A Trial Comparing the Efficacy and Safety of Insulin Degludec/Liraglutide and Insulin Degludec in Combination With Metformin in Chinese Subjects With Type 2 Diabetes Mellitus Inadequately Controlled With Basal Insulin Therapy and Metformin With or Without One Other OAD
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 
NCT03175120  
Sponsor trial ID: 
NN9068-4166 
Official title of study: 
A trial comparing the efficacy and safety of insulin 
degludec/liraglutide and insulin degludec in combination with 
metformin in Chinese subjects with type 2 diabetes mellitus 
inadequately controlled with basal insulin therapy and 
metformin ± one other OAD. DUAL™ II China 
Document date: 
04 December 2019 
 
 
 
 
 
 
Redacted protocol 
Includes redaction of personal identifiable information only. 
 
 
 
. 
 
 

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List of contents
Protocol - version 2.............................................................................................................................
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: NN9068-4166
Clinical Trial Report
Appendix 16.1.1
04 December 2019
1.0
Final
16.1.1 Protocol and protocol amendments
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Protocol
Trial ID: NN9068-4166
DUAL™ II China
A trial comparing the efficacy and safety of insulin degludec/liraglutide and insulin degludec in 
combination with metformin in Chinese subjects with type 2 diabetes mellitus inadequately 
controlled with basal insulin therapy and metformin ± one other OAD
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:
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Novo Nordisk
Trial ID: NN9068-4166
Version:
2.0
UTN:U1111-1154-6732
Status:
Final
Page:
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Table of Contents   
Page
Table of Contents..............................................................................................................................................2
Table of Figures................................................................................................................................................6
Table of Tables..................................................................................................................................................6
List of abbreviations.........................................................................................................................................7
1
Summary..................................................................................................................................................10
2
Flow chart ................................................................................................................................................14
3
Background information and rationale for the trial............................................................................17
3.1
Background information..............................................................................................................17
3.2
Rationale for the Trial..................................................................................................................17
4
Objectives and endpoints........................................................................................................................18
4.1
Objectives ....................................................................................................................................18
4.1.1
Primary objective.......................................................................................................18
4.1.2
Secondary objectives .................................................................................................18
4.2
Endpoints .....................................................................................................................................18
4.2.1
Primary endpoint........................................................................................................18
4.2.2
Secondary endpoints..................................................................................................18
4.2.2.1
Confirmatory secondary endpoints .....................................................18
4.2.2.2
Supportive secondary efficacy endpoints............................................19
4.2.2.3
Supportive secondary safety endpoints...............................................19
5
Trial design ..............................................................................................................................................21
5.1
Type of trial .................................................................................................................................21
5.2
Rationale for trial design..............................................................................................................22
5.3
Treatment of subjects...................................................................................................................22
5.4
Treatment in follow-up period.....................................................................................................23
5.5
Treatment after end of trial ..........................................................................................................23
5.6
Rationale for treatment ................................................................................................................23
6
Trial population.......................................................................................................................................25
6.1
Number of subjects......................................................................................................................25
6.2
Inclusion criteria ..........................................................................................................................25
6.3
Exclusion criteria.........................................................................................................................26
6.4
Withdrawal criteria ......................................................................................................................27
6.5
Subject replacement.....................................................................................................................28
6.6
Rationale for trial population.......................................................................................................28
7
Milestones.................................................................................................................................................29
8
Methods and assessments .......................................................................................................................30
8.1
Visit procedures...........................................................................................................................30
8.1.1
Fasting requirements for blood sampling ..................................................................30
8.1.2
Screening (Visit 1).....................................................................................................30
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8.1.3
Screening Failures......................................................................................................31
8.1.4
Randomisation (Visit 2).............................................................................................31
8.1.5
Treatment period (Visit 2 -Visit 33) ..........................................................................32
8.1.6
Follow-up visit (Visit 34) ..........................................................................................32
8.1.7
Unscheduled visit(s) ..................................................................................................32
8.1.8
Subject withdrawal ....................................................................................................33
8.2
Subject related information..........................................................................................................33
8.2.1
Demography...............................................................................................................33
8.2.2
Concomitant illness and medical history...................................................................33
8.2.3
Adverse events...........................................................................................................33
8.2.4
Diabetes complications and treatment history...........................................................34
8.2.5
Smoking habits ..........................................................................................................34
8.2.6
Concomitant medication............................................................................................34
8.2.7
Body measurements...................................................................................................34
8.2.8
Vital Signs (blood pressure and pulse) ......................................................................35
8.2.9
Physical Examination ................................................................................................35
8.2.10
Eye examination ........................................................................................................36
8.2.11
ECG ...........................................................................................................................36
8.2.12
Self-measured plasma glucose (SMPG) ....................................................................36
8.2.13
Self measured 9-point blood glucose profile .............................................................37
8.2.14
Hypoglycaemic episodes ...........................................................................................38
8.3
Laboratory assessments ...............................................................................................................39
8.3.1
Blood and urine sampling (central laboratory analysis) ............................................39
8.3.2
Calcitonin sampling (central laboratory analysis) .....................................................40
8.3.3
Antibodies sampling ..................................................................................................41
8.4
Pancreatitis...................................................................................................................................41
8.5
Thyroid disease............................................................................................................................41
8.6
Subject diaries..............................................................................................................................41
8.7
Subject compliance......................................................................................................................42
9
Trial supplies ...........................................................................................................................................43
9.1
Trial product ................................................................................................................................43
9.2
Non-Investigational Medicinal Product.......................................................................................43
9.3
Labelling......................................................................................................................................43
9.4
Storage .........................................................................................................................................44
9.5
Drug accountability and destruction............................................................................................44
9.6
Auxiliary supplies........................................................................................................................45
10 Interactive voice/web response system ..................................................................................................46
11 Randomisation procedure and breaking of blinded codes..................................................................47
11.1
Breaking of blinded codes ...........................................................................................................47
12 Adverse events, technical complaints, and pregnancies ......................................................................48
12.1
Definitions ...................................................................................................................................48
12.2
Reporting of adverse events.........................................................................................................51
12.3
Follow-up of adverse events........................................................................................................53
12.4
Technical complaints and technical complaint samples ..............................................................54
12.4.1
Reporting of technical complaints .............................................................................54
12.4.2
Collection, storage and shipment of technical complaint samples ............................55
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12.5
Pregnancies..................................................................................................................................56
12.5.1
Pregnancies in female subjects ..................................................................................56
12.6
Precautions and/or overdose ........................................................................................................57
12.7
Committees related to safety........................................................................................................58
12.7.1
Novo Nordisk safety committee ................................................................................58
12.7.2
Calcitonin monitoring committee ..............................................................................58
12.7.3
Event adjudication committee....................................................................................58
13 Case report forms....................................................................................................................................60
13.1
Corrections to case report forms..................................................................................................60
13.2
Case report form flow..................................................................................................................61
14 Monitoring procedures ...........................................................................................................................62
14.1
Source data verification and source data requirements................................................................62
15 Data management....................................................................................................................................63
16 Computerised systems.............................................................................................................................63
17 Statistical considerations ........................................................................................................................63
17.1
Sample size calculation................................................................................................................65
17.2
Definition of analysis sets............................................................................................................65
17.3
Primary endpoint..........................................................................................................................66
17.3.1
Sensitivity analysis ....................................................................................................67
17.4
Secondary endpoints....................................................................................................................67
17.4.1
Confirmatory secondary endpoints............................................................................67
17.4.2
Supportive secondary endpoints ................................................................................68
17.4.2.1
Efficacy endpoints...............................................................................68
17.4.2.2
Safety endpoints..................................................................................70
18 Ethics........................................................................................................................................................77
18.1
Informed consent .........................................................................................................................77
18.2
Data handling...............................................................................................................................78
18.3
Information to subject during trial...............................................................................................78
18.4
Premature termination of the trial and/or trial site.......................................................................78
19 Protocol compliance................................................................................................................................79
20 Audits and inspections ............................................................................................................................79
21 Critical documents ..................................................................................................................................80
22 Responsibilities........................................................................................................................................81
23 Reports and publications........................................................................................................................82
23.1
Communication of results............................................................................................................82
23.1.1
Authorship .................................................................................................................83
23.1.2
Site-specific publication(s) by investigator(s) ...........................................................83
23.2
Investigator access to data and review of results.........................................................................83
24 Retention of clinical trial documentation and human biospecimens..................................................84
24.1
Retention of clinical trial documentation.....................................................................................84
24.2
Retention of human biospecimens...............................................................................................84
25 Institutional Review Boards/Independent Ethics Committees and regulatory authorities..............85
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26 Indemnity statement ...............................................................................................................................86
27 References................................................................................................................................................87
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 – Global list of key staff and relevant departments and vendors
Attachment II – Country list of key staff and relevant departments
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Trial ID: NN9068-4166
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Table of Figures   
Page
Figure 5–1
Trial design.............................................................................................................................21
Figure 12–1
Initial reporting of AEs...........................................................................................................53
Figure 17–1
Novo Nordisk classification of hypoglycaemia......................................................................72
Figure 17–2
ADA classification of hypoglycaemia....................................................................................73
Table of Tables
Page
Table 9–1
Trial products..........................................................................................................................43
Table 9–2
Storage conditions for IMPs...................................................................................................44
Table 9–1
Trial products..........................................................................................................................43
Table 9–2
Storage conditions for IMPs...................................................................................................44
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Trial ID: NN9068-4166
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List of abbreviations
ADA
American Diabetes Association
AE
adverse event
AGI
α-glucose inhibitors
ALAT
alanine transaminase
ANCOVA
standard analysis of covariance 
ASAT
aspartate transaminase
BG
blood glucose
BMI
body mass index
CAS
completer analysis set
CRF
case report form
DPP-4
dipeptidyl peptidase-4 
DUN
dispensing unit number
EASD
European Association for the Study of Diabetes
ECG
electrocardiogram
eCRF
electronic case report form
EOT
end of treatment
FAS
full analysis set
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
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation 
IDeg
insulin degludec
IDegLira
insulin degludec/liraglutide
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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
MEN2
multiple endocrine neoplasia type 2
MESI
medical event of special interest
MMRM
mixed model for repeated measurement 
NYHA
New York Heart Association
OAD
oral anti-diabetic drug
OD
once daily
PP
per protocol
SAE
serious adverse event
SAS
safety analysis set 
SmPC
summary of product characteristics
SIF
safety information form
SMPG
self-measured plasma glucose
SU
sulphonylureas
SUSAR
suspected unexpected serious adverse reaction
T2DM
type 2 diabetes
TEAE
treatment emergent adverse event 
TMM
trial materials manual
TTT
treat-to-target
TZD
thiazolidinediones
U
Unit
UNR 
upper normal range 
UTN
universal trial number
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VLDL
very low-density lipoprotein
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1
Summary
Primary objective
To confirm the superiority of insulin degludec/liraglutide versus insulin degludec in controlling 
glycaemia in Chinese subjects with type 2 diabetes mellitus after 26 weeks of treatment.
Primary endpoint
Change from baseline in HbA1c after 26 weeks of treatment. 
Secondary objective
!
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 the overall efficacy and safety of insulin degludec/liraglutide to insulin 
degludec after 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
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Trial design
This is a 26 week, randomised, parallel two-arm, double-blind, multi-centre, treat-to-target trial in 
Chinese subjects with type 2 diabetes inadequately controlled with basal insulin therapy and 
metformin ± one other oral anti-diabetic agent: α-glucosidase inhibitors, sulphonylureas, glinides or 
thiazolidinediones.
Subjects will be randomised in a 2:1 manner to receive insulin degludec/liraglutide or insulin 
degludec once daily with metformin. The randomisation of subjects will be stratified with respect to 
their previous anti-diabetic treatment (basal insulin and metformin or basal insulin, metformin and
one other oral anti-diabetic agent).
The total trial duration for the individual subject will be approximately 29 weeks. 
Trial population:
A total of 450 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 procedures to determine suitability 
for the trial
!
Male or female, age ≥ 18 years at the time of signing inform consent
!
Type 2 diabetes mellitus (clinically diagnosed)
!
HbA1c ≥ 7.5% by central laboratory analysis, with the aim of a median of 8.5%. When 
approximately 50% of the randomised subjects have an HbA1c above 8.5%, the remaining 
