Clinical trial NCT02607306
Conditions: Diabetes Diabetes Mellitus, Type 2
Sponsor: Novo Nordisk A/S
Start date: 2015-11-18; Completion date: 2017-12-22
Enrollment: 819 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This trial is conducted in Asia. The aim of this trial is to compare the efficacy and safety of insulin degludec/liraglutide, insulin degludec and liraglutide in Japanese subjects with type 2 diabetes mellitus.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None
Interventions: intervention 1: insulin degludec/liraglutide intervention 2: insulin degludec intervention 3: liraglutide
Intervention descriptions: intervention 1: Injected s.c. / subcutaneously (under the skin) once daily (OD) , in combination with pre-trial OAD (oral antidiabetic drug)kept in unchanged dose. intervention 2: Injected s.c. / subcutaneously (under the skin) once daily (OD) , in combination with pre-trial OAD (oral antidiabetic drug)kept in unchanged dose. intervention 3: Injected s.c. / subcutaneously (under the skin) once daily (OD) , in combination with pre-trial OAD (oral antidiabetic drug)kept in unchanged dose.

Protocol documents:
Prot_SAP_000.pdf: 
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List of contents
Protocol - Version 2.0.........................................................................................................................
Appendix A - Insulin titration-and liraglutide dose escalation guidelines....................................
Appendix B - New York Heart Association criteria for functional capacity ................................
Appendix C - Medical events of special interest..............................................................................
Appendix D - Monitoring of Calcitonin ...........................................................................................
Attachment I.......................................................................................................................................
Protocol amendment 01 - JP..............................................................................................................
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
IDegLira
Trial ID: NN9068-4183
Clinical Trial Report
Appendix 16.1.1
01 June 2018
1.0
Final
16.1.1 Protocol and protocol amendments
CONFIDENTIAL
 
 
 
 
 
Redacted protocol 
Includes redaction of personal identifiable information only. 
 
 
 
. 
 
 


Protocol
CONFIDENTIAL
Date:
15 July 2015
Novo Nordisk
Trial ID: NN9068-4183
Version:
2.0
UTN: U1111-1170-1332 
Status:
Final
EudraCT no.: N/A
Page:
1 of 105
Protocol
DUAL™I Japan
Trial ID: NN9068-4183 
A trial comparing the efficacy and safety of insulin degludec/liraglutide, insulin 
degludec and liraglutide in Japanese subjects with type 2 diabetes mellitus
Trial phase: 3a
Protocol originator
Insulin & Diabetes Outcomes, Clinical Operations
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.
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


Protocol
CONFIDENTIAL
Date:
15 July 2015
Novo Nordisk
Trial ID: NN9068-4183
Version:
2.0
UTN: U1111-1170-1332 
Status:
Final
EudraCT no.: N/A
Page:
2 of 105
Table of Contents
Page
Table of Contents..............................................................................................................................................2
Table of Figures................................................................................................................................................6
Table of Tables..................................................................................................................................................6
List of abbreviations.........................................................................................................................................7
1
Summary..................................................................................................................................................11
2
Flow chart ................................................................................................................................................14
3
Background information and rationale for the trial............................................................................18
3.1
Background information..............................................................................................................18
3.2
Rationale for the trial...................................................................................................................19
4
Objectives and endpoints........................................................................................................................21
4.1
Objectives ....................................................................................................................................21
4.2
Endpoints .....................................................................................................................................21
4.2.1
Primary endpoint........................................................................................................21
4.2.2
Secondary endpoints..................................................................................................21
4.2.2.1
Confirmatory secondary endpoints .....................................................21
4.2.2.2
Supportive secondary endpoints..........................................................22
4.2.2.3
Supportive secondary pharmacokinetic endpoints..............................23
5
Trial design ..............................................................................................................................................24
5.1
Type of trial .................................................................................................................................24
5.2
Rationale for trial design..............................................................................................................25
5.3
Treatment of subjects...................................................................................................................25
5.4
Treatment in the follow up period ...............................................................................................25
5.5
Treatment after end of trial ..........................................................................................................26
5.6
Rationale for treatment ................................................................................................................26
6
Trial population.......................................................................................................................................27
6.1
Number of subjects......................................................................................................................27
6.2
Inclusion criteria ..........................................................................................................................27
6.3
Exclusion criteria.........................................................................................................................28
6.4
Withdrawal criteria ......................................................................................................................29
6.5
Subject replacement.....................................................................................................................30
6.6
Rationale for trial population.......................................................................................................31
7
Milestones.................................................................................................................................................32
7.1
Recruitment..................................................................................................................................32
7.2
Trial registration ..........................................................................................................................32
8
Methods and assessments .......................................................................................................................33
8.1
Visit procedures...........................................................................................................................33
8.1.1
Informed consent .......................................................................................................33
8.1.2
Investigators assessments ..........................................................................................34
8.1.3
Screening ...................................................................................................................34
8.1.4
Screening failures ......................................................................................................34
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 July 2015
Novo Nordisk
Trial ID: NN9068-4183
Version:
2.0
UTN: U1111-1170-1332 
Status:
Final
EudraCT no.: N/A
Page:
3 of 105
8.1.5
Visits attended fasting................................................................................................34
8.1.6
Randomisation visit ...................................................................................................35
8.1.7
Visits..........................................................................................................................35
8.1.8
End of treatment visit.................................................................................................35
8.1.9
Follow-up visit...........................................................................................................35
8.1.10
Unscheduled visits.....................................................................................................36
8.1.11
Re-scheduled visits ....................................................................................................36
8.1.12
Withdrawals...............................................................................................................36
8.2
Subject related information..........................................................................................................36
8.2.1
Concomitant illness and medical history...................................................................36
8.2.2
Concomitant medication............................................................................................37
8.2.3
OAD medication........................................................................................................37
8.2.4
Demography...............................................................................................................38
8.2.5
Tobacco use ...............................................................................................................38
8.3
Assessments for efficacy..............................................................................................................38
8.3.1
Blood samples for efficacy parameters......................................................................38
8.3.2
Self-measured blood glucose.....................................................................................39
8.3.3
9-point self-measured blood glucose profiles............................................................40
8.3.4
Body measurements...................................................................................................40
8.3.5
Blood pressure ...........................................................................................................41
8.4
Assessments for safety.................................................................................................................41
8.4.1
Adverse Events requiring special forms in the eCRF................................................42
8.4.2
Blood samples for safety parameters.........................................................................46
8.4.3
Pregnancy test............................................................................................................46
8.4.4
Assessments in case of suspicion of acute pancreatitis..............................................47
8.4.5
Antibody sampling.....................................................................................................47
8.4.6
ECG (electrocardiogram)...........................................................................................48
8.4.7
Eye Examination........................................................................................................48
8.4.8
Physical Examination ................................................................................................49
8.4.9
Hypoglycaemic episodes ...........................................................................................49
8.4.10
Pulse...........................................................................................................................51
8.4.11
Suspicion of acute hypersensitivity to trial products .................................................51
8.5
Laboratory assessments ...............................................................................................................51
8.6
Other assessments........................................................................................................................52
8.6.1
Pharmacokinetics.......................................................................................................52
8.6.2
Subject diary ..............................................................................................................53
8.6.3
Subject compliance....................................................................................................53
9
Trial supplies ...........................................................................................................................................55
9.1
Trial products...............................................................................................................................55
9.2
Labelling......................................................................................................................................55
9.3
Storage .........................................................................................................................................55
9.4
Drug accountability and destruction............................................................................................56
9.5
Auxiliary supplies........................................................................................................................57
10 Interactive web response system............................................................................................................58
11 Randomisation procedure ......................................................................................................................59
11.1
Randomisation .............................................................................................................................59
11.1.1
Stratification...............................................................................................................59
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 July 2015
Novo Nordisk
Trial ID: NN9068-4183
Version:
2.0
UTN: U1111-1170-1332 
Status:
Final
EudraCT no.: N/A
Page:
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12 Adverse events, and technical complaints and pregnancies................................................................60
12.1
Definitions ...................................................................................................................................60
12.2
Reporting of adverse events.........................................................................................................64
12.3
Follow-up of adverse events........................................................................................................66
12.4
Technical complaints and technical complaint samples ..............................................................67
12.4.1
Reporting of technical complaints .............................................................................67
12.4.2
Collection, storage and shipment of technical complaint samples ............................68
12.5
Pregnancies in female subjects ....................................................................................................68
12.6
Precautions and/or overdose ........................................................................................................70
12.7
Committees related to safety........................................................................................................70
12.7.1
Novo Nordisk safety committee ................................................................................70
12.7.2
Event adjudication committee....................................................................................71
13 Case report forms....................................................................................................................................72
13.1
Corrections to case report forms..................................................................................................72
13.2
Case report form flow..................................................................................................................73
13.2.1
Paper case report form flow.......................................................................................73
14 Monitoring procedures ...........................................................................................................................73
15 Data management....................................................................................................................................75
16 Computerised systems.............................................................................................................................75
17 Statistical considerations ........................................................................................................................76
17.1
Sample size calculation................................................................................................................77
17.2
Definition of analysis sets............................................................................................................78
17.3
Primary endpoint..........................................................................................................................79
17.3.1
Sensitivity analysis ....................................................................................................79
17.4
Secondary endpoints....................................................................................................................81
17.4.1
Confirmatory secondary endpoints............................................................................81
17.4.2
Supportive secondary endpoints ................................................................................84
17.4.2.1
Efficacy endpoints...............................................................................84
17.4.2.2
Safety endpoints..................................................................................86
17.5
Pharmacokinetic modelling .........................................................................................................92
18 Ethics........................................................................................................................................................93
18.1
Benefit-risk assessment of the trial..............................................................................................93
18.2
Data handling...............................................................................................................................95
18.3
Information to subject during trial...............................................................................................95
18.4
Premature termination of the trial and/or trial site.......................................................................95
19 Protocol compliance................................................................................................................................96
20 Audits and inspections ............................................................................................................................96
21 Critical documents ..................................................................................................................................97
22 Responsibilities........................................................................................................................................97
23 Reports and publications........................................................................................................................98
23.1
Communication of results............................................................................................................99
23.1.1
Authorship .................................................................................................................99
23.1.2
Site-specific publication(s) by investigator(s) .........................................................100
23.2
Investigator access to data and review of results.......................................................................100
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 July 2015
Novo Nordisk
Trial ID: NN9068-4183
Version:
2.0
UTN: U1111-1170-1332 
Status:
Final
EudraCT no.: N/A
Page:
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24 Retention of clinical trial documentation and human biospecimens................................................101
24.1
Retention of clinical trial documentation...................................................................................101
24.2
Retention of antibody samples...................................................................................................101
25 Institutional Review Boards and regulatory authorities ...................................................................102
26 Indemnity statement .............................................................................................................................102
27 References..............................................................................................................................................103
Appendix A; Insulin titration- and liraglutide dose escalation guidelines
Appendix B; New York Heart Association Criteria for Functional Capacity
Appendix C; Medical events of special interest, events with additional data collection and events 
requiring adjudication
Appendix D; Monitoring of Calcitonin
Attachment I – List of key staff and relevant departments and suppliers
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 July 2015
Novo Nordisk
Trial ID: NN9068-4183
Version:
2.0
UTN: U1111-1170-1332 
Status:
Final
EudraCT no.: N/A
Page:
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Table of Figures
Page
Figure 5–1
Trial design.............................................................................................................................24
Figure 12–1
Initial reporting of AEs...........................................................................................................66
Figure 17–1
Novo Nordisk classification of hypoglycaemia......................................................................88
Figure 17–2
ADA classification of hypoglycaemia....................................................................................89
Table of Tables
Page
Table 8–1
9-point profile (SMBG) (!) ....................................................................................................40
Table 9–1
Investigational medicinal products.........................................................................................55
Table 9–2
Storage conditions for investigational medicinal products.....................................................56
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 July 2015
Novo Nordisk
Trial ID: NN9068-4183
Version:
2.0
UTN: U1111-1170-1332 
Status:
Final
EudraCT no.: N/A
Page:
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List of abbreviations
ADA
American Diabetes Association
AE
adverse event
α-GI
alpha-glucosidase inhibitor
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AP
alkaline phosphatase
AST
aspartate aminotransferase
BG
blood glucose
BMI
body mass index
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration 
CLAE
clinical laboratory adverse event
CRF
case report form
CRO
clinical research organisation
CT
computerised axial tomography
CTR
clinical trial report
CV
coefficient of variation
DFU
direction for use
DUN
dispensing unit number
EAC
event adjudication committee
ECG
electrocardiogram
EDC
electronic data capture
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
ELISA
enzyme-linked immunosorbent assay
ESC
European Society of Cardiology
ESH
European Society of Hypertension
EOT
end of treatment
FAS
full analysis set
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 July 2015
Novo Nordisk
Trial ID: NN9068-4183
Version:
2.0
UTN: U1111-1170-1332 
Status:
Final
EudraCT no.: N/A
Page:
8 of 105
FDA
U.S. Food and Drug Administration
FDAAA
Food and Drug Administration Amendment Act
FPG
fasting plasma glucose
FSFV
first subject first visit
GCP
Good Clinical Practice
GLP-1
glucagon-like peptide-1
HbA1c
glycosylated haemoglobin
hCG
human chorionic gonadotropin
HDL
high density lipoprotein
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
ICMJE
International Committee of Medical Journal Editors
IDeg
Insulin degludec
IDegLira
Insulin degludec/liraglutide
IgE
immunoglobulin E
IMP
investigational medicinal product
IRB
institutional review board
ITT
Intention-to-treat
IWRS
interactive web response system
J-PI
Japanese package insert
LDL
low density lipoprotein
LLOQ
lower limit of quantification
LOCF
last observation carried forward
LSFV
last subject first visit
LSLV
last subject last visit
LSMeans
Least Square Means
MACE
major adverse cardiovascular event
MedDRA
Medical Dictionary for Regulatory Activities
MEN 2
multiple endocrine neoplasia syndrome type2 
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 July 2015
Novo Nordisk
Trial ID: NN9068-4183
Version:
2.0
UTN: U1111-1170-1332 
Status:
Final
EudraCT no.: N/A
Page:
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MESI
medical event of special interest
MHLW
Ministry of Health, Labour and Welfare
MI
myocardial infarction
MMRM
mixed model for repeated measurement
MRHD
maximum recommended tolerated dose
MRI
magnetic resonance imaging
MTC
medullary thyroid carcinoma
NDA
new drug application
NIMP
non-investigational medicinal product
NYHA
New York Heart Association
OAD
oral antidiabetic drug
OD
once daily
PG
plasma glucose
PK
pharmacokinetic(-s)
PMDA
Pharmaceuticals and Medical Devices Agency, Japan
PPG
postprandial glucose
SAE
serious adverse event
SAS
safety analysis set
s.c.
subcutaneous(ly)
SD
standard deviation
SDV
source data verification
SGLT2i
sodium glucose co-transporter 2 inhibitor
SMBG
self-measured blood glucose
SU
Sulfonylureas
SUSAR
suspected unexpected serious adverse reaction
T2DM
type 2 diabetes mellitus
TEAE
treatment emergent adverse event
TIA
transient ischemic attack
TMM
Trial Materials Manual
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 July 2015
Novo Nordisk
Trial ID: NN9068-4183
Version:
2.0
UTN: U1111-1170-1332 
Status:
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TSH
thyroid stimulating hormone
TZD
thiazolidinedione
T3
triiodothyronine
T4
Thyroxine
UNR
upper normal range
UTN
Universal Trial Number
VLDL
very low density lipoprotein
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 July 2015
Novo Nordisk
Trial ID: NN9068-4183
Version:
2.0
UTN: U1111-1170-1332 
Status:
Final
EudraCT no.: N/A
Page:
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1
Summary
Objectives and endpoints
Primary objective
To confirm the efficacy of insulin degludec/liraglutide (IDegLira) in combination with one oral 
antidiabetic drug in controlling glycaemia in Japanese subjects with type 2 diabetes mellitus.
This is done by showing superiority of IDegLira vs. liraglutide and non-inferiority of IDegLira vs. 
insulin degludec (IDeg) on glycaemic control after 52 weeks of treatment.
Secondary objectives
To confirm superiority of IDegLira vs. IDeg after 52 weeks of treatment in terms of change from 
baseline in body weight, number of hypoglycaemic episodes and glycaemic control.
To compare general efficacy and safety of IDegLira, IDeg and liraglutide after 52 weeks of 
treatment.
Primary endpoint
Change from baseline in HbA1c (glycosylated haemoglobin) after 52 weeks of treatment.
Key secondary endpoints
Confirmatory secondary endpoints
The following confirmatory secondary endpoints will be tested with the aim to confirm superiority 
of IDegLira vs. IDeg.
∀
Change from baseline in body weight (kg) after 52 weeks of treatment
∀
Number of treatment emergent severe or blood glucose (BG) confirmed  hypoglycaemic 
episodes during 52 weeks of treatment
∀
Change from baseline in HbA1c after 52 weeks of treatment
Supportive secondary endpoints
∀
Change from baseline in fasting plasma glucose (FPG) after 52 weeks of treatment
Trial design
This is a 52-week, multi-centre, randomised, parallel three arms, open label trial in Japanese
subjects with type 2 diabetes inadequately controlled with one oral antidiabetic drug
(OAD) belonging to the following 6 OAD classes: metformin, alpha-glucosidase inhibitor (α-GI), 
thiazolidinedione (TZD), sulphonylurea(SU), sodium-glucose co-transporter 2 inhibitors (SGLT2i) 
or glinide. 
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 July 2015
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Trial ID: NN9068-4183
Version:
2.0
UTN: U1111-1170-1332 
Status:
Final
EudraCT no.: N/A
Page:
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Subjects will receive either IDegLira, IDeg or liraglutide once daily (randomised 1:1:1) all in 
combination with the pre-trial OAD kept in unchanged dose.
The total trial duration will be approximately 55 weeks.
Trial population
The number of subjects to be randomised is 807 (269 per arm). 
Key inclusion criteria
∀
Male or female Japanese subjects, age ≥20 years at the time of signing informed consent. 
∀
Type 2 diabetes subjects (diagnosed clinically) ≥ 6 months prior to screening.
∀
HbA1c 7.0-11.0 % (both inclusive) by central laboratory analysis, with the aim of a median 
of 8.3%. When approximately 50% of the randomised subjects have a HbA1c above 8.3%, 
the remaining subjects randomised must have a HbA1c below or equal to 8.3%; or when 
approximately 50% of the randomised subjects have a HbA1c below or equal to 8.3%, the 
remaining subjects randomised must have a HbA1c above 8.3%
∀
Body-mass index (BMI) ≥20 kg/m2
∀
Subjects on stable therapy with one OAD (defined as unchanged medication and unchanged 
dose) for at least 60 days (metformin, α-GI, TZD, SU, SGLT2i or glinide) prior to screening 
according to current approved Japanese labelling.
Key exclusion criteria
∀
Previous treatment with insulin (except for short-term treatment in connection with 
intercurrent illness including gestational diabetes)
∀
Treatment with any medication for the indication of diabetes or obesity other than stated in 
the inclusion criteria in a period of 60 days before screening.
∀
Anticipated initiation or change in concomitant medications in excess of 14 days known to 
affect weight or glucose metabolism.
∀
Impaired liver function, defined as alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) ≥2.5 times upper limit of normal.
∀
Renal impairment estimated Glomerular Filtration Rate (eGFR) <60mL/min/1.73m2 as per 
Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI).  
∀
Screening calcitonin ≥50 ng/L
∀
History of pancreatitis (acute or chronic)
∀
Personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine 
neoplasia type 2 (MEN 2)
∀
Subjects presently classified as being in New York Heart Association (NYHA) Class III and
IV
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 July 2015
Novo Nordisk
Trial ID: NN9068-4183
Version:
2.0
UTN: U1111-1170-1332 
Status:
Final
EudraCT no.: N/A
Page:
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Assessments
Key efficacy assessments;
∀
HbA1c
∀
Body weight
∀
FPG
∀
Insulin dose at the end of treatment 
Key safety assessments;
∀
Hypoglycaemic episodes
∀
Adverse events
Trial products
∀
Insulin degludec/liraglutide, 100 units/mL + 3.6 mg/mL, 3 mL pre-filled PDS290 pen 
injector
∀
Insulin degludec (Tresiba®), 100 units/mL, 3 mL pre-filled PDS290 pen injector
∀
Liraglutide (Victoza®), 6.0 mg/mL, 3 mL pre-filled FlexPen® pen
CONFIDENTIAL


Protocol
UTN: U1111-1170-1332 
Date:
15 July 2015
Status:
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Novo Nordisk
Trial ID: NN9068-4183
EudraCT no.: N/A
Version:
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2
Flow chart
Screening (SC) 
Randomisation (R)
Site visit (V) 
Telephone contact(T)1
Follow-up visit (FU)
SC
R
T
V
T
V
T
T
T
V
T
V
T
V
T
V
T
V
T
V
T
V
T
V
T
V
T
V
T
V
FU
Visit number
1
2
2B
3
3B
4
4B
5
5B
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
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
Time of visit (week)
-2
02
0.53
1
1.53
2
2.53
3
3.53
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
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
Visit window (days)
±1
±1
±1
±1
±1
±1
±1
±1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+3
SUBJECT RELATED INFORMATION/ASSESSMENTS
Informed consent
x
In/exclusion criteria
x
x
Randomisation
x
Withdrawal criteria
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Medical history/
Concomitant illness
x
Concomitant medication
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Demography
x
Diagnosis of diabetes
x
Diabetes history/ Diabetes 
complications
x
Family history of diabetes 
x
NYHA classification
x
Tobacco use
x
EFFICACY
Body weight
x
x
x
x
x
x
Waist circumference
x
x
x
Height
x
Blood pressure
x
x
x
x
x
x
                                                
1 A telephone contact may be converted to a site visit.
2 Randomisation should take place as soon as all screening (including laboratory) results are available, reviewed and the subject is confirmed eligible and no later than 14 days after Visit 1. 
3 Corresponding to previous visit date plus 3 days


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UTN: U1111-1170-1332 
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Screening (SC) 
Randomisation (R)
Site visit (V) 
Telephone contact(T)1
Follow-up visit (FU)
SC
R
T
V
T
V
T
T
T
V
T
V
T
V
T
V
T
V
T
V
T
V
T
V
T
V
T
V
T
V
FU
Visit number
1
2
2B
3
3B
4
4B
5
5B
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
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
Time of visit (week)
-2
02
0.53
1
1.53
2
2.53
3
3.53
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
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
Visit window (days)
±1
±1
±1
±1
±1
±1
±1
±1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+3
Lipids4
x
x
x
x
x
Glucose metabolism 
HbA1c
x
x
x
x
x
x
x
x
x
x
x
x
x
Fasting plasma glucose4
x
x
x
x
x
x
x
x
x
x
x
x
Fasting human insulin4
x
x
x
x
x
Fasting pro-insulin4
x
x
x
x
x
Fasting glucagon4
x
x
x
x
x
Fasting C-peptide4
x
x
x
x
x
Pre-breakfast SMBG5
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
9-point SMBG profile6
x
x
x
SAFETY
Adverse events 
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Technical complaints
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Hypoglycaemic episodes
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
ECG7
x
x
Eye examination8
x
x
                                                
4 The subjects must attend visits fasting, having consumed only water for the last 8 hours prior to the visits. No diabetic medication is allowed during fasting. If a subject attends in a non-fasting condition, blood 
sampling should be re-scheduled, preferably within the visit window
5 For IDegLira and IDeg arm: Daily pre-breakfast SMBG values should be recorded. 
For liraglutide arm: Pre-breakfast SMBG values on 3 consecutive days prior to each visit/telephone contact should be recorded.
6 9-point SMBG profiles must be started in the morning on two consecutive days preferably in the week prior to the site visit where the subject does not anticipate unusual strenuous exercise. Measurements are to 
be performed before and after (90 min after the start of the meal) breakfast, lunch, dinner, at bedtime, at 4 am and before breakfast on the following day.  
7 ECG obtained within 14 days prior to Visit 2 as part of routine practice may replace the screening assessment and ECG obtained within 14 days prior to Visit 54 is acceptable, if results are available for 
evaluation at Visit 2 and Visit 54, respectively.
8 Eye examination (fundoscopy/fundus photography) obtained within 90 days prior to Visit 2 as part of routine practise may replace the screening assessment if results are available for evaluation at Visit 2. Eye 
examination obtained within 28 days prior to Visit 54 is acceptable.


