
investigator for storage at trial site.
The subject and any biological material obtained from the subject will be identified by subject 
number and trial identification number. Appropriate measures such as encryption or leaving out 
certain identifiers will be enforced to protect the identity of subjects in all presentations and 
publications as required by local, regional and national requirements.
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). The 
analysis of the primary endpoint will be repeated on the per-protocol (PP) analysis set and the 
completer analysis set (CAS) for sensitivity purposes. 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 observed data. After 26 weeks of treatment, 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.
A standard analysis of covariance (ANCOVA) model will be applied for the continuous primary 
and secondary endpoints. The model includes treatment and previous OAD treatment (metformin or 
metformin in combination with one of the following: AGI, SU, glinides and TZD as fixed effects 
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 5% p-value.
Handling of missing data
The expected percentage of missing data is around 15%. In accordance with industry guidance14
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.
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If an assessment has been made both at screening (Visit 1) and randomisation (Visit 2), and if not 
otherwise specified, the value from the randomisation visit will be used as the baseline value. If the 
value measured at the randomisation visit is missing and the assessment also has been made at 
screening, then the screening value will be used as the baseline value.
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. 
LOCF has been a standard approach in diabetes trials for many years, and was used as the primary 
analysis in both IDegLira and IDeg phase 3a trials. LOCF is considered to be an appropriate method 
in the context of TTT trials, where subjects after withdrawal typically continue their therapy using 
commercially available insulin. In previous TTT trials with IDegLira and IDeg, LOCF has 
generally provided similar results to alternative methods applied to handle missing data, such as 
repeated measures models and completer analyses. In this trial, similar sensitivity analyses will be 
made to examine the robustness of the LOCF method. The LOCF approach will also be used to 
impute missing values in CAS. 
17.1
Sample size calculation
The primary objective of this trial is to confirm the efficacy of IDegLira in controlling glycaemia as 
assessed by change from baseline in HbA1c after 26 weeks of treatment vs. IDeg and liraglutide,
respectively. This is done by comparing the difference in change from baseline in HbA1c after 26 
weeks of treatment to a non-inferiority margin of 0.4% for IDegLira vs. IDeg and to a superiority 
margin of 0.0% for IDegLira vs. liraglutide. The non-inferiority margin of 0.4% (absolute) was 
chosen in accordance with the Food and Drug Administration (FDA) guidance14. 
A hierarchical testing procedure is applied. This is based on an a priori ordering of the null-
hypotheses and testing them in this order using the two-sided 95% confidence interval approach 
until an insignificant result appears. Non-inferiority and superiority will thus be considered 
confirmed if the upper bound of the two-sided 95% confidence interval is below 0.4% and 0.0% 
respectively. 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%.
Formally, let D be the mean difference in change from baseline in HbA1c. The null-hypothesis are 
given as 
!
Non-inferiority: H0 D≥0.40% against HA D<0.40%, with an assumed mean difference in 
treatment of 0.0% and a standard deviation of 1.0%
!
Superiority: H0 D≥0.0% against HA D<0.0%, with an assumed mean difference in treatment of -
0.3% and a standard deviation of 1.0%
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For evaluation of non-inferiority the PP-population is used for the sample size calculations, while 
the FAS is used for evaluation of superiority. It is assumed that 15% of the randomised subjects will 
be excluded from the PP analysis set. The above assumptions are based on experience from the 
phase 3a development programmes for IDegLira and IDeg. The sample size is determined using a t-
statistic under the assumption of a one-sided test of size 2.5% for both the superiority and non-
inferiority testing. Based on these assumptions a sample size of 720 patients results in a non-
inferiority power of 98.1% and a superiority power of 90.7% i.e. the combined power for meeting 
the primary objective is 98.1% * 90.7% = 89.0%. A sample size of 720 patients with a 15% drop-
out rate and a 2:1:1 randomisation results in 306 PP patients in the IDegLira arm.
17.2
Definition of analysis sets
The following analysis sets are defined in accordance with the ICH-E9 guidance15.
!
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”
!
Per-Protocol (PP) analysis set: includes all subjects in the Full Analysis Set who fulfils the 
following criteria:
o
Have not violated any inclusion criteria
o
Have not fulfilled any exclusion criteria
o
Have a non-missing HbA1c at screening or randomisation
o
Have at least one non-missing HbA1c after 12 weeks of exposure
o
Have at least 12 weeks of exposure
Subjects will contribute to the evaluation “as treated”.
!
Safety Analysis Set (SAS): includes all subjects receiving at least one dose of the 
investigational product or comparator. Subjects in the safety set will contribute to the evaluation 
“as treated”
!
Completer Analysis Set (CAS): includes all randomised subjects who have completed the trial. 
Subjects in the completer analysis set will contribute to the evaluation “as randomised”
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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 defined as 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 
ANCOVA model with treatment and previous OAD treatment (metformin ± one other OAD) as 
fixed effects and baseline HbA1c as covariate. Missing values after 26 weeks of treatment will be 
imputed applying LOCF using HbA1c values at and after baseline.
Non-inferiority of IDegLira vs. IDeg will be considered as confirmed if the 95% confidence interval 
for the mean treatment difference lies entirely below 0.4%; equivalent to a one-sided test with 
significance level of 2.5%. Non-inferiority will be investigated on the FAS. Sensitivity analysis will 
be performed on the PP analysis set.
Superiority of IDegLira vs. liraglutide will be considered as confirmed if the 95% confidence 
interval for the mean treatment difference 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. The primary objective will be fulfilled only if both non-inferiority of IDegLira vs. 
IDeg and superiority of IDegLira vs. liraglutide are confirmed.
In addition to the non-inferiority margin of 0.4% the upper bound of the confidence interval for the 
mean treatment difference of IDegLira vs. IDeg will also be compared to a 0.0% margin. This 
comparison is not part of the hierarchical testing procedure.
17.3.1
Sensitivity analysis
The primary analysis will be repeated on the PP analysis set and the CAS as sensitivity analysis. 
Furthermore, sensitivity analysis will be performed on FAS using the mixed model for repeated 
measurement (MMRM) to evaluate the sensitivity of using LOCF. 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, visit, and previous OAD treatment as fixed effects and baseline 
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HbA1c as covariate. Interactions between visit and all factors and the covariate are also included in 
the model. The result will be compared to the result of the ANCOVA method using LOCF for 
imputation of missing data. Any marked difference between the MMRM and ANCOVA LOCF 
approach regarding the estimated treatment difference will be commented upon in the CTR.
17.4
Secondary endpoints
17.4.1
Confirmatory secondary endpoints
The following two confirmatory endpoints will be tested for superiority of IDegLira vs. IDeg.
!
Change from baseline in body weight after 26 weeks of treatment. 
!
Number of treatment emergent severe or BG confirmed hypoglycaemic episodes during 26 
weeks of treatment.
The tests for superiority of the confirmatory secondary endpoints will be based on the FAS and will 
only be carried out if non-inferiority of IDegLira vs. IDeg and superiority of IDegLira vs. 
liraglutide with regards to the primary endpoint are confirmed. 
In order to control the overall type I error on a 5% level with regards to the secondary endpoints, a 
hierarchical testing procedure will be used. If superiority is confirmed with respect to change from 
baseline in body weight after 26 weeks of treatment the number of treatment emergent severe or BG 
confirmed hypoglycaemic episodes during 26 weeks of treatment will be tested for superiority.
Superiority for change from baseline in body weight will be considered confirmed if the upper 
bound of the two-sided 95% confidence interval for the estimated mean treatment difference 
(IDegLira minus IDeg) is strictly below zero or equivalently if the p-value for the one-sided test of 
H0 D≥0.0% against HA D<0.0%,
is less than 2.5%, where D is the treatment difference.
Superiority for hypoglycaemic episodes will be considered confirmed if the upper bound of the two-
sided 95% confidence interval for the estimated mean treatment ratio (IDegLira vs. IDeg) is strictly 
below one or equivalently if the p-value for the one-sided test of 
H0 RR≥1.0 against HA RR<1.0,
is less than 2.5%, where RR is the estimated rate ratio.
The change from baseline in body weight after 26 weeks of treatment will be analysed using an 
ANCOVA model with treatment and previous OAD treatment (metformin ± one other OAD) as 
fixed effect and baseline weight as covariate. 
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Number of treatment emergent severe or BG confirmed hypoglycaemic episodes during 26 weeks 
of treatment will be analysed 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 treatment 
emergent as offset. The model will include treatment and previous anti-diabetic treatment as fixed 
factors and baseline HbA1c as covariate.
17.4.2
Supportive secondary endpoints
17.4.2.1
Efficacy endpoints
In the following the statistical models will be fitted to all data simultaneously (all treatment groups) 
and from this model the treatment differences for IDegLira vs. IDeg and IDegLira vs. liraglutide 
will be estimated.
Insulin dose after 26 weeks of treatment
The actual daily insulin dose after 26 weeks of treatment will be analysed using an ANCOVA 
model including treatment and previous anti-diabetic treatment as fixed factors and baseline HbA1c
value and baseline insulin dose as covariates.
Responder for HbA1c after 26 weeks of treatment
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:
!
ADA HbA1c target (HbA1c < 7.0%)
!
International Diabetes Federation (IDF) HbA1c target (HbA1c ≤ 6.5%)
Analysis of each of the two responder endpoints will be based on a logistic regression model with 
treatment and previous anti-diabetic treatment as fixed factors 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% or ≤ 6.5% at end of treatment and change from baseline in body weight below or equal to 
zero. Analysis of each of the two responder endpoints will be based on a logistic regression model 
with treatment and previous anti-diabetic treatment as fixed factors and baseline HbA1c and body 
weight values as covariates.
HbA1c responder endpoints without hypoglycaemic episodes
Responder for HbA1c without hypoglycaemic episodes after 26 weeks of treatment will be defined 
as HbA1c < 7.0% or ≤ 6.5% at end of treatment and without severe or BG confirmed episodes 
during the last 12 weeks of treatment. Analysis of each of the two responder endpoints will be based 
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on a logistic regression model with treatment and previous anti-diabetic treatment as fixed factors 
and baseline HbA1c values as a covariate.
HbA1c responder endpoints without hypoglycaemic episodes and weight gain
Responder for HbA1c without hypoglycaemic episodes and weight gain after 26 weeks of treatment 
will be defined as HbA1c < 7.0% or ≤ 6.5% at end of treatment, without severe or BG confirmed 
episodes during the last 12 weeks of treatment, and change from baseline in body weight below or 
equal to zero. Analysis of each of the two responder endpoints will be based on a logistic regression 
model with treatment and previous anti-diabetic treatment as fixed factors and baseline HbA1c and 
body weight values as covariates.
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.
Beta-cell function (fasting insulin, fasting C-peptide, fasting glucagon, and HOMA-β)
In addition to fasting insulin, fasting C-peptide, and fasting glucagon, one derived parameter will be 
calculated; beta-cell function (HOMA-β).
The calculation of the HOMA endpoint will be done as follows:
!
Beta-cell function (%) = 20·fasting insulin[μU/mL]/(FPG[mmol/L]-3.5)
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 
Cholesterol, LDL cholesterol, HDL 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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Self-measured plasma glucose 9-point profile
Three endpoints from the 9-point profile will be defined: 
!
9-point profile
!
Mean of the 9-point profile, defined as the area under the profile (calculated using the 
trapezoidal method) divided by the measurement time
!
Post-prandial plasma glucose 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 mixed effect model will be fitted to the 9-point profile data. The model will include treatment, 
time, interaction between treatment and time, and previous anti-diabetic treatment as fixed factors 
and the baseline value as a covariate. An unstructured residual covariance matrix within the same 
subject is employed. 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 9-point profile and post-prandial 
increment endpoints will be analysed separately using the standard ANCOVA model. 
17.4.2.2
Safety endpoints
Adverse events
AEs will be coded using the most recent version of the Medical Dictionary for Regulatory 
Activities coding.
A TEAE is defined as an event that has onset date on or after the first day of exposure to 
randomised treatment and no later than seven days after the last day of randomised treatment. If the 
event has onset date before the first day of exposure on randomised treatment 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.
TEAEs are summarised descriptively, whereas non-TEAEs are presented in listings. TEAE 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 TEAEs and of serious TEAEs 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.
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Furthermore summary tables based on system organ class and preferred terms are made for: 
!
All TEAEs 
!
Serious TEAEs
!
Possibly or probably related TEAEs
!
Severe, moderate and mild TEAEs
!
TEAEs reported by safety areas of interest
!
TEAEs 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-TEAEs with onset date before the first day of exposure to randomised treatment 
will be presented. A listing will also be presented for non-TEAEs 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 trial product administration, and no later than 7 
days after the last day on trial product.
Nocturnal hypoglycaemic episodes: are episodes with time of onset 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/L16. Therefore, Novo Nordisk has included hypoglycaemia with plasma glucose levels below 
this cut-off point in the definition of BG confirmed hypoglycaemia.
Novo Nordisk uses the following classification (in addition to the ADA classification):
!
Severe or BG confirmed symptomatic hypoglycaemia: An episode that is severe according to 
the ADA classification11 or BG confirmed by a plasma glucose value <3.1 mmol/L with
symptoms consistent with hypoglycaemia
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!
Severe or BG confirmed hypoglycaemia: An episode that is severe according to the ADA 
classification11 or BG confirmed by a plasma glucose value <3.1 mmol/L with or without
symptoms consistent with hypoglycaemia
Figure 17–1
Novo Nordisk classification of hypoglycaemia
ADA classification of hypoglycaemia11
!
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
!
Documented symptomatic hypoglycaemia: An episode during which typical symptoms of 
hypoglycaemia are accompanied by a measured plasma glucose concentration ≤ 3.9 mmol/L
!
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 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 
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Figure 17–2
ADA classification of hypoglycaemia
Data on treatment emergent hypoglycaemic episodes are presented 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 hypoglycaemic episodes, severe or BG 
confirmed symptomatic hypoglycaemic episodes, nocturnal severe or BG confirmed hypoglycaemic 
episodes, nocturnal severe or BG confirmed symptomatic hypoglycaemic episodes and the ADA 
classification of hypoglycaemia.
All endpoints based on hypoglycaemic episodes will be analysed using the same model as used for 
the treatment emergent severe or BG confirmed hypoglycaemic episodes.
Pulse
Change from baseline in pulse after 26 weeks of treatment will be analysed using the standard 
ANCOVA model.
Systolic and diastolic blood pressure
Change from baseline in systolic and diastolic blood pressure after 26 weeks of treatment will be 
analysed using the standard ANCOVA model.
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Clinical evaluations (physical examination, eye examination and ECG)
Eye examination (fundoscopy/fundusphotography) and ECG findings will be summarised 
descriptively, including:
!
summaries
!
the change from baseline after 26 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
!
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 applies in the evaluation of the result
!
If the amylase or lipase baseline (at screening) value is > 3xUNR the information will be
recorded as medical history for that subject. 
Calcitonin
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 event 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
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!
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 each gender, separately.
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).
Urinalysis
Categorical urinalysis parameters will be summarised descriptively by:
!
Shift from baseline to EOT (using the number of subjects in the different categories)
!
Subjects with at least one post baseline measurement outside reference range will be listed