subjects randomised must have an HbA1c below or equal to 8.5% or when approximately 50% 
of the subjects randomised have an HbA1c below or equal to 8.5%, the remaining subjects 
randomised must have an HbA1c above 8.5%
!
Current treatment for at least 90 calendar days prior to screening with basal insulin + metformin 
± α-glucosidase inhibitors, sulphonylureas, glinides or thiazolidinediones. Subjects should be on 
a stable dose for at least 60 calendar days prior to screening of: 
Basal insulin 20-50 units (U)/day (both inclusive)* on the day of screening in combination with
i. Metformin (≥1500 mg or max tolerated dose) or
ii. Metformin (≥1500 mg or max tolerated dose) and sulphonylureas (≥half of 
the max approved dose according to local label) or
iii. Metformin (≥1500 mg or max tolerated dose) and glinide (≥half of the max 
approved dose according to local label) or
iv. Metformin (≥1500 mg or max tolerated dose) and α-glucosidase inhibitors 
(AGI) (≥half of the max approved dose according to local label) or
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v. Metformin (≥1500 mg or max tolerated dose) and thiazolidinediones (≥half 
of the max approved dose according to local label)
*Individual fluctuations of ± 5U during the 60 day period prior to the day of screening are 
acceptable
!
Body mass index (BMI) ≥24 kg/m2
Key exclusion criteria
!
Current use of any anti-diabetic drug (except for basal insulin, metformin, α-glucosidase 
inhibitors, sulphonylureas, glinides or thiazolidinediones) or anticipated change in concomitant 
medication, that in the investigator´s opinion could interfere with glucose level (e.g. systemic 
corticosteroids)
!
Treatment with glucagon like peptide -1 receptor agonists, or dipeptidyl peptidase -4 inhibitors 
or insulin (except for basal insulin) within 90 days prior to Visit 1
!
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 (MTC) 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
!
Severe uncontrolled treated or untreated hypertension (systolic blood pressure ≥180 mm Hg or 
diastolic blood pressure ≥100 mm Hg)
!
Proliferative retinopathy or maculopathy (macular oedema) requiring acute treatment
!
History of pancreatitis (acute or chronic)
Key efficacy assessments
!
HbA1c
!
Weight
!
Fasting plasma glucose
Key safety assessments
!
Hypoglycaemic episodes
!
Adverse events
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Trial product(s)
The trial products for subcutaneous injection in the 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
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EudraCT no.:
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2
Flow chart
Screening (S)
Randomisation (R)
Visit (V)
Telephone contact (T)
Follow up visit (FU)
S
R
T
V
T
V
T
V
T
V
T
V
T
V
T
V
T
V
FU
Visit/Contact 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
30
31
32
33
34
Timing of visit (weeks)1
- 22
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
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)
±1
±1
±1
±1
±1
±1
±1
±3
±3
±3
±3
±3
±3
±3
±3
±3
+3
SUBJECT RELATED INFO/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
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
X
X
Smoking Habits
X
X
Demography
X
Diagnosis of diabetes
X
Diabetes treatment history
X
Family history of diabetes
X
Diabetes complications
X
Body measurements
Height
X
Body weight
X
X
X
X
X
X
X
X
BMI
X
X
Waist circumference
X
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
Self measured plasma 
glucose
9-point profile
X
X
X
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Protocol
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Status:
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EudraCT no.:
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Screening (S)
Randomisation (R)
Visit (V)
Telephone contact (T)
Follow up visit (FU)
S
R
T
V
T
V
T
V
T
V
T
V
T
V
T
V
T
V
FU
Visit/Contact 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
30
31
32
33
34
Timing of visit (weeks)1
- 22
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
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)
±1
±1
±1
±1
±1
±1
±1
±3
±3
±3
±3
±3
±3
±3
±3
±3
+3
Once daily
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SAFETY
Adverse events 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Technical complaints
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hypoglycaemic episodes
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECG
X3
X4
Eye examination
X5
X6
Physical examination
X
X
Vital signs
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 7
X
X
TRIAL MATERIAL
IV/WRS call 
X
X
X
X
X
X
X
X
Administration of trial 
product
X
X
X
X
X
X
Drug accountability 
X
X
X
X
X
X
X
REMINDERS
Hand out ID card
X
Handout and instruct in 
BG meter use
X
Training in trial product 
and pen handling 
X
Attend visit fasting
X
X
X
X
X
X
X
X8
Hand out and instruct in
diary
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
Dose of trial product to be 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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Protocol
CONFIDENTIAL
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Trial ID: NN9068-4166
Version:
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Screening (S)
Randomisation (R)
Visit (V)
Telephone contact (T)
Follow up visit (FU)
S
R
T
V
T
V
T
V
T
V
T
V
T
V
T
V
T
V
FU
Visit/Contact 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
30
31
32
33
34
Timing of visit (weeks)1
- 22
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
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)
±1
±1
±1
±1
±1
±1
±1
±3
±3
±3
±3
±3
±3
±3
±3
±3
+3
taken after titration 
Confirmation of 
unchanged metformin 
dose
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
End of trial and sign off 
case book
X
1 A 0.5 week interval is corresponding to previous visit plus three calendar days
2 Screening must take place within 14 calendar days prior to randomisation
3 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
4 ECG obtained within 14 calendar days prior to Visit 33 is acceptable, if the results are available for evaluation at Visit 33. See section 8.2.11
5 Eye examination performed within 90 calendar days prior to visit 2 as part of routine practise may replace the screening assessment if results are 
available for Visit 2. See section 8.2.10
6 Eye examination performed within 14 calendar days prior to Visit 33 is acceptable, if the results are available for evaluation at Visit 33. See section 
8.2.10
7 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 period at a phone contact, the subject must attend the site for an unscheduled visit as soon as possible to have 
a urine pregnancy test done. If positive a confirmatory serum hCG test should be sent to the central laboratory
8 For fasting requirements prior to Visit 34 see section 8.1.6
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3
Background information and rationale for the trial
The trial will be conducted in compliance with this protocol, ICH GCP1 and applicable regulatory 
requirements, and in accordance with the Declaration of Helsinki2 . In 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 
diabetes 3 4 . Given the progressive nature of T2DM, current anti-diabetic therapies, including 
treatment with basal insulin in combination 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 and American Diabetes Association (ADA)/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 progresses 5 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 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 human 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 confirmatory trial will be used for registration purposes in China to document the efficacy and 
safety of treatment with IDegLira OD in combination with metformin in Chinese subjects with 
T2DM. For detailed information on IDeg or IdegLira, see the Investigator´s Brochure, any updates 
hereof, and/or SmPC, as applicable. 
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4
Objectives and endpoints
4.1
Objectives
4.1.1
Primary objective 
To confirm the superiority of IDegLira versus IDeg in controlling glycaemia in Chinese subjects 
with T2DM after 26 weeks of treatment.
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. 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 the overall efficacy and safety of IDegLira to IDeg after 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
!
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
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 efficacy endpoints
!Insulin dose after 26 weeks of treatment
!Responder for HbA1c after 26 weeks of treatment (Yes/No)
o
HbA1c < 7.0%
o
HbA1c ≤ 6.5% 
o
HbA1c < 7.0% and change from baseline in body weight below or equal to zero
o
HbA1c ≤ 6.5% and change from baseline in body weight below or equal to zero
o
HbA1c <7.0% without severe or blood glucose (BG) confirmed hypoglycaemic episodes 
during the last 12 weeks of treatment
o
HbA1c ≤ 6.5% without severe or BG confirmed hypoglycaemic episodes during the last 12 
weeks of treatment
o
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
o
HbA1c ≤ 6.5% of treatment 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:
o
Fasting plasma glucose (FPG)
o
Waist circumference
o
Mean of the 9-point profile
!Mean post prandial increment (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 
incrementsFasting 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
4.2.2.3
Supportive secondary safety endpoints
!
Number of treatment emergent adverse events (TEAEs) during 26 weeks of treatment
!
Number of treatment emergent nocturnal severe or blood glucose (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
!
Number of treatment emergent hypoglycaemic episodes according to ADA definition
!
Change from baseline in clinical evaluations after 26 weeks of treatment
o
Physical examination
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o
Fundoscopy or fundus photography
o
Electrocardiogram (ECG)
o
Pulse
o
Blood pressure
!Change from baseline in laboratory assessments during 26 weeks of treatment
o
Biochemistry
o
Haematology 
o
Calcitonin
!Urinalysis (dipstick for erythrocytes, protein, glucose and ketones)
!Antibodies towards trial product
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5
Trial design
5.1
Type of trial
This is a 26 week, randomised, parallel two-arm, double-blind, multi-centre, treat-to-target (TTT)
trial in Chinese subjects with T2DM inadequately controlled with basal insulin therapy and 
metformin ± one other OAD: α-glucosidase inhibitors (AGI), sulphonylureas (SU), glinides or
thiazolidinediones (TZD). Inadequately controlled diabetes will be defined as HbA1c level of ≥ 
7.5%.
Subjects will be randomised in a 2:1 manner, using a centralised allocation via interactive 
voice/web response system (IV/WRS) to receive IDegLira or IDeg both once daily in combination 
with metformin. Other pre-trial OAD treatment will be discontinued at randomisation. Subjects will 
be stratified with respect to their previous anti-diabetic treatment (basal insulin and metformin or 
basal insulin, metformin and one other OAD).
A total of 450 subjects will be randomised.
The duration of the trial from screening (Visit 1) to follow-up (Visit 34) will be 29 weeks with 
treatment duration of 26 weeks. The trial will include a screening visit (Visit 1) at which the 
eligibility of the subjects is determined followed by randomisation (Visit 2). The follow-up (Visit 
34) will be conducted 1 week after end of treatment. 
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. 
The current trial is designed to demonstrate superiority in HbA1c of IDegLira as compared to IDeg 
in subjects with T2DM. To enable an evaluation of the contribution of the liraglutide component of
IDegLira to glycaemic control and secondary endpoints, the maximum dose of the IDeg in the IDeg 
arm is set to 50 units (U), i.e. equivalent to the maximum dose of the IDeg component with 
IDegLira. 
A double-blind design is feasible due to the similar titration and will limit the occurrence of 
conscious and unconscious bias in the conduct and the interpretation of this trial arising from the 
influence which the knowledge of treatment may have on the subjects case, the attitudes of subjects 
to the treatment, the assessment of endpoints, the handling of withdrawals, the exclusion of data 
from the analysis etc.
To obtain improved HbA1c results to allow for a valid comparison of safety endpoints the TTT
approach has been chosen in order to ensure optimal treatment with frequent visits and titration of 
IDegLira and IDeg based on pre-breakfast self-measured plasma glucose (SMPG) values. 
5.3
Treatment of subjects
Subjects with T2DM treated with basal insulin and metformin with or without one additional OAD 
(AGI, SU, glinides orTZD) in accordance with the inclusion criterionare eligible for the trial. At 
randomisation basal insulin andOADs except for metformin will be discontinued. Subjects will 
receive IDegLira or IDeg subcutaneous once daily in combination withmetforminfor the treatment 
duration of 26 weeks. 
Because of blinding during conduct of the trial a common terminology for both trial products have 
been chosen to be dose steps, thus one dose step corresponds to either 1 unit of IDeg or 1 dose step 
of IDegLira (1 unitinsulindegludec/0.036 mg liraglutide). IDegLira and IDeg added to current 
metformin therapywill be given subcutaneously once daily. The starting dose of IDegLira is 16 
dose steps (16 units insulin degludec /0.6 mg liraglutide)and starting dose of IDeg is 16 units. 
The dose of IDegLira and IDeg willthereafterbe titrated twice weekly according to the Titration 
guideline(Appendix A).
The treatment with metformin will be continued withpre-trial dose. 
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5.4
Treatment in follow-up period
After 26 weeks of trial product exposure, a 1 week interval between the end of treatment (Visit 33) 
and the follow-up (Visit 34) is necessary to allow for trial product wash out. Subjects should in this 
period be transferred to any other anti-diabetic treatment at the discretion of the investigator. 
However, treatment with IDeg, insulin detemir (Levemir ®) or any GLP-1 receptor agonist is not
permitted in the periods from the end of trial (Visit 33) to the follow up (Visit 34) due to the 
inference with the antibody measurements performed at Visit 34. If the subject refuses to come in 
for the follow up (Visit 34), the subject will be switched to a suitable marketed product as 
recommended by the investigator.
5.5
Treatment after end of trial
When completing the trial the subject should be switched to a suitable marketed product at the 
discretion of the investigator.
5.6
Rationale for treatment
Subjects will be treated with IDegLira or IDeg in order to demonstrate the efficacy and safety of 
IDegLira.
IDeg has been included as comparator in order to demonstrate a clinical benefit in terms of HbA1c
reduction of the fixed combination product as compared to this individual component. Given a TTT 
approach, the objective can only be achieved by capping the IDeg dose at 50U, leading to insulin 
dose equivalence in the two treatment arms, allowing a differentiation between the treatment arms 
based on the additional effects of the liraglutide component of IDegLira.
Start dose is 16 dose steps of IDeglira (16 units insulin degludec and 0,6 mg liraglutide) and IDeg 
(16 units insulin degludec) respectively. Due to the liraglutide component in IDegLira, the highest 
tolerable initiation dose of GLP-1 receptor agonist in GLP-1 naïve subjects is 16 dose steps (0.6 mg 
liraglutide, corresponding to maximum initial dose of liraglutide). 
In order to obtain differentiation between the two treatment arms as reflected in the liraglutide 
component of the combination, the highest dose at end of trial is pursued. Therefore, T2DM
subjects already treated – and inadequately controlled - with basal insulin are included to increase 
the chance of high dose at end of trial (i.e. approaching 50U or 50 dose steps). Pre-trial basal insulin 
therapy (treatment for at least 90 days and a total daily dose within the range of 20-50U, individual 
fluctuations of ∀5U within the 60 days prior to screening but not on the day of screening) will be 
discontinued at randomisation.
The current treatment cascade by the Chinese Diabetes Society and ADA/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 oral 
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anti-diabetic drugs (OADs), glucagon-like peptide 1 (GLP-1) receptor agonists or insulin as the 
disease progresses 5 6. Accordingly, the subjects will be on a background treatment including 
metformin in the present trial. The daily dose for metformin (# 1500 mg or maximum tolerated 
dose) is close to the maximum recommended dose for the treatment of T2DM according to local 
label. 
Subjects treated with AGI, SU, glinides or TZD will have this therapy discontinued at 
randomisation.
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6
Trial population
6.1
Number of subjects 
Country planned to participate: China
Number of subjects planned to be screened: 750
Number of subjects planned to be randomised: 450 (40% screening failure rate)
Number of subjects expected to complete the trial: 382 (withdrawal rate of 15%)
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 inform consent
3. Type 2 diabetes mellitus (clinically diagnosed)
4. HbA1c ≥ 7.5% by central laboratory analysis, with the aim of a median of 8.5%. When 
approximately 50% of the randomised subjects have an HbA1c above 8.5%, the remaining 
subjects must have an HbA1c of below or equal to 8.5% or when approximately 50% of the 
randomised subjects have an HbA1c below or equal to 8.5%, the remaining subjects 
randomised must have a HbA1c above 8.5%
5. Current treatment for at least 90 calendar days prior to screening with basal insulin + 
metformin ± AGI, SU, glinides and TZD. Subjects should be on a stable dose for at least 60 
calendar days prior to screening of: 
Basal insulin 20-50 U /day (both inclusive)* on the day of screening in combination with:
i. Metformin (≥1500 mg or max tolerated dose) or
ii. Metformin (≥1500 mg or max tolerated dose) and SU (≥half of the max 
approved dose according to local label) or
iii. Metformin (≥1500 mg or max tolerated dose) and glinide (≥half of the max 
approved dose according to local label) or
iv. Metformin (≥1500 mg or max tolerated dose) and AGI (≥half of the max 
approved dose according to local label) or
v. Metformin (≥1500 mg or max tolerated dose) and TZD (≥half of the max 
approved dose according to local label)
*Individual fluctuations of ± 5U during the 60 day period prior to the day of screening are 
acceptable
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6. Body mass index (BMI) ≥24 kg/m2
7. Able and willing to adhere to the protocol including performing self-monitoring of plasma 
glucose profiles, keeping a trial diary and to 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 before Visit 1
5. Current use of any anti-diabetic drug (except for basal insulin, AGI, SU, glinides and 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 GLP-1 receptor agonists, or DPP-4 inhibitors or insulin (except for basal 
insulin) within 90 days prior to Visit 1
8. Impaired liver function defined as alanine aminotransferase (ALAT) ≥ 2.5 times upper 
normal range (UNR)
9. Impaired renal function defined as serum-creatinine ≥133μmol/L (1.5 mg/dL) for males and 
≥125 μmol/L (1.4 mg/dL) for females, or as defined according to local contraindications for 
metformin
10. Screening calcitonin ≥ 50 ng/L
11. Personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine 
neoplasia type 2 (MEN2)
12. 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 period to screening and/or planned coronary, carotid or peripheral artery 
revascularisation procedures
13. Severe uncontrolled treated or untreated hypertension (systolic blood pressure ≥180 mm Hg 
or diastolic blood pressure ≥100 mm Hg)
14. Proliferative retinopathy or maculopathy (macular oedema) requiring acute treatment
15. Subject with a clinically significant, active (during the past 12 months) disease of the 
gastrointestinal, pulmonary, endocrinological (except for T2DM), neurological, 
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genitourinary or haematological system (except for conditions associated with T2DM) that 
in the opinion of the investigator may confound compliance and the results of the trial or 
pose additional risk in administering trial drug
16. Mental incapacity, unwillingness or language barrier precluding adequate understanding of 
the trial procedure or cooperation with the trial site personnel
17. Known or suspected abuse of alcohol or narcotics
18. History of  pancreatitis (acute or chronic)
19. Suffer from a life threatening disease including malignant neoplasms and medical history of 
malignant neoplasms and medical history of 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 providing an 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.
The subject must be withdrawn if the following applies:
1. Included 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 cortecoidsteroids)
5. If all  pre-breakfast SMPG values taken on three consecutive days or if any fasting plasma 
glucose (FPG) samples analysed by the central laboratory exceed 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 visit 
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. Subject must be withdrawn if diagnosed with acute pancreatitis must as a 
minimum have 2 out of 3: 
1. characteristic findings on ultrasound/computed axial tomography (CT)/magnetic 
resonance imaging (MRI)
2. characteristic abdominal pain
3. amylase and/or lipase >3x UNR
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6.5
Subject replacement
Subjects who are withdrawn will not be replaced.
6.6
Rationale for trial population
Subjects with T2DM on previous basal insulin therapy in need of treatment intensification (HbA1c≥ 
7.5%) to achieve glycaemic control are the target population for inclusion in this trial. 
Subjects should be on a stable insulin dose with basal insulin 20-50U/day (both inclusive, 
individual fluctuations of ± 5Uare acceptablebut not on the day of screening) for at least 60 days 
prior to screening and should be overweight (BMI ≥24 kg/m2) to ensure inclusion of subjects in 
which a high dose at the end of the trial can be expected. The rationale for including subjects on 
metformin with orwithout AGI, SU, glinides and TZDis to mimic common practise of diabetes 
treatment in subjects with T2DM failing on 1-2 OAD´s. When glycaemic control is not achieved or 
sustained on this background, the addition ofIDegLira can be considered.
The HbA1crange has been 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 median 
baseline HbA1clevel of 8.5% has been chosen to ensure to ensure somepatients in the study will be 
treated with the dose between 40-50 dosesteps.
Only serious concomitant conditions (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 the trial. 
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7
Milestones
Planned duration of recruitment period (first subject first visit - last subject last visit):
approximately 54 weeks. End of trial is defined as last subject last visit.
Recruitment will be performed according to an arrangement 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, agreed distribution of subjects between sites may be changed. 
The screening and randomisation rate will be followed closely via the IV/WRS in order to estimate 
when to stop screening. 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 Editors8, the Food and Drug Administration 
Amendment Act 9, European Commission Regulation for EudraCT 10 and other relevant 
recommendations or regulations. If a subject requests to be included in the trial via the Novo 
Nordisk e-mail contact at these web sites, Novo Nordisk may disclose the investigator's contact 
details to the subject. As a result of increasing requirements for transparency, some countries 
require public disclosure of investigator names and their affiliations.