Protocol
UTN: U1111-1170-1332 
Date:
15 July 2015
Status:
Final
Novo Nordisk
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Version:
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Screening (SC) 
Randomisation (R)
Site visit (V) 
Telephone contact(T)1
Follow-up visit (FU)
SC
R
T
V
T
V
T
T
T
V
T
V
T
V
T
V
T
V
T
V
T
V
T
V
T
V
T
V
T
V
FU
Visit number
1
2
2B
3
3B
4
4B
5
5B
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
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
Time of visit (week)
-2
02
0.53
1
1.53
2
2.53
3
3.53
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
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
Visit window (days)
±1
±1
±1
±1
±1
±1
±1
±1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+3
Physical examination
x
x
x
Pulse
x
x
x
x
x
x
Antibodies4
x
x
x
x
x
x
Biochemistry
x
x
x
x
x
x
x
Haematology
x
x
x
x
x
Calcitonin
x
x
x
x
x
Pregnancy test9   
x
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
x
OTHER ASSESSMENTS
PK sampling10
x
x
x
x
x
x
TRIAL MATERIAL
IWRS session
x
x
x
x
x
x
x
x
x
x
x
x
x
Dispensing visit
x
x
x
x
x
x
x
x
x
x
x
Drug accountability
x
x
x
x
x
x
x
x
x
x
x
x
Hand out and instruction 
in direction for use, DFU11
x
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
REMINDERS
Hand out ID card
x
Hand out and instruct in 
BG-meter use
x
Attend visit fasting4
x
x
x
x
x
x
x
x
x
x
x
x
x
                                                
9 For females of childbearing potential: A serum pregnancy test must be performed at Visit 1 and Visit 54. Urine pregnancy test should be performed at site if a menstrual period is missed, or if pregnancy is 
suspected, indicated by (x) in the flowchart. 
10 Exact date and time for pharmacokinetic (PK) sampling must be recorded by the investigator in the eCRF. The following dosing’s (dose, injection site, date and time) prior to PK blood sampling must be 
recorded by the subject in the diary; dosing’s from the three previous days and from the day of visit, if a dose is taken before blood sampling. For the IdegLira arm, two samples must be obtained from each visit 
and be handled separately to allow analysis of both components.
11 DFU must be handed out to the subjects at Visit 2. At subsequent dispensing visits it is up to the investigator to assess if it is needed to hand out the DFU as indicated by (x) in the flow chart.


Protocol
UTN: U1111-1170-1332 
Date:
15 July 2015
Status:
Final
Novo Nordisk
Trial ID: NN9068-4183
EudraCT no.: N/A
Version:
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Screening (SC) 
Randomisation (R)
Site visit (V) 
Telephone contact(T)1
Follow-up visit (FU)
SC
R
T
V
T
V
T
T
T
V
T
V
T
V
T
V
T
V
T
V
T
V
T
V
T
V
T
V
T
V
FU
Visit number
1
2
2B
3
3B
4
4B
5
5B
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
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
Time of visit (week)
-2
02
0.53
1
1.53
2
2.53
3
3.53
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
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
Visit window (days)
±1
±1
±1
±1
±1
±1
±1
±1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+3
Hand out and instruct 
in/collect diary
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Confirmation of 
unchanged dose of  OAD
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
For liraglutide arm:
Confirmation of 
unchanged dose of 
liraglutide12
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Make appointment for eye 
examination
x
x
End of trial13 and sign off 
on case book
x
                                                
12 Subjects are to confirm unchanged dose of liraglutide once they have reached a dose of 1.8 mg.
13 In case a subject is being withdrawn from the trial, the investigator must ensure that the procedures for the last treatment visit (Visit 54) and the follow up visit (Visit 55) are undertaken, if possible and that the 
end of trial form is completed.


Protocol
CONFIDENTIAL
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Trial ID: NN9068-4183
Version:
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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. 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 with monotherapy or two 
oral anti-diabetic drugs (OADs) combined often fail to provide sustained glycaemic control. 
Treatment guidance from the Japanese Diabetes Society5 suggests a stepwise approach comprising 
lifestyle changes followed by pharmacological intervention. Initial monotherapy is recommended, 
escalated with combination therapy with OADs, glucagon-like peptide 1 (GLP-1) receptor agonists 
Insulin degludec 
Insulin degludec (IDeg) is a long-acting basal insulin and the active ingredient used in Tresiba®, 
which has been approved for use in Japan and the European Union (EU), and several other 
countries.
For more details on IDeg see current Investigator’s Brochure (IB) and any updates hereof6 and 
locally approved Japanese labelling.7
Liraglutide 
Liraglutide is an analogue native (human) glucagon-like peptide-1 (GLP-1) receptor agonist and the 
active ingredient in Victoza®, which is approved in several countries e.g. Japan, Australia, Canada, 
China, EU and the US for the treatment of adults with T2DM to achieve glycaemic control. The 
approved maximum dose of liraglutide in Japan is 0.9 mg/day, in all other countries the approved 
dose is 1.8 mg/day. Furthermore 3.0 mg/day (maximum dose) of liraglutide for the treatment of 
obesity has recently been approved in the US and EU and is marketed as Saxenda®.
For more details on liraglutide, please see the current Investigator’s Brochure8 and the Japanese 
approved labelling for Victoza® 9
Insulin degludec/liraglutide (IDegLira)
IDegLira is a basal insulin and GLP-1 analogue combination solution for subcutaneous (s.c.) 
injection for treatment of T2DM with once daily (OD) use.10 The combination bring complimentary 
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 July 2015
Novo Nordisk
Trial ID: NN9068-4183
Version:
2.0
UTN: U1111-1170-1332 
Status:
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EudraCT no.: N/A
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effects of the two compounds on fasting (insulin degludec and liraglutide) and postprandial 
(liraglutide) glycaemic control. The addition of liraglutide to insulin degludec may reduce the 
requirement of exogenous insulin (i.e. insulin sparing effect), hence minimising the risk of 
hypoglycaemia and weight gain, often associated with basal insulin treatment. The inherent weight 
reducing effect of liraglutide further contributes to the favourable weight profile of the combination 
drug compared to basal insulin treatment. Moreover, given the glucose dependent effect of 
liraglutide, the liraglutide component reduces postprandial glucose excursions, while reducing the 
risk of unwanted lowering of inter-prandial or fasting glucose. IDegLira is to be initiated and 
titrated to achieve adequate glycaemic control in a similar way as basal insulin therapy. IDegLira is 
titrated in dose steps, one dose step equalling 1 unit of IDeg and 0.036 mg of liraglutide. The 
approved maximum dose of IDegLira is 50 dose steps, which equals 50 units of IDeg and 1.8 mg of 
liraglutide. Efficacy and safety of IDegLira has been demonstrated in previous randomised global 
clinical trials (NN9068-3697 DUAL™I, NN9068-3912 DUAL™II, which has formed the basis of 
the marketing authorisation application (MAA) in EU among others. In the global DUAL™I and II 
and all other finalised clinical trials in the IDegLira clinical development programme (including 
trials NN9068-3951, NN9068-3851 and NN9068-3952), IDegLira has shown to effectively improve 
the glycaemic control of the subjects, and no unexpected safety issues were identified.
For more information, see the IDegLira NN9068 IB current version or any updates hereof.11
Marketing authorisation has been granted in several countries, e.g. for countries in EU. IDegLira is 
marketed with the brand name Xultophy®.
IDegLira is not approved for use in Japan. The current trial, NN9068-4183 - DUAL™I Japan, is 
part of the Japanese IDegLira development programme which includes trials; NN2211-4174, a trial 
comparing the efficacy and safety of liraglutide 1.8 mg/day to liraglutide 0.9 mg/day in Japanese 
subjects with T2DM, and NN9068-4184 - DUAL™II Japan, a trial confirming efficacy and safety 
of IDegLira in subjects with T2DM previously treated with insulin.
For an assessment of benefits and risks of the trial, see section 18.1.
3.2
Rationale for the trial
Given the progressive nature of T2DM, current anti-diabetic therapies, including treatment with 
basal insulin may not provide adequate or sustained glycaemic control or may be associated with an 
unacceptable risk of hypoglycaemia and weight gain. In addition, these therapies are often 
complicated and difficult for subjects to adhere to. The combination of IDeg and liraglutide in 
IDegLira provides complimentary effects of the two compounds on glycaemic control, reduced risk 
of hypoglycemia, and reduced risk of weight gain, in a single daily injection. The successful 
outcome of recent global trials combining basal insulin and GLP-1 receptor agonist treatment as 
separate injections led to the inclusion of this treatment combination in the most recent guidelines 
from the Japanese Diabetes Society, the American Diabetes Association (ADA) and in the 
CONFIDENTIAL


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Trial ID: NN9068-4183
Version:
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UTN: U1111-1170-1332 
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European Association for the Study of Diabetes (EASD) position statement on management of 
hyperglycaemia in T2DM.12,5,13
Both IDeg and liraglutide are on the market in Japan. Liraglutide is approved up to 0.9 mg/daily and 
the efficacy of Liraglutide 1.8 mg/daily is currently to be investigated in Japanese subjects
(NN2211-4174). The present confirmatory trial (NN9068-4183 DUAL™I Japan) in Japanese 
subjects with T2DM treated with OAD monotherapy aims to confirm efficacy and safety of once 
daily treatment with IDegLira, as compared to each of the components. Furthermore, safety and 
efficacy data of 1.8 mg liraglutide daily in combinations with OADs will be collected in this trial. 
As such the present trial (together with NN9068-4184) will be used for registration of IDegLira in 
Japan, (J-NDA), as agreed with the Japanese Pharmaceuticals and Medical Devices Agency 
(PMDA), and approval of 1.8 mg of liraglutide daily in Japan (together with NN2211-4174).
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 July 2015
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Trial ID: NN9068-4183
Version:
2.0
UTN: U1111-1170-1332 
Status:
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EudraCT no.: N/A
Page:
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4
Objectives and endpoints
4.1
Objectives
Primary objective
To confirm the efficacy of IDegLira in combination with one oral antidiabetic drug in controlling 
glycaemia in Japanese subjects with type 2 diabetes mellitus.
This is done by showing superiority of IDegLira vs. liraglutide and non-inferiority of IDegLira vs. 
IDeg on glycaemic control after 52 weeks of treatment.
Secondary objectives
To confirm superiority of IDegLira vs. IDeg after 52 weeks of treatment in terms of change from 
baseline in body weight, number of hypoglycaemic episodes and glycaemic control.
To compare general efficacy and safety of IDegLira, IDeg and liraglutide after 52 weeks of 
treatment.
Pharmacokinetic objective
The objective for the population pharmacokinetic (PK) analysis is to compare the pharmacokinetics 
of IDegLira and its mono-components given separately at clinically relevant doses during 52 weeks 
of treatment. Furthermore, the effects of pre-specified covariates on plasma concentrations of 
IDegLira will be evaluated.
4.2
Endpoints
4.2.1
Primary endpoint
Change from baseline in HbA1c (glycosylated haemoglobin) after 52 weeks of treatment.
4.2.2
Secondary endpoints
4.2.2.1
Confirmatory secondary endpoints
The following confirmatory secondary endpoints will be tested with the aim to confirm superiority 
of IDegLira vs. IDeg.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
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Trial ID: NN9068-4183
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∀
Change from baseline in body weight (kg) after 52 weeks of treatment*
∀
Number of treatment emergent severe or blood glucose (BG) confirmed  hypoglycaemic 
episodes during 52 weeks of treatment*
∀
Change from baseline in HbA1c after 52 weeks of treatment*
4.2.2.2
Supportive secondary endpoints
Supportive secondary efficacy endpoints:
∀
Insulin dose after 52 weeks of treatment
∀
Responder after 52 weeks of treatment (yes/no):
o
HbA1c < 7.0% 
o
HbA1c < 7.0% and change in body weight from baseline below or equal to zero
o
HbA1c < 7.0% without treatment emergent severe or BG confirmed symptomatic 
hypoglycaemic episodes during the last 12 weeks of treatment.
o
HbA1c < 7.0% and change in body weight from baseline below or equal to zero and 
without treatment emergent severe or BG confirmed symptomatic hypoglycaemic 
episodes during the last 12 weeks of treatment 
o
HbA1c ≤ 6.5% 
o
HbA1c ≤ 6.5% and change in body weight from baseline below or equal to zero
o
HbA1c ≤ 6.5% without treatment emergent severe or BG confirmed symptomatic 
hypoglycaemic episodes during the last 12 weeks of treatment
o
HbA1c ≤ 6.5% and change in body weight from baseline below or equal to zero and
without treatment emergent severe or BG confirmed symptomatic hypoglycaemic 
episodes during the last 12 weeks of treatment 
∀
Change from baseline after 52 weeks of treatment in: 
o
Fasting plasma glucose (FPG)*
o
Waist circumference
o
Blood pressure (systolic and diastolic)
o
Self-Measured Blood Glucose (SMBG) 9-point profile
o
9-point profile (individual points in the profile)
o
Mean of the 9-point profile
o
Mean of postprandial increments (from before meal to 90 min after for breakfast, 
lunch and dinner). The mean increment overall meals will be derived as the mean of 
all available meal increments.
CONFIDENTIAL