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Antibodies towards trial product
Anti-IDeg antibodies, anti-human insulin antibodies, anti-liraglutide antibodies, anti-liraglutide 
antibodies cross reacting with native GLP-1 and in vitro neutralising effect of anti-liraglutide 
antibodies will be summarised and tabulated. The correlation between change from baseline after 26 
weeks of treatment in anti-IDeg and anti-insulin antibodies respectively, to insulin dose after 26 
weeks of treatment, HbA1c after 26 weeks of treatment and change from baseline after 26 weeks of 
treatment in HbA1c will be illustrated using scatter plots.
For the liraglutide component of IDegLira and liraglutide, the number of subjects (N) and the 
percentage of subjects (%) with positive, cross-reacting to native GLP-1 and neutralising antibodies 
will be summarised.
Listing with subjects with liraglutide positive antibody formation will be produced. These listings 
should include efficacy information as minimum HbA1c and body weight over time.
17.5
Pharmacokinetic modelling
Population pharmacokinetic analysis
The objective for this analysis is to compare the pharmacokinetics of IDegLira and its individual 
components at clinically relevant doses during 26 weeks of treatment. Furthermore, dose-
proportionality of IDeg and liraglutide exposures following doses of IDegLira will be evaluated and 
the effects of pre-specified covariates on exposures of IDeg and liraglutide will be investigated.PK 
samples for IDeg and liraglutide sampled at site visits will be included in the analysis. No pre-
defined time of day is specified for the sampling, but the date and exact clock time of sampling will 
be recorded by the Investigator. The subjects must be instructed to write in their diary the date, 
exact clock time, dose, and injection site of the previous three days of dosing as well as the dose on 
the day of the visit, if taken before PK blood sampling.
The population PK analysis will be performed by the Quantitative Clinical Pharmacology 
Department at Novo Nordisk A/S. A more technical and detailed elaboration of the population PK 
analysis will be given in the modelling analysis plan (MAP) which will be finalised before DBL. 
The pre-specified analysis will explore the effects of covariates on the IDeg and liraglutide 
exposure. The structural models and covariate relationships will be predefined in detail in the MAP. 
In brief, previously developed population PK models for IDeg and liraglutide will be used. For both 
PK models, the absorption rate constant (Ka) will be fixed and the apparent clearance (CL/F) and 
the apparent volume of distribution (Vd/F) will be estimated.
The covariates of interest will be evaluated using criteria which will be specified in the MAP.
The following covariates will be tested on the apparent clearance (CL/F):
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!
Dose
!
Treatment (IDegLira, IDeg, liraglutide)
!
Injection site area (Abdomen, Upper arm, Thigh)
!
Body weight
!
Age group (<65, ≥65 years)
!
Gender (Male/Female)
For the categorical variables, it is a requirement to have at least 20 subjects in each category.
Exposure-response analysis
The exposure-response relationship will be investigated for selected response variables, such as 
HbA1c. Individual drug concentration data will be tabulated in the clinical trial report.
The population PK and exposure-response analyses will be reported in a separate modelling report, 
which will not be a part of the clinical trial report.
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18 Ethics
All subjects included in the trial will be treated with IDeglira, IDeg or liraglutide in combination 
with metformin in order to improve their glycaemic control.
Subjects randomised to the trial will be transferred to a treatment regimen anticipated to be better 
than or equal to the treatment they receive at the time they enter the trial. However, they will have
to spend some extra time for trial related visits and some of the assessments performed during the 
trial go beyond normal practice.
When a subject’s participation in the trial ends, the subject will consult his/her investigator to 
decide on the best available marketed treatment. 
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 has ample time to ask questions and 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 subject must be provided with a copy of this.
The responsibility for seeking informed consent must remain with the investigator, but the task may 
be delegated by the investigator to a medically qualified person, in accordance with local 
requirements. The written informed consent 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 affect subject's willingness to continue in the trial, the 
investigator must inform the subject in a timely manner. Revised written subject information must 
be provided and a new informed consent must be obtained.
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If a female trial subject becomes pregnant and an abnormality is found in the foetus or newborn 
infant, a separate written information and informed consent form must be given to the subject’s 
male partner for consent to obtain information on paternal health and medical history.
For all of the specific informed consents the subject and/or subject’s partner must have the option to 
abstain from these, while still participating in the trial as per the initial informed consent.
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 29) 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/IECs.
18.3
Information to subject during trial
All information provided to the subjects during the trial will be translated to local language and 
submitted to the health authorities and IECs/IRBs for approval according to local regulations.
18.4
Premature termination of the trial and/or trial site
Novo Nordisk, the investigator, the IRBs/IECs or a regulatory authority may decide to stop the trial, 
part of the trial or a trial site at any time, but agreement on procedures to be followed must be 
obtained.
If a trial is suspended or prematurely terminated, the investigator must inform the subjects promptly 
and ensure appropriate therapy and follow-up. The investigator and/or Novo Nordisk must also 
promptly inform the IRBs/IECs and provide a detailed written explanation. The relevant regulatory 
authorities must be informed.
If, after the termination of the trial, the risk/benefit analysis changes, the new evaluation must be 
provided to the IRBs/IECs in case it has an impact on the planned follow-up of subjects who have 
participated in the trial. If it has an impact, the actions needed to inform and protect the subjects 
should be described.
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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 file and Novo Nordisk 
trial master file.
20 Audits and inspections
Any aspect of the clinical trial may be subject to audits conducted by Novo Nordisk or inspections 
from domestic or foreign regulatory authorities or from IRBs/IECs. Audits and inspections may 
take place during or after the trial. The investigator and the trial 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/IECs clearly identifying the documents reviewed as 
follows: protocol, any protocol amendments, subject information/informed consent form, any 
other written information to be provided to the subject and subject recruitment materials
!
List of IRB/IEC members and/or constitution
!
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
!
SmPC as appropriate
!
Signed and dated agreement on the final protocol
!
Signed and dated agreement on protocol amendment, if applicable
!
Financial agreement(s)
!
Source document agreement
!
Central laboratory certification and normal ranges
!
Insurance statement
!
Signed and dated Investigator Agreement
!
Financial disclosure form from investigator and sub-investigator(s)
Novo Nordisk will analyse and report data from all sites together.
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 making 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 list of appropriately qualified persons to whom he/she has 
delegated specified significant 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.
22.1
Source data handling
The investigator is responsible for filing essential documents (i.e. those documents which 
individually and collectively permit evaluation of the conduct of a trial and the quality of the data 
produced) in the investigator's trial file. The documents should be kept in a secure locked facility, 
so no unauthorized persons can get access to the data. The subject identification code list must be 
kept securely and separate from the personal data.
The investigator will take all necessary technical and organisational safety measures to prevent 
accidental or wrongful destruction, loss or deterioration of data. The investigator will prevent any 
unauthorised access to data or any other processing of data against applicable law. The investigator 
must be able to provide the necessary information or otherwise demonstrate to Novo Nordisk that 
such technical and organisational safety measures have been taken.
22.2
Delegation of responsibilities
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 tasks.
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23 Reports and publications
The information obtained during the conduct of this trial is considered confidential, and may be 
used by Novo Nordisk for regulatory purposes and for the general development of the trial product. 
All information supplied by Novo Nordisk in connection with this trial shall remain the sole 
property of Novo Nordisk and is to be considered confidential information. No confidential 
information shall be disclosed to others without prior written consent from Novo Nordisk. Such 
information shall not be used except in the performance of this trial. The information obtained 
during this trial may be made available to other physicians who are conducting other clinical trials 
with the trial product, if deemed necessary by Novo Nordisk.
One Principal Investigator will be appointed 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 ICMJE for research publications8.
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 Disclosure.
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.
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.
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Where required by the journal, the principal 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 ICMJE8
(sometimes referred to as the Vancouver Criteria).
The investigator(s) offered authorship will be asked to comment and approve the publication. The 
authorship of publications of all trial results will be determined by the Publication group.
23.1.2
Site-specific publication(s) by investigator(s)
For a multi-centre clinical trial, analyses based on single-site data usually have significant statistical 
limitations and frequently do not provide meaningful information for healthcare professionals or 
subjects, and therefore may not be supported by Novo Nordisk. It is a Novo Nordisk policy that 
such individual reports do not precede the primary manuscript and should always reference the 
primary manuscript of the trial.
Novo Nordisk reserves the right to prior review of such publications. 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 for publication of such primary 
policy will take place no later than 18 months after trial completion.
23.2
Investigator access to data and review of results
As owner of the trial database, Novo Nordisk has the discretion to determine who will have access 
to the database. 
Individual investigators will have access to their own research subjects' data.
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24 Retention of clinical trial documentation and human bio
specimens
24.1
Retention of clinical trial documentation
Subject's medical records must be kept for the maximum period permitted by the hospital, 
institution or private practice.
The investigator must agree to archive the documentation (this includes both electronic and paper-
based records) pertaining to the trial in an archive after completion or discontinuation of the trial if 
not otherwise notified. The investigator should not destroy any documents without prior permission 
from Novo Nordisk. If the investigator cannot archive the documents at the trial site, Novo Nordisk 
can refer the investigator to an independent archive provider that has a system in place to allow only 
the investigator to access the files.
The investigator must be able to access his/her trial documents without involving Novo Nordisk in 
any way. Site-specific CRFs and other subject data (in an electronic readable format or as paper 
copies or prints) will be provided to the investigator before access is revoked to the systems
supplied by Novo Nordisk. These data must be retained by the trial site. If the Novo Nordisk 
provided data (e.g. the CD-ROM) is not readable during the entire storage period, the investigator
can request a new copy. A copy of all data will be stored by Novo Nordisk.
Novo Nordisk will maintain Novo Nordisk documentation pertaining to the trial for as long as the 
product is on the market plus 20 years. 
The files from the investigator site/institution must be retained for 15 years after the completion of 
the trial, or longer if required by local regulations. The deletion process must ensure confidentiality 
of data and must be done in accordance with local regulatory requirements.  
24.2
Retention of human bio specimens
Antibody samples will be analysed and then stored at a special laboratory outside of China until 
final feedback from the Chinese regulatory authorities, but no longer than 15 years from end of trial. 
Only Novo Nordisk will have access to these samples. Further characterisation of the antibody 
response may be requested by the regulatory authorities. 
None of the data will be identified by name. Antibody samples will be identified only by a subject 
number, a visit number and a trial identification number. In the event that the collected antibody 
samples will be used in the future, the investigator will become directly informed by Novo Nordisk 
about the results if the findings are deemed clinically relevant. In such case, a written summary of 
the findings, including listings of subject specific values, will be provided once a firm conclusion 
from the results has been drawn by Novo Nordisk.
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25 Institutional Review Boards/Independent Ethics Committees and 
regulatory authorities
IRB/IEC: Written approval or favourable opinion must be obtained from IRB/IEC prior to 
commencement of the trial.
During the trial, the investigator or sponsor, as applicable, must promptly report the following to the 
IRB/IEC, in accordance with local requirements: updates to Investigator's Brochure, unexpected 
SAEs where a causal relationship cannot be ruled out, protocol amendments according to local 
requirements, deviations to the protocol implemented to eliminate immediate hazards to the 
subjects, new information that may affect adversely the safety of the subjects or the conduct of the 
trial (including new risk/benefit analysis in case it will have an impact on the planned follow-up of 
the subjects), annually written summaries of the trial status, and other documents as required by the 
local IRB/IEC.
The investigator must ensure submission of the clinical trial report synopsis to the IRB/IEC.
Protocol amendments must not be implemented before approval or favourable opinion according to 
local regulations, unless necessary to eliminate immediate hazards to the subjects.
The investigator must maintain an accurate and complete record of all submissions made to the 
IRB/IEC. The records must be filed in the investigator's trial 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.
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
1 International Conference on Harmonisation (ICH). ICH Harmonised Tripartite Guideline: 
Guideline for Good Clinical Practice. J Postgrad Med 2001; 47(3):199-203.
2 Declaration of Helsinki. Ethical Principles for Medical Research Involving Human Subjects. 
Last amended by the 64th WMA General Assembly, Fortaleza, Brazil. World Medical 
Association. 20 A.D.
3 The Diabetes Control and Complications Trial Research Group. The effect of intensive 
treatment of diabetes on the development and progression of long-term complications in 
insulin-dependent diabetes mellitus. New Engl J Med 1993; 329(14):977-986.
4 UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with 
sulphonylureas or insulin compared with conventional treatment and risk of complications in 
patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352(9131):837-853.
5 Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M et al. Management 
of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position statement of the 
American Diabetes Association (ADA) and the European Association for the Study of 
Diabetes (EASD). Diabetologia 2012; 55(6):1577-1596.
6 Chinese diabetes society. China guideline for type 2 diabetes. Chinese J diabetes mellitus 2, 6-
56. 2010.
7 Novo Nordisk A/S. Investigator's Brochure, insulin degludec/liraglutide (6th Edition).  10-1-
2014. 
8 Recommendations for the conduct, reporting, editing and publication of scholarly work in 
Medical Journals. International Committee of Medical Journal Editors. Dec-2013.
9 Food and Drug Administration. Food and Drug Administration Amendments Act of 2007: 
http://www.fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFD
CAct/SignificantAmendmentstotheFDCAct/FoodandDrugAdministrationAmendmentsActof2
007/default.htm. 2007.
10 European Commission Regulation for EudraCT. 
http://www.emea.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_00
0044.jsp&mid=WC0b01ac05800260a3. 2011.
11 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 Endocrine 
Society. J Clin Endocrinol Metab 2013; 98(5):1845-1859.
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12 McAulay V, Deary IJ, Frier BM. Symptoms of hypoglycaemia in people with diabetes. Diabet 
Med 2001; 18(9):690-705.
13 European Union. The rules governing medicinal products in the European Union, volume 4, 
Annex 13, Manufacture of Investigational Products - Brussels. 2003.
14 Food and Drug Administration. Guidance for Industry. Diabetes Mellitus: Developing Drugs 
and Therapeutic Biologics for Treatment and Prevention .  2008. 
15 International Conference on Harmonisation. ICH Harmonised Tripartite Guideline. Statistical 
principles for clinical trials E9. International Conference on Harmonisation E9 Expert 
Working Group.  5-2-1998. 
16 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.
CONFIDENTIAL