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Version:
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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 describe in more details. 
The investigator must keep a subject screening log, a subject identification code list and a subject 
enrolment log. The subject screening log and subject enrolment log may be combined in one list. 
8.1.1
Fasting requirements for blood sampling
As outlined in the flow chart subject must attend most of the visits fasting, i.e. at least eight hours 
without food and drink intake, except for water and any other prescribed medication. Trial products 
and metformin should be withheld on the day of the visit until blood sampling and body weight (if 
applicable) has been performed. Any other prescribed medication should be taken as usual. If the 
subject attend the site in a non-fasting state the blood sampling should be re-scheduled, see section 
8.1.7 for instructions. 
See section 8.1.6 for special requirements in relation to fasting prior to the follow up (Visit 34). 
8.1.2
Screening (Visit 1)
Must take place within 14 calendar days prior randomisation. 
Before screening, the Investigator must provide the subject 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 the subjects will be assigned a unique number which will remain the same throughout 
the trial. This number will be registered in the IV/WRS which will be used for screening,
randomisation and allocation of trial product to each subject throughout the trial (see section 9.5 and 
section 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 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 visit or destroy the card after the last visit. 
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 
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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, see section 8.1.3 how to 
screen fail the subject.
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 that will be reviewed by the 
investigator at all site visits/telephone contacts. See section 8.6 for source data to be captured in the 
diaries. 
Subjects will be provided with a BG meter for use throughout the trial. 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 to the electronic case 
report form (eCRF). Only serious adverse events (SAEs) from screening failures must be 
transcribed by the investigator into the eCRF. Follow-up of SAEs must be carried out according to 
section 12.3. 
Screening failures experiencing an adverse event (AE) that would otherwise qualify 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 the current insulin and OAD treatment andremain 
only on metformin. Subjects will then be randomised to receive IDegLira orIDeg in combination 
with metformin. See the Titration Guideline (Appendix A) for start doses and titration of 
randomised treatment. The dose of metformin should remain unchanged throughout the trial.
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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 subjects should demonstrate to the investigator, that they can use the pens correctly prior to 
leaving the site. Sites should, as necessary, repeat the directions for use to the subject at subsequent 
visits.
8.1.5
Treatment period (Visit 2 -Visit 33)
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.
A telephone contact may be changed into a site visit if needed. It is the responsibility of the 
investigator to ensure that the contact regardless of the format takes place.
At the end of treatment (Visit 33) subjects will be switched from trial product to an appropriate anti-
diabetic treatment at the discretion of the investigator. However, IDeg, insulin detemir (Levemir®) 
and any GLP-1 receptor agonists are not allowed, since they may interfere with antibodies 
measured at follow-up (Visit 34). 
8.1.6
Follow-up visit (Visit 34)
Due to the long half-life of IDeg, the procedures of the follow-up visit should be undertaken no 
earlier than 7 calendar days after Visit 33. 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 Visit 34 the subjects may be switched to any other suitable marketed product at the investigator’s 
discretion.
8.1.7
Unscheduled visit(s)
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)
For all of the above an unscheduled visit form must be completed in the eCRF, indicating the reason 
for the visit. 
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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, 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 for Visit 33 and 34 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 CRF.
8.2
Subject related information 
8.2.1
Demography
Demography 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 other) 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.
8.2.3
Adverse events
AE´s will be recorded throughout the trial in accordance with the procedure described in section 12.
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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 habits must be recorded at Visit 1 and Visit 33. 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 33.
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 to 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 recorded in the eCRF. 
If a change in concomitant medication 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 the nearest cm.
Body weight
Body weight should be measured without shoes and only wearing light clothing in kilograms (kg) 
with one decimal. The measurements are to be performed in a fasting state, except for the screening 
(Visit 1). Body weight should be assessed on the same equipment throughout the trial, if possible. 
Body Mass Index (BMI)
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Body mass index will be automatically calculated in the eCRF once height and weight are entered. 
At the Visit 1 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 circumference located midway 
between the lower rib margin and the iliac crest. 
Three consecutive measurements of waist circumference should be taken and recorded in the eCRF. 
The waist circumference will be measured to the nearest 0.5 cm using a non-stretchable measuring 
tape (will be provided to the site by Novo Nordisk). 
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 skin but not compress soft tissue and twists in the tape should be 
avoided. The subject should be asked to breathe normally and the measurement should be taken 
when the subject is breathing out gently. 
8.2.8
Vital Signs (blood pressure and pulse)
The measurement of systolic, diastolic blood pressure and pulse (beats per minute) should be 
assessed while the subject is in a sitting position and after 5 minutes of rest. 
Blood pressure must be measured three times and all three values must be entered to the eCRF. The 
mean value will be calculated by the eCRF and must be in accordance with the relevant exclusion 
criteria (see section 6.3).
If the investigator suspects white coat hypertension at Visit 1 and/or Visit 2, one re-assessment of 
the systolic and diastolic blood pressure (as described above) is allowed. 
8.2.9
Physical Examination
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
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The investigator must interpret if the results are “normal” or “abnormal”, and if “abnormal” 
whether the abnormality is “not clinically significant” or “clinically significant”.
8.2.10
Eye examination 
Eye examination (a fundoscopy or fundusphotography) must be performed by the investigator, a 
local ophthalmologist or an optometrist according to local practise. Dilation is not a requirement.
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 last 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 33 the procedure 
does not need to be repeated, if the results are available for evaluation at Visit 33 and no worsening 
of visual function since the last examination has occurred.
For all eye examinations the investigator must interpret if the results are “normal” or “abnormal”, 
and if “abnormal” whether the abnormality is “not clinically significant” or “clinically significant”. 
The investigator must sign and date the eye examination results to verify the review. 
8.2.11
ECG 
A 12-lead ECG must be performed as part of screening procedures so that results are available at 
Visit 2 prior to randomisation.
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 within14 calendar days prior to Visit 33 is acceptable, if the results are 
available for evaluation at Visit 33.
The investigator must interpret if the results are “normal” or “abnormal”, and if “abnormal” 
whether the abnormality is “not clinically significant” or “clinically significant”. The investigator 
must sign and date the ECG to verify the review.
8.2.12
Self-measured plasma glucose (SMPG)
At the screening visit, subjects will be provided with a blood glucose (BG) meter which must be 
used for all measurements during the trial. The subject should be supplied with oral and written 
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Trial ID: NN9068-4166
Version:
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directions for use of the device including the performance of regular calibrations according to the 
manufacturer’s instructions. Sites should, as necessary, repeat the directions for use to the subject at 
subsequent visits. 
The BG meters use test strips calibrated to plasma glucose value. 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 self-measured plasma 
glucose (SMPG)values. 
Subjects should beinstructed how to record the values in the provided diaries and should only 
record the SMPG values based on measurements obtained with the provided BG meter. The 
recording of each measurement should include dateand value. 
Once daily SMPG valuesshould be obtainedfasting before breakfast. Diabetes medication should 
be withheld until after the measurement.
For telephone contacts the investigator or delegated site staff must transcribe the data used for the 
titration into the eCRF during/after the telephone contact. See Appendix A.  
8.2.13
Self measured 9-point blood glucose profile
Subjects will be instructed to perform measurements and record the SMPG values for a 9-point 
SMPG profile within one week prior to the site Visit 2, 19 and 33 on days where the subject does 
not anticipate unusual strenuous exercise. Anti-diabetic medication should be withheld until after 
the SMPG values have been obtained from the pre-breakfast measurement. 
The SMPG values should recorded in the diary (including actual clock time and date for the 
measurement) at the following time points, always starting with the measurement just 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
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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 34. 
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 and time and dose of last trial product administration (or other anti-diabetic treatment) 
prior to episode 
!
Type of last administered product (trial product or other anti-diabetic treatment) prior to the 
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" if oral 
carbohydrates, glucagon or IV glucose had to be administered to the subject by another person. 
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 11.
If the question "Was subject able to treat him/herself?" is answered "No", the following information 
should be recorded:
!
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)
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!
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 insulin 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 and storage of samples and 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
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 is retained at the investigator’s 
site as source documentation. Laboratory results will be sent by the central laboratory to the 
investigator on an ongoing basis. 
The central laboratory equipment may provide analysis not requested in the protocol but produced 
automatically in connection with the requested analyses. Such data will not be transferred to the 
trial database but may be reported to the investigator according to specifications in the laboratory 
standard operating procedures and requirements. The investigator must review all laboratory results 
for concomitant illnesses and AEs and report these according to this protocol.
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Blood sampling will be performed on subjects throughout the trial to determine levels of the 
following efficacy and safety parameters: 
Efficacy parameters
Glucose metabolism: HbA1c, FPG, Fasting insulin, Fasting glucagon, Fasting C-peptide and
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 dip stick
*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 hCG test should be sent to the central laboratory. 
Blood samples analysed at the central laboratory will be analysed and destroyed on an ongoing 
basis.
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 (CMC) of thyroid experts. The CMC will provide guidance to the investigator with 
regards to treatment and further investigations. If a subject is screen failed for other reasons than 
calcitonin exclusion criterion # 10 (calcitonin ≥ 50 ng/L), but has a value of calcitonin ≥10 ng/L, it 
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is recommended that they are referred to a thyroid expert for further evaluation.For details see 
Appendix D.
8.3.3
Antibodies sampling
Blood samples will be drawn as per flow chart (section 2) 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 34 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 sampling assessment should be performed prior to administering trial 
product. 
Antibody results will not be provided to the investigator as these results will not be used for any 
clinical evaluation during the trial. Instead they will be included in an analytical report after end of 
trial and retained at Novo Nordisk. For storage of blood samples used for the analysis of antibodies 
see section 24.2.
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 the subject 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 site as source data in accordance 
with section 14.1. From hand out 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. 
!
Date and dose of first trial product
!
Date and dose of last trial product
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!
Daily pre-breakfast SMPG values. See section 8.2.12
!
Last dose of last trial product taken prior to titration
!
New dose to be taken after titration
!
9-point SMPG profile, see section 8.2.13
!
Any AEs, hypoglycaemic episodes and changes in concomitant medication since last site
visit/telephone contact.
Based on the SMPG values the investigator/subject will assess whether the trial product dose needs 
adjustment according the Titration Guideline (see AppendixA).
The completed diary must be reviewed by the investigator to ensure that AEs, including any overall 
changes in health, and concomitant medication is reported. The review of the diary must be 
documented either on the front page of the diary and/or in the subjects medical records.
The investigator must transcribe data from the diary into the eCRF after each site visit or telephone
contactaccording 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records. 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. 
If a subject is found to be non-compliant, the investigator will remind the subject of the importance 
of following the instructions given including taking the trial products as prescribed. Substantial
failure to comply with the prescribed trial product 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 (TMM). 
Trial products 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 product
The following trial products are 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 in pre-
filled pen
subcutaneous
injection
Insulin degludec
100 units/mL
The insulin degludec/liraglutide and insulin degludec solutions are visually identical.
9.2
Non-Investigational Medicinal Product
Metformin is Non-Investigational Medicinal Product and is not considered trial product. Metformin 
will not be provided by Novo Nordisk. 
9.3
Labelling
IMPs will be packaged and labelled by Novo Nordisk A/S, and provided in non-subject specific 
boxes. Labelling of the trial products will be in accordance with Annex 1313, local regulations and 
trial requirements.
Each investigator site will be supplied with sufficient trial products for the trial on an on-going basis 
controlled by the IV/WRS. Dispensing units will be distributed to the sites according to enrolment 
and randomisation. Please refer to the IV/WRS user guidelines provided for detailed instructions of 
the IV/WRS. 
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Subjects will be provided with directions for use for the pre-filled pens by the investigator at each 
dispensing visit according the flow chart in section 2. The investigator must document that direction 
for use is given to the subject orally and/or in writing at each dispensing visit.
9.4
Storage 
The trial products must be stored according the storage conditions described below.
Table 9–2
Storage conditions for IMPs
Trial product
Storage 
conditions
(not-in-use)
In-use conditions
In-use time*
Insulin degludec/liraglutide 
Store in 
refrigerator (2°C 
to 8°C)
Do not freeze
Protect from light
Do not 
refrigerate.
Store below 30∃C
Protect from light
Use within 3 
weeks
Insulin degludec
* In-use time starts when first dose is taken
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.
9.5
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 (DUNs) 
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 must ensure: 
!
The correct DUN(s) are dispensed to the subject
!
The dispense date for any dispensed DUN should be confirmed in the IV/WRS drug 
accountability module after each dispensing
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!
Drug accountability is performed using the IV/WRS drug accountability module. Only 
dispensed DUNs returned by the subject (used/ partly used or returned unused) is accounted 
for
!
Subjects are instructed to return all used, partly used and unused trial products including 
empty packaging material at each dispensing visit. Returned trial product (used/partly used 
or unused including empty packaging material) trial product can be stored at room
temperature and must be stored separately from non-allocated trial product
Destruction will be done according to local procedures after accountability is finalised and verified 
by the monitor. Destruction of products must be documented.
9.6
Auxiliary supplies
The following auxiliary supplies will be provided by Novo Nordisk: 
!
Directions for use
!
Needles for pre-filled 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 which can be accessed at any time via the internet or 
telephone. Access to the IV/WRS must be restricted to and controlled by authorised persons. 
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 a 
sufficient amount of trial product 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
!
Withdrawal
!
Completion
!
Code break
!
Drug accountability
!
Data change
IV/WRS user manuals will be provided to each trial site.
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11 Randomisation procedure and breaking of blinded codes
Randomisation will be done using the IV/WRS at Visit 2. The trial is a double-blinded trial. 
Randomisation will be carried out in a 2:1 manner and the subject will be assigned to one of the two 
treatment arms:
!
IDegLira
!
IDeg
Subjects will be stratified with respect to their previous anti-diabetic treatment (basal insulin and
metformin or basal insulin, metformin ± oneother OAD). 
When randomising subjects the IV/WRS is also used to ensure a trial population with a median 
HbA1clevelof 8.5%. When the number of subjects with an HbA1cbelow or equal to 8.5% reach 
50% of the required numberof subjects to be randomised, it will only be possible to randomise 
subjects with an HbA1cabove 8.5%and vice versa. The distribution of subjects having an HbA1c
above or below 8.5%will be followedclosely and investigators will be notified in due time before 
randomisation is closed. 
All investigators will be notified immediately when the recruitment period ends, after which no 
further subjects may be screened and the IV/WRS will be closed for further screening. All subjects 
included in the screening period and eligible for randomisation will be randomised.
11.1
Breaking of blinded codes
The IV/WRS will notify Novo Nordisk (monitor and the Global Safety department) immediately 
after the code is broken.
The code for a particular subject may be broken in a medical emergency if knowing the actual 
treatment would influence the treatment of the subject. Whenever a code is broken the person 
breaking the code must print the Code Break Confirmation Notification generated by the IV/WRS, 
record the reason, and sign and date the document.
When the code is broken, the treatment allocation will be accessible to the investigator and the 
Novo Nordisk Global Safety department.If IV/WRS is not accessible at the time of code break the 
IV/WRS vendor helpdesk should be contacted. Contact details are listed in Attachment I.
If the code has been broken the subject must be withdrawn and a withdrawal session must be 
completed in IV/WRS.
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12 Adverse events, technical complaints, and pregnancies
12.1
Definitions
Adverse event 
An adverse event (AE) is any untoward medical occurrence in a subject administered a product, and 
which does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom or disease temporally associated with the use of a product, whether or not 
considered related to the product. 
An AE includes:
!
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 an AE:
!
Severity assessment
–
Mild - no or transient symptoms, no interference with the subject's daily activities.
–
Moderate - marked symptoms, moderate interference with the subject's daily activities.
–
Severe - considerable interference with the subject's daily activities; unacceptable.
!
Causality assessment
The following terms are used when assessing the relationship between an AE and the relevant 
trial product(s): 
–
Probable - Good reason and sufficient documentation to assume a causal relationship.
–
Possible - A causal relationship is conceivable and cannot be dismissed.
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–
Unlikely - The event is most likely related to aetiology other than the trial product.
!
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
A serious adverse event (SAE) is an experience that at any dose results in any of the following:
!
Death.
!
A life-threateninga experience.
!
In-patient hospitalisationb or prolongation of existing hospitalisation.
!
A persistent or significant disability or incapacityc.
!
A congenital anomaly or birth defect.
!
Important medical events that may not result in death, be life threatening 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.
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b. The term "hospitalisation" is used when a subject:
–
Is admitted to a hospital or in-patient, irrespective of the duration of physical stay, or
–
Stays at the hospital for treatment or observation for more than 24 hours
Medical judgement must always be exercised, and when in doubt, the hospital contact should be 
regarded as a hospitalisation. Hospitalisations for administrative, trial related and social 
purposes 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, see section 8.4.
6. Neoplasm
7. Thyroid disease, see section 8.5
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 lower or
higher than 20 % of the intended dose; however the administered dose must deviate from
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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.
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 