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Date:
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Trial ID: NN9068-4183
Version:
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∀
Fasting lipid profile (total cholesterol, low density lipoprotein cholesterol [LDL cholesterol], 
high density lipoprotein cholesterol [HDL cholesterol], very low density lipoprotein 
cholesterol [VLDL cholesterol], triglycerides, and free fatty acids) after 52 weeks of 
treatment 
∀
Fasting C-peptide, fasting human insulin,  fasting glucagon and proinsulin after 52 weeks of 
treatment
*Key secondary endpoint prospectively selected for disclosure on clinicaltrials.gov, clinicaltrials.jp 
and novonordisk-trials.com
Supportive secondary safety endpoints
∀
Number of treatment emergent adverse events (TEAEs) during 52 weeks of treatment
∀
Number of treatment emergent severe or blood glucose (BG) confirmed symptomatic 
hypoglycaemic episodes during 52 weeks of treatment.
∀
Number of treatment emergent nocturnal severe or BG confirmed symptomatic 
hypoglycaemic episodes during 52 weeks of treatment
∀
Number of treatment emergent hypoglycaemic episodes according to ADA definition during 
52 weeks of treatment
∀
Anti-drug antibodies, i.e. anti-IDeg antibodies including both IDeg specific and antibodies 
cross reacting with human insulin and anti-liraglutide antibodies including cross reactivity to 
GLP-1 and neutralising effect.
∀
Change from baseline in clinical evaluation after 52 weeks of treatment:
o
Physical examination
o
Fundoscopy or fundusphotography
o
Electrocardiogram (ECG)
o
Pulse
∀
Change from baseline in laboratory assessments after 52 weeks of treatment:
o
Biochemistry (including amylase and lipase)
o
Haematology
o
Calcitonin
4.2.2.3
Supportive secondary pharmacokinetic endpoints
∀
Serum concentrations of insulin degludec and plasma concentrations of liraglutide to be 
evaluated in a population PK analysis.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
15 July 2015
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Trial ID: NN9068-4183
Version:
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UTN: U1111-1170-1332 
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5
Trial design
5.1
Type of trial
This is a 52-week, multi-centre, randomised, parallel three arms open label trial, in Japanese
subjects with type 2 diabetes inadequately controlled with one oral antidiabetic drug
(OAD) belonging to the following 6 OAD classes: metformin, alpha-glucosidase inhibitor (α-GI), 
thiazolidinedione (TZD), sulphonylurea(SU), sodium-glucose co-transporter 2 inhibitors (SGLT2i) 
or glinide - hereafter commonly referred to as OADs in this document. Inadequately controlled 
diabetes will be defined as HbA1c level of 7.0-11.0 %, both inclusive.
A total of 807 subjects will be randomised into three treatment arms in a 1:1:1 manner, using a 
centralised allocation via interactive web response system (IWRS). Subjects will receive either 
IDegLira-, IDeg- or liraglutide once daily (OD), all in combination with pre-trial OAD kept in 
unchanged dose, see Figure 5-1 for trial design. Approximately 50% of the randomised subjects 
should have an HbA1c above 8.3%. Further, it will be aimed for an even number of subjects with an 
HbA1c ≤ 8.3% and > 8.3% within each pre-trial OAD class. In formal agreement with PMDA, 
randomisation will be stratified based on pre-trial treatment aiming to obtain approximately 50 
completers on SGLT2i- and 35 completers of each of the remaining 5 OAD classes, in each 
treatment arm.
Figure 5–1
Trial design
The total trial duration will be approximately 55 weeks, consisting of 2 weeks screening period, a 
52-week treatment period, and a follow-up visit (FU, i.e. Visit 55) 7 days after end of treatment 
(EOT, i.e. Visit 54). The purpose of the FU visit is to collect samples for antibody measurements 
and all adverse events (AEs) occurring in the week after end of treatment.
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5.2
Rationale for trial design
The rationale for a treatment period of 52 weeks is to assess and compare efficacy and safety of the 
3 treatments after longer-term exposure according to local requirement and agreement with PMDA. 
The randomisation is stratified with regard to use of OAD at baseline, since this may influence the 
glycaemic control.
An open-label design has been chosen due to two different treatment regimens; fixed dose treatment 
of liraglutide arm and treat-to-target (TTT) for the IDeg and IDegLira arms. 
Blinding of the trial by use of a double dummy design would mean an unacceptable number of 
injections, increase the complexity and thereby introduce an increased risk of non-compliance or 
withdrawal. The double-dummy design is therefore considered unacceptable for this trial. 
The TTT approach is used in the IDeg and IDegLira trial arms (and thereby the high frequency of 
visits) has been chosen in order to ensure optimal titration of insulin degludec and insulin 
degludec/liraglutide based on pre-breakfast SMBG values and thereby to obtain improved HbA1c
results.
5.3
Treatment of subjects
IDegLira, IDeg and liraglutide will be given as an addon to the pre-trial OAD therapy, which 
should be continued in unchanged dose, except for safety issues, as judged by the investigator. The 
use of OAD should be in accordance with current approved Japanese labelling. Antidiabetic drugs 
other than IDegLira, IDeg and liraglutide and pre-trial OAD are not to be used during the treatment 
period. For IDegLira and IDeg the subjects will initiate on a starting dose (recommended starting 
dose is 10 dose steps for IDegLira and 10 units of IDeg, respectively)and twice weekly titration 
will ensure that subjects are treated to target. For liraglutide, subjects will initiate a 6 weeks planned 
dose escalation period which can be prolonged with a total maximum of 7 days and there after 
remain on a stable daily doseof 1.8 mg/dayin a maintenance period, this dose can be reduced for a 
total maximum of 7 days, until end of treatment. Dose reduction or treatmentpause of longer 
duration unrelated to the tolerability of liraglutide is acceptable. For further details on treatment see 
Appendix Aand withdrawal criteria 10.
The investigational medicinal products (IMPs) used in this trial are described in section 9.
5.4
Treatment in the follow up period
After 52 weeks of trial product exposure, a 1-week interval between the end of treatment (Visit 54) 
and the follow-up (Visit 55) is necessary to allow for trial product washout. Subjects can at the 
investigator’s discretion be switched to a suitable marketed product excluding long acting insulin
analogues such as insulin degludec (Tresiba®), insulin detemir (Levemir®) and insulin glargine 
(Lantus®), or any GLP-1 receptor agonists as these may interfere with antibody measurements 
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performed at Visit 55. For instance intermediate acting human insulin like NPH may be used in the 
follow up period at the investigator’s discretion limiting the risk of interference with antibody 
measurements performed at Visit 55. 
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
IDegLira will be investigated in this trial to demonstrate efficacy and safety, when administered to 
insulin-naïve subjects with T2DM, inadequately controlled on a stable dose of one OAD. This is in 
line with clinical practice to escalate treatment in this setting when glycaemic control is not 
achieved or sustained with the addition of another OAD, or initiation of GLP-1 receptor agonists, 
basal insulin or a combination of a basal insulin and a GLP-1 receptor agonists, such as IDegLira.
Pre-trial OAD treatment should be in accordance with current Japanese approved labelling. Subjects 
should be on 60 days of stable treatment defined as unchanged medication and unchanged dose. 
OAD treatment should remain unchanged during the trial, however in case of safety concerns the 
dose may be reduced at the discretion of the investigator.
IDeg and liraglutide have been included as comparators in order to comply with regulatory 
requirements to assess the risk benefit profile of the combination product as compared to the 
individual components. 
For further information regarding dosing and treatment refer to Appendix A.
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6
Trial population
6.1
Number of subjects
Planned number of subjects to be screened (i.e. documented informed consent): 960
Number of subjects planned to be randomised: 807
Number of subjects expected to complete the trial: 675
The screening failure- and withdrawal rates are both assumed to be approximately 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 Japanese subjects, age ≥20 years at the time of signing informed consent. 
3. Type 2 diabetes subjects (diagnosed clinically) ≥ 6 months prior to screening.
4. HbA1c 7.0-11.0 % (both inclusive) by central laboratory analysis, with the aim of a median of 
8.3%. When approximately 50% of the randomised subjects have an HbA1c above 8.3%, the 
remaining subjects randomised must have an HbA1c below or equal to 8.3%; or when 
approximately 50% of the randomised subjects have an HbA1c below or equal to 8.3%, the 
remaining subjects randomised must have an HbA1c above 8.3%.
5. Body-mass index (BMI) ≥20 kg/m2
6. Subjects on stable therapy with one OAD (defined as unchanged medication and unchanged 
dose) for at least 60 days (metformin, α-GI, TZD, SU, SGLT2i or glinide) prior to screening 
according to current approved Japanese labelling. 
Rational for inclusion criteria
∀
Criterion 1 is applied through an ethical consideration, in accordance with the GCP1.
Criterion 2 is applied to exclude minors through an ethical consideration. Subjects aged 65 
year or older are included in accordance with the ICH guideline: Studies in support of 
special populations: Geriatrics.14
∀
Criteria 3 and 4 are chosen according to the objective of the trial. Being diagnosed for 6 
months or more is required in order to ensure correct diagnosis and metabolic stabilisation.
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HbA1c range (7.0-11.0 %) is chosen to include subjects whose glycaemic control is not 
adequate on OAD treatment and treatment with insulin and/or liraglutide is considered 
possible. The upper limit of HbA1c is chosen in order to exclude subjects with unacceptable 
glycaemic control who need a more intensive therapy. The split by HbA1c at 8.3% is 
included to ensure inclusion of subjects at both high and low levels of HbA1c within the 
specified range as done in previous phase 3a trials with IDegLira, based on upon the 
knowledge of the mono-components.
∀
Criterion 5 is chosen in order to assure that subject's BMI will not change to the low BMI 
category, since weight loss has been observed in global trials with liraglutide 1.8 mg/day.
∀
Criterion 6 is applied to ensure that the subject's glycemic control is stabilised at 
randomisation. Sixty (60) days of unchanged pre-trial OAD treatment are required.
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 signed 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 (e.g., abstinence, diaphragm, condom 
[by the partner], intrauterine device, sponge, spermicide or oral contraceptives).  
4. Receipt of any investigational medicinal product within 30 days before screening.
5. Previous treatment with insulin (except for short-term treatment in connection with inter current 
illness including gestational diabetes)
6. Treatment with any medication for the indication of diabetes or obesity other than stated in the 
inclusion criteria in a period of 60 days before screening.
7. Anticipated initiation or change in concomitant medications in excess of 14 days known to 
affect weight or glucose metabolism.
8. Impaired liver function, defined as alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) ≥2.5 times upper limit of normal.
9. Renal impairment estimated Glomerular Filtration Rate (eGFR) <60ml/min/1.73m2 as per 
Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI).  
10. Screening calcitonin ≥50 ng/L
11. History of pancreatitis (acute or chronic)
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12. Personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine
neoplasia type 2 (MEN 2)
13. Subjects presently classified as being in New YorkHeart Association (NYHA) Class III andIV,
see Appendix B for definitions.
14. Within the past 180 days any of the following: myocardial infarction, stroke or hospitalisation
for unstable angina and/or transient ischemic attack prior to screening.
15. Inadequately treated blood pressure as defined as Class 2 hypertension or higher
(Systolic≥160mmHg or diastolic ≥100 mmHg) in accordance with National High Blood
Pressure Education Program, 7th Joint National Committee and European Societies of
Hypertension/Cardiology (ESH/ESC) 2013 guidelines.
16. Proliferative retinopathy or maculopathy requiring acute treatment as verified by fundoscopy or
fundus photography performed within 90 days prior to screening.
17. Diagnosis of malignant neoplasms within the last 5 years (except basal and squamous cell skin
cancer, polyps and in-situ carcinomas) prior to screening.
18. History of diabetic ketoacidosis
19. Any condition that, in the opinion of the investigator might jeopardise subject’s safety or
compliance with the protocol.
Rationale for the Exclusion Criteria: 
∀
Criteria 1, 8-19 are chosen to ensure the safety of the subjects.
∀
Criterion 2 is chosen in order to exclude subjects who were judged as ineligible more than
once, since such subjects may be in an unstable condition and at risk for drop out.
∀
Criterion 3 is chosen as it is standard requirement for clinical trials with new chemical and
biological entities.
∀
Criteria 4-7 are chosen to minimise factors that may influence the results.
6.4
Withdrawal criteria
The subject may withdraw at will at any time. The subject’s request to discontinue must always be 
respected. 
The subject may be withdrawn from the trial at any time at the discretion of the investigator due to a 
safety concern. Subjects not tolerating the target dose of 1.8 mg liraglutide/day must be withdrawn 
from the trial due to safety concern, reporting the AE that led to the withdrawal.
The subject must be withdrawn from the trial if the following applies:
1. Included in the trial in violation of the inclusion and/or exclusion criteria and/or randomised in
error 
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2. Withdrawal of consent to proceed in the trial
3. Pregnancy
4. Intention of becoming pregnant
5. Initiation of any systemic treatment with products which in the investigator's opinion could
interfere with glucose or lipid metabolism (e.g. systemic corticosteroids)
6. Any of the calcitonin samples analysed by the central laboratory are ≥50 ng/L (see Appendix
D)
7. Subjects that are diagnosed with acute pancreatitis must be withdrawn from the trial (see 8.4.4).
8. Receipt of any investigational medicinal products after screening other than trial product.
9. If the pre-breakfast SMBG values taken on three consecutive days or if any of the FPG samples
analysed by the central laboratory exceeds the limit of:
∀
15.0 mmol/L (270 mg/dl) from baseline to week 6
∀
13.3 mmol/L (240 mg/dl) from week 7 to week 12
∀
11.1 mmol/l (200 mg/dl ) from  week 13 to week 52
Given there is no intercurrent cause for the hyperglycaemia, action is to be taken by the 
investigator as soon as possible to obtain a confirmatory FPG from central laboratory. If there is 
no intercurrent cause for the hyperglycaemia, and FPG exceeds the limits stated above, the 
subject must be withdrawn.
10. If subjects randomised to liraglutide do not tolerate the dose escalation or the target dose of 1.8
mg/day in the maintenance period as described in Appendix A, due to safety concern, they must 
be withdrawn. Dose reduction or treatment pause of longer duration than 7 days is acceptable, if 
unrelated to the tolerability of liraglutide. 
Rationale for the Withdrawal Criteria
∀
Criterion 1 is applied to withdraw the subjects enrolled or randomised in error.
∀
Criterion 2 is applied since subjects can withdraw at will at any time.
∀
Criteria 3 and 4 are applied as it is standard requirement for clinical trials with new chemical
and biological entities.
∀
Criterion 5 is applied to minimise any factors influencing the results of efficacy and safety
in the trial.
∀
Criteria 6-8 are applied for general safety concerns.
∀
Criterion 9 is applied to withdraw subjects who have persistently unacceptable poor
glycaemic control from an ethical and safety viewpoints.
∀
Criterion 10 is applied to withdraw subjects who do not tolerate the maximum dose of 1.8
mg liraglutide/day, since the study objective is to investigate this maximum dose compared
to IDegLira combination treatment.
6.5
Subject replacement
Withdrawn subjects will not be replaced.
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6.6
Rationale for trial population 
Japanese subjects with T2DM insulin naïve and inadequately controlled (HbA1c within 7.0-11.0%) 
with one oral antidiabetic drug (OAD) are eligible for inclusion in the trial. 
The rationale for the trial population, selected according to inclusion and exclusion criteria (see 6.2
and 6.3), is to ensure representation of subjects resembling the target T2DM population treated with 
OAD in need of increased glycaemic control with e.g. insulin and/or GLP1-analogue and to provide 
data on efficacy of IDegLira in combination with OAD treatment and safety of liraglutide 1.8 
mg/day in combination with OAD treatment. 
Only serious concomitant conditions (i.e. NYHA Class III and IV, history of recent serious cardiac 
event, neoplastic disease, renal or hepatic impairment, major surgery etc.), which could interfere 
with trial schedule/procedures, preclude subjects from entering into the trial.
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7
Milestones
Planned duration of recruitment period (FSFV – LSFV): 44 weeks.
End of trial is defined as LSLV.
7.1
Recruitment
Recruitment will be done according to agreements with the individual investigational sites. The 
screening and distribution within the pre-specified OAD classes and defined HbA1c distribution (see 
section 5.1 will be monitored closely during the entire recruitment period. In order to secure 
recruitment timelines, the agreed distribution of subjects between sites may be changed. The 
screening and randomisation rate will be followed closely in order to estimate when to stop 
screening, see section 11 for randomisation procedure.
7.2
Trial registration
Information of the trial will be disclosed at clinicaltrials.gov, novonordisk-trials.com and the 
Clinical Trials Information/JapicCTI site (clinicaltrials.jp). According to the Novo Nordisk Code of 
Conduct for Clinical Trial Disclosure, it will also be disclosed according to other applicable 
requirements such as those of the International Committee of Medical Journal Editors (ICMJE)15, 
the Food and Drug Administration Amendment Act (FDAAA)16, European Commission 
Requirements 17, 18 and other relevant recommendations or regulations. If a subject requests to be 
included in the trial via the Novo Nordisk e-mail contact at these web sites, Novo Nordisk may 
disclose the investigator’s contact details to the subject. As a result of increasing requirements for 
transparency, some countries require public disclosure of investigator names and their affiliations.
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8
Methods and assessments
8.1
Visit procedures
Timing of assessments and procedures are specified in the flow chart in section 2. This section 8 
includes a description of the procedures and assessments.
The investigator must ensure that trial procedures and assessments are performed as described in the 
protocol. Any discrepancies are considered protocol deviations and the investigator must take 
appropriate actions to avoid recurrence.
The investigator must keep a subject screening log, a subject identification code list and a subject 
enrolment log. In addition, the investigator must keep a log of staff and a delegation of task(s) list at 
the site. The subject screening log and subject enrolment log may be combined in one list.
8.1.1
Informed consent
A voluntary, signed and personally dated informed consent must be obtained from the subject 
before any trial-related activity.
All subjects should be provided with a copy of their own signed and dated informed consent form. 
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 come to a decision whether or not to 
participate in the trial. 
The responsibility for seeking informed consent must remain with the investigator, but the 
investigator may delegate the task to a medically qualified person, in accordance with local 
requirements. The written informed consent must be signed and personally dated
by the person who seeks the informed consent before any trial-related activity.
If information becomes available that may be relevant to the subject’s willingness to continue 
participating in the trial, the investigator must inform the subject in a timely manner, and a revised 
written subject information form must be provided and a new informed consent must be obtained.
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8.1.2
Investigators assessments 
Review of diaries, laboratory reports, ECGs, eye examinations, physical examinations, AEs etc. 
must be documented with the investigator´s dated signature either on the front page of the document 
and/or in the subject´s medical records. The signed documents must be retained at the trial site as 
source documentation.
8.1.3
Screening
Screening must take place within 14 days prior to randomisation. For procedures and assessments at 
screening visit please see flow chart, section 2. 
At screening, subjects will be provided with a card stating that they are participating in a trial and 
giving contact address(es) and telephone number(s) of relevant trial site staff. Subjects should be 
instructed to return the card to the investigator at the last trial visit or to destroy the card after the 
last visit.
Each subject will be assigned a unique 6-digit subject number which will remain the same 
throughout the trial. The first three digits in the subject number will consist of the site number and 
the last three digits of the subject number will indicate the individual number.
Subjects will continue on their current diabetes treatment until randomisation.
8.1.4
Screening failures
For screening failures the screening failure form in the case report form (eCRF) must be completed 
with the reason for not continuing in the trial. The reason(s) for failure should also be completed on 
the inclusion- and or exclusion form in the eCRF. Serious adverse events from screening failures 
must be transcribed by the investigator into the eCRF. Follow-up of serious adverse events (SAEs) 
must be carried out according to section 12.
A screening failure session must be made in the IWRS.  The case book must be signed.
Re-sampling (unless samples are lost or unsuitable for analysis e.g. haemolysed) or re-screening is 
not allowed if the subject has failed one of the inclusion or exclusion criteria.
8.1.5
Visits attended fasting
At the time points specified in the flowchart (section 2), subjects must attend the visits fasting. 
Fasting is defined as having consumed no food and drink except for water for the last 8 hours prior 
to visit. No diabetes treatment is allowed during fasting but other concomitant medication should be 
taken.
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If the subject attends a fasting visit in a non-fasting state, subject should be asked to return to the 
site in a fasting state to have fasting assessments done preferably within the visit window for the 
relevant visit.
8.1.6
Randomisation visit
Randomisation (Visit 2) must take place within 14 days after the screening visit. All results from 
screening assessments, including laboratory results, ECG and eye examination must be available 
and reviewed by the investigator and the inclusion/exclusion criteria must be carefully reviewed to 
ensure the subject is eligible prior to the randomisation. 
The subjects must attend the randomisation visit fasting. 
Randomisation of subjects will be done using the IWRS (see section 10).
The subject should take the first dose of trial product on the day of Visit 2 after randomisation is 
done or the day after. The date of the first dose of trial product should be recorded in the diary and 
transcribed to the eCRF.
8.1.7
Visits
For visit numbers, timing of visits, phone contacts and visit windows during the trial period, please 
refer to the flow chart (section 2). Visits can be re-scheduled within the allowed visit window.
8.1.8
End of treatment visit
At the end of treatment visit (Visit 54), a completion session must be done in the IWRS and last 
date on trial product must be captured in the IWRS. Further, the final drug accountability must be 
performed via IWRS. Subjects can at the investigator’s discretion be switched to a suitable 
marketed product at Visit 54 according to section 5.4, to be taken in the follow up period.
8.1.9
Follow-up visit
The follow-up visit should be undertaken no earlier than 7 days after Visit 54. Subjects must attend 
this visit in a fasting state prior to the blood sampling for antibody analysis. Subjects on any type of 
insulin should not have administered this within 12 hours of the blood sampling, see section 8.4.5
for rationale. 
At completion of this visit, subjects may be switched to another suitable marketed product at the 
discretion of the investigator.
The end-of-trial form (EOT form) must be completed in the eCRF.
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8.1.10
Unscheduled visits
Unscheduled visits can be performed at any time at the discretion of the investigator. An 
unscheduled visit should be performed if, e.g. an AE occurs that needs further attention or blood 
samples needs to be re-taken (out of visit window).
An unscheduled visit form must be completed in the eCRF stating the reason for the visit. 
If the subject attends the clinic only to obtain trial supplies, no unscheduled visit form should be 
completed but an additional dispensing call in the IWRS must be performed.
8.1.11
Re-scheduled visits
If the subject attends a fasting visit in a non-fasting condition, blood sampling should be re-
scheduled, preferably within the visit window.
8.1.12
Withdrawals
If a subject is withdrawn from the trial, the investigator must aim to undertake procedures similar to 
those for Visit 54 as soon as possible and the procedures similar to those for the follow-up visit 
(Visit 55) not earlier than 7 days after Visit 54.
The end-of-trial form (EOT 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 IWRS. The case book in the eCRF must be signed.
Although a subject is not obliged to give his/her reason(s) for withdrawing from a trial, the 
investigator must make a reasonable effort to ascertain the reason(s), while fully respecting the 
subject’s rights. Where the reasons are obtained, the primary reason for not completing the trial 
must be specified on the end-of-trial form in the eCRF.
8.2
Subject related information 
8.2.1
Concomitant illness and medical history
A concomitant illness is any illness that is present at the start of the trial i.e. at the first visit or 
found as a result of a screening procedure which also includes assessments performed between Visit 
1 and Visit 2 and at Visit 2. T2DM should not be recorded as concomitant illness.
Any change to a concomitant illness should be recorded in the eCRF during the trial. A clinically 
significant worsening of a concomitant illness must be reported as an AE.
Medical history is a medical event that the subject has experienced in the past. Only relevant 
medical history related to the evaluation of this trial should be reported at the investigator’s 
discretion. 
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Information about the subject’s medical history and history of diabetes should be recorded at the 
screening visit (Visit 1) in the eCRF at the medical history/concomitant illness form and diabetes 
history/diabetes complications form, respectively. Family history of diabetes should be reported at 
the family history form.
The following should be recorded in the diabetes history/diabetes complications form;
∀
Date of diagnosis of diabetes
∀
Diabetes complications
The following should be recorded in the family history form
∀
Family history of diabetes
The information collected for concomitant illness and medical history should include diagnosis, 
date of onset and date of resolution or continuation, as applicable.
8.2.2
Concomitant medication
A concomitant medication is any medication, other than the trial products and OADs, which is 
taken during the trial, including the screening and follow-up periods.
Details of any concomitant medication must be recorded at Visit 1. Changes in concomitant 
medication must be recorded at each visit as they occur. 
The information collected for each concomitant medication includes trade name or generic name, 
indication, start date and stop date or continuation. 
If a change is due to an AE, then this must be reported according to section 12. If the change 
influences the subject’s eligibility to continue in the trial, the monitor must be informed.
Concomitant medication and anti-diabetic therapy initiated at end of treatment visit (Visit 54) and at 
the follow up visit (Visit 55) should not be recorded in the eCRF.
8.2.3
OAD medication
OADs are considered non-investigational medicinal products (NIMPs) and dosing information 
should be recorded at the Concomitant Specific Drug - OAD form in the eCRF.
All subjects should continue treatment with the pre-trial OAD and the dose should be kept 
unchanged, unless for safety reasons. If case of changes, it must be reported in the eCRF.
The information collected for OAD medication includes trade name or generic name, dose, start 
date and stop date or continuation. 
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8.2.4
Demography
Demography will be recorded in the IWRS system at screening visit (Visit 1) and consist of:
∀
Date of birth
∀
Sex
In addition, the following should be captured in the eCRF:
∀
Race (according to regulation in Japan)
8.2.5
Tobacco use
Details of tobacco use (smoking status) must be recorded in the eCRF at the screening visit (Visit 
1). Smoking is defined as smoking at least one cigarette or equivalent daily. The collected 
information should include whether the subject is a current or previous smoker or never has 
smoked.
8.3
Assessments for efficacy
8.3.1
Blood samples for efficacy parameters
Blood samples will be drawn according to flow chart (see section 2) and analysed at the central- or 
special laboratories to determine levels of the following efficacy laboratory parameters:
Glucose metabolism
∀
HbA1c
∀
Fasting plasma glucose (FPG)
∀
Fasting human insulin
∀
Fasting pro-insulin
∀
Fasting glucagon
∀
Fasting C-peptide
Pro-insulin/fasting human insulin ratio will be calculated on glucose metabolism parameters to 
assess beta-cell function and insulin resistance.
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Lipids (fasting)
∀
Total cholesterol
∀
LDL-cholesterol
∀
VLDL-cholesterol
∀
HDL-cholesterol
∀
Triglycerides
∀
Free fatty acids
8.3.2
Self-measured blood glucose
At Visit 1, subjects will be provided with blood glucose (BG) meters to be used for all self-
measured blood glucose (SMBG) measurements during the trial. The subjects will receive written 
instructions for use and demonstration on how to use the device including performance of regular 
calibrations according to the manufacturer´s instructions. As necessary, the instructions will be 
repeated during the trial.
The blood glucose meters use test strips calibrated to plasma values. Therefore, all measurements 
performed with capillary blood are automatically calibrated to plasma equivalent glucose values, 
which will be shown on the display. The term SMBG will be used consequently also for plasma 
values.
Subjects should be instructed in how to record the results of the SMBGs in the diaries. The record 
of each pre-breakfast SMBG should include date, and value and additionally the 9-point SMBG 
profiles must also include the actual clock time of each measurement. All data from the diary must 
be transcribed into the eCRF during or following the contact. If obtained via phone and a 
discrepancy is later detected, the values in the eCRF should be corrected.
For SMBG values that meet the definition of a hypoglycaemic episode (see section 8.4.9), relevant 
information must be registered in the subject diary and a hypoglycaemic episode form must be 
completed in the eCRF.
Subjects randomised to IDegLira and IDeg
Subjects randomised to IDegLira or IDegshould perform once daily SMBG measurement prior to 
breakfastand preferably after having only water since midnight. SMBG data from 3 consecutive 
days is used for titration, see Appendix A.
Subjects randomised to liraglutide
Subjects randomised to liraglutide should perform SMBG measurements prior to breakfast on 3 
consecutive days prior to each visit/telephone contact. The SMBG data is used to assess subject’s 
glucose control. 
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8.3.3
9-point self-measured blood glucose profiles
Subjects will be instructed to perform a 9-point self-measured blood glucose (SMBG) profiles three 
times during the trial according to the flow chart in section 2. The measurements should take place 
on two consecutive days preferably within the week prior to the site visit on days where the subject 
does not anticipate unusual strenuous exercise. 
The points of SMBG measurements are listed in Table 8.1 below. The subjects should always start 
with the pre-breakfast measurement and the SMBG values should be recorded in the diary including 
actual clock time and date for the measurements.
Trial product and OAD treatment should be withheld until after the pre-breakfast SMBG
measurements have been performed.
Table 8–1
9-point profile (SMBG) (!) 
Time point
Day 1
The following day 
Before breakfast
!
! 
90 min after start of breakfast
! 
Before lunch
! 
90 min after start of lunch
! 
Before dinner
! 
90 min after  start of dinner
! 
At bedtime
! 
At 4 a.m.
! 
8.3.4
Body measurements
Height
Height is measured without shoes in centimetres (cm) and recorded in the eCRF to nearest ½ cm. 
Height measured at Visit 1 will only be used for calculation of BMI.
Body weight
Body weight should be measured (kilogram [kg], with one decimal) without shoes and only wearing 
light clothing and recorded in the eCRF.
Preferably the same equipment should be used throughout the trial.
Body Mass Index
The body mass index (BMI) will be calculated at Visit 1 for assessment of eligibility (section 6.2) 
and at the other visits for efficacy assessment.
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The BMI will be calculated by the eCRF once body weight at the visit specified in the flow chart 
(section 2 and height at Visit 1 are entered.
BMI will be calculated as follows:
BMI (kg/m2) = Body weight (kg)/(Height [m] × Height [m])
Waist circumference
The waist circumference is defined as the minimal abdominal circumferences located midway 
between the lower rib margin and the iliac crest.
Three consecutive measurements of waist circumference must be performed and recorded in the 
eCRF. The waist circumferences will be measured in cm using a non-stretchable measuring tape 
provided by Novo Nordisk. It should be recorded to the nearest ½ cm preferably using the same 
measuring tape throughout the trial.
The subject should be measured in a standing position with an empty bladder and wearing light 
clothing with accessible waist. The subject should be standing with arms down their side and feet 
together. The tape should touch the skin but not compress soft tissue and twists in the tape should 
be avoided. The subject should be asked to breathe normally and the measurement should be taken 
when the subject is breathing out gently. 
8.3.5
Blood pressure
Blood pressure (systolic and diastolic) must be measured at the visits specified in the flowchart in 
section 2.
The blood pressure must be measured after the subject has been resting for at least 5 minutes in a 
sitting position.
At Visit 1 the blood pressure should be measured three times and all three values should be entered 
into 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).
It is recommended to use the same arm, device and cuff as used at the first visit for the subsequent 
measurements. For the subsequent visits, one measurement needs to be performed.
If the investigator suspects white coat hypertension, re-assessment of the blood pressure (as 
described above) is allowed.
8.4
Assessments for safety
Any abnormal clinically significant finding that is present at the start of the trial, i.e. at the first visit 
or found as a result of a screening procedure which also includes assessments performed between 
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Visit 1 and Visit 2 and at Visit 2 should be recorded as a concomitant illness. Any new abnormal, 
clinically significant finding during the trial and any clinically significant worsening from baseline 
(up to Visit 2) must be reported as an AE (see section 12). 
All adverse events (AEs) must be collected and reported according to the procedures described in 
section 12.
8.4.1
Adverse Events requiring special forms in the eCRF 
For some AEs the investigator must fill in special forms in the eCRF. The AEs that require special 
forms in the eCRF are:
∀
Cardiovascular events
∀
Pancreatitis
∀
Thyroid disease
∀
Neoplasm
∀
Renal failure
In case any of these events fulfil the criteria for a SAE, report according to section 12.2.
Cardiovascular events
Cardiovascular events that are suspected as being related tobelow, requires special forms in the 
eCRF (see also Appendix C);
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Acute coronary syndrome
All types of myocardial infarction or hospitalisation for unstable angina. If an event of acute 
coronary syndrome is observed during the trial, this must be recorded as an AE and on a specific 
acute coronary syndrome form in the eCRF. The following information must be reported if 
available:
∀
Duration of symptoms
∀
Changes in ECG
∀
Collection of cardiac biomarkers
∀
Cardiac imaging
∀
Cardiac stress testing
∀
Angiography
∀
Use of thrombolytic drugs
∀
Revascularisation procedures
Cerebrovascular events, e.g. transient ischemic attack (TIA), stroke
If a cerebrovascular event is observed during the trial, this must be recorded as an AE and on a 
specific cerebrovascular event form in the eCRF. The following information must be reported if 
available:
∀
Type of event (e.g. TIA, Stroke)
∀
Contributing condition
∀
Neurologic signs and symptoms
∀
History of neurologic disease
∀
Imaging supporting the condition
∀
Treatment given for the condition
Heart failure requiring hospitalisation
If an event of heart failure requiring hospitalisation (admission to an in-patient unit or a visit to an 
emergency department that results in at least a 24 hour stay) is observed during the trial, this must 
be recorded as an SAE and in addition on a specific cardiovascular event form in the eCRF.
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The following information must be reported if available:
∀
Signs and symptoms of heart failure
∀
NYHA Class, see Appendix Bfor definition
∀
Supportive imaging
∀
Supportive laboratory measurements
∀
Initiation or intensification of treatment for this condition
Pancreatitis
If an event of pancreatitis is observed during the trial, this must be recorded as an AE and on a 
specific pancreatitis event form in the eCRF. The following information must be reported if 
available:
∀
Signs and symptoms of pancreatitis
∀
Specific laboratory test supporting a diagnosis of pancreatitis:
o
Amylase
o
Lipase
o
ALT and AST
o
Bilirubin
o
Alkaline Phosphatase (AP)
∀
Imaging performed and consistency with pancreatic disease
∀
Complications to the event
∀
Relevant risk factors for pancreatic disease including:
o
History of gallstones
o
History of pancreatitis
o
Family history of pancreatitis
o
Trauma
Thyroid disease
If an event of thyroid disease, including any thyroid neoplasms observed during the trial, this must 
be recorded as an AE and on a specific thyroid disease event form in the eCRF. The following 
information must be reported if available:
∀
History of thyroid disease
∀
Signs and symptoms leading to investigations of thyroid disease
∀
Specific laboratory tests describing thyroid function including:
o
Thyroid stimulating hormone (TSH)
o
Total and free triiodothyronine (T3) and thyroxine (T4) and Free Thyroid Index
o
Calcitonin
o
Thyroid peroxiodase antibodies
o
Thyroglobulin and thyroglobulin antibody
o
Thyroid stimulating hormone receptor antibody
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∀
Diagnostic imaging performed and any prior imaging supporting the disease history 
∀
Pathologic examinations
∀
Treatment given for the condition
∀
Risk factors identified
∀
Family history of thyroid disease
Neoplasm
All events of neoplasm (excluding thyroid neoplasm, but including malignant neoplasm, in situ 
neoplasm and benign neoplasm) must be recorded as an AE and on a specific neoplasm event form 
in the eCRF. The following information must be reported if available:
∀
Type of neoplasm
∀
Symptoms leading to identification of event
∀
Diagnostic imaging
∀
Pathological examination results
∀
Treatment for the event
∀
Participation in screening programs
∀
Risk factors associated to the event
Renal failure
If an event of renal failure is observed during the trial the following additional information should 
be reported if available: 
∀
Signs and symptoms of renal failure
∀
Specific laboratory test supporting a diagnosis of renal failure
∀
Imaging performed supporting the diagnosis
∀
Kidney biopsy results
∀
Relevant risk factors associated to the event
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8.4.2
Blood samples for safety parameters
Blood samples must be drawn according to flow chart (section 2) and will be analysed at the 
central- or specialised laboratory to determine levels of the following safety laboratory parameters:
∀
Haematology:
o
Haemoglobin
o
Haematocrit
o
Thrombocytes
o
Erythrocytes
o
Leucocytes
o
Differential count (eosinophils, neutrophils, basophils, monocytes and lymphocytes)
∀
Biochemistry:
o
Creatinine
o
eGFR value will be calculated using the serum creatinine result and the CKD-EPI
formula by the central laboratory.
o
Alanine aminotransferase (ALT)
o
Aspartate aminotransferase (AST)
o
Alkaline phosphatase
o
Sodium
o
Potassium
o
Albumin
o
Bilirubin (total)
o
Urea
o
Creatine kinase
o
Calcium total
o
Calcium (albumin corrected)
o
Lipase
o
Amylase
∀
Hormones:
o
Calcitonin, if  ≥ 10 ng/L, see Appendix D for monitoring of calcitonin
∀
Antibodies; see section 8.4.5
∀
Pregnancy test:
o
Human serum chorionic gonadotrophin (hCG), see section 8.4.3 below
8.4.3
Pregnancy test
Females of childbearing potential must have a serum pregnancy test (beta-human chorionic 
gonadotropin [beta-hCG]) performed according to the flow chart, section 2.
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Urine pregnancy tests will be performed at site during the trial for females of childbearing potential 
if a menstrual period is missed or if pregnancy is suspected.
If at telephone contact, subject reports missing menstrual period, the subject will have to attend the 
site as soon as possible to have a urine-stick pregnancy test done.
Pregnancy test will not be required for women who have undergone a hysterectomy or tubal
ligation, or for women above the age of 50 years, who have been without menses for at least 1 year. 
This must be documented in the subject’s medical record and eCRF.
8.4.4
Assessments in case of suspicion of acute pancreatitis
In case of acute, severe persistent abdominal pain leading to a suspicion of acute pancreatitis, the 
trial product should promptly be interrupted until pancreatitis is ruled out. Appropriate additional 
examinations must be performed, including local measurement of amylase and lipase. Subjects that 
are diagnosed with acute pancreatitis must be withdrawn from the trial. Diagnosis is usually based 
on at least 2 of the following 3 criteria: 
∀
characteristic abdominal pain
∀
amylase and/or lipase > 3x upper normal range (UNR) or
∀
characteristic findings on ultrasound /computerised axial tomography [CT]/magnetic
resonance imaging [MRI]
If acute pancreatitis is ruled out,trial product should be re-initiated. If, in subjects treated with 
liraglutide 1.8 mg/day, the discontinuation period is for three days or more, the trial product should 
be restarted with a dose of 0.3 mg/day, and dose escalation procedure described in Appendix A 
should be followed. In all other subjects the re-initiation should be at the discretion of the 
investigator. The investigator should consider both the last number ofunitsor dose steps of last 
dose of IDeg or IDegLira and the recommendations outlined in Appendix A.
Appropriate treatment and careful monitoring of the subject should be initiated if pancreatitis is 
confirmed as per at least 2 of the criteria´s listed above.
8.4.5
Antibody sampling
Blood samples will be drawn as per flow chart for determination of serum antibodies to insulin 
degludec (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. 
Samples from follow up visit (Visit 55) positive for anti-liraglutide antibodies will in addition be 
analysed for in vitro neutralising effect in a cell based assay. 
Subjects should be fasting at blood sampling for antibody assessment and the sampling should be 
prior to administering the trial product in the treatment period and prior to other insulin products, if 
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administered, at the follow up visit (Visit 55). This will ensure that the drug concentrations are at 
their lowest at the time of sampling limiting the level of drug interference with the antibody 
analysis.
Antibody results will not be provided to the investigator during the trial conduct as these are not 
used for clinical evaluation. The results will be described in the clinical trial report (CTR) after end 
of trial.
Please see section 24.2 for information on storage/retention of antibody samples.
8.4.6
ECG (electrocardiogram)
A 12-lead ECG must be performed by the investigator or delegated staff and interpreted by the 
investigator. To document this, the investigator must sign and date the ECG print out and the 
interpretation must follow the categories:
∀
Normal
∀
Abnormal
o
Specify abnormality
o
Was the result clinically significant? (Yes/No)
The ECG at screening must be done at the latest at Visit 2 and the results must be interpreted by the 
investigator prior to performing any procedures related to Visit 2.
ECG obtained within 14 days prior to Visit 2 as part of routine practise may replace the screening 
assessment, if results are available for evaluation at Visit 2. 
ECG obtained within 14 days prior to Visit 54 is acceptable, if results are available for evaluation.
8.4.7
Eye Examination
Eye examination (fundoscopy/fundus photography) must be performed at the visits specified in the 
flowchart (see section 2) by the investigator or a local Ophthalmologist according to local practice. 
Dilation is not a requirement. The result of the fundoscopy/fundus photography will be interpreted 
locally by the investigator. To document this, the investigator must sign and date the result page and 
the interpretation must follow the categories:
∀
Normal
∀
Abnormal
o
Specify abnormality
o
Was the result clinically significant? (Yes/No)
Fundoscopy/fundus photography performed within 90 days prior to Visit 2 is acceptable. If a 
funduscopy/fundus photography has been performed prior to the screening visit (Visit 1) the 
procedure does not need to be repeated, unless worsening of visual function since the last 
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examination has been noted. The investigator must still interpret, sign and date the result page. If 
fundoscopy or fundus photography is performed before a subject has signed the informed consent
form, it must be documented in the medical record that the reason for performing the procedure was
not related to the present trial.
Eye examination performed within a period of 28 days before Visit 54 is acceptable if results are 
available at Visit 54.
8.4.8
Physical Examination
A physical examination must be performed at the visits specified in the flowchart (section 2) and 
includes:
∀
Head, ears, eyes, nose, throat, neck
∀
Respiratory system
∀
Cardiovascular system
∀
Gastrointestinal system incl. mouth
∀
Musculoskeletal system
∀
Central and peripheral nervous system
∀
Skin
∀
General appearance
∀
Lymph node palpation
∀
Thyroid gland
The interpretation must follow the categories;
∀
Normal
∀
Abnormal
o
Specify abnormality
o
Was the result clinically significant? (Yes/No)
Relevant findings present at or prior to screening should be recorded on the concomitant 
illness/medical history form in the eCRF in accordance with section 8.2.1. Findings not present at 
screening must be reported as AE according to section 12.
8.4.9
Hypoglycaemic episodes
Blood glucose should always be measured and recorded when a hypoglycaemic episode is 
suspected. 
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All plasma glucose values:
∀
≤ 3.9 mmol/L (70 mg/dL) or 
∀
> 3.9 mmol/L (70 mg/dL) when they occur in conjunction with hypoglycaemic symptoms 
should be recorded by the subject. These must be transcribed into the eCRF (hypoglycaemic 
episode form) throughout the trial from Visit 2 to follow up visit. 
The record should include the following information:
∀
Date and time of hypoglycaemic episode
∀
The plasma glucose level before treating the episode (if available) 
∀
Whether the episode was symptomatic 
∀
Whether the subject was able to treat him/herself (if no, see below)
∀
Type, date, time and dose of last trial product and OAD administration prior to episode 
∀
Date and time of last main meal prior to episode 
∀
Whether the episode occurred in relation to physical activity
∀
Any sign of fever or other disease 
∀
Whether the subject was asleep when the episode occurred
o
If yes, whether the symptoms of the episode woke up the subject
If the subject was not able to treat him/herself
The answer to the question: "Was subject able to treat him/herself?" must be answered "No" for an 
episode requiring assistance of another person to actively administer carbohydrate, glucagon, or 
take other corrective actions. Plasma glucose concentrations may not be available during an event, 
but neurological recovery following the return of plasma glucose to normal is considered sufficient 
evidence that the event was induced by a low plasma glucose concentration.19
Oral carbohydrates should not be given if the subject is unconscious.
If the question "Was the 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)
∀
Type of treatment provided by other person (i.e. oral carbohydrates, glucagon, IV glucose or 
other, please specify)
∀
Were symptoms alleviated after 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 trial product
dose, other factors not listed, please specify or none)
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∀
Did the subject experience seizure?
∀
Was the subject unconscious/comatose?
∀
Did the subject experience any of the following symptoms20
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
∀
Description of the episode, if applicable 
A hypoglycaemic episode form must be filled in for each hypoglycaemic episode. If the 
hypoglycaemic episode fulfils the criteria for a SAE then an AE form and a safety information form 
(SIF) must also be filled in, see section 12.
8.4.10
Pulse
Pulse (beats per minute) should be recorded in the eCRF at site visits according to section 2 after 
resting at least 5 minutes in a sitting position.
8.4.11
Suspicion of acute hypersensitivity to trial products
If trial product is discontinued as a consequence of suspicion of severe acute hypersensitivity 
(anaphylactic reaction) to the trial product, blood sampling for assessment of binding antibodies and 
IgE antibodies against the active components in the trial products, i.e. insulin degludec and 
liraglutide, should be conducted. Depending on treatment arm, samples will be analysed for anti-
liraglutide antibodies, anti-insulin degludec antibodies including cross reacting antibodies to human 
insulin, anti-liraglutide IgE antibodies and anti-insulin degludec IgE antibodies. 
Blood sampling should be performed at least 7 days after but no later than 6 months after the event. 
Treatment with insulin degludec (Tresiba®), insulin degludec/insulin aspart (Ryzodeg®) and any 
GLP-1 receptor agonists (e.g. Victoza® and Byetta®) is not permitted in this period.
8.5
Laboratory assessments
All laboratory samples will be analysed by a central- and specialised laboratories contracted by 
Novo Nordisk. The central laboratory will provide all laboratory supplies for the sampling and 
transportation of all blood samples taken during the trial. The central laboratory may utilise 
subcontractors.
Description of assay methods and a detailed description of the procedures for obtaining samples, 
handling, storage and shipment of the samples are specified in a trial-specific laboratory manual 
provided to the sites by the central laboratory. Information regarding laboratory materials such as 
tubes and labels are also described. 
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Laboratory samples can be drawn another day than on the day of the actual visit as long as it is 
within the visit window stated in the flow chart (section 2).
Samples will be coded in order to keep subject’s identity anonymous.
Laboratory results (except PK and antibodies results) will be made available on an ongoing basis by 
the central laboratory. Laboratory reports must be reviewed, dated and signed by the investigator. It 
should be specified whether out of range results are clinically significant.
The laboratory equipment may provide analyses not requested in the protocol but produced 
automatically in connection with the requested analyses according to specifications in the laboratory 
standard operating procedures. Such data will not be transferred to the trial database, but abnormal 
values will be reported to the investigator. The investigator must review all laboratory results for 
concomitant illnesses and AEs and report these according to this protocol.
Antibody samples: The investigator will not be able to review the results of antibody measurements 
in relation to AEs as these are often analysed after LSLV.
8.6
Other assessments
8.6.1
Pharmacokinetics 
Blood samples for PK will be drawn in all subjects at visits specified in the flow chart in section 2. 
Blood samples will be drawn once per subject per visit. Samples from the IDegLira and IDeg arms 
will be analysed for serum concentrations of insulin degludec and samples from the IDegLira and 
liraglutide arms will be assayed for plasma concentrations of liraglutide using validated ELISA 
assays. For subjects in the IDegLira arm, two samples must be obtained from each visit and be 
handled separately: a serum sample for insulin degludec assay and a plasma sample for liraglutide 
assay. 
For a detailed description of the handling of the samples is referred to the laboratory manual. 
The investigator must record the exact date and time for blood sampling in the eCRF. 
Subjects must be instructed to write in their diary:
∀
Date, dose, injection site and exact clock time for injection from the previous three days of 
dosing and on the day of the visit, if a dose is taken before blood sampling
It is important to explain to the subjects the necessity of accurate diary recording as the investigator 
must transcribe all data into the eCRF subsequently and to ensure accurate PK evaluation.
The population PK analysis is outlined in section 17.5.
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Date:
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Trial ID: NN9068-4183
Version:
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UTN: U1111-1170-1332 
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PK results will not be provided to the investigator as these are not used for clinical evaluation 
during the trial. The data will be included in a bio-analytical report that will be available before 
finalising the CTR and the data will be retained at Novo Nordisk.
PK samples will be destroyed no later than at the completion of the CTR.
Destruction of PK samples must only occur with permission from Novo Nordisk.
8.6.2
Subject diary
The subjects must be provided with the subject diaries at the specified visits (section 2). The 
investigator and/or delegate or site staff must instruct subjects to record the following in the diary:
∀
Date and dose of trial product (including first and last dose)
∀
Date and value of all SMBG measurements and also actual clock time of the 9-point SMBG 
measurements (see sections 8.3.2 and 8.3.3)
∀
PK sampling visits: date, dose, injection site and exact clock time for injection from the 
previous three days of dosing and on the day of the visit, if a dose is taken before blood 
sampling 
∀
Hypoglycaemic episodes (see section 8.4.9)
∀
Medical problems (e.g. AEs)
∀
Changes in concomitant medication including OAD dose
The investigator and/or delegate or site staff are allowed to record the following in the diary:
∀
Prescribed doses of trial product
∀
Time and date of next visit and/or phone contact
∀
Subject ID and site contact details
The diary must be reviewed by the investigator to ensure that AEs, including overall change in 
health and concomitant medication, are reported see section 8.2.2 and 12. Review of the diaries 
must be documented either on the front page of the documents and/or in the subject’s medical 
record. The investigator and/or delegate or site staff must transcribe data from the diary into the 
eCRF throughout the trial. If necessary, the investigator and/or delegate or site staff should convert 
the format of data used by the subject into the format used in the eCRF. The diaries dispensed to 
subjects at a previous visit should be collected at the following site visit.  
If clarification of entries or discrepancies in the diary is needed, the subject should be questioned 
and a conclusion made in the medical record. Care should be taken not to bias the subject.
8.6.3
Subject compliance
Throughout the trial, the investigator will remind the subjects to follow the trial procedures and 
requirements to ensure subject compliance. The investigator should assess the compliance of the 
subject at each visit based on a review of glycaemic control, adherence of the visit schedule, 
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Protocol
CONFIDENTIAL
Date:
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Novo Nordisk
Trial ID: NN9068-4183
Version:
2.0
UTN: U1111-1170-1332 
Status:
Final
EudraCT no.: N/A
Page:
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completion of the subject diary including SMBG measurements. Subject compliance will further be 
assessed by monitoring the drug accountability. The unused amount of trial product will be assessed 
against the dispensed amount and, in case of discrepancies, the subject must be asked. Further, the 
investigator will monitor the treatment compliance of the subjects during trial conduct by e.g. 
assessing the results of the laboratory samples on an ongoing basis.  
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Protocol
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Date:
15 July 2015
Novo Nordisk
Trial ID: NN9068-4183
Version:
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UTN: U1111-1170-1332 
Status:
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EudraCT no.: N/A
Page:
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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 products must not be used, if they do not appear clear and colourless. 
9.1
Trial products
The following investigational medicinal products (IMPs) will be provided by Novo Nordisk A/S, 
Denmark:
Table 9–1
Investigational medicinal products
Trial product
Strength
Dosage form
Route of 
administration
Container/
delivery device 
Insulin degludec/
liraglutide
100 units/mL + 
3.6 mg/mL
Solution for
Injection
Subcutaneous 
(s.c.)
3 mL pre-filled 
PDS290 pen injector
Insulin degludec
(Tresiba®)
100 units/mL
Liraglutide
(Victoza®)
6.0 mg/mL
3 mL pre-filled
FlexPen®
OADs are considered as non-investigational medicinal products (NIMPs) and hence will not be 
provided by Novo Nordisk. 
9.2
Labelling
The trial products will be labelled in accordance with Annex 1321, local regulations and trial 
requirements.
Each trial site will be supplied with sufficient trial products for the trial on an ongoing basis 
controlled by the IWRS. Dispensing unit numbers (DUNs) will be distributed to the trial sites 
according to enrolment and randomisation.
The investigator must document that direction for use (DFU) is given to the subject orally and in 
writing at the first dispensing visit (Visit 2).  At subsequent dispensing visits it is up to the 
investigator to assess if it is needed to hand out the DFU as indicated in the flow chart in section 2.
9.3
Storage 
Storage conditions and in-use conditions of the trial products are outlined in Table 9–2.
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Trial ID: NN9068-4183
Version:
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Status:
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Table 9–2
Storage conditions for investigational medicinal products
Trial product
Storage conditions
(not-in-use)
In-use conditions
In-use 
time*
Insulin degludec/
liraglutide
Store in refrigerator (2ºC-8ºC)
Do not freeze
Protect from light
Store below 30°C
Do not freeze
Protect from light
Use within 
3 weeks
Insulin degludec
Store in refrigerator (2ºC-8ºC)
Do not freeze
Protect from light
Do not store above 
30°C
Protect from light
Use within 
8 weeks
Liraglutide
Store in refrigerator (2ºC-8ºC)
Do not freeze
Protect from light
Store at room 
temperature (not 
above 30°C) 
Do not freeze
Protect from light
Use within 
30 days
*In-use time starts when the product is taken out of the refrigerator in the subject’s home. 
The investigator, the head of the study site or the trial product storage manager (if assigned by the 
head of the study site) must ensure the availability of proper storage conditions, and also record and 
evaluate the temperature. The investigator must inform Novo Nordisk immediately if any trial 
product has been stored outside specified conditions (e.g. outside temperature range). A temperature 
log must be kept to document storage within the right temperature interval and storage facilities 
should be checked frequently.
Trial product that has been stored improperly must not be dispensed to any subject and must be 
stored separately from other trial products but within allowed temperature range before it has been 
evaluated and approved for further use by Novo Nordisk. The investigator must take appropriate 
action to ensure correct storage.
9.4
Drug accountability and destruction
Drug accountability is the responsibility of the investigator, the head of the study site or the trial 
product storage manager if assigned by the head of the study site.
Subjects must be 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) can be 
stored at room temperature and must be stored separately from non-allocated trial product.
Drug accountability is performed by using the IWRS. Only dispensed DUNs returned by the subject 
(used/partly used or unused) are accounted for.
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Trial ID: NN9068-4183
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Destruction will be done according to local procedures after accountability is finalised and verified 
by the monitor. Destruction of products must be documented.
9.5
Auxiliary supplies
The following will be provided by Novo Nordisk A/S:
∀
Directions for Use (DFU) for pen devices
The following will be provided by Novo Nordisk Pharma Ltd. in accordance with the TMM:
∀
Needles for pen devices
∀
Blood glucose meters (BG meters) and BG meter auxiliaries
∀
Glucose for treating a hypoglycaemia
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Protocol
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Date:
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Novo Nordisk
Trial ID: NN9068-4183
Version:
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UTN: U1111-1170-1332 
Status:
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10
Interactive web response system
A trial-specific interactive web response system (IWRS) will be set up which can be accessed at any 
time via the internet or telephone. Access to the IWRS must be restricted to and controlled by 
authorised persons. IWRS user manuals will be provided to each trial site.
IWRS is used for: 
∀
Screening
∀
Screening failure
∀
Randomisation
∀
Medication arrival
∀
Dispensing (including additional dispensing)
∀
Withdrawal
∀
Completion
∀
Drug accountability
∀
Data change
It is important that only DUNs allocated by the IWRS are dispensed to the subject. By doing this it 
will ensure that;
∀
The right trial product is dispensed to the right subject
∀
Needed stock is available at a site for the subjects
∀
Drug accountability can be made in the IWRS
If a subject requires additional trial product between dispensing visits, the site must perform an 
additional dispensing session in IWRS.
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Protocol
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Date:
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Novo Nordisk
Trial ID: NN9068-4183
Version:
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UTN: U1111-1170-1332 
Status:
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EudraCT no.: N/A
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11 Randomisation procedure
11.1
Randomisation
The IWRS, a centralised randomisation /allocation system, must be used for randomisation. Only 
eligible subjects are allowed to be randomised. The subjects will be randomised into three treatment 
arms in a 1:1:1 manner and the randomisation will be stratified based on pre-trial OAD.
It will be strived for a trial population with a median HbA1c level of 8.3%. When the number of 
subjects with an HbA1c below or equal to 8.3% reach approximately 50% of the required number of 
subjects to be randomised, it will only be possible to randomise subjects with an HbA1c above 
8.3%, or vice versa.
The HbA1c distribution of subjects (including the OAD stratification) will be followed closely and 
investigators will be notified before screening is closed. Eligible subjects for randomisation will be 
randomised if closing occurs while they are in the screening period.
11.1.1
Stratification
To ensure a fixed proportion of subjects on each of the 6 OAD classes (metformin, α-GI, TZD, SUs, 
SGLT2i or glinide), in each of the treatment arms, the randomisation will be stratified with regards 
to pre-trial OAD treatment (see section 5.1 for number of completers within each strata). Further, it 
will be aimed for an even number of subjects with an HbA1c ≤ 8.3% and > 8.3% within each pre-
trial OAD class. The stratification will be controlled by Novo Nordisk trial management in close 
collaboration with the sites participating in the trial.
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12 Adverse events, and technical complaints and pregnancies
12.1
Definitions
Adverse event 
An adverse event (AE) is any untoward medical occurrence in a subject administered a product, and 
which does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom or disease temporally associated with the use of a product, whether or not 
considered related to the product. AEs should be reported from the first trial-related activity after 
the subject has signed the informed consent until the end of the post treatment follow-up period 
(Visit 55).
An AE includes:
∀
A clinically significant worsening of a concomitant illness.
∀
A clinical laboratory adverse event (CLAE): a clinical laboratory abnormality which is 
clinically significant, i.e. an abnormality that suggests a disease and/or organ toxicity and is 
of a severity that requires active management. Active management includes active treatment 
or further investigations, for example change of medicine dose or more frequent follow-up 
due to the abnormality.
The following should not be reported as AEs:
∀
Pre-existing conditions, including those found as a result of screening procedures (pre-
existing conditions should be reported as medical history or concomitant illness).
∀
Pre-planned procedures unless the condition for which the procedure was planned has 
worsened from the first trial related activity after the subject has signed the informed 
consent.
∀
Non-serious hypoglycaemia is an AE, but is reported on a hypoglycaemic episode form 
instead of on an AE form, see section 8.4.9.
The following three definitions are used when assessing an AE:
Severity
∀
Mild - no or transient symptoms, no interference with the subject's daily activities.
∀
Moderate - marked symptoms, moderate interference with the subject's daily activities.
∀
Severe - considerable interference with the subject's daily activities; unacceptable.
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Causality
Relationship between an AE and the relevant trial product(s): 
∀
Probable - Good reason and sufficient documentation to assume a causal relationship.
∀
Possible - A causal relationship is conceivable and cannot be dismissed.
∀
Unlikely - The event is most likely related to aetiology other than the trial product.
Final outcome
∀
Recovered/resolved - The subject has fully recovered, or by medical or surgical treatment 
the condition has returned to the level observed at the first trial-related activity after the 
subject signed the informed consent.
∀
Recovering/resolving - The condition is improving and the subject is expected to recover 
from the event. This term is only applicable if the subject has completed the trial or has died 
from another AE.
∀
Recovered/resolved with sequelae - The subject has recovered from the condition, but with 
lasting effect due to a disease, injury, treatment or procedure. If a sequela meets an SAE 
criterion, the AE must be reported as an SAE.
∀
Not recovered/not resolved - The condition of the subject has not improved and the 
symptoms are unchanged, or the outcome is not known.
∀
Fatal - This term is only applicable if the subject died from a condition related to the 
reported AE. Outcomes of other reported AEs in a subject before he/she died should be 
assessed as "recovered/resolved", "recovering/resolving", "recovered/resolved with 
sequelae" or "not recovered/not resolved". An AE with fatal outcome must be reported as an 
SAE.
∀
Unknown - This term is only applicable if the subject is lost to follow-up.
Serious adverse event
A serious adverse event (SAE) is an experience that at any dose results in any of the following:
∀
Death.
∀
A life-threateninga experience.
∀
In-patient hospitalisationb or prolongation of existing hospitalisation.
∀
A persistent or significant disability or incapacityc.
∀
A congenital anomaly or birth defect.
∀
Important medical events that may not result in death, be life threateninga or require 
hospitalisationb may be considered an SAE when - based on appropriate medical judgement 
- they may jeopardise the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in the definition of SAEd. 
∀
Suspicion of transmission of infectious agents via the trial product must always be 
considered an SAE. 
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a.
The term "life threatening" in the definition of SAE refers to an event in which the subject was 
at risk of death at the time of the event. It does not refer to an event which hypothetically might 
have caused death if it was more severe.
b. The term "hospitalisation" is used when a subject: 
o
Is admitted to a hospital or in-patient, irrespective of the duration of physical stay, or 
o
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 a SAE.
Medical event of special interest
A medical event of special interest (MESI) is an event which, in the evaluation of safety, has a 
special focus. A MESI is an AE (SAE or non-serious AE) which fulfils one or more of the below 
defined MESI criteria.
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Medication errors concerning trial products:
∀
Administration of wrong drug or use of wrong device.
∀
Note: Use of wrong DUN is not considered a medication error unless it results in
administration of wrong drug.
∀
Wrong route of administration, such as intramuscular instead of subcutaneous.
∀
Administration of an 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 the
intended dose to an extent where clinical consequences for the trial subject were likely to
happen as judged by the investigator, although they did not necessarily occur.
When reporting a MESI, the following forms must be completed: the AE form, safety information 
form (SIF) and specific MESI form as described in section 12.2 and also illustrated Figure 12–1.
Adverse events with additional data collection
AEs with additional data collection are AEs defined as critical for the evaluation of product safety.
For these AEs the investigator must fill in additional forms in the eCRF. The AEs that require 
additional forms in the eCRF are:
1. Acute coronary syndrome (MI or hospitalisation for unstable angina)
2. Cerebrovascular event (stroke or TIA)
3. Heart failure requiring hospital admission
4. Neoplasms
5. Pancreatitis
6. Thyroid disease
7. Renal failure
For detailed information on AEs with additional data collection, see section 8.4.1.
Along with fatal events, the above mentioned events with additional data collectionwill be 
adjudicated by an external independentevent adjudication committee (EAC)as described in section 
12.7.2. For further information regarding definitions, rationales, and events that will be adjudicated, 
see Appendix C.
Technical complaint
A technical complaint is any written, electronic, or oral communication that alleges product 
(medicine or device) defects. The technical complaint may be associated with an AE, but does not 
concern the AE itself.
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Examples of technical complaints:
∀
The physical or chemical appearance of trial products (e.g. discoloration, particles or 
contamination)
∀
The packaging material (e.g. leakage, cracks, rubber membrane issues or errors in labelling 
text)
∀
Problems related to devices (e.g. to the injection mechanism, dose setting mechanism, push 
button or interface between the pen and the needle)
12.2
Reporting of adverse events
All events meeting the definition of an AE must be collected and reported. This includes events 
from the first trial-related activity after the subject has signed the informed consent until the end of 
the post-treatment follow-up period (Visit 55). Please be aware that hypoglycaemic episodes should 
not be reported before any trial drug is given e.g. hypoglycaemic episodes should be reported from 
Visit 2.The AEs 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, IDeg, liraglutide: Current version of the product specific company core data sheets
(CCDSs) or any updates thereto.
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 (SIF) must be completed in addition to the AE form. If several 
symptoms or diagnoses occur as part of the same clinical picture, one safety information form can 
be used to describe all the SAEs. 
For AEs requiring additional information, a specific event form in addition to the AE form must be 
completed.
MESIs, regardless of seriousness, must be reported using 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.
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The AE form for a non-serious AE not fulfilling the MESI criteria should be signed when the event 
is resolved or at the end of the trial.
Timelines for initial reporting of AEs:
The investigator must complete the following forms in the eCRF within the specified timelines:
∀
SAEs: The AE form within 24 hours and the safety information form within 5 calendar
days of the investigator's first knowledge of the SAE. For SAEs with additional data 
collection; in addition also the specific event form within 14 calendar days of the 
investigator’s first knowledge of the AE. Both forms must be signed within 7 calendar days
from the date the information was entered in the eCRF. 
∀
SAEs fulfilling the MESI criteria: In addition to above, the MESI form within 14 
calendar days of the investigator's first knowledge of the AE.
∀
Non-serious AE fulfilling the MESI criteria: The AE form, and safety information form 
and MESI form within 14 calendar days of the investigator's first knowledge of the event.
∀
Non-serious AEs with additional data collection: The AE form and the specific event 
form within 14 calendar days of the investigator's first knowledge of the event
∀
Events for adjudication: Event Adjudication Document Collection Form must be 
populated within 14 calendar days. The investigator should provide the medical 
documentation within 4 weeks of event identification
If the eCRF is unavailable, the concerned AE information must be reported on paper forms and sent 
to Novo Nordisk by fax, e-mail or courier within the same timelines as stated above. When the 
eCRF becomes available again, the investigator must enter the information on the appropriate forms 
in the eCRF.
Contact details (fax, telephone, e-mail and address) are provided in the investigator trial master file.
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An AE is 
observed and 
reported 
It is an SAE
complete:
∀
AE form ≤ 24 hours
∀
SIF ≤ 5 calendars days
It is a non-serious AE
complete:
∀
AE form ≤ 14 calendar
days
Fulfilling 
seriousness 
criteria?
Additional 
data 
collection 
requeried?
Additional 
data 
collection 
required?
Complete ≤ 14 calendar days:
∀
Specific event form
∀
For medication Error
(MESI): Medication Error
form
No additional forms to 
be completed
Yes
No
Complete ≤ 14 calendar days: 
∀
Specific event form
∀
For Medication Error
(MESI):  SIF and 
Medication Error form
Yes
No
No
Yes
Is the AE 
category selected 
for adjudication?
Complete ≤ 14 
calendar days:
∀
Adjudication
form 
Yes
AE: Adverse Event
SIF: safety information form
All timelines are from the investigator’s
first knowledge of the event
Addtional data collection described in chapter 8.4
Events for adjudication described in chapter 12.7
No
Figure 12–1
Initial reporting of AEs 
Reporting of trial product-related SUSARs by Novo Nordisk:
Novo Nordisk will notify the investigator of trial product-related suspected unexpected serious 
adverse reactions (SUSARs) in accordance with local requirements and 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 PMDA of trial product-related SUSARs. In addition, Novo Nordisk will inform the IRBs 
of trial product-related SUSARs in accordance with local requirement and GCP1, unless locally this 
is an obligation of the investigator.
12.3
Follow-up of adverse events
The investigator must record follow-up information by updating the forms in the eCRF. 
Follow up information must be reported to Novo Nordisk according to the following:
∀
SAEs: All SAEs must be followed until the outcome of the event is “recovered/resolved”,
“recovered/resolved with sequelae” or “fatal”, and until all queries have been resolved.
Cases of chronic conditions, cancer or AEs ongoing at time of death (where death is due to
another AE) may be closed with the outcome “recovering/resolving” or “not recovered/not
resolved”. Cases 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