Protocol - Appendix A
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Date:
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Appendix A
Titration Guideline
Trial ID: NN9068-4148
DUAL! I - China
A trial comparing the efficacy and safety of insulin 
degludec/liraglutide, insulin degludec, and liraglutide in 
Chinese subjects with type 2 diabetes inadequately controlled 
on oral anti-diabetic drugs (OADs)
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
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disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.

Protocol - Appendix A
CONFIDENTIAL
Date:
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Trial ID: NN9068-4148
Version:
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UTN: U1111-1154-6671 
Status:
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Table of Contents
Page
Table of Contents..............................................................................................................................................2
List of in-text tables..........................................................................................................................................2
1
Introduction...............................................................................................................................................3
2
Treatment regimens..................................................................................................................................4
2.1
Injection area..................................................................................................................................4
2.2
Time of injection............................................................................................................................4
3
Initiation and titration ..............................................................................................................................5
3.1
Initiation.........................................................................................................................................5
3.2
Titration .........................................................................................................................................5
3.3
Deviations from the algorithm.......................................................................................................5
4
Data collection ...........................................................................................................................................6
5
Review procedure......................................................................................................................................7
6
References..................................................................................................................................................8
List of in-text tables
Page
Table 1
IDegLira and IDeg dose adjustment ..............................................................................................5
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1
Introduction
The goal of insulin therapy is to achieve near normoglycaemia, i.e. to reach a pre-defined HbA1c
level with a low rate of hypoglycaemic episodes and as little weight gain as possible. Several trials 
have shown that this is difficult to achieve, unless plasma glucose (PG) values are intensively 
monitored and the insulin dose(s) frequently adjusted1-7.
To ensure treatment uniformity between the sites, as well as to ensure that subjects receive an 
optimal treatment, titration algorithms have been developed specifying recommended dose 
adjustments at different PG levels.
It is recognised that treatments differ between different regions and countries. Likewise, specific 
titration guidelines may not be applicable in certain clinical situations. It is important that other 
information, such as symptoms of hypo/hyperglycaemia, previous response to dose adjustments, 
other glucose measurements and other indicators of the subject’s level of glycaemic control, is 
taken into consideration when decisions on dosing are made. The investigator should always use his 
clinical judgement to avoid safety hazards. The investigator is responsible for the treatment of the 
subjects and can therefore overrule the guideline.
To optimise and maintain glycaemic control, the investigator should, throughout the trial be at least 
in weekly contact with the subjects to assist the subjects in adjusting insulin doses and to ensure the 
subjects’ welfare.
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2
Treatment regimens
At randomisation all subjects will be randomised in a 2:1:1 manner into three parallel treatment 
groups:
∀
Insulin degludec/liraglutide (IDegLira) OD + metformin
∀
Insulin degludec (IDeg) OD + metformin
∀
Liraglutide OD + metformin 
First dosing should take place on day of randomisation or on the day following randomisation.
Maximum dose for IDegLira is 50 dose steps (50 units of IDeg and 1.8 mg of liraglutide). 
There is no maximum dose for IDeg.
There is no minimum dose for IDeg and IDeglira.
Instructions on the use of liraglutide have not been included in this guideline as no titration will take 
place. Instead, please refer to the protocol section 5.3 for instructions on start dose and dose 
escalation.
2.1
Injection area
IDegLira or IDeg should be injected subcutaneously into the thigh, upper arm (deltoid area) or the 
abdomen. The chosen region should be the same throughout the trial. Rotation of injection sites 
within a given region is recommended.
2.2
Time of injection
IDegLira or IDeg should be injected once daily at any time of the day, but should approximately be 
the same time of the day throughout the trial. 
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3
Initiation and titration
3.1
Initiation
At randomisation (Visit 2), all subjects randomised to IDegLira or IDeg will start on 10 dose steps 
of IDegLira (10 U of IDeg and 0.36 mg of liraglutide) or 10 U of IDeg once daily.
3.2
Titration
Dose will be adjusted twice weekly by the subject 3-4 days apart. The investigator will support 
titration at all contacts. 
Titration should be performed based on the mean of three pre-breakfast self-measured plasma 
glucose (SMPG) values measured two days before and on day of titration. Titration should 
preferably be performed on the same days of the week throughout the trial. The dose adjustment 
will be performed according to Table 1.
Table 1
IDegLira and IDeg dose adjustment
Mean of three pre-breakfast SMPG 
values 
Dose adjustment
mmol/L
U/Dose steps
<4.0
-2
4.0 – 5.0
No adjustment
> 5.0
+ 2
If one or more SMPG values are missing, the adjustment should be performed on the remaining 
SMPG value(s). However, the first time titration is performed after randomisation all three SMPG 
values must be available. If this is not the case, subjects must wait for the next titration day to adjust 
the dose.
3.3
Deviations from the algorithm
It is strongly recommended that the algorithm is followed. However, it is also important that the 
decision to adjust the IDegLira or IDeg doses are based on all relevant information as described in 
Section 1. A reason for deviating from the algorithm should be entered into the eCRF.
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Protocol - Appendix A
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4
Data collection
The following data must preferably be entered into the eCRF within 24 hours (on week days) after a 
site visit/telephone contact:
∀
Per protocol pre-breakfast SMPG values measured since last visit/telephone contact as 
described in section 3.2
∀
Last IDegLira or IDeg dose taken prior to titration
∀
New IDegLira or IDeg dose to be taken after titration
∀
Reasons for deviation from the titration algorithms, if applicable
∀
Hypoglycaemic episodes
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Protocol - Appendix A
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5
Review procedure
Surveillance of titration data from subjects on IDegLira and IDeg will be performed centrally by 
Novo Nordisk in an unbiased manner. It is important that data regarding dose titration is entered 
into the eCRF within 24 hours (on week days). If delays occur, action cannot be taken in due time 
before the subject’s next site visit/telephone contact. The aim is to reduce the time periods in which 
a subject may receive suboptimal treatment.
The data listed in section 4 will be reviewed by Novo Nordisk within 24 hours (on weekdays). The 
reviewer may contact the investigator to get clarification regarding the reason for deviation or to 
request entry of missing data.
When the investigator receives a query, a response should be received at Novo Nordisk within 24 
hours (on week days). 
During the trial HbA1c will be monitored by Novo Nordisk for additional surveillance of the
glycaemic control. Novo Nordisk may be in contact with sites (visit or telephone contact) to discuss 
progress in glycaemic control and titration of individual subjects based on SMPG values and HbA1c. 
This will be done in an unbiased and whenever possible blinded manner.
CONFIDENTIAL