the end of the first 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. from 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 
and Figure 12–1.
During each contact with the trial site staff, the subject must be asked about AEs and technical 
complaints, for example by asking: "Have you experienced any problems since the last contact?"
All AEs, either observed by the investigator or subject, must be reported by the investigator and 
evaluated. Novo Nordisk assessment of expectedness is performed according to the following 
reference documents: 
IDegLira: NN9068 Investigator´s Brochure or any updates thereto
IDeg: NN1250 CCDS or any updates thereto
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All AEs must be recorded by the Investigator on an AE form. The investigator should report the 
diagnosis, if available. If no diagnosis is available, the investigator should record each sign and 
symptom as individual AEs using separate AE forms.  
For SAEs, a safety information form must be completed in addition to the AE form. If several 
symptoms or diagnoses occur as part of the same clinical picture, one safety information form can 
be used to describe all the SAEs. 
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
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 GCP.1 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 European Medicines Agency (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 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, 3 mL pre-filled pen.
!
Insulin degludec 100 units/mL, 3 mL pre-filled pen
!
Novo Nordisk needles for pre-filled pen 
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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 code or lot number or more than one DUN, 
a technical complaint form for each codeor lot number or for each DUN must be completed.
The investigator must complete the technical complaint form in the eCRF within the following 
timelines of the trial site obtaining knowledge of the technical complaint:
!
Technical complaint assessed as related to an SAE within 24 hours
!
All other technical complaints within 5 calendar days
If the eCRF is unavailable or when reporting a technical complaint that is not subject related, the 
information must be provided on a paper form by fax, e-mail or courier to Customer Complaint 
Center, Novo Nordisk, within the same timelines as stated above.
12.4.2
Collection, storage and shipment of technical complaint samples
The investigator must collect the technical complaint sample and notify the monitor within 5 
calendar daysof obtaining the sample at trial site. The monitor must coordinate the shipment to 
Customer Complaint Center, Novo Nordisk (the address is provided in Attachment I) and ensure 
that the sample is sent as soon as possible. A print or copy of the technical complaint form must be 
sent with the sample.
The investigator must ensure that the technical complaint sample contains thecode or lot number 
and, if available, the DUN.
If the technical complaint sample is unobtainable, the investigator must specify on the technical 
complaint form why it is unobtainable. 
Storage of the technical complaint sample must be done in accordance with the conditions 
prescribed for the product. The shipment of the technical complaint sample should be done in 
accordance with the same conditions as for storage (see section 9.4).
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12.5
Pregnancies
12.5.1
Pregnancies in female subjects
Female subjects must be instructed to notify the investigator immediately if they become pregnant 
during the trial. The investigator must report any pregnancy in subjects who have received trial 
products.
The investigator must follow the pregnancy until the pregnancy outcome and the newborn infant is 
one month of age.
The investigator must report information about the pregnancy, pregnancy outcome, and health of 
the newborn infant(s), as well as AEs in connection with the pregnancy, and AEs in the foetus and 
newborn infant.
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 pregnancies:
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Non-serious AEs: 
–
Paper AE form* within 14 calendar days of the investigator's first knowledge of the initial 
or follow-up information to the non-serious AE.
SAEs: 
–
Paper AE form* within 24 hours of the investigator's first knowledge of the SAE.
–
Paper safety information form within 5 calendar days of the investigator's first knowledge 
of the SAE.
–
SAE follow-up information to the AE form and/or safety information form within 24 
hours of the investigator's first knowledge of the follow-up information.
*
It must be clearly stated in the AE diagnosis field on the AE form if the event occurred in the 
subject, foetus or newborn infant.
Any queries or follow-up requests from Novo Nordisk to non-serious AEs, SAEs and pregnancy 
forms must be responded to by the investigator within 14 calendar days from the date of receipt of 
the request, unless otherwise specified in the follow-up request.
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 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. 
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For further information see the IDegLira IB or any updates thereto.
For IDeg see the IB or the SmPC or any updates thereto.
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, insulin degludec and liraglutide. The 
IDegLira/NN9068 safety committee may recommend unblinding of any data for further analysis, 
and in this case an independent ad hoc group will be established in order to maintain the blinding of 
the trial personnel.
12.7.2
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
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AEs for adjudication must be reported according to 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.
Ensure that all relevant questions are answered, and that no empty data field exists. If a test or an 
assessment has not been done and will not be available, or if the question is irrelevant (e.g. is not 
applicable), indicate this according to the data entry instructions.
The following will be provided as paper CRFs only:
!
Pregnancy forms
In addition paper AE forms, safety information forms and technical complaints 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.
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 
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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 the site visit/telephone contact. The SMPG values and corresponding insulin 
doses for titration purpose must preferably be entered within 24 hours on week days after the site 
visit/telephone contact 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 as soon as possible after FPFV and 
no later than 6 weeks after the FPFV. The monitoring visit intervals will depend on the outcome of 
the remote monitoring of the CRFs, the trial site's recruitment rate and the compliance of the trial 
site to the protocol and GCP1, but will not exceed 8 weeks. A follow up letter (paper or electronic)
will be sent to the investigator following each monitoring visit addressing any action to be taken. 
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).
All data must be verifiable in source documentation other than the CRF. For all data recorded the 
source document must be defined in a source document agreement at each trial site. There must 
only be one source defined at any time for any data element.
Monitors must review the subject´s medical records and other source data (e.g. the diaries) to ensure 
consistency and/or identify omissions compared to the CRF. If discrepancies are found, the 
investigator must be questioned about these. The original diaries must not be removed from the trial 
site, unless they form part of the CRF and a copy is kept at the site. The monitor will ensure that the 
CRFs are completed and that any paper CRFs are collected.
For SMPG values it is accepted that the earliest practically retainable record should be considered 
as the source data. Therefore, the data recorded by the BG meter and transcribed into the diary by 
the subject will be considered as the 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
The monitor will collect CRF pages and other trial related forms containing data from screening 
failures. Source data requirements for screening failures are described in section 8.1.3. 
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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.
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 from the laboratory performing the 
analyses. In cases where data is transferred via non-secure electronic networks, data will be 
encrypted during transfer.
The subject and any biological material obtained from the subject will be identified by subject 
number and trial 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.
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. 
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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.
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 anti-diabetic treatment (basal 
insulin and metformin or basal insulin, metformin and other OAD(s)) as fixed factors and the 
corresponding baseline value as a covariate. In the following, this model will be referred to as the 
standard ANCOVA model.
Presentation of results from a statistical analysis will include the estimated mean treatment effects 
(Least Square Means [LSMeans]) for absolute values and change from baseline. In addition, 
estimated mean treatment difference (or ratio) will be presented together with the two-sided 95% 
confidence interval and corresponding two-sided 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.
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 
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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 superiority of IDegLira vs. IDeg in controlling 
glycaemia in Chinese subjects with type 2 diabetes after 26 weeks of treatment. 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. IDeg.
Superiority in the primary endpoint for IDegLira versus  IDeg will be considered confirmed if the 
upper bound of the two-sided 95% confidence interval for the estimated mean treatment difference 
in change from baseline in HbA1c (for IDegLira - IDeg) is strictly below 0% or equivalently if the 
p-value for the two-sided test of
H0 D=0 against HA D≠0, 
is less than 5% and D<0, where D is the estimated  treatment difference. This is equivalent to using 
a one-sided test of size 2.5%, which means that the type 1 error rate is controlled at 2.5%.
The sample size is determined using a t-statistic under the assumption of a two-sided test of size 
5%, a mean difference in treatment of - 0.4%, and a standard deviation of SD=1.2%. It is also
assumed that 15% of the randomised subjects will be excluded from the PP analysis set. Superiority 
will be investigated for both the FAS and the PP analysis set in line with the Committee for 
Proprietary Medicinal Products (CPMP) Points to Consider 15. The above assumptions are based on 
experience from the phase 3a development programmes for IDegLira and IDeg. From these 
assumptions and based on a 2:1 randomisation the sample size is set to 300 subjects in the IDegLira 
arm and 150 subjects in the IDeg arm; in total 450 subjects will be randomised. This will ensure a 
power of 91.4% for confirming the primary objective in the full analysis set. Reducing the mean 
difference to -0.35% yields a power of 83%. 
17.2
Definition of analysis sets
The following analysis sets are defined in accordance with the ICH-E9 guidance 16.
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
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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”.
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, previous anti-diabetic treatment (basal insulin and metformin or 
basal insulin, metformin and other OAD(s)) as fixed effects and baseline HbA1c as covariate. 
Missing values after 26 weeks of treatment will be imputed LOCF using HbA1c values at and after 
baseline. 
Superiority of IDegLira vs. IDeg 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. Analysis based on the PP analysis set will be regarded as sensitivity analysis. 
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17.3.1
Sensitivity analysis
The primary efficacy 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 anti-diabetic treatment as fixed factors 
and baseline HbA1c as a 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 
clinical trial report.
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 superiority of IDegLira vs. IDeg with regards to the primary endpoint is 
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.
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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 (basal insulin and metformin or basal 
insulin, metformin and other OAD(s)) as fixed effect and baseline weight as covariate. 
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 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
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
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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 
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)
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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, low density lipoprotein cholesterol (LDL cholesterol), high density lipoprotein 
cholesterol (HDL cholesterol), very low density lipoprotein cholesterol (VLDL cholesterol), 
triglycerides, and free fatty acids after 26 weeks of treatment will be analysed separately using the 
standard ANCOVA model. In these statistical analyses the endpoint will be log-transformed and so 
will the baseline covariate.
Self measured plasma glucose (SMPG) 9-point profile
Three endpoints from the 9 point SMPG 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 PG 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 
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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-treatment emergent AE’s 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.
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-treatment emergent adverse events with onset date before the first day of exposure 
to randomised treatment will be presented. A listing will also be presented for non-treatment 
emergent adverse events collected after the treatment emergent period according to the definition of 
TEAE.
Classification of Hypoglycaemia
Treatment emergent: hypoglycaemic episodes will be defined as treatment emergent if the onset 
of the episode occurs on or after the first day of 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 
hypoglycaemia17 (see Figure 17–1) and the ADA7 classification of hypoglycaemia (see Figure 17–
2).
Novo Nordisk classification of hypoglycaemia
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In normal physiology, symptoms of hypoglycaemia occur below a plasma glucose level of 3.1 
mmol/L (56 mg/dL) 17. Therefore, Novo Nordisk has included hypoglycaemia with plasma glucose 
levels below this cut-off point in the definition of blood glucose (BG) confirmed hypoglycaemia.
Novo Nordisk use the following classification (see Figure 17–1) in addition to the ADA 
classification: 
!
Severe or BG confirmed symptomatic hypoglycaemia: An episode that is severe according to 
the ADA classification or BG confirmed by a plasma glucose value <3.1 mmol/L (56 mg/dL) 
with symptoms consistent with hypoglycaemia. 
!
Severe or BG confirmed hypoglycaemia: An episode that is severe according to the ADA 
classification or BG confirmed by a plasma glucose value <3.1 mmol/L (56 mg/dL) 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 (70 
mg/dL).
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!
Documented symptomatic hypoglycaemia: An episode during which typical symptoms of 
hypoglycaemia are accompanied by a measured plasma glucose concentration ≤ 3.9 mmol/L 
(70 mg/dL).
!
Pseudo-hypoglycaemia: An episode during which the person with diabetes reports any of the 
typical symptoms of hypoglycaemia with a measured plasma glucose concentration > 3.9 
mmol/L (70 mg/dL) but approaching that level.
!
Probable symptomatic hypoglycaemia: An episode during which symptoms of 
hypoglycaemia are not accompanied by a plasma glucose determination but that was 
presumably caused by a plasma glucose concentration ≤ 3.9 mmol/L (70 mg/dL).
Figure 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.  
The number of hypoglycaemic episodes during 26 weeks of treatment will be analysed separately 
for each endpoint using a negative binominal regression model with a log-link function and the 
logarithm of the time period in which a hypoglycaemic episode is considered treatment emergent as 
offset. The model will include treatment and previous anti-diabetic treatment as fixed factor. 
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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.
Clinical evaluations (physical examination, fundoscopy or fundus photography and ECG)
Eye examination (fundoscopy/fundus photography) 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 will apply in the evaluation of the result:
!
If the amylase or lipase baseline (at screening) value is > 3xUNR the information were
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.
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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
!
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)
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!
Subjects with at least one post baseline measurement outside reference range will be listed
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.
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18 Ethics
All subjects included in the trial will be treated with IDeglira or IDeg 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 
Helsinki 2.
Before any trial-related activity, the investigator must give the subject verbal and written 
information about the trial and the procedures involved in a form that the subject can read and 
understand. 
The subjects must be fully informed of their rights and responsibilities while participating in the 
trial as well as possible disadvantages of being treated with the trial products.
The investigator must ensure the subject ample time to 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 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 (for Ideg and IDeglira)
!
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, if applicable
!
Signed and dated Investigator Agreement
!
Financial disclosure form from investigator and sub-investigator(s)
Novo Nordisk will analyse and report data from all trial sites together.
By signing the protocol, each investigator agrees to comply fully with ICH GCP 1 1, applicable 
regulatory requirements and the Declaration of Helsinki 22. 
By signing the protocol, each investigator also agrees to allow Novo Nordisk making investigator's 
name and information about trial 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.
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.
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 trial site personnel must have sufficient English skills according to their 
assigned task(s).
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23 Reports and publications
The information obtained during the conduct of this trial is considered confidential, and may be 
used by 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 International Committee of Medical Journal 
Editors 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 
International Committee of Medical Journal Editors (sometimes referred to as the Vancouver 
Criteria)18.
The investigator(s) offered authorship will be asked to comment and approve the publication. No 
permission to publish will be granted to any vendor involved in the trial described in this protocol. 
23.1.2
Site-specific publication(s) by investigator(s)
For a multi-centre clinical trial, analyses based on single-trial 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 trial 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 their own research subjects' data, and can be provided with the 
randomisation code after results are available if requested. 
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24 Retention of clinical trial documentation and human biospecimens
24.1
Retention of clinical trial documentation
Subject's medical records must be kept for the maximum period permitted by the hospital, 
institution or private practice.
The investigator must agree to archive the documentation (this includes both electronic and paper-
based records) pertaining to the trial in an archive after completion or discontinuation of the trial if 
not otherwise notified. The investigator should not destroy any documents without prior permission 
from Novo Nordisk. If the investigator cannot archive the documents at the trial site, Novo Nordisk 
can refer the investigator to an independent archive provider that has a system in place to allow only 
the investigator to access the files.
The investigator must be able to access his/her trial documents without involving Novo Nordisk in 
any way. Site-specific CRFs and other subject data (in an electronic readable format or as paper 
copies or prints) will be provided to the investigator before access is revoked to the systems 
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 biospecimens
Antibody sample will be analysed and stored at a special laboratory outside of China until final 
feedback from the regulatory authorities in China 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 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.
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26 Indemnity statement
Novo Nordisk carries product liability for its products, and liability as assumed under the special 
laws, acts and/or guidelines for conducting clinical trials in any country, unless others have shown 
negligence.
Novo Nordisk assumes no liability in the event of negligence, or any other liability of the trial sites 
or investigators conducting the trial, or by persons for whom the said trial 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 World Medical Association. Declaration of Helsinki. Ethical principles for medical research 
involving human subjects. J Indian Med Assoc 2009; 107(6):403-405.
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. N 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 Jan 
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.
12 McAulay V, Deary IJ, Frier BM. Symptoms of hypoglycaemia in people with diabetes. Diabet 
Med 2001; 18(9):690-705.
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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. Food and Drug Administration, Code of Federal Regulations, 
Guidance for Industry, Diabetes Mellitus: Developing Drugs and Therapeutic Biologics for 
Treatment and Prevention. Draft Guidance.  Feb 2008. 
15 EMEA-Committee for Proprietary Medicinal Products. CPMP/EWP/482/99 - Points to 
consider on switching between superiority and non-inferiority.  27 Jul 2000. 
16 International Conference on Harmonisation. ICH Harmonised Tripartite Guideline. Statistical 
principles for clinical trials E9. International Conference on Harmonisation E9 Expert 
Working Group.  5 Feb 1998. 
17 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.
18 De Angelius C, Drazen JM, Frizelle FA, Haug C, Hoey J, Horton R et al. Clinical trial 
registration: a statement from the International Committee of Medical Journal Editors. New 
Engl J Med 2004; 351(12):1250-1251.
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Appendix A: Titration Guideline
NN9068-4166
DUAL! II China
A trial comparing the efficacy and safety of insulin 
degludec/liraglutide and insulin degludec in combination with 
metformin in Chinese subjects with type 2 diabetes mellitus 
inadequately controlled with basal insulin therapy and 
metformin ± one other OAD
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.