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information. This is also the case for previously non-serious AEs which subsequently 
become SAEs. 
∀
Non-serious AEs: Non-serious AEs must be followed until the outcome of the event is
“recovering/resolving”, “recovered/resolved” or “recovered/resolved with sequelae” or until
the end of the follow-up period stated in the protocol, whichever comes first, and until all
queries related to these AEs have been resolved. Cases of chronic conditions, cancer or AEs
ongoing at time of death (where death is due to another AE) may be closed with the
outcome “recovering/resolving” or “not recovered/not resolved”. Cases can be closed with
the outcome of “recovering/resolving” when the subject has completed the follow-up period
and is expected by the investigator to recover.
∀
Non-serious AE fulfilling the MESI criteria: Non-serious AE fulfilling the MESI criteria
must be followed as specified for non-serious AEs. 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.
∀
Non-serious AE with additional data collection: Non-serious AE with additional data
collection must be followed as specified for non-serious AEs. Follow-up information on AE
with additional data collection 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.
The investigator must ensure that the worst case severity and seriousness assessment 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 PDS290 pen
injector
∀
Insulin degludec (Tresiba®), 100 units/mL, 3 mL pre-filled PDS290 pen injector
∀
Liraglutide (Victoza®), 6.0 mg/mL, 3 mL pre-filled FlexPen® pen
∀
Needles for prefilled pens
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.
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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. A technical 
complaint form for each batch or lot number or for each DUN must be completed.
The investigator must complete the technical complaint form in the eCRF within the following 
timelines of the trial site obtaining knowledge of the technical complaint:
∀
Technical complaint assessed as related to an SAE within 24 hours
∀
All other technical complaints within 5 calendar days
If the eCRF is unavailable or when reporting a technical complaint that is not subject related, the 
information must be provided on a paper form by fax, e-mail or courier to Customer Complaint 
Center, Novo Nordisk, within the same timelines as stated above. When the eCRF becomes 
available again, the investigator must enter the information on the technical complaint form in the 
eCRF.
12.4.2
Collection, storage and shipment of technical complaint samples
The investigator must collect the technical complaint sample and notify the monitor within 5 
calendar daysof obtaining the sample at trial site. The monitor must coordinate the shipment to 
Customer Complaint Center, Novo Nordisk (the address is provided in Attachment I) and ensure 
that the sample is sent as soon as possible. Aprint or copy of the technical complaint form must be 
sent with the sample.
The investigator must ensure that the technical complaint sample contains the batch, or lot number 
and, if available, the DUN.
If the technical complaint sample is unobtainable, the investigator must specify on the technical 
complaint form why it is unobtainable. 
Storage of the technical complaint sample must be done in accordance with the conditions 
prescribed for the product. The shipment of the technical complaint sample should be done in 
accordance with the same conditions as for storage (see section 9). 
12.5
Pregnancies in female subjects
Female subjects must be instructed to notify the investigator immediately if they become pregnant 
during the trial. The investigator must report any pregnancy in subjects who have received trial 
product(s).
The investigator must follow the pregnancy until the pregnancy outcome, and until the newborn 
infant is one month of age.
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The investigator must report information about the pregnancy, pregnancy outcome, and health of 
the newborn infant(s), as well as AEs in connection with the pregnancy, and AEs in the foetus and 
newborn infant.
The following must be collected and reported by the investigator to Novo Nordisk - electronically 
(e.g. in PDF format), or by fax or courier:
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.
Reporting of AE information
The investigator has to report AEs in connection with the pregnancy as well as in the foetus and 
newborn infant(s). The SAEs that must be reported include abnormal outcome, such as foetal death 
(including spontaneous abortion), and congenital anomalies (including those observed at gross 
examination or during autopsy of the foetus), as well as other pregnancy complications fulfilling the 
criteria of an SAE.
Forms and timelines for reporting AEs:
∀
Non-serious AEs:
o
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: 
o
Paper AE form* within 24 hours of the investigator's first knowledge of the SAE.
o
Paper safety information form within 5 calendar days of the investigator's first 
knowledge of the SAE.
o
SAE follow-up information to the AE form and/or safety information form within 24 
hours of the investigator's first knowledge of the follow-up information.
*It must be clearly stated in the AE diagnosis field on the AE form if the event occurred in the 
subject, foetus or newborn infant.
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Any queries or follow-up requests from Novo Nordisk to non-serious AEs, SAEs and pregnancy 
forms must be responded to by the investigator within 14 calendar days from the date of receipt of 
the request, unless otherwise specified in the follow-up request.
12.6
Precautions and/or overdose
Treatment with glucose-lowering agents such as insulin and GLP-1 therapies carry the risk of 
hypoglycemia.
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 flat and of somewhat longer duration than currently marketed long-acting 
insulin preparations. It may therefore take several hours more before stable normal blood glucose is 
achieved after a hypoglycaemic episode when comparing to existing long acting insulin analogues.
Symptoms of minor hypoglycaemia should be treated with ingestion of carbohydrate. Severe 
hypoglycaemia resulting in loss of consciousness must be treated according to best medical practice 
(e.g. 25mL of 50% dextrose solution given intravenously, or 0.5-1mg of glucagon given s.c. or 
intramuscularly).
From clinical trials and marketed use of liraglutide (Victoza®) overdoses up to 40 times the 
recommended maintenance dose of 1.8 mg (72 mg) outside Japan 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 and liraglutide, the subject may in some cases experience 
loss of fluids/dehydration, due to vomiting, nausea or diarrhoea. It is important to avoid dehydration 
by drinking plenty of fluids.
For further information see the NN9068, NN1250 and NN2211 IB’s or any update hereof. 11 ,6,8
12.7
Committees related to safety
12.7.1
Novo Nordisk safety committee
Novo Nordisk has an established internal IDegLira safety committee overseeing ongoing safety 
surveillance. The IDegLira safety committee will be informed about the results of continuous on-
going safety surveillance activities for IDegLira.
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12.7.2
Event adjudication committee
An independent external event adjudication committee (EAC) is established to perform qualitative 
or quantitative validation of selected AEs according to pre-defined diagnostic criteria. The 
validation is based on review of pre-defined clinical data related to the specific AE.
The events are reviewed by the EAC in a blinded manner.
The following AEs will be adjudicated in this trial:
∀
Fatal events
∀
Acute coronary syndrome (MI or hospitalisation for unstable angina)
∀
Cerebrovascular event (stroke or TIA)
∀
Heart failure requiring hospital admission
∀
Neoplasms including thyroid neoplasm (all kinds of abnormal growth)
∀
Pancreatitis
∀
Thyroid disease requiring thyroidectomy
Event adjudication will be performed for AEs in randomised subjects including AEs with an onset 
date during the screening period. Event adjudication will not be performed for AEs in screening 
failures.
The EAC is composed of permanent members who cover required medical specialities. The EAC 
members must disclose any potential conflicts of interest and must be independent of Novo 
Nordisk. The role of the EAC is solely to adjudicate events in a blinded manner. The EACs will 
have no authorisations to impact on trial conduct, trial protocol or amendments.
The EAC will review translated copies in English of medical documentation received in the 
adjudication packages (for example X-ray, ECGs, ultrasound images, discharge summaries, 
pathology reports, and death certificates). The investigator must provide medical documentation as 
soon as possible, when they receive the request from Novo Nordisk.
The EAC can evaluate an event not initially reported as an AE for adjudication to be adjudicated. If 
so then the investigator must provide medical documentation as soon as possible, when they receive 
the request from Novo Nordisk or the Event Adjudication vendor.
AEs for adjudication must be reported according to section 12.2 and all relevant predefined 
documents provided according to instructions in the event adjudication site manual.
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13 Case report forms 
Novo Nordisk will provide a system for the electronic case report forms (eCRF). This system and 
support services to the system will be provided by an external supplier.
Ensure that all relevant questions are answered, and that no empty data field exists. If a test or an 
assessment has not been done and will not be available, or if the question is irrelevant (e.g. is not 
applicable), indicate this according to the data entry instructions.
The following will be provided as paper CRFs;
∀
Pregnancy forms
In addition paper AE forms, safety information forms (SIFs) and technical complaint forms will be 
provided. These must be used when access to the eCRF is revoked or if the eCRF is unavailable. 
On the paper CRF forms the investigator must print legibly, using a ballpoint pen. The investigator 
must ensure that all questions are answered, and that no empty data blocks exist. It must be ensured 
that no information is recorded outside the data blocks. If a test/assessment has not been done and 
will not be available, the investigator must 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) the 
investigator must indicate this by writing "NA" (not applicable) in the appropriate answer field. 
Further guidance can be obtained from the instructions in the CRF.
The investigator must ensure that all information is consistent with the source documentation. By 
electronically signing the case book in the eCRF, the investigator confirms that the information in 
the eCRF and related forms is complete and correct.
13.1
Corrections to case report forms 
Corrections to the CRF data may be made by the investigator or the investigator's delegated staff. 
An audit trail will be maintained in the eCRF application containing as a minimum: the old and the 
new data, identification of the person entering the data, date and time of the entry and reason for the 
correction.
If corrections are made by the investigator's delegated staff after the date the investigator has signed 
the case book, the case book must be signed and dated again by the investigator.
Corrections to the data in the paper CRFs should be made by drawing a straight line through the 
incorrect data and then writing the correct entry next to the data that were crossed out. Each 
correction must be initialled, dated and explained (if necessary) by the investigator or the 
investigator’s authorised staff.
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13.2
Case report form flow 
The investigator must ensure that data is recorded in the eCRF as soon as possible, preferably 
within 5 days after the visit. Once data has been entered, it will be available to Novo Nordisk for 
data verification and validation purposes. Queries will be generated on an ongoing basis and 
investigator must ensure that queries are resolved as soon as possible, preferable within 5 calendar 
days.
The SMBG measurements and corresponding trial drug doses for titration purpose should be 
entered within 24 hours after the site visit/phone contact throughout the trial.
At the end of trial the investigator should ensure that all remaining data have been entered into the 
eCRF no later than 3 days after LSLV at the site in order to ensure the planned lock of the database.
Site specific eCRF data (in an electronic readable format) will be provided to the trial site before 
access to the eCRF is revoked. This data must be retained at the trial site.
13.2.1
Paper case report form flow
The pregnancy forms are paper based CRFs. Also, the technical complaint form, SIF and AE form 
will be provided in paper but are only to be used if for any reason the eCRF is unavailable. If 
corrections are needed, see section 13.1
14 Monitoring procedures 
During the course of the trial, the monitor will visit the trial site to ensure that the protocol is 
adhered to, that all issues have been recorded, to perform source data verification and to monitor 
drug accountability. The first monitoring visit will be performed as soon as possible after FSFV at 
the trial site and no later than 4 weeks after. The monitoring visit intervals will depend on the 
outcome of the remote monitoring of the eCRFs, the trial site's recruitment rate and the compliance 
of the trial site to the protocol and GCP, but will not exceed 12 weeks.
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, except age and BMI which 
are calculated by the EDC system.
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For all data recorded the source document must be defined in a source document agreement at each 
trial site. There must only be one source defined at any time for any data element.
Considering the electronic source data environment, it is accepted that the earliest practically 
retainable record should be considered as the location of the source data and therefore the source 
document. 
The diary is considered source document for the SMBG values, trial product dosing information 
and hypoglycaemic episodes.
Source data generated by the trial site can be corrected by another person than the person entering 
the source data; any correction must be explained, signed and dated by the person making the 
correction.
The original completed diaries must not be removed from the trial site, unless they form part of the 
eCRF and a copy is kept at the site.
The monitor will ensure that the eCRFs are completed on an ongoing basis.
The following data will be source data verified for screening failures: 
∀
Date for obtaining informed consent.
∀
Reason for screening failure
Monitors must review the subject's medical records and other source data (e.g. the diaries) to ensure 
consistency and/or identify omissions compared to the CRF. If discrepancies are found, the 
investigator must be questioned about these.
A follow-up letter (paper or electronic) will be sent to the investigator following each monitoring 
visit. This should address any action to be taken.
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15 Data management
Data management is the responsibility of Novo Nordisk. 
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 
analysis. Data from special laboratories will be transferred to Novo Nordisk via the central 
laboratory.  In cases where data is transferred via non-secure electronic networks, data will be 
encrypted during transfer.
The subject and any biological material obtained from the subject will be identified by subject 
number and trial ID. Appropriate measures such as encryption or leaving out certain identifiers will 
be enforced to protect the identity of subjects in all presentations and publications as required by 
local, regional and national requirements.
16 Computerised systems
Novo Nordisk will capture and process clinical data using computerised systems that are described 
in Novo Nordisk Standard Operating Procedures and IT architecture documentation. The use and 
control of these systems are documented.
Investigators working on the trial may use their own electronic systems to capture source data. 
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17 Statistical considerations
Novo Nordisk will analyse and report data from all trial 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 52 weeks of treatment, descriptive statistics will be 
presented based both on observed and last observation carried forward (LOCF) imputed data. 
Endpoints that are analysed untransformed and endpoints that are not formally analysed are 
summarised by the arithmetic mean, standard deviation (SD), median, and minimum and maximum 
value. Endpoints that are analysed log-transformed are supplemented with the geometric mean and 
coefficient of variation (CV).
For measurements over time, mean values will be plotted to explore the trajectory over time. LOCF 
imputed data will be used as the basis for plotting data, if not otherwise specified. For endpoints 
that are analysed log-transformed, the geometric mean values will be plotted.
A standard analysis of covariance (ANCOVA) model will be applied for the continuous primary 
and secondary endpoints. The model includes treatment and pre-trial OAD treatment (metformin, α-
GI, TZD, SU’s, SGLT2i or glinide) as fixed factors and the corresponding baseline value as 
covariate. In the following, this model will be referred to as the standard ANCOVA model.
Presentation of results from a statistical analysis will include the estimated mean treatment effects 
(Least Square Means [LSMeans]) for absolute values and change from baseline. In addition, 
estimated mean treatment difference (or ratio) will be presented together with the two-sided 95% 
confidence interval and corresponding two-sided p-value.
Handling of missing data
The expected percentage of missing data is around 15%. In accordance with industry 
guidance22 endpoints will be assessed at frequent visits and also on subjects who withdraw 
prematurely. 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 
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value measured at the randomisation visit is missing and the assessment also has been made at 
screening, then the screening value will be used as the baseline value.
Missing values (including intermittent missing values) will be imputed using the LOCF method. 
Subjects without data after randomisation will be included by carrying forward their baseline value. 
LOCF has been a standard approach in diabetes trials for many years, and was used as the primary 
analysis in both IDegLira and IDeg phase 3a trials. LOCF is considered to be an appropriate method 
in the context of TTT trials, where subjects after withdrawal typically continue their therapy using 
commercially available insulin. In previous TTT trials with IDegLira and IDeg, LOCF has 
generally provided similar results to alternative methods applied to handle missing data, such as 
repeated measures models and completer analyses. In this trial, similar sensitivity analyses will be 
made to examine the robustness of the LOCF method. The LOCF approach will also be used to 
impute missing values in CAS.
17.1
Sample size calculation
The primary objective of this trial is to confirm the efficacy of IDegLira in combination with one 
oral antidiabetic drug in controlling glycaemia in Japanese subjects with type 2 diabetes mellitus. 
This is done by comparing the difference in change from baseline in HbA1c after 52 weeks of 
treatment to a non-inferiority margin of 0.3% for IDegLira vs. IDeg and to a superiority margin of 
0.0% for IDegLira vs. liraglutide. The non-inferiority margin of 0.3% was chosen in accordance 
with the Food and Drug Administration (FDA) guidance.22 The primary objective will be fulfilled 
only if both non-inferiority of IDegLira vs. IDeg and superiority of IDegLira vs. liraglutide are 
confirmed.
Formally, let D be the mean difference (IDegLira minus IDeg and IDegLira minus liraglutide 
respectively) in change from baseline in HbA1c. Non-inferiority and superiority will thus be 
considered confirmed if the upper bound of the two-sided 95% confidence interval for D is below 
0.3% and 0.0% respectively. This is equivalent to using a one-sided test of size 2.5%, which means 
that the type 1 error rate is controlled at 2.5%.
The null-hypotheses (H0) are given as
∀
Non-inferiority: H0 D≥0.30% against HA D<0.30%
∀
Superiority: H0 D≥0.0% against HA D<0.0%
For sample size calculations for non-inferiority a mean difference in treatment of -0.1% and a 
standard deviation of 1.0% are assumed. For superiority an assumed mean difference in treatment of 
-0.3% and a standard deviation of 1.0% are applied in sample size calculations.
For evaluation of non-inferiority per protocol (PP) population is used for the sample size 
calculations, while the full analysis set (FAS) is used for evaluation of superiority. It is assumed that 
15% of the randomised subjects will be excluded from the PP analysis set. The above assumptions 
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are based on experience from the phase 3a development programmes for IDegLira and IDeg. The 
sample size is determined using a t-statistic under the assumption of a one-sided test of size 2.5% 
for both the superiority and non-inferiority testing. Based on these assumptions a sample size of 807 
patients results in a non-inferiority power of 98.9% and a superiority power of 93.5%  i.e. the 
combined power for meeting the primary objective is 98.9% * 93.5% = 92.5%. 
Considering 0% efficacy retention as the most conservative approach for the anticipated 15% of 
subjects discontinuing randomised treatment reduces the expected treatment difference to -0.26% 
for the superiority test and to -0.085% for the non-inferiority test. A total of 269 subjects per 
treatment arm will then yield a superiority power of at least 83.9%, a non-inferiority power of at 
least 98.4% and a combined power of at least 98.4%*83.9% = 82.6%.
17.2
Definition of analysis sets
The following analysis sets are defined in accordance with the ICH-E9 guidance23
∀
Full Analysis Set (FAS): includes all randomised subjects. In exceptional cases, subjects 
may be eliminated from the full analysis set. In such cases the elimination will be justified 
and documented. The statistical evaluation of the FAS will follow the intention-to-treat 
(ITT) principle and subjects will contribute to the evaluation “as randomised”
∀
Per-Protocol (PP) analysis set: includes all subjects in the Full Analysis Set who fulfils the 
following criteria:
o
Have not violated any inclusion criteria
o
Have not fulfilled any exclusion criteria
o
Have a non-missing HbA1c at screening or randomisation
o
Have at least one non-missing HbA1c after 12 weeks of exposure
o
Have at least 12 weeks of exposure
Subjects will contribute to the evaluation “as treated”.
∀
Safety Analysis Set (SAS): includes all subjects receiving at least one dose of the 
investigational product or comparator. Subjects in the safety set will contribute to the 
evaluation “as treated”
∀
Completer Analysis Set (CAS): includes all randomised subjects who have completed the 
trial. Subjects in the completer analysis set will contribute to the evaluation “as randomised”
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 sponsor 
study group. The subjects or observations to be excluded, and the reasons for their exclusion must 
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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 52 weeks of treatment.
The change from baseline in HbA1c after 52 weeks of treatment will be analysed using the standard 
analysis of covariance (ANCOVA) model with treatment and pre-trial OAD treatment (metformin, 
α-GI, TZD, SU’s, SGLT2i or glinide) as fixed factors and baseline HbA1c as covariate. Missing 
values after 52 weeks of treatment will be imputed applying LOCF using HbA1c values at and after 
baseline.
Non-inferiority of IDegLira vs. IDeg will be considered as confirmed if the 95% confidence interval 
for the mean treatment difference lies entirely below 0.3%; equivalent to a one-sided test with 
significance level of 2.5%. Non-inferiority will be investigated on the FAS. Sensitivity analysis will 
be performed on the PP analysis set.
Superiority of IDegLira vs. liraglutide will be considered as confirmed if the 95% confidence 
interval for the mean treatment difference for change from baseline in HbA1c lies entirely below 
0.0%; equivalent to a one-sided test with significance level of 2.5%. Conclusion of superiority will 
be based on FAS. The primary objective will be fulfilled only if both non-inferiority of IDegLira vs. 
IDeg and superiority of IDegLira vs. liraglutide are confirmed.
17.3.1
Sensitivity analysis
The primary analysis will be repeated on the PP analysis set and the completer analysis set (CAS) 
as sensitivity analysis. Furthermore, sensitivity analysis will be performed on FAS using the mixed 
model for repeated measurement (MMRM) to evaluate the robustness 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 pre-trial OAD treatment as fixed factors
and baseline HbA1c as covariate. Interactions between visit and all factors and between visit and 
baseline HbA1c are also included in the model.
Further, a pattern mixture model approach, mimicking an ITT scenario will be applied. The 
imputation will follow the hypothesis being tested. i.e., when deriving the IDegLira vs. IDeg 
contrast the imputation in the IDegLira arm will be based on IDeg values, whereas for the IDegLira 
vs. Liraglutide contrast the imputation in the IDegLira arm will be based on Liraglutide values. In 
each of the analysis the third arm will be kept in the model. Furthermore, 0.3 will be added to the 
imputed values in the IDegLira arm for the non-inferiority comparison against IDeg to mimic a 
scenario where subjects discontinued from IDegLira treatment are assumed to be switched to a 
treatment inferior to IDeg. In other words: two imputation datasets will be made for IDegLira and 
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only one for each of the comparator arms. Which imputed IDegLira dataset to include in the model 
depends on the treatment contrast to be estimated. The imputations will be done as follows:
∀
In the first step intermittent missing values are imputed using a Markov Chain Monte Carlo 
(MCMC) method, in order to obtain a monotone missing data pattern. This imputation is 
done for each treatment group separately and 1000 copies of the dataset will be generated
∀
In the second step, for each of the 1000 copies of the dataset, an analysis of variance model 
with treatment and pre-trial OAD treatment as fixed factors, and baseline HbA1c as 
covariates is fitted to the change in HbA1c from baseline to 4 weeks (Visit 6) for the 
comparator group only. The estimated parameters, and their variances, from this model are 
used to impute missing values at 4 weeks for subjects in comparator and IDegLira treatment 
groups, based on pre-trial OAD treatment and HbA1c at baseline.
∀
In the third step, for each of the 1000 copies of the dataset, missing HbA1c values at 8 weeks 
(Visit 10) are imputed in the same way as for 4 weeks. Now the imputations are based on an 
analysis of variance model with the same factors and the HbA1c values at baseline and 4 
weeks as covariates, fitted to the comparator group.
∀
This stepwise procedure is then repeated sequentially over the available planned visits, 
adding one visit in each step until the last planned visit at 52 weeks (Visit 54)
∀
For each subject discontinued from treatment in the IDegLira treatment group, a value of 
0.3% (the non-inferiority limit) is added to the change in HbA1c at 52 weeks for the 
comparison against IDeg.
∀
For each of the complete data sets, the change from baseline to 52 weeks is analysed using 
an analysis of variance model with treatment and pre-trial OAD treatment as fixed factors 
and baseline HbA1c value as a covariate.
The estimates and standard deviations for the 1000 data sets are pooled to one estimate and 
associated standard deviation using Rubin’s rule.24 From these pooled estimates the confidence 
interval for the treatment differences and the associated p-value are calculated.
The results of sensitivity analyses will be compared to the result of the standard ANCOVA method 
using LOCF for imputation of missing data. Any marked difference between the MMRM, the 
pattern mixture approach and ANCOVA LOCF approach regarding the estimated treatment 
difference will be commented upon in the CTR.
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17.4
Secondary endpoints
17.4.1
Confirmatory secondary endpoints
The following three confirmatory endpoints will be tested for superiority of IDegLira vs. IDeg.
∀
Change from baseline in body weight (kg) after 52 weeks of treatment.
∀
Number of treatment emergent severe or blood glucose (BG) confirmed hypoglycaemic 
episodes during 52 weeks of treatment.
∀
Change from baseline in HbA1c after 52 weeks of treatment
In order to control the overall type I error on a 5% level with regards to the confirmatory secondary 
endpoints, a hierarchical testing procedure will be used. The tests for superiority of the confirmatory 
secondary endpoints will be based on the FAS and will only be carried out if non-inferiority of 
IDegLira vs. IDeg and superiority of IDegLira vs. liraglutide with regards to the primary endpoint 
are confirmed.
If and only if superiority is confirmed with respect to change from baseline in body weight after 52 
weeks of treatment the number of treatment emergent severe or BG confirmed hypoglycaemic 
episodes during 52 weeks of treatment will be tested for superiority. If and only if superiority is 
confirmed with respect to the number of treatment emergent severe or BG confirmed 
hypoglycaemic episodes during 52 weeks of treatment the change from baseline in HbA1c after 52 
weeks of treatment will be tested for superiority.
None of the sensitivity analysis are part of the hierarchical testing procedure.
The change from baseline in body weight after 52 weeks of treatment will be analysed using the 
standard ANCOVA model with treatment and pre-trial OAD treatment as fixed factors and baseline 
body weight as covariate. Missing values after 52 weeks of treatment will be imputed applying 
LOCF using body weight values at and after baseline.
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 kg against HA D<0.0 kg,
is less than 2.5%, where D is the treatment difference. Conclusion of superiority will be based on 
FAS.
As sensitivity analyses for body weight the 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 
MMRM to evaluate the robustness of using LOCF. All body weight values available post baseline 
at scheduled measurement times will be analysed in a linear mixed normal model using an 
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unstructured residual covariance matrix for body weight measurements within the same subject. 
The model will include treatment, visit and pre-trial OAD treatment as fixed factors and baseline 
body weight as covariate. Interactions between visit and all factors and between visit and baseline 
body weight are also included in the model. Finally, a pattern mixture model approach similar to 
that described for HbA1c but without the added non-inferiority penalty, will be applied.
Number of treatment emergent severe or BG confirmed hypoglycaemic episodes during 52 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 OAD treatment as fixed factors.
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.
A sensitivity analysis will carried out to evaluate the impact of subject withdrawing from the trial. 
A pattern mixture approach using a copy difference from control method will be applied.25  
∀
In the first step samples from the posterior distribution of model parameters using a Bayes 
negative binomial log-link model with the same covariates as in the original hypo analysis and
log of the treatment emergent exposure time as an offset will be extracted. 1000 samples are to 
be made. Number of burn-in iterations will be set to nbi=1000, number of iterations after burn-
in, nmc=1000, and thinning set to thin=10. This leaves 1000 different sets of imputed parameter 
estimates to be used
∀
For each imputation the expected number of events is calculated for the period before and after 
withdrawal. The period after withdrawal (missing the exposure) is derived as the max of either 
27 weeks or max over all the exposure times for withdrawn subjects within a trial minus that 
subjects the exposure. For the copy reference approach a subject expected event rate both before 
and after withdrawal is assumed to be the same as the reference group.
∀
The total number of hypos for each subject is then derived as number of observed hypos plus a 
random sample from a negative binomial distribution with the first parameter being (the inverse 
of the dispersion parameter + expected number of hypos before withdrawal) divided by (the 
inverse of the dispersion parameter + expected number of hypos before withdrawal + expected 
number of hypos after withdrawal), and the second parameter being the inverse of the dispersion 
parameter + number of observed hypos) 
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∀
For each imputation, the imputed numbers are then analysed using a negative binomial model 
with log link and the same covariates as in the original hypo analysis and the log of the total 
subjects treatment emergent exposure (observed treatment emergent exposure plus missing 
exposure for withdrawn subjects) as offset.
∀
The estimates for the 1000 data sets are pooled to one estimate and associated standard 
deviation using Rubin’s rule. From these pooled estimates the confidence interval for the 
treatment differences and the associated p-value are calculated.
∀
Subjects with missing treatment emergent exposure time will not contribute to the analysis
The imputation will follow the hypothesis being tested. i.e., first step getting samples from the 
posterior distribution is unchanged. The derivation of period after withdrawal is also unchanged, 
i.e., max is taken over all subjects in all 3 treatment arms. When deriving the IDegLira vs. IDeg 
contrast this will be based on a dataset with all 3 treatment arms, where event rate before and after 
withdrawal is assumed to be the same as in the IDeg group. An imputation of events in the missing 
period is only done for the IDegLira and IDeg arm, but all 3 arms will enter the model. Similarly 
for the IDegLira vs liraglutide contrast, the event rate before and after withdrawal is assumed to be 
the same as in the liraglutide arm. In other words: two imputation datasets will be made based on 
different reference groups. Which imputed IDegLira dataset to be included in the model will depend 
on the treatment contrast to be estimated.
The change from baseline in HbA1c after 52 weeks of treatment will be analysed using the standard 
ANCOVA model with treatment and pre-trial OAD treatment as fixed factors and baseline HbA1c as 
covariate. Missing values after 52 weeks of treatment will be imputed applying LOCF using HbA1c 
values at and after baseline.
Superiority for change from baseline in HbA1c 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. Conclusion of superiority will be based on 
FAS. As sensitivity analyses for the superiority of HbA1c the same sensitivity analyses will be 
applied as for the primary endpoint as described in section 17.3.1, only without adding non-
inferiority margin of 0.3% for subjects discontinuing IDegLira. 
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17.4.2
Supportive secondary endpoints
17.4.2.1
Efficacy endpoints
In the following the statistical models will be fitted to all data simultaneously (all treatment groups) 
and from this model the treatment differences for IDegLira vs. IDeg and IDegLira vs. liraglutide 
will be estimated.
Insulin dose after 52 weeks of treatment
The actual daily dose after 52 weeks of treatment will be analysed using the standard ANCOVA 
model including treatment and pre-trial OAD treatment as fixed factors and baseline HbA1c value 
and baseline insulin dose as covariates.
Responder after 52 weeks of treatment
Two dichotomous endpoints (responder/non-responder) will be defined based on whether a subject 
has met a specific target level after 52 weeks of treatment:
∀
HbA1c < 7.0%26
∀
HbA1c ≤ 6.5%26, 27   
Analysis of each of the two responder endpoints will be based on a logistic regression model with
treatment and pre-trial OAD treatment as fixed factors and baseline HbA1c values as a covariate.
HbA1c responder endpoints and change in body weight from baseline below or equal to zero
Responder for HbA1c without weight gain after 52 weeks of treatment will be defined as HbA1c  
< 7.0% or ≤ 6.5%  at end of treatment and change from baseline in body weight bellow or equal to 
zero. Analysis of each of the two responder endpoints will be based on a logistic regression model 
with treatment and pre-trial OAD treatment as factors and baseline HbA1c and baseline body weight 
values as covariates.
HbA1c responder endpoints without hypoglycaemic episodes
Responder for HbA1c without hypoglycaemic episodes after 52 weeks of treatment will be defined 
as HbA1c  < 7.0% or ≤ 6.5%  at end of treatment and without treatment emergent severe or BG 
confirmed symptomatic hypoglycaemic 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 
pre-trial OAD treatment as fixed factors and baseline HbA1c values as a covariate.
HbA1c responder endpoints without hypoglycaemic episodes change in body weight from 
baseline below or equal to zero
Responder for HbA1c without hypoglycaemic episodes and weight gain after 52 weeks of treatment 
will be defined as HbA1c  < 7.0% or ≤ 6.5%  at end of treatment, without treatment emergent severe 
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or BG confirmed symptomatic hypoglycaemic episodes during the last 12 weeks of treatment, and 
change from baseline in body weight bellow or equal to zero. Analysis of each of the two responder 
endpoints will be based on a logistic regression model with treatment and pre-trial OAD treatment 
as fixed factors and baseline HbA1c and body weight values as covariates.
Fasting plasma glucose (FPG)
Change from baseline in FPG after 52 weeks of treatment will be analysed using the standard 
ANCOVA model.
Waist circumference
Change from baseline in waist circumference after 52 weeks of treatment will be analysed using the 
standard ANCOVA model.
Blood pressure (systolic and diastolic)
Change from baseline in blood pressure after 52 weeks of treatment will be analysed using the 
standard ANCOVA model.
Self-measured blood glucose (SMBG) 9-point profile
Three endpoints from the 9-point profile will be defined:
∀
9-point profile
∀
Mean of the 9-point profile, defined as the area under the profile (calculated using the 
trapezoidal method) divided by the measurement time
∀
Prandial plasma glucose increments (from before meal to 90 min after for breakfast, lunch 
and dinner). The mean increment over all meals will be derived as the mean of all available 
meal increments
A linear mixed effect model will be fitted to the 9-point SMBG profile data. The model will include 
treatment, pre-trial OAD treatment, time, the interaction between treatment and time and the 
interaction between pre-trial OAD treatment and time as fixed factors and subject as random effect. 
From the model mean profile by treatment and relevant treatment differences will be estimated and 
explore
Change from baseline after 52 weeks of treatment in mean of the 9-point profile and post-prandial 
increment endpoints will be analysed separately using the standard ANCOVA model.
Fasting lipid profile 
Total cholesterol, low density lipoprotein cholesterol (LDL cholesterol), high density lipoprotein 
cholesterol (HDL cholesterol), very low density lipoprotein cholesterol (VLDL cholesterol), 
triglycerides, and free fatty acids after 52 weeks of treatment will be analysed separately were using
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the standard ANCOVA model. In these statistical analyses the endpoint will be log-transformed and 
so will the baseline covariate.
Fasting C-peptide, fasting human insulin, fasting glucagon and proinsulin
These endpoints after 52 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.
17.4.2.2
Safety endpoints
Adverse events
AEs will be coded using the most recent version of the Medical Dictionary for Regulatory 
Activities (MedDRA).
A treatment emergent adverse event (TEAE) is defined as an event that has onset date on or after 
the first day of exposure to randomised treatment and no later than seven days after the last day of 
randomised treatment. If the event has onset date before the first day of exposure on randomised 
treatment and increases in severity during the treatment period and until 7 days after the last drug 
date, then this event should also be considered as a TEAE. Here the first day of IMP administration 
is defined as the first day of exposure to randomised treatment.
TEAEs are summarised descriptively, whereas non-TEAEs are presented in listings. TEAE data 
will be displayed in terms of the number of subjects with at least one event (N), the percentage of 
subjects with at least one event (%), the number of events (E) and the event rate per 100 years of 
exposure (R).
Summaries of TEAEs and of serious TEAEs will be presented as an overview including all AEs, 
serious AEs, number of deaths, AEs by severity, AEs by relation to treatment and AEs of special 
interest including AEs leading to withdrawal.
Furthermore summary tables based on system organ class and preferred terms are made for:
∀
All TEAEs
∀
Serious TEAEs
∀
Possibly or probably related TEAEs
∀
Severe, moderate and mild TEAEs
∀
TEAEs reported by safety areas of interest
∀
TEAEs with preferred term that are experienced by at least 5% of the subjects in any 
treatment arm or by at least 5% of all subjects
A listing for non-TEAEs with onset date before the first day of exposure to randomised treatment 
will be presented. A listing will also be presented for non-TEAEs collected after the treatment 
emergent period according to the definition of TEAE.
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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 occurring between 00:01 and 05.59 both 
inclusive.
Hypoglycaemic episodes are classified according to the Novo Nordisk classification of 
hypoglycaemia (see Figure 17.1) and the ADA classification of hypoglycaemia (see Figure 17.2).
Novo Nordisk classification of hypoglycaemia
In normal physiology, symptoms of hypoglycaemia occur below a plasma glucose level of 3.1 
mmol/L (56 mg/dL).28 Therefore, Novo Nordisk has included hypoglycaemia with plasma glucose 
levels below this cut-off point in the definition of blood glucose (BG) confirmed hypoglycaemia.
Novo Nordisk uses the following classification (see Figure 17.1) in addition to the ADA 
classification:
∀
Severe or BG confirmed symptomatic hypoglycaemia: An episode that is severe according 
to the ADA classification26 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 
classification26 or BG confirmed by a plasma glucose value <3.1 mmol/L (56 mg/dL) with
or without symptoms consistent with hypoglycaemia. 
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Figure 17–1
Novo Nordisk classification of hypoglycaemia 
ADA classification19of hypoglycaemia
∀
Severe hypoglycaemia: An episode requiring assistance of another person to actively 
administer carbohydrate, glucagon, or take other corrective actions. Plasma glucose 
concentrations may not be available during an event, but neurological recovery following 
the return of plasma glucose to normal is considered sufficient evidence that the event was 
induced by a low plasma glucose concentration.
∀
Asymptomatic hypoglycaemia: An episode not accompanied by typical symptoms of 
hypoglycaemia, but with a measured plasma glucose concentration ≤ 3.9 mmol/L (70 
mg/dL).
∀
Documented symptomatic hypoglycaemia: An episode during which typical symptoms of 
hypoglycaemia are accompanied by a measured plasma glucose concentration ≤ 3.9 mmol/L 
(70 mg/dL).
∀
Pseudo-hypoglycaemia: An episode during which the person with diabetes reports any of the 
typical symptoms of hypoglycaemia with a measured plasma glucose concentration > 3.9 
mmol/L (70 mg/dL) but approaching that level.
∀
Probable symptomatic hypoglycaemia: An episode during which symptoms of 
hypoglycaemia are not accompanied by a plasma glucose determination but that was 
presumably caused by a plasma glucose concentration ≤ 3.9 mmol/L (70 mg/dL).
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Figure 17–2
ADA classification of hypoglycaemia 
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 symptomatic 
hypoglycaemic episodes and the ADA classification of hypoglycaemia.
The number of severe or BG confirmed symptomatic hypoglycaemic episodes and nocturnal severe 
or BG confirmed symptomatic hypoglycaemic episodes will be analysed separately using the same 
model as used for the treatment emergent severe or BG confirmed hypoglycaemic episodes.
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Clinical evaluations (physical examination, eye examination and ECG)
Eye examination (fundoscopy/fundusphotography) and ECG findings will be summarised 
descriptively, including:
∀
summaries for each visit
∀
shift table from baseline to after 52 weeks of treatment
Any findings in the physical examination evaluation at screening will be presented as listings. Any 
clinically significant deterioration of a pre-existing condition after the screening visit, as well as any 
new clinically significant findings will be recorded as adverse events.
Pulse
Change from baseline in pulse after 52 weeks of treatment will be analysed using the standard 
ANCOVA model.
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 52 weeks of treatment
∀
Proportion of subjects with measurements outside reference range by treatment and week
Laboratory values will be presented graphically as box plots by treatment and week.
For each laboratory parameter, individual values outside the reference ranges (abnormal values) 
will be listed.
Calcitonin
The purpose of the calcitonin analysis is to evaluate longitudinal changes in calcitonin, with main 
focus on subjects who develop persistently high levels of calcitonin during the trial.
Calcitonin will be displayed in terms of the number of subjects (N), the percentage of subjects (%) 
and the incidence rate per 100 years of exposure (R). The following criteria are defined for 
tabulations:
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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).
Anti-drug antibodies
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 52 
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weeks of treatment in anti-IDeg and anti-insulin antibodies respectively, to insulin dose after 52 
weeks of treatment, HbA1c after 52 weeks of treatment and change from baseline after 52 weeks of 
treatment in HbA1c will be illustrated using scatter plots.
For the liraglutide component of IDegLira and liraglutide, the number of subjects (N) and the 
percentage of subjects (%) with positive, cross-reacting to native GLP-1 and neutralising antibodies 
will be summarised.
Listing with subjects with liraglutide positive antibody formation will be produced. These listings 
should include efficacy information as minimum HbA1c and body weight over time.
17.5
Pharmacokinetic modelling
Population pharmacokinetic analysis
The objective for the population pharmacokinetic (PK) analysis is to compare the pharmacokinetics 
of IDegLira and its mono-components given separately at clinically relevant doses during 52 weeks 
of treatment. Furthermore, the effects of pre-specified covariates on plasma concentrations of 
IDegLira will be evaluated.
The population PK analysis will be performed by the Quantitative Clinical Pharmacology 
Department at Novo Nordisk A/S. A more technical and detailed elaboration of the population PK 
analysis will be given in the modelling analysis plan (MAP) which will be finalised before DBL. 
The pre-specified analysis will explore the effects of covariates on the insulin degludec and 
liraglutide exposure. The structural models and covariate relationships will be predefined in detail 
in the MAP. In brief, previously developed population PK models for insulin degludec and 
liraglutide will be used. For both PK models, the absorption rate constant (Ka) will be fixed and the 
apparent clearance (CL/F) and the apparent volume of distribution (Vd/F) will be estimated.
The covariates of interest will be incorporated into the PK models using criteria which will be 
specified in the MAP. 
Exposure-response analysis
The exposure-response relationship will be investigated for selected response variables, such as 
HbA1c.
The population PK and exposure-response analyses will be reported in a separate modelling report, 
which will not be a part of the clinical trial report.
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18 Ethics
18.1
Benefit-risk assessment of the trial
The trial will be conducted in compliance with ICH GCP1 and applicable regulatory requirements, 
and in accordance with the Declaration of Helsinki2. All subjects will be included after a thorough 
evaluation in regards to inclusion/exclusion criteria defined in order to ensure that subjects are 
eligible for trial treatment. Randomised subjects will be treated with IDegLira, IDeg or liraglutide
and pre-trial OAD, a regimen anticipated being equal to or better than the OAD treatment they 
received prior to entering the trial. A potential benefit of participating in the trial is that the 
investigator will obtain an additional knowledge of the subjects’ disease and will therefore be able 
to provide recommendations for the best treatment to be used following the trial participation.
All three trial products are used in the clinic in several countries. There is no information available 
today indicating that an overall risk associated with the use of IDegLira could exceed the risks 
associated with the use of the individual compounds.
The trial product may be associated with AEs, but relevant precautions have been implemented in 
the design and planned conduct of the trial in order to minimise the risks and inconveniences of 
participating in the trial. These precautions include thorough information regarding the correct 
administration of the trial product and gradual dose adjustment. Furthermore, subjects will be fully 
informed about possible AEs and inconveniences and will be instructed to contact the investigator 
in case of any concerns regarding the trial participation.
Withdrawal criteria have been defined to ensure that subjects are considered for discontinuation if 
the level of glycaemic control exceeds unacceptable limits during trial participation.
IDeg and liraglutide have shown to be effective in lowering BG levels.29, 30, 31, 32, 33
It can therefore be expected that the majority of subjects with insufficiently controlled BG, 
randomised to treatment with fixed combination of IDegLira, will experience an improved glucose 
control during the trial as also shown in clinical trials conducted outside Japan.10 In addition, these 
subjects may benefit from the effect of treatment on weight previously demonstrated for 
liraglutide. 29, 30, 31, 32, 33
The most common side effect of all available insulin products is hypoglycaemic episodes. IDeg is a 
basal insulin preparation with a long acting effect and so recovery from a hypoglycaemic episode, 
as with other long acting insulins, may be delayed.
There have been a few reported events of acute pancreatitis (inflammation of the pancreas) 
presenting (with persistent severe abdominal pain usually accompanied by vomiting) with 
liraglutide treatment. As a consequence of the known rare events of acute pancreatitis, Novo 
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Nordisk will analyse blood samples for amylase and lipase during the trial to monitor the subjects’ 
safety.
In both genders of rats and mice, liraglutide causes dose-dependent and treatment-duration-
dependent thyroid C-cell tumours at clinically relevant exposures. It is unknown whether liraglutide 
causes thyroid C-cell tumours, including MTC, in humans, as human relevance could not be ruled 
out by clinical or non-clinical studies. Liraglutide is contraindicated in subjects with a personal or 
family history of MTC and in subjects with MEN2. Based on the findings in rodents, monitoring 
with serum calcitonin or thyroid ultrasound was performed during clinical trials, but this may have 
increased the number of unnecessary thyroid surgeries. It is unknown whether monitoring with 
serum calcitonin or thyroid ultrasound will mitigate human risk of thyroid C-cell tumours.Based on 
the above, monitoring of serum calcitonin will be performed during the trial according to the flow 
chart, section 2. Subjects with thyroid disease will be closely monitored and in case of elevated 
calcitonin a recommendation for follow-up is included in AppendixD. 
In reproduction and development toxicity studies liraglutide has been shown to be teratogenic in 
rats and rabbits including reduced growth and major abnormalities at systemic exposures below 
human exposure at the maximum recommended human dose (MRHD) of 1.8 mg/day. The US 
Victoza® Prescribing Information includes the Pregnancy Category C (US FDA Pharmaceutical 
Pregnancy Categories: “Animal reproduction studies have shown an adverse effect on the foetus 
and there are no adequate and well-controlled studies in humans, but potential benefits may warrant 
use of the drug in pregnant women despite potential risks”). Due to this pregnant women and 
women with the intention to become pregnant, are excluded from the trial
It is concluded that the potential benefits from participating in the trial outweigh the potential risks. 
The safety profile for the IMPs generated from the clinical and nonclinical development programme 
has not revealed any safety issues that would prohibit administration of those in accordance with the 
planned clinical trial. 
Areas of special interest with regards to safety of trial product are described in detail in the current 
versions of the IB´s of the trial products 6,8,11, and in the Japanese approved labelling for IDeg and 
liraglutide, respectively.
When treatment with trial product ends, the subject and investigator will decide on the best 
available. Novo Nordisk will not offer investigational drugs after the end of trial treatment. 
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18.2
Data handling
If the subject is withdrawn from the trial or lost to follow up, then the subject’s data will be handled 
as follows:
∀
Data already collected and data collected at the end-of-trial visit will be retained by Novo 
Nordisk, entered into the database and used for the trial report. 
∀
Safety events will be reported to Novo Nordisk and regulatory authorities according to 
local/national requirements.
If data is used, it will always be in accordance with local regulations and IRBs.
18.3
Information to subject during trial
The subject may receive information provided to the site by Novo Nordisk, examples of this may be 
a “welcome to the trial letter” and a “thank you for your participation letter” after completion of the 
trial.  
All written information to subjects must be sent to IRB for approval/favourable opinion and to 
regulatory authorities for approval or notification according to local regulations.
18.4
Premature termination of the trial and/or trial site
Novo Nordisk, the IRBs or a regulatory authority may decide to stop the trial, part of the trial or a 
trial site at any time, but agreement on procedures to be followed must be obtained.
If a trial is suspended or prematurely terminated, the investigator must inform the subjects promptly 
and ensure appropriate therapy and follow-up. The investigator and/or Novo Nordisk must also 
promptly inform the regulatory authorities and IRBs and provide a detailed written explanation. 
If, after the termination of the trial, the benefit-risk analysis changes, the new evaluation must be 
provided to the IRBs in case it has an impact on the planned follow-up of subjects who have 
participated in the trial. If it has an impact, the actions needed to inform and protect the subjects 
should be described.
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19 Protocol compliance
Deviations from the protocol should be avoided.
If deviations do occur, the investigator must inform the monitor and the implications of the 
deviation must be reviewed and discussed.
Deviations must be documented and explained in a protocol deviation by stating the reason, date, 
and the action(s) taken. Some deviations, for which corrections are not possible, can be 
acknowledged and confirmed via edit checks in the eCRF or via listings from the clinical database. 
Documentation on protocol deviations must be kept in the investigator's trial master file and 
sponsor trial master file.
20 Audits and inspections
Any aspect of the clinical trial may be subject to audits conducted by Novo Nordisk or inspections 
from domestic or foreign regulatory authorities or from IRBs. Audits and inspections may take 
place during or after the trial. The investigator and the site staff as well as Novo Nordisk staff have 
an obligation to cooperate and assist in audits and inspections. This includes giving auditors and 
inspectors direct access to all source documents and other documents at the trial site relevant to the 
clinical trial. This includes permission to examine, analyse, verify and reproduce any record(s) and 
report(s) that are relevant to the evaluation of the trial.
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21
Critical documents
Before a trial site is allowed to start screening subjects, the following documents must be available 
to Novo Nordisk:
∀
Regulatory approval and/or acknowledgement of notification as required 
∀
Approval/favourable opinion from IRBs clearly identifying the documents reviewed as 
follows: protocol, any protocol amendments, subject information/informed consent form, 
any other written information to be provided to the subject and subject recruitment materials
∀
List of IRB members and/or constitution (or a general assurance number/statement of 
compliance)
∀
Curricula vitae of investigator and sub-investigators (current, dated and signed - must 
include documented GCP training or a certificate)
∀
Signed receipt of Investigator's Brochure 
∀
Signed and dated Agreement on Protocol
∀
Signed and dated agreement on protocol amendment, if applicable
∀
Contract, signed by the investigator and/or appropriate parties on behalf of the investigator’s 
site and Novo Nordisk
∀
Source document agreement
∀
Central laboratory certification and normal ranges
∀
Insurance statement, if applicable
∀
Financial disclosure form from investigator and sub-investigator(s)
By signing the protocol, each investigator agrees to comply fully with ICH GCP1, applicable 
regulatory requirements and the Declaration of Helsinki.2
By signing the protocol, each investigator also agrees to allow Novo Nordisk to make investigator's 
name and information about site name and address publically available if this is required by 
national or international regulations.
22 Responsibilities
The investigator is accountable for the conduct of the trial at his/her site. If any tasks are delegated, 
the investigator must maintain a log of appropriately qualified persons to whom he/she has 
delegated specified trial-related duties. The investigator must ensure that there is adequate training 
for all staff participating in the conduct of the trial. It is the investigator's responsibility to supervise 
the conduct of the trial and to protect the rights, safety, and well-being of the subjects.
A qualified physician, who is an investigator or a sub-investigator for the trial, must be responsible 
for all trial-related medical decisions.
The investigator must ensure adequate supervision of the conduct of the trial at the trial site. 
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The investigator will follow instructions from Novo Nordisk when processing data.
The investigator is responsible for filing essential documents (i.e. those documents which 
individually and collectively permit evaluation of the conduct of a trial and the quality of the data
produced) in the investigator trial master file. The documents including the subject identification 
code list should be kept in a secure locked facility, so no unauthorized persons can get access to the 
data. 
The investigator will take all necessary technical and organisational safety measures to prevent 
accidental or wrongful destruction, loss or deterioration of data. The investigator will prevent any 
unauthorised access to data or any other processing of data against applicable law. The investigator 
must be able to provide the necessary information or otherwise demonstrate to Novo Nordisk that 
such technical and organisational safety measures have been taken.
During any period of unavailability, the investigator must delegate responsibility for medical care of
subjects to a specific qualified physician who will be readily available to subjects during that time.
If the investigator is no longer able to fulfil the role as investigator (e.g. if he/she moves or retires), 
a new investigator will be appointed in consultation with Novo Nordisk. 
The investigator and other site personnel must have sufficient English skills according to their 
assigned tasks.
23 Reports and publications
The information obtained during the conduct of this trial is considered confidential, and may be 
used by or on behalf of Novo Nordisk for regulatory purposes as well as for the general 
development of the trial product. All information supplied by Novo Nordisk in connection with this 
trial shall remain the sole property of Novo Nordisk and is to be considered confidential 
information. 
No confidential information shall be disclosed to others without prior written consent from Novo 
Nordisk. Such information shall not be used except in the performance of this trial. The information 
obtained during this trial may be made available to other physicians who are conducting other 
clinical trials with the trial product, if deemed necessary by Novo Nordisk. Provided that certain 
conditions are fulfilled, Novo Nordisk may grant access to information obtained during this trial to 
researchers who require access for research projects studying the same disease and/or trial product 
studied in this trial.
Novo Nordisk may publish on its clinical trials website a redacted clinical trial report for this trial.
One investigator will be appointed by Novo Nordisk to review and sign the clinical trial report 
(signatory investigator) on behalf of all participating investigators. The signatory investigator will 
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be appointed based upon the criteria defined by the International Committee of Medical Journal 
Editors for research publications.34
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.35
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.
Where required by the journal, the investigator from each trial site will be named in an 
acknowledgement or in the supplementary material, as specified by the journal. 
Novo Nordisk maintains the right to be informed of plans by any investigator to publish and to 
review any scientific paper, presentation, communication or other information concerning the 
investigation described in this protocol. Any such communication must be submitted in writing to 
Novo Nordisk before submission for comments. Comments will be given within four weeks from 
receipt of the planned communication.
23.1.1
Authorship
Authorship of publications should be in accordance with the Uniform Requirements of the 
International Committee of Medical Journal Editors18 (sometimes referred to as the Vancouver 
Criteria).
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Publication(s) will be prepared for submission to scientific congresses and peer-reviewed journals 
in collaboration between Novo Nordisk and investigator(s) appointed by Novo Nordisk. These 
investigator(s) must meet the ICMJE authorship criteria to be named authors on publications.
23.1.2
Site-specific publication(s) by investigator(s)
For a multi-centre clinical trial, analyses based on single-site data usually have significant statistical 
limitations and frequently do not provide meaningful information for healthcare professionals or 
subjects, and therefore may not be supported by Novo Nordisk. It is a Novo Nordisk policy that 
such individual reports do not precede the primary manuscript and should always reference the 
primary manuscript of the trial.
Novo Nordisk reserves the right to prior review of such publications. Further to allow for the 
primary manuscript to be published as the first, Novo Nordisk asks for deferment of publication of 
individual site results until the primary manuscript is accepted for publication. As Novo Nordisk 
wants to live up to the industry publication policy, submission of a primary publication will take 
place no later than 18 months after trial completion. 
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 will be provided with the 
randomisation code after results are available.
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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 and/or 
electronic devices supplied by Novo Nordisk. These data must be retained by the trial site. If the 
provided data (e.g. the CD-ROM) is not readable during the entire storage period, the investigator 
can request a new copy. A copy of all data will be stored by Novo Nordisk.
Novo Nordisk will maintain Novo Nordisk documentation pertaining to the trial for as long as the 
product is on the market plus 20 years. 
The files from the trial site/institution must be retained for 15 years after the completion of the trial, 
or longer if required by local regulations or Novo Nordisk. In any case trial files cannot be 
destroyed until the trial site/institution is notified by Novo Nordisk. The deletion process must 
ensure confidentiality of data and must be done in accordance with local regulatory requirements.
24.2
Retention of antibody samples
Antibody samples will be analysed and then stored by the special laboratory analysing the samples
until final feedback from the Japanese regulatory authorities, but no longer than 15 years from end 
of trial. Only Novo Nordisk will have access to these samples. Further characterisation of antibody 
response may be requested by the regulatory authorities.
None of the data will be identified by name. Antibody samples will be identified only by a subject 
number, a visit number and a trial identification number. In the event that the collected antibody 
samples will be used in the future, the investigator will become directly informed by Novo Nordisk 
about the results if the findings are deemed clinically relevant. In such case, a written summary of 
the findings, including listings of subject specific values, will be provided once a firm conclusion 
from the results has been drawn by Novo Nordisk. 
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The antibody samples will be destroyed in a way not revealing the identity of the subjects.
25 Institutional Review Boards and regulatory authorities
Institutional Review Boards (IRBs)
Written approval or favourable opinion must be obtained from IRB prior to commencement of the 
trial.
During the trial, the investigator or Novo Nordisk, as applicable, must promptly report the 
following to the IRB, in accordance with local requirements: updates to Investigator's Brochure, 
unexpected SAEs where a causal relationship cannot be ruled out, protocol amendments according 
to local requirements, deviations to the protocol implemented to eliminate immediate hazards to the 
subjects, new information that may affect adversely the safety of the subjects or the conduct of the 
trial (including new benefit-risk analysis in case it will have an impact on the planned follow-up of 
the subjects), annually written summaries of the trial status, and other documents as required by the 
local IRB.
The investigator must ensure submission of the clinical trial report synopsis to the IRB according to 
local regulatory requirements.
Protocol amendments must not be implemented before approval or favourable opinion according to 
local regulations, unless necessary to eliminate immediate hazards to the subjects.
The investigator must maintain an accurate and complete record of all submissions made to the 
IRB. The records must be filed in the investigator trial master file and copies must be sent to Novo 
Nordisk.
Regulatory Authorities
Regulatory authorities will receive the clinical trial application, protocol amendments, reports on 
SAEs, and the clinical trial report according to national requirements.
26 Indemnity statement
Novo Nordisk carries product liability for its products, and liability as assumed under the special 
laws, acts and/or guidelines for conducting clinical trials in any country, unless others have shown 
negligence.
Novo Nordisk assumes no liability in the event of negligence, or any other liability of the sites or 
investigators conducting the trial, or by persons for whom the said site or investigator are 
responsible.
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27 References
1 International Conference on Harmonisation. ICH Harmonised Tripartite Guideline. Good 
Clinical Practise.  1 May 1996. 
2 Declaration of Helsinki. Ethical Principles for Medical Research Involving Human Subjects. 
Last amended by the 64th WMA General Assembly, Fortaleza, Brazil. World Medical 
Association. 20 A.D.
3 The Diabetes Control and Complications Trial Research Group. The effect of intensive 
treatment of diabetes on the development and progression of long-term complications in 
insulin-dependent diabetes mellitus. 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 Edited by Japan Diabetes Society. Treatment guideline from the Japanese Diabetes Society. 
2015.
6 Investigator's Brochure, insulin degludec (10th Edition). Novo Nordisk A/S. 16 Dec 2014.
7 Tresiba Penfill Japanese Pakage Insert.  2014. 
8 Liraglutide (NN2211) Abbreviated Investigator´s Brochure, Edition 16. Novo Nordisk A/S. 26 
Aug 2014.
9 Victoza Japanese Packing Insert.  1 Aug 2014. 
10 Gough SC, Bode B, Woo V, Rodbard HW, Linjawi S, Poulsen P et al. Efficacy and safety of a 
fixed-ratio combination of insulin degludec and liraglutide (IDegLira) compared with its 
components given alone: results of a phase 3, open-label, randomised, 26-week, treat-to-target 
trial in insulin-naive patients with type 2 diabetes. Lancet Diabetes Endocrinol 2014; 
2(10):885-893.
11 Investigator's Brochure, NN9068 insulin degludec/liraglutide (7th Edition). Novo Nordisk 
A/S. 2015.
12 Eng C, Kramer CK, Zinman B, Retnakaran R. Glucagon-like peptide-1 receptor agonist and 
basal insulin combination treatment for the management of type 2 diabetes: a systematic 
review and meta-analysis. Lancet 2014; 384(9961):2228-2234.
13 Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M et al. Management 
of Hyperglycemia in Type 2 Diabetes, 2015: A Patient-Centered Approach: Update to a 
Position Statement of the American Diabetes Association and the European Association for 
the Study of Diabetes. Diabetes Care 2015; 38(1):140-149.
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14 International Conference on Harmonisation and Topic E 7 Studies in Support of Special 
Populations: Geriatrics. CPMP/ICH/379/95 - Note for Guidance on Studies in Support of 
Special Populations: Geriatrics. Mar 1994.
15 De AC, Drazen JM, Frizelle FA, Haug C, Hoey J, Horton R et al. Clinical trial registration: a 
statement from the International Committee of Medical Journal Editors. N Engl J Med 2004; 
351(12):1250-1251.
16 Food and Drug Administration. Food and Drug Administration Amendments Act (FDAAA) 
of 2007.  
17 Directive 2001/20/EC of the European Parliament and of the Councill of 4 April 2001 on the 
approximation of the laws, regulations and administrative provisions of the Member States 
relating to the implementation of good clinical practice in the conduct of clinical trials on 
medicinal products for human use, article 11. Official Journal of the European Communities. 
The European Parliament and the Council of the European Council. 1 May 2001.
18 The European Parliament and the Council of the European Council. Regulation (EC) No 
726/2004 of the European Parliament and of the Council of 31 March laying down 
Community procedures for the authorisation and supervision of medicinal products for human 
and veterinary use and establishing a European Medicines Agency, article 57. Official Journal 
of the European Communities. April 2001.  
19 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.
20 McAulay V, Deary IJ, Frier BM. Symptoms of hypoglycaemia in people with diabetes. Diabet 
Med 2001; 18(9):690-705.
21 European Union. The rules governing medicinal products in the European Union, Volume 4, 
Annex 13, manufacture of investigational products - Brussels, Feb 2010.  
22 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.
23 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.
24 Little RJA, Rubin D.B. Statistical analysis with missing data. New York: John Wiley & Sons, 
1987.
25 Keene ONea. Missing data sensitivity analysis for recurrent event data using controlled 
imputation. Pharm Stat 2014; 13:258-264.
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26 American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes 
cars. 2014;37 (Suppl.1):23.  2014. 
27 Garber AJ, Abrahamson MJ, Barzilay JI, Blonde L, Bloomgarden ZT, Bush MA et al. 
American Association of Clinical Endocrinologists' comprehensive diabetes management 
algorithm 2013 consensus statement--executive summary. Endocr Pract 2013; 19(3):536-557.
28 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.
29 Buse JB, Rosenstock J, Sesti G, Schmidt WE, Montanya E, Brett J et al. Liraglutide once a 
day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, 
multinational, open-label trial (LEAD-6). Lancet 2009; 374:39-47.
30 Garber A, Henry R, Ratner R, Garcia-Hernandez PA, Rodriguez-Pattzi H, Olvera-Alvarez I et 
al. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a 
randomised, 52-week, phase III, double-blind, parallel-treatment trial. Lancet 2009; 373:473-
481.
31 Marre M, Shaw J, Brandle M, Bebakar WM, Kamaruddin NA, Strand J et al. Liraglutide, a 
once-daily human GLP-1 analogue, added to a sulphonylurea over 26 weeks produces greater 
improvements in glycaemic and weight control compared with adding rosiglitazone or placebo 
in subjects with Type 2 diabetes (LEAD-1 SU). Diabet Med 2009; 26(3):268-278.
32 Russell-Jones D, Vaag A, Schmitz O, Sethi BK, Lalic N, Antic S et al. Liraglutide vs insulin 
glargine and placebo in combination with metformin and sulfonylurea therapy in type 2 
diabetes mellitus (LEAD-5 met+SU): a randomised controlled trial. Diabetologia 2009; 
52(10):2046-2055.
33 Heise T, Nosek L, Bottcher SG, Hastrup H, Haahr H. Ultra-long-acting insulin degludec has a 
flat and stable glucose-lowering effect in type 2 diabetes. Diabetes Obes Metab 2012; 
14(10):944-950.
34 International Committee of Medical Journal Editors. Recommendations for the Conduct, 
Reporting, Editing and Publication of Scholarly Work in Medical Journals. Dec 2014.
35 Novo Nordisk Code of Conduct for Clinical Trial Disclosure. http: and novonordisk-
trial.com/website/content/how-we-disclose-trial-information.aspx. 11 Jan 2015.
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Protocol - Appendix A
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Appendix A
Insulin titration-and liraglutide dose escalation guidelines
Trial ID: NN9068-4183
DUAL™I Japan
A trial comparing the efficacy and safety of insulin
degludec/liraglutide, insulin degludec and liraglutide in
Japanese subjects with type 2 diabetes mellitus
Protocol originator
Insulin & and Diabetes Outcomes, Clinical Operations
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
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
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Protocol - Appendix A
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Table of Contents
Page
Table of Contents .............................................................................................................................................2
List of in-text tables..........................................................................................................................................2
1
Introduction...............................................................................................................................................3
2
Treatment regimens..................................................................................................................................3
2.1
Injection area..................................................................................................................................4
2.2
Injection time.................................................................................................................................4
3
Initiation and titration of IDegLira and IDeg ........................................................................................4
3.1
Initiation of IDegLira.....................................................................................................................4
3.2
Initiation of IDeg ...........................................................................................................................4
3.3
Titration of IDegLira and IDeg......................................................................................................4
3.4
Deviation from the algorithm ........................................................................................................5
4
Initiation and dose escalation of liraglutide............................................................................................6
4.1
Escalation period............................................................................................................................6
4.1.1
Extension of dose escalation period.............................................................................6
4.2
Maintenance period........................................................................................................................6
4.2.1
Dose reduction in maintenance period.........................................................................6
5
Data collection for IDegLira and IDeg....................................................................................................7
6
Review procedure of titration data for IDegLira and IDeg ..................................................................7
7
References..................................................................................................................................................8
List of in-text tables
Page
Table 3-1
Twice weekly titration on fixed days (Tue/Fri) .............................................................................5
Table 3-2
Adjustment of IDeg and IDegLira doses .......................................................................................5
Table 4-1
Liraglutide dose escalation ............................................................................................................6
CONFIDENTIAL