Protocol - Appendix A
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Date:
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Trial ID: NN9068-4148
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6
References 
1 Garber AJ, King AB, Del PS, Sreenan S, Balci MK, Munoz-Torres M et al. Insulin degludec, an 
ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime 
insulin aspart in type 2 diabetes (BEGIN Basal-Bolus Type 2): a phase 3, randomised, open-
label, treat-to-target non-inferiority trial. Lancet 2012; 379(9825):1498-1507.
2 Heller S, Buse J, Fisher M, Garg S, Marre M, Merker L et al. Insulin degludec, an ultra-
longacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin 
aspart in type 1 diabetes (BEGIN Basal-Bolus Type 1): a phase 3, randomised, open-label, treat-
to-target non-inferiority trial. Lancet 2012; 379(9825):1489-1497.
3 Hermansen K, Davies M, Derezinski T, Martinez RG, Clauson P, Home P. A 26-week, 
randomized, parallel, treat-to-target trial comparing insulin detemir with NPH insulin as add-on 
therapy to oral glucose-lowering drugs in insulin-naive people with type 2 diabetes. Diabetes 
Care 2006; 29(6):1269-1274.
4 Philis-Tsimikas A, Charpentier G, Clauson P, Ravn GM, Roberts VL, Thorsteinsson B. 
Comparison of once-daily insulin detemir with NPH insulin added to a regimen of oral 
antidiabetic drugs in poorly controlled type 2 diabetes. Clin Ther 2006; 28(10):1569-1581.
5 Riddle MC, Rosenstock J, Gerich J. The treat-to-target trial: randomized addition of glargine or 
human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care 2003; 
26(11):3080-3086.
6 Rosenstock J, Davies M, Home PD, Larsen J, Koenen C, Schernthaner G. A randomised, 52-
week, treat-to-target trial comparing insulin detemir with insulin glargine when administered as 
add-on to glucose-lowering drugs in insulin-naive people with type 2 diabetes. Diabetologia 
2008; 51(3):408-416.
7 Gough S, Buse J, Woo V, Rodbard H, Linjawi S, Poulsen P et al. IDegLira, a novel fixed-ratio 
combination of insulin degludec and liraglutide is efficaious and safe in subjects with type 2 
diabetes: a large randomised phase 3a trial. Diabetologia 2013; 56(Suppl 1):96(abstract 219).
CONFIDENTIAL

Protocol - Appendix B
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Date:
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Appendix B
Medical events of special interest and events requiring 
adjudication
Trial ID: NN9068-4148
DUAL! I - China
A trial comparing the efficacy and safety of insulin 
degludec/liraglutide, insulin degludec, and liraglutide in 
Chinese subjects with type 2 diabetes inadequately controlled 
on oral anti-diabetic drugs (OADs)
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
UTN: U1111-1154-6671 
Date:
07 October 2014
Status:
Final
Novo Nordisk
Trial ID: NN9068-4148
     
Version:
2.0
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1
Medical Events of Special Interest (MESI) and events requiring adjudication
Fatal events and MESIs
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
Fatal events are not considered MESIs as per definition they will always be 
considered SAEs.
An FDA guidance document 1
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 myocardial ischemia 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 as a result of hemorrhage or infarction 2
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 B
UTN: U1111-1154-6671 
Date:
07 October 2014
Status:
Final
Novo Nordisk
Trial ID: NN9068-4148
     
Version:
2.0
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Fatal events and MESIs
Definitions
Rationale
Event Adjudication 
Committee
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 
inpatient unit or a 
visit to an 
emergency 
department that 
results in at least a 
24 hour stay, will 
be adjudicated
Revascularisation procedure
Coronary revascularisation procedure (Coronary Artery Bypass Graft 
Surgery and Percutaneous Coronary Intervention): 
Coronary revascularisation procedure is a catheter-based or open surgical 
procedure designed to improve myocardial blood flow.
Peripheral Arterial Revascularization Procedure (lower extremity, renal, 
mesenteric, iliac, subclavian, aortic etc.):
Peripheral arterial revascularisation procedure is a catheter-based or open 
surgical procedure designed to improve peripheral arterial blood flow. This 
procedure may include thrombectomy, embolectomy, atherectomy, 
dissection repair, angioplasty, and stent placement.
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.
Only coronary 
revascularisation
will be adjudicated
Pancreatitis or clinical 
suspicion of 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))
Treatment with GLP-1 receptor 
agonists has been associated with 
acute pancreatitis. Novo Nordisk 
therefore monitors these events 
closely.
All events will be 
adjudicated

Protocol - Appendix B
UTN: U1111-1154-6671 
Date:
07 October 2014
Status:
Final
Novo Nordisk
Trial ID: NN9068-4148
     
Version:
2.0
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Fatal events and MESIs
Definitions
Rationale
Event Adjudication 
Committee
Chronic pancreatitis will be defined by characteristic imaging finding 
(ultrasound, CT, MRI) with abnormal pancreatic function tests or 
characteristic histological findings.
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
thyroid MESI and should not be reported as a Neoplasm MESI)
Fibrosarcomas has been reported in 
rats and mice treated with GLP-1 
receptor agonists in pre-clinical 
studies.
All neoplasm 
events, irrespective 
of malignancy 
stage, will be 
adjudicated
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
Only thyroid 
disorders requiring 
thyroidectomy and 
thyroid neoplasms 
will be adjudicated
Medication errors concerning 
trial products
a.
Administration of wrong drug or use of wrong device
b.
Wrong route of administration, such as intramuscular instead of 
subcutaneous
c.
Administration of a high dose with the intention to cause harm, e.g. 
suicide attempt
d.
Accidental administration of a lower or higher dose than intended. That 
is a dose lower or higher than 20 % of the intended dose; 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.
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 B
CONFIDENTIAL
Date:
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Trial ID: NN9068-4148
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2
Reference
1 Standardized Definitions for Endpoint Events Cardiovascular Trials: Draft Recommendations. 
Division: Draft Recommendations. FDA Center for Drug Evaluation and Research (CDER). 20-
Oct-2010.
2 Standardized Definitions for Cardiovascular and Stroke End Point Events in Clinical Trials 
(DRAFT). Karen A. Hicks, H. M. James Hung, Kenneth W. Mahaffey, Roxana Mehran, Steven 
E. Nissen; Norman L. Strockbridge, Shari L. Targum, Robert Temple; on behalf of the 
Standardized Data Collection for Cardiovascular Trials Initiative. November 9, 2012, or any 
updates hereof.
CONFIDENTIAL

Protocol - Appendix C
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Date:
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Appendix C
New York Heart Association criteria                                
for functional capacity in heart failure
Trial ID: NN9068-4148
DUAL! I - China
A trial comparing the efficacy and safety of insulin 
degludec/liraglutide, insulin degludec, and liraglutide in 
Chinese subjects with type 2 diabetes inadequately controlled 
on oral anti-diabetic drugs (OADs)
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
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Date:
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Trial ID: NN9068-4148
Version:
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1
Criteria for functional capacity
Functional Capacity 
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.
*The 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 D
CONFIDENTIAL
Date:
07 October 2014
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Trial ID: NN9068-4148
Version:
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UTN: U1111-1154-6671 
Status:
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Appendix D
Monitoring of calcitonin levels 
Trial ID: NN9068-4148
DUAL! I - China
A trial comparing the efficacy and safety of insulin 
degludec/liraglutide, insulin degludec, and liraglutide in 
Chinese subjects with type 2 diabetes inadequately controlled 
on oral anti-diabetic drugs (OADs)
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 D
CONFIDENTIAL
Date:
07 October 2014
Novo Nordisk
Trial ID: NN9068-4148
Version:
2.0
UTN: U1111-1154-6671 
Status:
Final
     
Page:
2 of 6
Table of Contents
..............................................................................................................................................................Page
Table of Contents..............................................................................................................................................2
1
Background................................................................................................................................................3
2
Calcitonin and C-cell abnormalities - evaluation and follow-up ..........................................................3
2.1
CT ≥ 100 ng/L................................................................................................................................3
2.2
CT ≥ 50 and < 100 ng/L.................................................................................................................4
2.3
CT ≥ 20 and <50 ng/L....................................................................................................................4
2.4
CT ≥ 10 and < 20 ng/L...................................................................................................................4
3
References..................................................................................................................................................6
CONFIDENTIAL

Protocol - Appendix D
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Date:
07 October 2014
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Trial ID: NN9068-4148
Version:
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Page:
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1
Background
The approach that follows was developed in collaboration with two leading clinical thyroid experts: 
Dr. 
 of the 
 and 
 and Dr. 
 of 
 and represents a synthesis of the medical 
literature and extensive personal experience. 
All previous calcitonin screening studies in the literature have been performed in patients with 
thyroid nodular disease. The nodular status of the subjects in the current trial will mostly be 
unknown. Nevertheless, for the purpose of follow-up, it will be assumed that the same calcitonin 
cut-offs will apply. Up to 50% of subjects in the age group to be studied in the current trial will 
have clinical or subclinical thyroid nodules1 the majority of which will be clinically apparent. 
Subjects with a known personal or family history of medullar thyroid cancer (MTC) or multiple 
endocrine neoplasia type 2 (MEN 2) and subjects with a screening calcitonin of ≥ 50ng/l will be 
excluded from the trial.
2
Calcitonin and C-cell abnormalities - evaluation and follow-up
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.
All calcitonin values ≥20 ng/L (except for screening failures) will be submitted to an independent 
Calcitonin Monitoring Committee (CMC) of thyroid experts, together with relevant supplementary 
data, i.e. subject’s demographics, diabetes history, concomitant medical history, concomitant 
medications, smoking status as well as information about relevant adverse events reported during 
the trial.
The CMC will provide recommendations to the investigators with regards to further investigation 
and treatment of the individual subject. The CMC will be blinded to trial treatment. 
The summary for the rationale for the use of specific calcitonin values to trigger medical evaluation 
and an overview of the algorithm is provided in the following sections.
2.1
CT ≥ 100 ng/L  
The value will be submitted to the CMC and the subject should be discontinued from trial product. 
If the value is a screening value the subject cannot be randomised and the subject must be referred 
to a thyroid specialist. 
These values were found in 0.15% of the population 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, 
CONFIDENTIAL