Trial ID: NN9068-4166
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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
Basal insulin 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 adjusted 1 2 3 4 5 6 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 
subject’s welfare.
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2
Treatment regimens
At randomisation all subjects will be randomised 2:1 into two parallel treatment groups:
∀
Insulin degludec/liraglutide once daily + metformin
∀
Insulin degludec once daily+ metformin
First dosing should take place on day of randomisation or on the day following randomisation.
Maximum dose for insulin degludec/liraglutide and insulin degludec is 50 dose steps (50 units of 
insulin degludec and 1.8 mg of liraglutide/50 units of insulin degludec). 
There is no minimum dose for IDegLira or IDeg. 
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 will start on 16 dose steps of IDegLira (16 U of degludec 
and 0.6 mg of liraglutide) or 16 U IDeg once daily.
3.2
Titration
Dose will be adjusted twice weekly by the subject on two days 3-4 days apart. The investigator will 
support titration at all contacts. 
Titration should be performed based on the mean of three pre-breakfast 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
Basal insulin adjustment
Mean of three pre-breakfast SMPGs 
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, the subject must wait for the next titration day.
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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4
Data collection
The following data should be entered into the eCRF within 24 hours (on weekdays) after a site 
visit/telephone contact:
∀
Per protocol pre-breakfast SMPG values measured since last visit/telephone contact as 
described in sections 3.2
∀
Last dose of trial product taken prior to the titration
∀
New dose of trial product  to be taken after titration
∀
Reasons for deviation from the titration algorithms, if applicable
∀
Hypoglycaemic episodes
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5
Review procedure
Surveillance of titration data 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 
weekdays). 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 an inquiry, a response should be received at Novo Nordisk within 24 
hours (on weekdays). 
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 in a blinded manner.
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6
References
1 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.
2 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.
3 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.
4 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.
5 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.
6 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.
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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Trial ID: NN9068-4166
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Appendix B: Medical events of special interest and events requiring 
adjudication
Trial ID: NN9068-4166
DUAL! II - China
A trial comparing the efficacy and safety of insulin 
degludec/liraglutide and insulin degludec in combination with 
metformin in Chinese subjects with type 2 diabetes mellitus 
inadequately controlled with basal insulin therapy and 
metformin ± one other OAD
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: U1111-1154-6732 
Date:
07 October 2014
Status:
Final
Novo Nordisk
Trial ID: NN9068-4166
     