Protocol - Appendix A
CONFIDENTIAL
Date:
02 October 2015
Novo Nordisk
Trial ID: NN9068-4183
Version:
3.0
UTN: U1111-1170-1332 
Status:
Final
EudraCT No.: N/A
Page:
3 of 8
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 (1-4).
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 degludec/liraglutide 
(IDegLira) or insulin degludec (IDeg) doses and to ensure the subject’s welfare.
Liraglutide treatment information is further described in this document. Please notice that the 
glycaemic control of liraglutide will not be monitored. 
2
Treatment regimens
At randomisation the subjects will be randomised 1:1:1 into three parallel arms:
!
IDegLira once daily 
!
IDeg once daily 
!
Liraglutide once daily
First dosing should take place on the day of randomisation or on the day following randomisation.
Maximum dose of IDegLira is 50 dose steps (50U insulin degludec/1.8 mg liraglutide).
There is no maximum dose of IDeg.
Liraglutide dose is 1.8 mg (fixed dose).
CONFIDENTIAL


Protocol - Appendix A
CONFIDENTIAL
Date:
02 October 2015
Novo Nordisk
Trial ID: NN9068-4183
Version:
3.0
UTN: U1111-1170-1332 
Status:
Final
EudraCT No.: N/A
Page:
4 of 8
All subjects will continue with the pre-trial OAD at pre-trial dose.
2.1
Injection area
IDegLira, IDeg and liraglutide should be injected subcutaneously once daily in the thigh, the upper 
arm (deltoid area) or abdomen. The chosen injection region should remain unchanged throughout 
the trial, although rotation within a given area is recommended.
2.2
Injection time
IDegLira and IDeg should be injected once daily at any time of the day, but should approximately 
be at the same time of the day throughout the trial. 
Liraglutide should be injected once daily in the morning or the evening, and approximately be at the 
same time of the day throughout the trial.
3
Initiation and titration of IDegLira and IDeg
3.1
Initiation of IDegLira
The recommended start dose of IDegLira is 10 dose steps (10U of insulin degludec and 0.36 mg
liraglutide) daily.
3.2
Initiation of IDeg
The recommended start dose of IDeg is 10U of insulin degludec.
3.3
Titration of IDegLira and IDeg
IDegLira and IDeg will be titrated twice weekly according to a predefined titration algorithm 
aiming to reach a fasting plasma glucose (FPG) target of  4.0-5.0 mmol/L (72-90 mg/dL) 
The doses of IDegLira or IDeg should be adjusted twice weekly by the subject on fixed days 
(Tuesdays and Fridays), see table 3.1 for illustration, according to a predefined titration algorithm 
described in table 3.2. The investigator will support titration at all contacts. 
CONFIDENTIAL