Protocol - Appendix D
CONFIDENTIAL
Date:
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Trial ID: NN9068-4148
Version:
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UTN: U1111-1154-6671 
Status:
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Page:
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the subject should be assumed to have 
 and a high likelihood of having 
 of the 
. Diagnostic evaluation should consist of 
 ultrasound, fine
needle aspiration of any nodules >1 cm and potentially surgery with 
 dissection. Family history 
of MTC or MEN2 should be evoked and a RET proto-oncogene analysis should be performed. 
2.2
CT ≥ 50 and < 100 ng/L
The value will be submitted to the CMC and the investigator will receive guidance from the CMC 
with regards to continuation of trial product. If the value is a screening value the subject cannot be 
randomised and the subject should be referred to a thyroid specialist.
These values were found in 0.18% of a population with thyroid nodular disease published by 
Costante et al1. 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 positive pentagastrin stimulation tests will be considered to undergo surgery. Where 
pentagastrin is not available, thyroid ultrasound and fine needle aspiration biopsy may add 
important clinical information informing the need for surgery. 
2.3
CT ≥20 and <50 ng/L
The value will be submitted to the CMC. If a subject is screen failed for other reasons than 
calcitonin exclusion criterion # 11 (calcitonin ≥ 50 ng/L), but has a value of calcitonin ≥10 ng/L, it 
is recommended that they are referred to a thyroid expert for further evaluation.
These values are expected to be found in up to 1% of subjects. At this level of calcitonin based on 
data from Costante et al1, the predictive value of the level itself 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
CT ≥ 10 and < 20 ng/L
Confounding factors should be evaluated. If drugs potentially affecting calcitonin can be 
discontinued safely, calcitonin can be repeated after a washout period. Gastrin levels return to the 
normal range by ~ 10 days after stopping proton pump inhibitors.  No further actions are needed 
during the trial if the next calcitonin values remain below 20 ng/L.
If the subject is a screening failure or if the value is the last one taken in the trial, the subject should 
preferably be referred to a thyroid specialist for further evaluation.
These values may be found in ~ 2.5 to 4% of the trial population. Costante et al1 had 216 patients in 
this category. /216 had a subsequent basal (unstimulated) calcitonin of 
 ng/L, and had 
 
. Two other studies used a cutoff of 
CONFIDENTIAL

Protocol - Appendix D
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Trial ID: NN9068-4148
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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.
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Protocol - Appendix D
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3
References
1 Costante G, Meringolo D, Durante C, Bianchi D, Nocera M, Tumino S et al. Predictive value of 
serum calcitonin levels for preoperative diagnosis of medullary thyroid carcinoma in a cohort of 
5817 consecutive patients with thyroid nodules. J Clin Endocrinol Metab 2007; 92(2):450-455.
2 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.
3 Scheuba C, Kaserer K, Moritz A, Drosten R, Vierhapper H, Bieglmayer C et al. Sporadic 
hypercalcitoninemia: clinical and therapeutic consequences. Endocr Relat Cancer 2009; 
16(1):243-253.
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
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Date:
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Version:
Status:
IDegLira
Trial ID: NN9068-4148
Clinical Trial Report
Appendix 16.1.1
16 December 2019
1.0
Final
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Protocol Amendment
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Protocol Amendment
no 1
to Protocol, final version 2.0
dated 07 October 2014
Trial ID: NN9068-4148
DUAL™ I - China
A trial comparing the efficacy and safety of insulin
degludec/liraglutide, insulin degludec, and liraglutide in Chinese
subjects with type 2 diabetes inadequately controlled on oral antidiabetic
drugs (OADs)
Trial phase: 3a
Applicable to China
Amendment originator:
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
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Protocol Amendment
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Table of Contents   
Page
Table of Contents..............................................................................................................................................2
1
Introduction including rationale for the protocol amendment.............................................................3
2
Changes......................................................................................................................................................4
2.1.1
Changes to Protocol.....................................................................................................4
2.1.2
Optimisation and standardisation of safety reporting ..................................................4
2.1.2.1
Introducing: “Medication error” and ‘Adverse Events with 
additional data collection’ .....................................................................4
2.1.2.2
Deletion of Medical event of special interest (MESI) definition 
and term.................................................................................................4
2.1.3
Events in scope for adjudication added .......................................................................4
2.1.4
Reporting of adverse events.........................................................................................4
2.1.5
Extra follow-up visit added at the end of trial .............................................................5
2.1.6
Collection of data describing ‘severe hypoglycaemic episodes’ .................................5
2.1.7
Hypoglycaemia unawareness.......................................................................................5
2.1.8
Smoking habits ............................................................................................................5
2.1.9
Eye examination and ECG...........................................................................................5
2.1.10
Laboratory analysis......................................................................................................6
2.1.10.1
Fasting insulin .......................................................................................6
2.1.10.2
Pregnancy test .......................................................................................6
2.1.11
Calcitonin.....................................................................................................................6
2.1.12
Trial product details.....................................................................................................6
2.1.13
IWRS ...........................................................................................................................7
2.1.14
Monitoring procedures more clearly specified ............................................................7
2.1.15
Statistical considerations..............................................................................................7
2.1.16
Ethics ...........................................................................................................................7
2.1.17
Reports and publications..............................................................................................7
2.1.18
Retention of human biosamples...................................................................................8
2.1.19
Flow Chart updates......................................................................................................8
2.1.20
List of abbreviations ....................................................................................................8
2.2
Changes to the SI/IC......................................................................................................................8
2.2.1
Adhering to local regulations and legal requirement...................................................8
2.2.1.1
Blood sample handling & exportation...................................................8
2.2.1.2
Funding of research...............................................................................8
2.2.1.3
Liability information .............................................................................8
2.2.1.4
Subject reimbursement fee....................................................................8
2.2.2
Trial product market availability .................................................................................9
2.2.3
Text describing cardiovascular safety and DEVOTE..................................................9
2.2.3.1
Signal of increased cardiovascular risk.................................................9
2.2.4
Update of section 2.3 If you become pregnant ............................................................9
2.2.5
Other SI/IC updates .....................................................................................................9
2.2.5.1
30 days follow up visit (FU 2) named phone contact 30, added...........9
2.2.5.2
Extra SI/IC version to male partners.....................................................9
2.2.5.3
Extra SI/IC version for genetic testing obsolete....................................9
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Protocol Amendment
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1
Introduction including rationale for the protocol amendment
The CFDA approved the NN9068-4148 protocol version 2.0, dated 07 October 2014 on 
06 June 2016. Since the preparation of the trial protocol in 2014, some of the Novo Nordisk 
standards and processes have evolved and updated, which is the reason for preparing the 
amendment and updating the protocol. This is in accordance with the feed-back received from 
CFDA; please refer to below text copied from the IDegLira IDL approval letter, optimization of the 
protocol is allowed:
“Before the clinical trial operation, clinical research organization should further refine and 
optimize the protocol, pay attention to the exposed and potential safety risk of the product, and 
make a risk control and management plan.”
While amending the protocol special attention has been on patient safety and reporting, data quality
and GCP compliance. This means that minor refinements have been made throughout the protocol 
with the purpose of improving data quality and clarifying issues, where applicable. Additionally, 
typos and minor formatting corrections have been implemented throughout the protocol.
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Protocol Amendment
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2
Changes
2.1.1
Changes to Protocol
2.1.2
Optimisation and standardisation of safety reporting
Rationale: Since IB version 6, the identified and potential risks included in the minimum 
mandatory safety text have been updated based on the clinical development of IDegLira. 
Additionally, standardisation and alignment with the current and future internal safety reporting 
processes within Novo Nordisk will result in a more systematic way of colleting safety data and 
improve the quality of data collected. Further, by updating the protocol, the safety processes and 
reporting will be simplified including reporting of medication error as AE requiring additional data 
rather than MESI.
Impact: The impact of the above is mentioned in sections below:
2.1.2.1
Introducing: “Medication error” and ‘Adverse Events with additional data 
collection’
Impact: Section 12 updated with relevant sections, new sections 8.2.3.1 and 8.2.3.2 introduced and 
Appendix B updated.
2.1.2.2
Deletion of Medical event of special interest (MESI) definition and term
Impact: Throughout the protocol MESI has been deleted and medication errors are changed to AE 
requiring additional data collection.
2.1.3
Events in scope for adjudication added
Rationale: All coronary revascularisations (CR) occurring as a result of an Myocardial Infarction 
(MI) will be captured on the specific event form for the corresponding Acute Coronary Syndrome 
(ACS) event and source documents from the procedure will be reviewed by the Event Adjudication 
Committee (EAC) when adjudicating this ACS event.
Impact: Coronary revascularisation (CR) has been removed as event in scope for adjudication as 
only MIs and not the procedure itself will be adjudicated.
2.1.4
Reporting of adverse events
Rationale: This is in order to align with the new Novo Nordisk processes for reporting of adverse 
events.
Impact: Protocol sections 8 and 12 updated.
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Protocol Amendment
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2.1.5
Extra follow-up visit added at the end of trial
Rationale: In line with current FDA guidance, an additional follow-up visit (30 days after last dose 
on trial product) was added at the end of trial in order to collect further safety information on 
subject reported SAEs and concomitant antidiabetic treatment.
Impact: This will increase the trial duration with approximately 3 weeks – which has been updated 
in protocol where applicable (e.g. also figure 5.1 updated). Further, the terms 7-days follow up visit 
(FU1) and 30-days follow-up visit FU2 (Phone contact 30) have been introduced throughout the 
protocol – especially Sections 1, 2, 5 and 8.
2.1.6
Collection of data describing ‘severe hypoglycaemic episodes’
Rationale: The protocol was written in 2014 based on 
. Since then the 
hypoglycaemia episode form has been updated to capture additional structured information on 
severe hypoglycaemia symptoms and resource use. Therefore a number of additional questions was
added to the subject diaries.
Impact: The severe hypoglycaemia data being collected in the diaries has been added to protocol 
Sections 8.2.15 and other text corrections made to comply with current standards and improve 
narrative quality.
2.1.7
Hypoglycaemia unawareness
Rationale: Since the protocol was written in 2014 a new section “Hypoglycaemia unawareness” 
has been included in the protocol 
. Because this trial does not exclude 
inclusion of subjects with impaired hypoglycaemia awareness the information about hypoglycaemia 
unawareness will be collected at the screening visit.
Impact: A new section 8.2.5 has been added to the protocol.
2.1.8
Smoking habits
Rationale: The protocol was written in 2014 based on 
 Since then section
“8.2.6 Smoking habits” has been renamed to “Tobacco use” and the question about when the 
subject stopped smoking has been deleted.
Impact: Flowchart and section 8.2.6 updated.
2.1.9
Eye examination and ECG
Rationale: To be aligned with the global DUAL I trial collection of details of an abnormality of eye 
examination and ECG will be collected.
Impact: Section 8.2.11 and 8.2.12 updated.
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Protocol Amendment
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Date:
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Trial ID: NN9068-4148
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2.1.10
Laboratory analysis
2.1.10.1
Fasting insulin
Rationale: In line with other DUAL trials the fasting insulin results will not be provided to the 
investigator as these are not used for clinical evaluation during the trial. Instead they will be 
included in an analytical report after end of trial and retained at Novo Nordisk. Also, fasting insulin 
is measured at a special lab and samples are stored until final CTR.
Impact: Section 8.3.1 updated, new section 8.3.5 added and section 24.2 updated.
2.1.10.2
Pregnancy test
Rationale: The text from flowchart foot note i was not mentioned anywhere else in the protocol.
The text reads: “For females of child-bearing potential a urine pregnancy test should be performed 
at site, if pregnancy is suspected or if a menstrual period is missed. If the subject reports missing 
menstrual at a phone contact, the subject must attend the site for an unscheduled visit as soon as 
possible to have a urine test done. If positive, a confirmatory serum hCG sample should be sent to 
the central laboratory”
Impact: Section 8.3.1 updated.
2.1.11
Calcitonin
Rationale: The Calcitonin section in the protocol including an additional withdrawal criteria #7 and 
the Appendix D have been updated to align with the monocomponent of liraglutide based on 
minutes from liraglutide safety committee (SC) Mar 2015 and the IDegLira SC agreed on May-
2015 that:
MTC monitoring set-up (no RET tests will be performed, deletion of the external CMC which is 
replaced by a guideline in the protocol and training of the investigators on handling of elevated 
calcitonin values consistent with the current guideline developed by the CMC) will be implemented 
in the DURABILITY trial (NN9068-4228) and other future NN9068 trials.
Impact: Sections 6.4, 8.3.2 and Appendix D updated.
2.1.12
Trial product details
Rationale: Since the protocol was written in 2014 product information concerning IDegLira, IDeg 
and liraglutide has been updated. Therefore the references to Investigator’s Brochures and local
labelling have been updated to the most updated editions.
Impact: References updated throughout the protocol.
CONFIDENTIAL