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: U1111-1154-6732 
Date:
07 October 2014
Status:
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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: U1111-1154-6732 
Date:
07 October 2014
Status:
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Version:
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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
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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 Karen A.Hicks HMJHKWM, Roxana Mehran, Steven E.Nissen, Norman L.Stockbridge, Shaari 
L.Targum, Robert Temple -on behalf of the Standardized Data Collection for Cardiovascular
Trials Initiative. Standardized Definitions for Cardiovascular and Stroke End Point Events in
Clinical Trials. https://www.cardiac-safety.org/think-tanks/ecrf-forms-for-
posting/Draft%20Definitions%20for%20Testing%20November%209-
%202012%20with%20MI%20Preamble%20CLEAN.pdf. 9 Nov 2012.
CONFIDENTIAL

Protocol - Appendix C
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Appendix C: New York Heart Association criteria for functional capacity in 
heart failure
Trial ID: NN9068-4166
DUAL! II - China
A trial comparing the efficacy and safety of insulin 
degludec/liraglutide and insulin degludec in combination with 
metformin in Chinese subjects with type 2 diabetes mellitus 
inadequately controlled with basal insulin therapy and 
metformin ± one other OAD
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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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
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Date:
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Trial ID: NN9068-4166
Version:
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Appendix D: Monitoring of calcitonin levels 
Trial ID: NN9068-4166
DUAL! II - China
A trial comparing the efficacy and safety of insulin 
degludec/liraglutide and insulin degludec in combination with 
metformin in Chinese subjects with type 2 diabetes mellitus 
inadequately controlled with basal insulin therapy and 
metformin ± one other OAD
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
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Trial ID: NN9068-4166
Version:
2.0
UTN: U1111-1154-6732 
Status:
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Page:
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Table of Contents
..............................................................................................................................................................Page
Table of Contents..............................................................................................................................................2
1
Background................................................................................................................................................3
2
Calcitonin and C-cell abnormalities - evaluation and follow-up ..........................................................4
2.1
CT ≥ 100 ng/L................................................................................................................................4
2.2
CT ≥ 50 and < 100 ng/L.................................................................................................................4
2.3
CT ≥ 20 and <50 ng/L....................................................................................................................5
2.4
CT ≥ 10 and < 20 ng/L...................................................................................................................5
3 References ......................................................................................................................................................6
CONFIDENTIAL