Protocol - Appendix A
CONFIDENTIAL
Date:
02 October 2015
Novo Nordisk
Trial ID: NN9068-4183
Version:
3.0
UTN: U1111-1170-1332 
Status:
Final
EudraCT No.: N/A
Page:
5 of 8
Table 3-1
Twice weekly titration on fixed days (Tue/Fri)
Sun
Mon
Tue
Wed
Thu
Fri
Sat
SMBG
X1
X1
X1
X2
X2
X2
X3
Dose 
titration
Titration1
Titration2
Dose (D)
D2
D2
D1
D1
D1
D2
D2
1 The dose for Tuesday, Wednesday and Thursday will be determined based on the mean pre-breakfast SMBG values, 
obtained on the last Sunday, Monday and Tuesday.
2 The dose for Friday, Saturday, Sunday and Monday will be determined based on the mean pre-breakfast SMBG values, 
obtained on the last Wednesday, Thursday and Friday.
3 SMBG measurements on Saturdays, are not used for titration
Dose adjustment will be based on the mean of three pre-breakfast SMBG values measured on the 
day of the titration and the two days prior to the titration in accordance with Table 3-2.
Table 3-2
Adjustment of IDeg and IDegLira doses
Mean pre-breakfast SMBG values
Dose adjustment
mmol/L
mg/dL
Dose steps/U
< 4.0
< 72
-2
4.0-5.0
72-90
0
> 5.0
> 90
+2
If one SMBG value is missing, the adjustment should be performed by the mean of the two
available SMBG values. If two SMBG values are missing the adjustment should be made on the 
one SMBG value. 
3.4
Deviation from the algorithm
It is recommended that the algorithm is followed. However, it is also important that the decision to 
adjust the trial drug doses are based on all relevant information as described in section 3.3. A reason 
for deviating from the algorithm should be entered into the eCRF.
CONFIDENTIAL