Protocol Amendment
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Date:
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Trial ID: NN9068-4148
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Status:
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2.1.13
IWRS
Rationale: Since the protocol was written in 2014 the IWRS system has been upgraded to 
Config. 3.1 to improve drug accountability and drug destruction. Further, dispensing verification 
has been included following introduction of the barcode scanner.
Impact: Updated section 9 and 10.
2.1.14
Monitoring procedures more clearly specified
Rationale: In order to comply with 
 and to ensure subject safety and 
GCP compliance as early as possible at trial sites, the protocol will be updated to define the 
maximum allowed time (4 weeks) from FPFV until the first monitoring at site and 12 weeks for 
subsequent monitoring visits.
Impact: Updated Section 14 Monitoring Procedures.
2.1.15
Statistical considerations
Rationale: To be compliant with the updates made in other sections of the protocol the statistical 
considerations have been updated accordingly. Main update is related to hypoglycaemia definitions.
Impact: Section 17 updated.
2.1.16
Ethics
Rationale: In order to comply with 
 and to ensure subject safety and 
GCP compliance the protocol has been updated with the mandatory SOP template text. Section 18 
of the protocol has been updated to include benefit-risk assessment section, which has previously 
been provided as a separate benefit-risk assessment document. The text in section 18 has been 
updated to align with updates from liraglutide and IDegLira programme
Impact: Section 18 updated.
2.1.17
Reports and publications
Rationale: In order to comply with 
 the protocol has been updated to 
reflect resent disclosure requirements.
Impact: Section 23 updated.
CONFIDENTIAL

Protocol Amendment
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Date:
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Trial ID: NN9068-4148
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2.1.18
Retention of human biosamples
Rationale: In order to comply with 
 and to ensure subject safety and 
GCP compliance the protocol has been updated to more clearly describe which blood samples are 
exported out of China and for how long the samples will be stored.
Impact: Section 24.2 and SI/IC updated.
2.1.19
Flow Chart updates
Rationale: Based on above mentioned changes related to additional FU2 the flowchart has been 
updated displaying what procedures are to be performed at FU1 and FU2. Additionally, the 
flowchart is updated with tobacco use and hypoglycaemia unawareness as described previously.
Impact: Flow chart and footnotes updated accordingly.
2.1.20
List of abbreviations
Rationale: Since protocol preparation back in 2014, new standard abbreviations have been 
implemented and the following terms will be modified throughout the protocol. Also a few new 
terms have been added, refer to below.
Impact: IV/WRS replaced by IWRS, ASAT replaced by AST and ALAT replaced by ALAT
throughout the protocol. Additionally, MESI and SmPC have been deleted throughout the protocol.
2.2
Changes to the SI/IC
2.2.1
Adhering to local regulations and legal requirement
Rationale: Below sections have been added based on experience with EC requested information.
2.2.1.1
Blood sample handling & exportation 
Impact: Section 1.17 about antibody exportation, PK and fasting insulin sampling added.
2.2.1.2
Funding of research
Impact: Section 4.1 is updated.
2.2.1.3
Liability information 
Impact: Section 4.2 updated.
2.2.1.4
Subject reimbursement fee
Impact: Section 4.3 updated.
CONFIDENTIAL

Protocol Amendment
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Date:
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Trial ID: NN9068-4148
Version:
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Status:
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2.2.2
Trial product market availability
Rationale: The description about cardiovascular safety is already included in the market launch 
information for the trial products in section 2.1.
Impact: Last part of section 1.2 about trial product market availability is deleted. 
2.2.3
Text describing cardiovascular safety and DEVOTE
Rationale: In order to present the most recent status on the CV outcome trial initiated based on
FDA request the below section has been updated.
Impact: The previous text in section 2.5.1 has been replaced by updated text in section 2.1.14.
2.2.3.1
Signal of increased cardiovascular risk
Impact: The previous text in safety section 2.0 about CV has been updated.
2.2.4
Update of section 2.3 If you become pregnant
Rationale: Section 2.3 has been updated based on the updated Minimum Mandatory Safety text 
from IDegLira.
2.2.5
Other SI/IC updates
Rationale: Based on updates made to the trial protocol.
2.2.5.1
30 days follow up visit (FU 2) named phone contact 30, added
Impact: Section 1.1, 1.3, 1.4, 1.5.3 and 3.1 updated.
2.2.5.2
Extra SI/IC version to male partners
Impact: The version and date is updated to be aligned with the main SI/IC. Section 3 and 5 
updated.
2.2.5.3
Extra SI/IC version for genetic testing obsolete
Impact: The SI/IC for genetic testing is no longer applicable for IDegLira trials. Therefore it will 
not be resubmitted.
CONFIDENTIAL

Protocol Amendment
CONFIDENTIAL
Date:
31 August 2016
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Trial ID: NN9068-4148
Version:
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Status:
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Protocol Amendment
no 2
to Protocol, final version 2.0
dated 07 October 2014
Trial ID: NN9068-4148
DUAL™ I - China
A trial comparing the efficacy and safety of insulin
degludec/liraglutide, insulin degludec, and liraglutide in Chinese
subjects with type 2 diabetes inadequately controlled on oral antidiabetic
drugs (OADs)
Trial phase: 3a
Applicable to China
Amendment originator:
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.

Protocol Amendment
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Date:
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Trial ID: NN9068-4148
Version:
1.0
UTN: U1111-1154-6671
Status:
Final
     
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Introduction including rationale for the protocol amendment
During the approval process of amendment 01 the below refinement related to improved data 
quality has been discussed in the Biostatistics department. We therefore apply for approval of the
below updates to section 17.4.2.2 to be made in the NN9068-4148 protocol. The reasons for the 
update are:
!
More clearly addresses whether as to an endpoint is of continuous or categorical nature (i.e. 
summary statistics will be on the form {N,mean(SD),min,max,median} or {N,percentage})
!
Specifies scatter plots that are better suited to detect unwanted anti body development
Current text to be deleted in section 17.4.2.2:
Antibodies towards trial product
Anti-insulin degludec antibodies including anti-human insulin antibodies, anti-liraglutide 
antibodies, anti-liraglutide antibodies cross reacting with native GLP-1 and in vitro neutralising 
effect of anti-liraglutide antibodies will be summarised and tabulated. The correlation between 
change from baseline after 26 weeks of treatment in anti-insulin degludec and anti-human insulin 
antibodies respectively, to insulin dose after 26 weeks of treatment, HbA1c after 26 weeks of 
treatment and change from baseline after 26 weeks of treatment in HbA1c will be illustrated using 
scatter plots.
For the liraglutide component of IDegLira and liraglutide, the number of subjects (N) and the 
percentage of subjects (%) with positive, cross-reacting to native GLP-1 and neutralising antibodies 
will be summarised.
Listing with subjects with liraglutide positive antibody formation will be produced. These listings 
should include efficacy information as minimum HbA1c and body weight over time.
New text to be inserted in section 17.4.2.2:
17.4.2.2 Safety endpoints
Insulin and GLP-1 antibodies
Insulin antibodies (IDeg specific, cross-reacting to human insulin and total) will be summarised 
with arithmetic mean, standard deviation (SD), median, and minimum and maximum value by 
treatment and treatment week, and their mean over time will be plotted. Correlations will be 
explored graphically as follows. Insulin antibodies (IDeg specific, cross-reacting to human insulin 
and total) will be plotted against HbA1c after 26 weeks, HbA1c change from baseline after 26 weeks, 
and dose after 26 weeks. Change from baseline to FU1 in insulin antibodies (IDeg specific, cross-
CONFIDENTIAL

Protocol Amendment
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Trial ID: NN9068-4148
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reacting to human insulin and total) will be plotted against HbA1c after 26 weeks, HbA1c change 
from baseline after 26 weeks, and dose after 26 weeks.
GLP-1 antibodies (liraglutide specific, cross-reacting to native GLP-1, liraglutide in vitro
neutralising and in vitro neutralising to native GLP-1) will be summarised by number of subjects 
(N) and percentage of subjects (%) with positive and negative samples.
Antibody measurements will be listed by subject and visit together with associated age, sex, BMI, 
HbA1c and dose.
CONFIDENTIAL

Protocol Amendment
CONFIDENTIAL
Date:
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Trial ID: NN9068-4148
Version:
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UTN: U1111-1154-6671
Status:
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Protocol Amendment
no 3
to Protocol, final version 2.0
dated 07 October 2014
Trial ID: NN9068-4148
DUAL™ I - China
A trial comparing the efficacy and safety of insulin
degludec/liraglutide, insulin degludec, and liraglutide in Chinese
subjects with type 2 diabetes inadequately controlled on oral antidiabetic
drugs (OADs)
Trial phase: 3a
Applicable to China
Amendment originator:
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
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disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.