Protocol - Appendix D
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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.
CONFIDENTIAL

Protocol - Appendix D
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Trial ID: NN9068-4166
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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 section:
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, 
the subject should be assumed to have significant C-cell disease and a high likelihood of having 
medullary carcinoma of the thyroid. Diagnostic evaluation should consist of thyroid ultrasound, fine 
needle aspiration of any nodules >1 cm and potentially surgery with neck dissection. Family history 
of MTC or MEN2 should be evoked and a RET proto-oncogene analysis should be performed. 
2.2
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 
CONFIDENTIAL

Protocol - Appendix D
CONFIDENTIAL
Date:
07 October 2014
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Trial ID: NN9068-4166
Version:
2.0
UTN: U1111-1154-6732 
Status:
Final
     
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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 # 10 (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. 1/216 had a subsequent basal (unstimulated) calcitonin of 33 ng/L, and had C-cell 
hyperplasia at surgery, a lesion of unknown clinical significance. Two other studies used a cutoff of 
CT > 10 ng/L to screen for C-cell disease, but they do not provide sufficient information on patients 
with basal CT >10 and <20 ng/L to allow conclusions2,3.
CONFIDENTIAL

Protocol - Appendix D
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Date:
07 October 2014
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Trial ID: NN9068-4166
Version:
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Status:
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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
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
IDegLira
Trial ID: NN9068-4166
Clinical Trial Report
Appendix 16.1.1
04 December 2019
1.0
Final
CONFIDENTIAL

Protocol Amendment
CONFIDENTIAL
Date:
04 November 2016
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Trial ID: NN9068-4166
Version:
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UTN: U1111-1154-6732
Status:
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Protocol Amendment
no 1
to Protocol, final version 2.0
dated 07 October 2014
Trial ID: NN9068-4166
DUAL™ II China
A trial comparing the efficacy and safety of insulin degludec/liraglutide and insulin degludec in
combination with metformin in Chinese subjects with type 2 diabetes mellitus inadequately
controlled with basal insulin therapy and metformin ± one other OAD
Trial phase: 3a
Applicable to China and Hong Kong
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
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Date:
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Trial ID: NN9068-4166
Version:
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UTN: U1111-1154-6732
Status:
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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
Data on effect of time point for dosing........................................................................6
2.1.13
Trial product details.....................................................................................................7
2.1.14
IWRS ...........................................................................................................................7
2.1.15
Monitoring procedures more clearly specified ............................................................7
2.1.16
Statistical considerations..............................................................................................7
2.1.17
Ethics ...........................................................................................................................7
2.1.18
Reports and publications..............................................................................................7
2.1.19
Retention of human biosamples...................................................................................8
2.1.20
Flow Chart updates......................................................................................................8
2.1.21
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 re-imbursement 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 35, 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
CONFIDENTIAL

Protocol Amendment
CONFIDENTIAL
Date:
04 November 2016
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Trial ID: NN9068-4166
Version:
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UTN: U1111-1154-6732
Status:
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1
Introduction including rationale for the protocol amendment
The CFDA approved the NN9068-4166 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.
CONFIDENTIAL

Protocol Amendment
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Date:
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Trial ID: NN9068-4166
Version:
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UTN: U1111-1154-6732
Status:
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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.
CONFIDENTIAL

Protocol Amendment
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Date:
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Trial ID: NN9068-4166
Version:
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UTN: U1111-1154-6732
Status:
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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 SOP 110079 ed. 7.0. 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 SOP 110079 edition 9.0. 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 SOP 110079 ed. 7.0. 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 II 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.
CONFIDENTIAL

Protocol Amendment
CONFIDENTIAL
Date:
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Trial ID: NN9068-4166
Version:
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UTN: U1111-1154-6732
Status:
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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 8.3.4 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
Data on effect of time point for dosing
Rationale: To be able to provide data on the effect of time point for dosing being the same 
whatever medication is taken morning or evening which if we are asked to make analysis of this 
post hoc (we were asked from FDA about this).
Impact: Section 8.6 updated with additional bullet point for what to collect in diary.
CONFIDENTIAL

Protocol Amendment
CONFIDENTIAL
Date:
04 November 2016
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Trial ID: NN9068-4166
Version:
3.0
UTN: U1111-1154-6732
Status:
Final
     
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2.1.13
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.
2.1.14
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.
2.1.15
Monitoring procedures more clearly specified
Rationale: In order to comply with current edition of SOP 110079 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.
2.1.16
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.
2.1.17
Ethics
Rationale: In order to comply with current edition of SOP 110079 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.
2.1.18
Reports and publications
Rationale: In order to comply with current edition of SOP 110079 the protocol has been updated to 
reflect resent disclosure requirements.
CONFIDENTIAL

Protocol Amendment
CONFIDENTIAL
Date:
04 November 2016
Novo Nordisk
Trial ID: NN9068-4166
Version:
3.0
UTN: U1111-1154-6732
Status:
Final
     
Page:
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Impact: Section 23 updated.
2.1.19
Retention of human biosamples
Rationale: In order to comply with current edition of SOP 110079 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.
2.1.20
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.
2.1.21
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 ALT 
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 1.7 named Information about antibody sampling and exportation 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 re-imbursement fee
Impact: Section 4.3 updated.
CONFIDENTIAL

Protocol Amendment
CONFIDENTIAL
Date:
04 November 2016
Novo Nordisk
Trial ID: NN9068-4166
Version:
3.0
UTN: U1111-1154-6732
Status:
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Page:
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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 2.2.16 has been replaced by updated text in section 2.1.13.
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 35, 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
Novo Nordisk
Trial ID: NN9068-4166
Version:
1.0
UTN: U1111-1154-6732
Status:
Final
     