Protocol - Appendix A
CONFIDENTIAL
Date:
02 October 2015
Novo Nordisk
Trial ID: NN9068-4183
Version:
3.0
UTN: U1111-1170-1332 
Status:
Final
EudraCT No.: N/A
Page:
6 of 8
4
Initiation and dose escalation of liraglutide
The maintenance dose of liraglutide in this trial is 1.8 mg/day, this dose will be reached after a dose 
escalation period of 6 weeks. Trial product will be provided in a prefilled device. 
4.1
Escalation period 
Liraglutide will be initiated with 0.3 mg/day and subsequent weekly dose escalation by 0.3 mg 
weekly to a maximum dose of 1.8 mg/day during the first 6 weeks, see Table 4-1.
Table 4-1
Liraglutide dose escalation
1st week
2nd week
3rd week
4th week
5th week
6th week
Liraglutide 0.3 mg/day
(50 μL=5 
clicks)
0.6 mg/day
(100 μL=10 
clicks)
0.9 mg/day
(150 μL=15 
clicks)
1.2 mg/day
(200 μL=20 
clicks)
1.5 mg/day
(250 μL=25 
clicks)
1.8 mg/day
(300 μL=30 
clicks)
4.1.1
Extension of dose escalation period 
If subjects do not tolerate an increase in dose during dose escalation, e.g. due to safety reasons, the 
total dose escalation period can be extended with 1 week at the discretion of the investigator. The 
Investigator must emphasise to subjects the necessity of reaching the target dose of 1.8 mg.
4.2
Maintenance period 
The dose of liraglutide should remain unchanged in the maintenance period (i.e. after the escalation 
period) at 1.8 mg/day. 
If subjects do not tolerate the target dose they must be withdrawn from the trial due to safety 
concerns, reporting the AE that led to the withdrawal.
4.2.1
Dose reduction in maintenance period 
After the end of dose escalation, dose reduction in the 1.8 mg/day treatment arm to 1.5 mg or 1.2 
mg is allowed at the discretion of the investigator due to safety reasons. This should not extend 
more than 7 days in total from end of dose escalation to end of treatment. Dose reduction or 
treatment pause of longer duration unrelated to the tolerability of liraglutide is acceptable. Dose 
reduction lower than 1.2 mg/day is not allowed except temporarily for safety reasons, at the 
discretion of the investigator (as for instance while ruling out a suspected pancreatitis). The 
Investigator must emphasise to subjects the necessity of maintaining the target dose of 1.8 mg. 
CONFIDENTIAL