Protocol Amendment
CONFIDENTIAL
Date:
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Trial ID: NN9068-4148
Version:
1.0
UTN: U1111-1154-6671
Status:
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1
Changes to SI/IC
At the IDegLira safety committee meeting on 30-Aug-2016, it was endorsed to update the MMST 
with the below stated text for the SI/IC. 
Current text to be deleted in section 2.2.5:
1.1.1
Gallstone disease
Cases of gallstones (cholelithiasis) and inflammation of the gallbladder (cholecystitis) have 
been reported from long-term clinical trials with liraglutide (component of IDegLira). These 
events may lead to hospitalisation and removal of the gallbladder. If you experience recurring 
upper abdominal pain, you should contact your trial doctor, who will decide whether you 
should discontinue trial product and/or undergo additional diagnostic procedures.
New text to be inserted in section 2.2.5:
Gallstone disease
Cases of gallstones (cholelithiasis) and inflammation of the gallbladder (cholecystitis) have been 
reported from clinical trials with IDegLira. These events may lead to hospitalisation and removal of 
the gallbladder. If you experience recurring upper abdominal pain, you should contact your trial 
doctor who will decide whether you should discontinue trial medication and/or undergo additional 
diagnostic procedures
New text to be inserted as section 2.2.17
2.2.17 Other adverse events
Feeling tired has been reported with IDegLira in 1 to 10 out of 1000 patients in clinical trials.
Non MMST related update to section 1.5 to be consistent with the protocol
Throughout the trial you must continue your metformin treatment. at the same stable dose and 
frequency as before your trial participation. The dose and frequency should not be changed at any 
time during the trial until the end of treatment visit”.
CONFIDENTIAL

Protocol Amendment
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Date:
28 September 2016
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Trial ID: NN9068-4148
Version:
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UTN: U1111-1154-6671
Status:
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EudraCT No.:
Page:
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Protocol Amendment
no 4
to Protocol, final version 2.0
dated 07 October 2014
Trial ID: NN9068-4148
DUAL™ I - China
A trial comparing the efficacy and safety of insulin
degludec/liraglutide, insulin degludec, and liraglutide in Chinese
subjects with type 2 diabetes inadequately controlled on oral antidiabetic
drugs (OADs)
Trial phase: 3a
Applicable to China
Amendment originator:
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
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disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.

Protocol Amendment
CONFIDENTIAL
Date:
28 September 2016
Novo Nordisk
Trial ID: NN9068-4148
Version:
1.0
UTN: U1111-1154-6671
Status:
Final
EudraCT No.:
Page:
2 of 4
Introduction including rationale for the protocol amendment
After finalisation of NN9068-4148 protocol version 3.0 dated 29-Aug-2016 and the subject 
information/informed consent form version 3.0 dated 31-Aug-2016 the following changes have 
been identified why an amendment is needed:
1.1
Update of safety section
The IDegLira safety committee agreed on 30-Aug-2016 to classify ‘acute gallstone disease’ as an 
important identified risk. Section 18 in the protocol has been updated to include ‘acute gallstone 
disease’ as an important identified risk and section 2.2.5 has been updated in the SI/IC.
Updated in SI/IC section 2.2.5:
Gallstone disease
Cases of gallstones (cholelithiasis) and inflammation of the gallbladder (cholecystitis) have been 
reported from clinical trials with IDegLira and liraglutide. These events may lead to hospitalisation 
and removal of the gallbladder. If you experience recurring upper abdominal pain, you should 
contact your trial doctor, who will decide whether you should discontinue the trial medication 
and/or undergo additional diagnostic procedures.
Updated in protocol section 18.1.1.1 Important identified risks:
Acute gallstone disease
Although infrequent, cases of gallstones (cholelithiasis) and inflammation of the gallbladder 
(cholecystitis) have been reported from clinical trials with IDegLira. Both cholelithiasis and 
cholecystitis have possible clinical implications for the patients as the events might lead to 
hospitalisation and cholecystectomy. If cholelithiasis is suspected, treatment should be discontinued 
and gallbladder examination and appropriate clinical follow-up should be initiated. If acute 
gallstone disease is confirmed, the trial product must be permanently discontinued.
1.2
Update of Statistical considerations
The statistical models for the confirmatory secondary endpoints, hypoglycaemic episodes and dose, 
have been updated to be in alignment with the models for the global DUAL trials. In addition, 
clarifications around 1-sided versus 2-sided testing has been added and minor errors corrected.
Updated in protocol section 17:
“Unless otherwise specified, all continuous measurements will be summarised descriptively at each 
visit by treatment using observed data. After 26 weeks of treatment, descriptive statistics will be 
presented based both on observed and last observation carried forward (LOCF) imputed data. 
CONFIDENTIAL

Protocol Amendment
CONFIDENTIAL
Date:
28 September 2016
Novo Nordisk
Trial ID: NN9068-4148
Version:
1.0
UTN: U1111-1154-6671
Status:
Final
EudraCT No.:
Page:
3 of 4
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 summarised by supplemented with the 
geometric mean and coefficient of variation (CV).”
“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 5% p-value.”
From section 17.1 Sample size calculation
“A hierarchical testing procedure is applied. This is based on an a priori ordering of the null-
hypotheses and testing them in this order using the two-sided 95% confidence interval approach 
until an insignificant result appears. Non-inferiority and superiority will thus be considered 
confirmed if the upper bound of the two-sided 95% confidence interval is below 0.4% and 0.0% 
respectively. 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% (one-sided).”
From section 17.4.1 Confirmatory secondary endpoints
The following two confirmatory endpoints will be tested for superiority of IDegLira vs. IDeg.
Change from baseline in body weight after 26 weeks of treatment.
Number of treatment emergent severe or BG confirmed hypoglycaemic episodes during 
26 weeks of treatment.
The tests for superiority of the confirmatory secondary endpoints will be based on the FAS and will 
only be carried out if non-inferiority of IDegLira vs. IDeg and superiority of IDegLira vs. 
liraglutide with regards to the primary endpoint are confirmed.
In order to control the overall type I error on a 2-sided 5% level with regards to the secondary 
endpoints, a hierarchical testing procedure will be used. If superiority is confirmed with respect to 
change from baseline in body weight after 26 weeks of treatment the number of treatment emergent 
severe or BG confirmed hypoglycaemic episodes during 26 weeks of treatment will be tested for 
superiority. Superiority for change from baseline in body weight will be considered confirmed if the 
upper bound of the two-sided 95% confidence interval for the estimated mean treatment difference 
(IDegLira minus IDeg) is strictly below zero or equivalently if the p-value for the one-sided test of
H0 D≥0.0% against HA D<0.0%,
is less than 2.5%, where D is the treatment difference.
CONFIDENTIAL

Protocol Amendment
CONFIDENTIAL
Date:
28 September 2016
Novo Nordisk
Trial ID: NN9068-4148
Version:
1.0
UTN: U1111-1154-6671
Status:
Final
EudraCT No.:
Page:
4 of 4
Superiority for hypoglycaemic episodes will be considered confirmed if the upper bound of the two-
sided 95% confidence interval for the estimated mean treatment ratio (IDegLira vs. IDeg) is strictly 
below one or equivalently if the p-value for the one-sided test of
H0 RR≥1.0 against HA RR<1.0,
is less than 2.5%, where RR is the treatment estimated rate ratio.
The change from baseline in body weight after 26 weeks of treatment will be analysed using an 
ANCOVA model with treatment and previous OAD treatment (metformin ± one other OAD) as 
fixed factors and baseline weight as covariate.
Number of treatment emergent severe or BG confirmed hypoglycaemic episodes during 26 weeks 
of treatment will be analysed 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 treatment 
emergent as offset. The model will include treatment and previous antidiabetic treatment as fixed 
factors and baseline HbA1c as covariate.
From section 17.4.2.1 Efficacy endpoints
In the following the statistical models will be fitted to all data simultaneously (all treatment groups) 
and from this model the treatment differences for IDegLira vs. IDeg and IDegLira vs. liraglutide 
will be estimated.
Insulin dose after 26 weeks of treatment
The actual daily insulin dose after 26 weeks of treatment will be analysed using an ANCOVA 
model including treatment and previous antidiabetic treatment as fixed factors and baseline HbA1c
value and baseline insulin dose as covariate.
From section 17.4.2.2 Safety endpoints, Calcitonin
The distribution of all calcitonin measurements across treatment groups and time will be shown 
with box plots histograms and corresponding cumulative plots for actual levels of calcitonin and 
change from baseline. The plots will be presented by treatment group (using at EOT using
measurement LOCF) imputed values and within treatment group by week. Plots will be done by 
each gender, separately.
CONFIDENTIAL

Protocol Amendment
CONFIDENTIAL
Date:
05 December 2016
Novo Nordisk
Trial ID: NN9068-4148
Version:
1.0
UTN: U1111-1154-6671
Status:
Final
     
Page:
1 of 9
Protocol Amendment
no 5
to Protocol, final version 2.0
dated 07 October 2014
Trial ID: NN9068-4148
DUAL™ I - China
A trial comparing the efficacy and safety of insulin
degludec/liraglutide, insulin degludec, and liraglutide in Chinese
subjects with type 2 diabetes inadequately controlled on oral antidiabetic
drugs (OADs)
Trial phase: 3a
Applicable to China
Amendment originator:
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.

Protocol Amendment
CONFIDENTIAL
Date:
05 December 2016
Novo Nordisk
Trial ID: NN9068-4148
Version:
1.0
UTN: U1111-1154-6671
Status:
Final
     
Page:
2 of 9
Table of Contents
1
Introduction including rationale for the protocol amendment.............................................................3
2
Changes to protocol version 4.0 dated 28-Sep-2016...............................................................................4
2.1
Affected section 8.3.3: Baseline antibody samples shipped from 
 to Novo Nordisk 
Måløv, Denmark............................................................................................................................4
2.2
Affected section 24.2: Storage time for antibody samples ............................................................5
2.3
Affected section 8.3: Reporting of laboratory results not provided to Investigator.......................5
2.4
Affected sections 9.1 and 12.4.1: Mistake in pen description for Liraglutide in section 9; in 
section 12 this is correctly listed....................................................................................................6
2.5
Affected section 6.4 Withdrawal criteria#5...................................................................................6
3
Changes to Subject information/informed consent form version 4.0 dated 08-Sep-2016...................8
3.1
Affected section 1.7: Baseline antibody samples shipped from 
 to Novo Nordisk 
Måløv, Denmark............................................................................................................................8
3.2
Affected section 3.3: Storage time for antibody samples ..............................................................8
3.3
Affected section 2.1: What are the possible risks if you participate in this trial............................8
CONFIDENTIAL

Protocol Amendment
CONFIDENTIAL
Date:
05 December 2016
Novo Nordisk
Trial ID: NN9068-4148
Version:
1.0
UTN: U1111-1154-6671
Status:
Final
     
Page:
3 of 9
1
Introduction including rationale for the protocol amendment
After finalisation of NN9068-4148 protocol version 4.0 dated 28-Sep-2016 and the subject 
information/informed consent form version 4.0 dated 28-Sep-2016 the following changes have been 
identified why an amendment is needed:
!
To update with description of shipment of baseline antibody samples from 
, 
, to Novo Nordisk, Denmark
!
To update storage time for antibody samples
!
To align where laboratory results will be reported
!
To correct description of pen to be used for liraglutide arm
!
To align withdrawal criteria #5
!
To update SI/IC risk section with FDA approval of Xultophy
In this substantial protocol amendment global:
!
Any new text is written in italic.
!
Any text deleted from the protocol is written with a strike through
CONFIDENTIAL