Page:
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Protocol Amendment
no 2
to Protocol, final version 2.0
dated 07 October 2014
Trial ID: NN9068-4166
DUAL™ II China
A trial comparing the efficacy and safety of insulin degludec/liraglutide and insulin degludec in
combination with metformin in Chinese subjects with type 2 diabetes mellitus inadequately
controlled with basal insulin therapy and metformin ± one other OAD
Trial phase: 3a
Applicable to China and Hong Kong
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:
31 August 2016
Novo Nordisk
Trial ID: NN9068-4166
Version:
1.0
UTN: U1111-1154-6732
Status:
Final
     
Page:
2 of 3
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 NN9068-4166 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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Date:
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Trial ID: NN9068-4166
Version:
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UTN: U1111-1154-6732
Status:
Final
     
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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:
31 August 2016
Novo Nordisk
Trial ID: NN9068-4166
Version:
1.0
UTN: U1111-1154-6732
Status:
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Protocol Amendment
no 3
to Protocol, final version 2.0
dated 07 October 2014
Trial ID: NN9068-4166
DUAL™ II China
A trial comparing the efficacy and safety of insulin degludec/liraglutide and insulin degludec in
combination with metformin in Chinese subjects with type 2 diabetes mellitus inadequately
controlled with basal insulin therapy and metformin ± one other OAD
Trial phase: 3a
Applicable to China and Hong Kong
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:
31 August 2016
Novo Nordisk
Trial ID: NN9068-4166
Version:
1.0
UTN: U1111-1154-6732
Status:
Final
     
Page:
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1
Changes to protocol
Section 8.4 subject diaries
Rationale: In the diary we collect the date, dose, injection site and exact clock time for injection 
from the previous 3 days of dosing. This was not included in the original protocol, but was added 
with amendment 1 for the purpose of being able to provide data on the effect of time point for 
dosing being the same whatever medication is taken morning or evening. The protocol text 
describing this procedure was copied from the NN9068-4148 protocol. However, in trial NN9068-
4148 the purpose of this text is to register data prior to PK sampling. When copying the text from 
NN9068-4148 to NN9068-4166 too much of the text was included (“Date, dose, injection site and 
exact clock time for injection from the previous three days of dosing and on the day of the visit”). 
The text which describes collecting the information “and on the day of the visit” does not apply to 
NN9068-4166 where the purpose is to document the dosing time and not register data prior to PK 
sampling. There is no PK sampling in NN9068-4166. Therefore the text in the protocol should be 
updated as follows: 
Current text: Date, dose, injection site and exact clock time for injection from the previous three 
days of dosing and on the day of the visit.
Updated text: Date, dose, injection site and exact clock time for injection from the previous three 
days of dosing.
Impact: Updated section 8.4.
CONFIDENTIAL

Protocol Amendment
CONFIDENTIAL
Date:
31 August 2016
Novo Nordisk
Trial ID: NN9068-4166
Version:
1.0
UTN: U1111-1154-6732
Status:
Final
     
Page:
3 of 3
2
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:
2.1.1
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
CONFIDENTIAL
Date:
07 October 2016
Novo Nordisk
Trial ID: NN9068-4166
Version:
2.0
UTN: U1111-1154-6732
Status:
Final
     
Page:
1 of 5
Protocol Amendment
no 4
to Protocol, final version 2.0
dated 07 October 2014
Trial ID: NN9068-4166
DUAL™ II China
A trial comparing the efficacy and safety of insulin degludec/liraglutide and insulin degludec in
combination with metformin in Chinese subjects with type 2 diabetes mellitus inadequately
controlled with basal insulin therapy and metformin ± one other OAD
Trial phase: 3a
Applicable to China and Hong Kong
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:
07 October 2016
Novo Nordisk
Trial ID: NN9068-4166
Version:
2.0
UTN: U1111-1154-6732
Status:
Final
     
Page:
2 of 5
Introduction including rationale for the protocol amendment
After finalisation of NN9068-4166 protocol version 3.0 dated 31-Aug-2016 the following changes 
have been identified why an amendment is needed:
1.1
Section 18.1.1.1 Important identified risks
Rationale: 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.
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
Figure 5.1
Rationale: In protocol version 3.0 the below table is included:
Basal insulin and 
metformin ± one 
other OAD (AGI, 
SU, glinides or TZD)
-2
Insulin degludec/liraglutide OD ± metformin
Insulin degludec OD ± metformin
0
33
34
Screening
FU1
FU2
Week
Visit
Randomisation
Treatment period
26
2
1
35
27
30
End of
treatment
Figure 5.1 from protocol version 3.0 – to be replaced with figure below
This table mistakenly lists +/- metformin, which is not correct as all patients on both arms are to 
receive metformin +/- one other OAD. The figure has therefore been updated to include the 30-day 
FU2 visit based on the figure included in protocol version 2.0 as shown below:
CONFIDENTIAL

Protocol Amendment
CONFIDENTIAL
Date:
07 October 2016
Novo Nordisk
Trial ID: NN9068-4166
Version:
2.0
UTN: U1111-1154-6732
Status:
Final
     
Page:
3 of 5
Figure 5.1 from protocol version 3.3 – to be inserted instead of figure above
1.3
Section 7 Milestones
Rationale: Topographical correction to be compliant with Protocol SOP 110079 version 9.0 
template:
“Planned duration of recruitment period (First Subject First Visit – Last Subject FirstLast Visit): 54 
weeks. End of trial is defined as Last Subject Last Visit.”
1.4
Section 8.2.13
Rationale: A 9-point SMPG is to be performed between visit1 to visit2 according to flow chart, so 
the BG-meter should be handed out to the subject at visit1 and not visit 2:
“At visit 12, subjects will be provided with a BG-meter which must be used for all measurements 
during the trial. The subject 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. Sites 
should, as necessary, repeat the directions for use to the subject at subsequent visits.
1.5
Section 17 Statistical considerations
Rationale: 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.
From 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. 
Endpoints that are analysed untransformed and endpoints that are not formally analysed are 
CONFIDENTIAL

Protocol Amendment
CONFIDENTIAL
Date:
07 October 2016
Novo Nordisk
Trial ID: NN9068-4166
Version:
2.0
UTN: U1111-1154-6732
Status:
Final
Page:
4 of 5
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
“Superiority in the primary endpoint for IDegLira versus  IDeg will be considered confirmed if the 
upper bound of the two-sided 95% confidence interval for the estimated mean treatment difference 
in change from baseline in HbA1c (for IDegLira - IDeg) is strictly below 0% or equivalently if the 
p-value for the two-sided test of
H0 D=0 against HA D≠0,
is less than 5% and D<0, where D is the estimated  treatment difference. This is equivalent to using 
a one-sided test of size 2.5%, which means that the type 1 error rate is controlled at 2.5% (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 superiority of IDegLira vs. IDeg with regards to the primary endpoint is 
confirmed.
In order to control the overall type I error on a two-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. 
CONFIDENTIAL

Protocol Amendment
CONFIDENTIAL
Date:
07 October 2016
Novo Nordisk
Trial ID: NN9068-4166
Version:
2.0
UTN: U1111-1154-6732
Status:
Final
     
Page:
5 of 5
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.
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.
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.
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 17.4.2.2 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:
06 December 2016
Novo Nordisk
Trial ID: NN9068-4166
Version:
1.0
UTN: U1111-1154-6732
Status:
Final
     
Page:
1 of 7
Protocol Amendment
no 5
to Protocol, final version 2.0
dated 07 October 2014
Trial ID: NN9068-4166
DUAL™ II China
A trial comparing the efficacy and safety of insulin degludec/liraglutide and insulin degludec in
combination with metformin in Chinese subjects with type 2 diabetes mellitus inadequately
controlled with basal insulin therapy and metformin ± one other OAD
Trial phase: 3a
Applicable to China and Hong Kong
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:
06 December 2016
Novo Nordisk
Trial ID: NN9068-4166
Version:
1.0
UTN: U1111-1154-6732
Status:
Final
     
Page:
2 of 7
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 section 18.1.1.1: Starting dose of liraglutide component................................................5
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...................7
3.1
Affected section 1.7: Baseline antibody samples shipped from 
to Novo Nordisk 
Måløv, Denmark............................................................................................................................7
3.2
Affected section 3.3: Storage time for antibody samples ..............................................................7
3.3
Affected section 2.1: What are the possible risks if you participate in this trial............................7
CONFIDENTIAL

Protocol Amendment
CONFIDENTIAL
Date:
06 December 2016
Novo Nordisk
Trial ID: NN9068-4166
Version:
1.0
UTN: U1111-1154-6732
Status:
Final
     
Page:
3 of 7
1
Introduction including rationale for the protocol amendment
After finalisation of NN9068-4166 protocol version 4.0 dated 28-Sep-2016 and the Subject 
information/informed consent form version 4.0 dated 08-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 the starting dose of the liraglutide component
!
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:
06 December 2016
Novo Nordisk
Trial ID: NN9068-4166
Version:
1.0
UTN: U1111-1154-6732
Status:
Final
     
Page:
4 of 7
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:
06 December 2016
Novo Nordisk
Trial ID: NN9068-4166
Version:
1.0
UTN: U1111-1154-6732
Status:
Final
     
Page:
5 of 7
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, so it has been decided that Fasting insulin 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 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 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 and fasting insulin). Because all results 
are summarised in the CTR the affected section is updated for consistency.
Updated text section 8.3.4 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.
2.4
Affected section 18.1.1.1: Starting dose of liraglutide component
Rationale: The starting dose of the liraglutide component is correctly listed as 0.6 mg in section 5.5 
Rationale for treatment but in section 18.1.1.1 Gastrointestinal adverse events it’s mistakenly listed 
as 0.36 mg. This means that the starting dose of liraglutide is the same and not less than the starting 
dose of liraglutide when administered as the mono-component.
Updated text section 18.1.1.1 Gastrointestinal adverse events
CONFIDENTIAL

Protocol Amendment
CONFIDENTIAL
Date:
06 December 2016
Novo Nordisk
Trial ID: NN9068-4166
Version:
1.0
UTN: U1111-1154-6732
Status:
Final
     
Page:
6 of 7
Gastrointestinal adverse events are considered class effects for GLP-1 RAs and are among the most 
frequently reported events in patients treated with IDegLira. The titration of IDegLira is slow and 
has previously shown to result in a lower frequency of gastrointestinal adverse effects. The dose of 
the liraglutide component in the start dose of IDegLira in the present trial is 0.36 0.6 mg, which is 
the same as less than the starting dose of liraglutide when administered as the mono-component 
(Victoza®).
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.
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:
06 December 2016
Novo Nordisk
Trial ID: NN9068-4166
Version:
1.0
UTN: U1111-1154-6732
Status:
Final
     
Page:
7 of 7
3
Changes to Subject information/informed consent form version 
4.0 dated 08-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. 
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 and fasting 
insulin samples including yours, will be shipped to a special laboratoriesy outside of China and 
Hong Kong. The antibody samples will be shipped to
 located in
 and to Novo 
Nordisk, located in Denmark, for analysis. and fFasting insulin samples will be shipped to
 
located in
 By involving only two one special laboratoriesy, 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 or Hong Kong.
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
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