Protocol Amendment
CONFIDENTIAL
Date:
05 December 2016
Novo Nordisk
Trial ID: NN9068-4148
Version:
1.0
UTN: U1111-1154-6671
Status:
Final
     
Page:
4 of 9
2
Changes to protocol version 4.0 dated 28-Sep-2016 
2.1
Affected section 8.3.3: Baseline antibody samples shipped from 
 to Novo 
Nordisk Måløv, Denmark
Rationale: Analysis of in vitro neutralising activity of anti-drug antibodies (ADA) is a requirement 
from the health authorities (FDA, EMA, CFDA) (ref 1, 2, 3). According to the guidelines, antibody 
negative samples/baseline samples from the same population as is investigated for ADA 
development should be used for determining the cut point in the antibody analyses. Therefore, 
commercially obtained human serum samples should not be used to determine the cut point. 
To comply with the recommendations, approximately 30 baseline (visit 2 samples) antibody 
samples will be shipped to a laboratory at Novo Nordisk, Måløv, Denmark to be used for the 
neutralising antibody cut point determination. These samples will consist of visit 2 antibody 
samples from the patients that are ADA positive at the follow up 1visit, as well as an additional 
number of antibody negative visit 2 samples randomly chosen among the antibody negative trial 
subjects. This procedure is in accordance with the previous global trials in the NN9068 phase 3 trial 
programme.
No results from the antibody negative visit 2 samples will be reported to the OC database or the 
investigator as these are only used for calculation of the neutralising cut point and not for any 
clinical relevant results. The only results to be reported in the CTR from the in vitro neutralising 
anti-liraglutide antibody analysis are the results of the antibody positive follow-up visit 1 samples .
1: FDA Draft guidance: Assay Development and Validation for Immunogenicity testing of 
Therapeutic Protein Products. Guidance for Industry. 2016
2: EMA Guideline on Immunogenicity assessment of biotechnology-derived therapeutic proteins 
draft 2015
3: CFDA Guideline for quality control of recombinant DNA products 2003
Updates text section 8.3.3 in protocol version 4.0:
FU1 samples positive for anti-liraglutide antibodies will in addition be analysed for in vitro 
neutralising effect in a cell based assay. In vitro neutralising effect will be analysed by Novo 
Nordisk. Anti-liraglutide antibody positive FU1 samples and baseline(visit 2) samples belonging to 
the same subject will be forwarded by the special lab performing the antibody analysis to Novo 
Nordisk. Additionally, a number of baseline samples from subjects with antibody negative FU1 
samples will also be forwarded to Novo Nordisk to set a cut point for the analysis.
CONFIDENTIAL

Protocol Amendment
CONFIDENTIAL
Date:
05 December 2016
Novo Nordisk
Trial ID: NN9068-4148
Version:
1.0
UTN: U1111-1154-6671
Status:
Final
     
Page:
5 of 9
2.2
Affected section 24.2: Storage time for antibody samples 
Rationale: To be aligned with previous trial NN5401-3598 conducted in China and OHGRA 
guidance on storage time for antibody samples the protocol text has been updated to be aligned with 
the 3598 study protocol section 8.5 (EN version 3.0, dated 27-Aug-2015). 
In section 24.2 storage time for antibody samples and Fasting insulin samples are on purpose 
differently described. The long term storage for antibody samples is requested by the FDA but is 
not applicable for any other parameters or samples. There are no clear rules for retaining samples 
for biomarkers or PK, so it has been decided that Fasting insulin and PK samples are stored until 
final CTR. This is contrary to the regular safety samples at central laboratories which are discarded 
a few days after analysis. Reason for the difference is that sample results are released (and 
considered final) continuously from the central labs whereas the special labs release results at DBL 
due to limitations in the special lab LIMS systems. This keep the option for re-analysis open until 
PK and biomarker data has been evaluated. So it will not be advisable to store the Insulin samples 
as long as the antibody samples.
Updated text section 24.2 in protocol version 4.0:
Antibody samples will be stored until after end of trial and until marketing authorisation approval or 
until the research project terminates, but no longer than 15 years from end of trial after which they 
will be destroyed. Fasting insulin and PK samples will be stored until final CTR after which they 
will be destroyed.
2.3
Affected section 8.3: Reporting of laboratory results not provided to Investigator
Rationale: Based on guidance from the China Human Genetic Resources Administration Office 
(OHGRA) it is a concern that the protocol is not consistent as to where laboratory results that are 
not provided to the investigator will be published (antibody, PK and fasting insulin). . Because all 
results are summarised in the CTR the affected section is updated for consistency.
Updated text section 8.3.5 in protocol version 4.0:
Results from fasting insulin samples will not be provided to the investigator as these are not used 
for clinical evaluation during the trial. Instead they will be included in an analytical report after 
end of trial. The results will be described in the CTR after end of trial.
Updated text section 8.3.4 in protocol version 4.0:
PK results will not be provided to the investigator as these are not used for clinical evaluation 
during the trial. Instead they will be included in a bio-analytical report that will be available at 
data base lock and retained at Novo Nordisk. The results will be described in the CTR after end of 
trial.
CONFIDENTIAL

Protocol Amendment
CONFIDENTIAL
Date:
05 December 2016
Novo Nordisk
Trial ID: NN9068-4148
Version:
1.0
UTN: U1111-1154-6671
Status:
Final
     
Page:
6 of 9
2.4
Affected sections 9.1 and 12.4.1: Mistake in pen description for Liraglutide in section 
9; in section 12 this is correctly listed
Rationale: A discrepancy was discovered in the pen description for liraglutide between table 9-1 
and section 12.4.1. The wrong device was listed for liraglutide in table 9-1 whereas it was correctly 
listed in section 12.4.1. Table 9.1 was updated to specify the dosage form and delivery device for all 
trial products. Furthermore, the brand name for liraglutide (Victoza®) was deleted from both table 9-
1 and section 12.4.1.
Updated table 9-1:
Table 9-1 Trial products (version 4.0 – to be replaced)
Table 9-1 Trial products (protocol version 5.0 – to be inserted)
Updated text section 12.4.1
All technical complaints on any of the following products:
•Insulin degludec/liraglutide 100 units/mL + 3.6 mg/mL (IDegLira), 3 mL pre-filled PDS290 pen
•Insulin degludec 100 units/mL (IDeg), 3 mL pre-filled PDS290 pen
•Liraglutide (Victoza®) 6 mg/mL, 3 mL pre-filled pen injector
•Novo Nordisk needles for pre-filled pens
2.5
Affected section 6.4 Withdrawal criteria#5
Rationale: The week intervals for withdrawal criteria #5 are not clearly defined and not similar to 
Global DUAL I protocol; week 6 and 12 were included in two intervals.
Trial product (IMP)
Strength
Dosage form
Route of 
administration
Insulin 
degludec/liraglutide
100 units/mL +
3.6 mg/mL
Solution for 3 mL pre-
filled PDS290 pen
Subcutaneous injection
Insulin degludec
100 units/mL
Liraglutide (Victoza®)
6 mg/mL
Trial product (IMP)
Strength
Dosage form
Route of 
administration
Delivery device
Insulin 
degludec/liraglutide
100 units/mL +
3.6 mg/mL
Solution for 
injection
Subcutaneous 
injection
3 mL pre-filled 
PDS290 pen
Insulin degludec
100 units/mL
Solution for 
injection
3 mL pre-filled 
PDS290 pen
Liraglutide
6 mg/mL
Solution for 
injection
3 mL pre-filled 
Pen-injector
CONFIDENTIAL

Protocol Amendment
CONFIDENTIAL
Date:
05 December 2016
Novo Nordisk
Trial ID: NN9068-4148
Version:
1.0
UTN: U1111-1154-6671
Status:
Final
     
Page:
7 of 9
Updated text section 6.4 in protocol version 4.0:
1. If all pre-breakfast SMPG values taken on three consecutive days or if any FPG samples 
analysed by the central laboratory exceeds the limit of:
15.0 mmol/L after baseline to week 6
13.3 mmol/L from week 76 to week 12
11.1 mmol/L from week 132 to last week prior to end of treatment
and given there is no intercurrent cause for the hyperglycaemia, a confirmatory FPG must be 
performed  at the next scheduled visit, or if deemed necessary by the investigator at an unscheduled.
CONFIDENTIAL

Protocol Amendment
CONFIDENTIAL
Date:
05 December 2016
Novo Nordisk
Trial ID: NN9068-4148
Version:
1.0
UTN: U1111-1154-6671
Status:
Final
     
Page:
8 of 9
3
Changes to Subject information/informed consent form version 
4.0 dated 28-Sep-2016 
3.1
Affected section 1.7: Baseline antibody samples shipped from 
 to Novo 
Nordisk Måløv, Denmark
Rationale: To be aligned with the update in the protocol and to delete sentence about NN 
permission as the content is not meaningful and not applicable.
Updated section 1.7 Information about laboratory sampling and exportation:
In order to standardise the sample analysis used in this trial, all serum antibody samples, fasting 
insulin samples and insulin level samples including yours, will be shipped to special laboratories 
outside of China. The antibody samples will be shipped to 
, located in 
, and to 
Novo Nordisk, located in Denmark, for analysis , fFasting insulin samples and one of the insulin 
level samples will be shipped to 
, located in 
. The other insulin level sample 
will be shipped to 
, located in the 
. By involving only two three
special laboratories, comparability of results from subjects at all investigational sites involved in the 
trial will be ensured. 
Further, the serum antibody samples must only be used in relation to this trial, and all samples will 
be destroyed as biological/medical waste at 
and Novo Nordisk, after receiving marketing 
authorisation from the authorities and never shipped back to China.
Similarly, fasting insulin and insulin level samples will be destroyed as biological/medical waste at 
ands
no later than at the completion of the clinical trial report. The insulin 
level samples must only occur with permission from Novo Nordisk.
3.2
Affected section 3.3: Storage time for antibody samples 
Rationale: To be aligned with the update in the protocol.
Updated section 3.3 Will my participation in the trial be kept confidential?
Antibody samples will be stored until marketing authorisation approval or until the research 
project terminates. final feedback from the Chinese health authorities. but no longer than maximum 
15 years from end of trial.
3.3
Affected section 2.1: What are the possible risks if you participate in this trial
Rationale: Xultophy was approved by FDA on 21-Nov-2016. Adding this information to the SI/IC 
will ensure that patients receive the most updated safety information.
Updated section 2.1: What are the possible risks if you participate in this trial
CONFIDENTIAL

Protocol Amendment
CONFIDENTIAL
Date:
05 December 2016
Novo Nordisk
Trial ID: NN9068-4148
Version:
1.0
UTN: U1111-1154-6671
Status:
Final
     
Page:
9 of 9
You must inform the trial staff about any other medications (including over-the-counter drugs and 
herbal remedies) that you are using during the trial. If you are prescribed new medicines or start 
taking a new over-the-counter drug, you should inform the trial staff immediately.
IDegLira, which is approved in EU and US under the names Xultophy® and Xultophy® 100/3.6, 
respectively , is well tolerated. In the clinical development programme IDegLira did not show 
increased incidence of side effects compared to its two monocomponents, Tresiba® (insulin 
degludec) and Victoza® (liraglutide).
CONFIDENTIAL