Protocol - Appendix A
CONFIDENTIAL
Date:
02 October 2015
Novo Nordisk
Trial ID: NN9068-4183
Version:
3.0
UTN: U1111-1170-1332 
Status:
Final
EudraCT No.: N/A
Page:
7 of 8
5
Data collection for IDegLira and IDeg
The following data should be entered into the eCRF within 24 hours (on weekdays) after a site 
visit/phone contact:
!
Per protocol pre-breakfast SMBG values measured since last visit/telephone contact as 
described in section 3.3
!
Doses of IDegLira or IDeg taken before and after titration
!
Reasons for deviation from the titration algorithms, if applicable
!
Hypoglycaemic episodes
6
Review procedure of titration data for IDegLira and IDeg 
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/phone contact. The aim is to reduce the time periods in which a subject may receive 
suboptimal treatment.
The data listed in section 5 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 phone contact) to discuss 
progress in glycaemic control and titration of individual subjects based on SMBG values and 
HbA1c. This will be done in an unbiased and whenever possible in a blinded manner.
CONFIDENTIAL


Protocol - Appendix A
CONFIDENTIAL
Date:
02 October 2015
Novo Nordisk
Trial ID: NN9068-4183
Version:
3.0
UTN: U1111-1170-1332 
Status:
Final
EudraCT No.: N/A
Page:
8 of 8
7
References
1 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.
2 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.
3 Hermansen K, Davies M, Derezinski T, Martinez RG, Clauson P, Home P. A 26-week, 
randomized, parallel, treat-to-target trial comparing insulin detemir with NPH insulin as add-on 
therapy to oral glucose-lowering drugs in insulin-naive people with type 2 diabetes. Diabetes 
Care 2006; 29(6):1269-1274.
4 Philis-Tsimikas A, Charpentier G, Clauson P, Ravn GM, Roberts VL, Thorsteinsson B. 
Comparison of once-daily insulin detemir with NPH insulin added to a regimen of oral 
antidiabetic drugs in poorly controlled type 2 diabetes. Clin Ther 2006; 28(10):1569-1581.
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
02 October 2015
Novo Nordisk
Trial ID: NN9068-4183
Version:
3.0
UTN: U1111-1170-1332 
Status:
Final
EudraCT No.: N/A
Page:
1 of 2
Appendix B
New York Heart Association Criteria for Functional Capacity
Trial ID: NN9068-4183
DUAL™ I Japan
A trial comparing the efficacy and safety of insulin 
degludec/liraglutide, insulin degludec and liraglutide in 
Japanese subjects with type 2 diabetes mellitus
Trial Phase: 3a
Protocol originator
Insulin & Diabetes Outcomes, Clinical Operations
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
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


Protocol - Appendix B
CONFIDENTIAL
Date:
02 October 2015
Novo Nordisk
Trial ID: NN9068-4183
Version:
3.0
UTN: U1111-1170-1332 
Status:
Final
EudraCT No.: N/A
Page:
2 of 2
1
Criteria for Functional Capacity１
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.
2
Reference
                                                
１
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 C
CONFIDENTIAL
Date:
02 Oct 2015
Novo Nordisk
Trial ID: NN9068-4183
Version:
3.0
UTN: U1111-1170-1332
Status:
Final
EudraCT No.: N/A
Page:
1 of 4
Appendix C
Medical events of special interest, events with additional data 
collection and events requiring adjudication 
Trial ID: NN9068-4183
DUAL™I Japan
A trial comparing the efficacy and safety of insulin degludec/liraglutide, insulin 
degludec and liraglutide in Japanese subjects with type 2 diabetes mellitus
Protocol originator
Insulin and Diabetes Outcomes, Clinical Operations
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.
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


Protocol - Appendix C
CONFIDENTIAL
Date:
02 Oct 2015
Novo Nordisk
Trial ID: NN9068-4183
Version:
3.0
UTN: U1111-1170-1332
Status:
Final
EudraCT No.: N/A
Page:
2 of 4
1
Events with additional data collection and events requiring 
adjudication
Events with 
additional data 
collection and/or 
events requiring 
adjudication 
Definitions
Rationale
Event Adjudication 
Committee
Fatal events
All fatal events must be reported including 
all-cause mortality: 
!
Cardiovascular death 
!
Non-cardiovascular death
!
Undetermined cause of death
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 unstable 
angina requiring hospitalization must be 
reported.
An FDA guidance document1
requests that Sponsors 
demonstrate the cardiovascular 
safety profile of any new 
therapy for type 2 diabetes in 
order to ensure, that the new 
therapy does not increase the 
cardiovascular risk to an 
unacceptable extent.
All events will be 
adjudicated
Cerebrovascular 
event; 
stroke or transient 
ischemic attack
Stroke (ischemic, haemorrhagic or 
undetermined) is defined as an acute 
episode of neurological dysfunction, 
caused by focal or global brain, spinal 
cord, or retinal vascular injury.
Transient Ischemic Attack (TIA) is 
defined as a transient (<24 hours) episode 
of neurological dysfunction caused by 
focal brain, spinal cord, or retinal 
ischemia, without acute infarction.
An FDA guidance document1
requests that Sponsors 
demonstrate the cardiovascular 
safety profile of any new 
therapy for type 2 diabetes in 
order to ensure, that the new 
therapy does not increase the 
cardiovascular risk to an 
unacceptable extent.
All events will be 
adjudicated
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 
All cases of heart 
failure requiring 
hospitalisation,
defined as an 
admission to an 
CONFIDENTIAL


Protocol - Appendix C
CONFIDENTIAL
Date:
02 Oct 2015
Novo Nordisk
Trial ID: NN9068-4183
Version:
3.0
UTN: U1111-1170-1332
Status:
Final
EudraCT No.: N/A
Page:
3 of 4
Events with 
additional data 
collection and/or 
events requiring 
adjudication 
Definitions
Rationale
Event Adjudication 
Committee
order to ensure, that the new 
therapy does not increase the 
cardiovascular risk to an 
unacceptable extent.
inpatient unit or a 
visit to an emergency 
department that 
results in at least a 24
hour stay, will be 
adjudicated
Pancreatitis
Two of the following three diagnostic 
criteria fulfilling the diagnosis of acute 
pancreatitis: 
!
Severe acute upper abdominal pain 
!
Elevated blood levels of pancreatic 
enzymes (lipase, amylase) > 3xUNR
!
Characteristic imaging finding 
(ultrasound, computerised axial 
tomography (CT), magnetic 
resonance imaging (MRI))
Chronic pancreatitis will be defined by 
characteristic imaging finding (ultrasound, 
CT, MRI) with abnormal pancreatic 
function tests or characteristic histological 
findings.
Treatment with GLP-1 receptor 
agonists has been associated 
with acute pancreatitis. Novo 
Nordisk therefore monitors 
these events closely.
All events will be 
adjudicated
Neoplasm
All types of neoplasms (i.e. all new 
growth incl. polyps, warts etc.) must be 
reported including:
!
Malign neoplasm
!
In situ neoplasm
!
Benign neoplasm
!
Neoplasms of uncertain or unknown 
behaviour
(Please note: for operational reasons 
thyroid neoplasms will be reported as per 
thyroid events and should not be reported 
as a Neoplasm MESI)
Neoplasm is an event we follow 
closely for GLP-1 analogues 
due to non-clinical findings in 
rats and mice treated with GLP-
1 agonists.
All neoplasm events, 
irrespective of 
malignancy stage,
will be adjudicated
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
Renal failure
All events of renal failure should be 
reported, including events fulfilling one of 
Liraglutide (a component of 
IDegLira) and SGLT2i have 
No adjudication 
CONFIDENTIAL


Protocol - Appendix C
CONFIDENTIAL
Date:
02 Oct 2015
Novo Nordisk
Trial ID: NN9068-4183
Version:
3.0
UTN: U1111-1170-1332
Status:
Final
EudraCT No.: N/A
Page:
4 of 4
Events with 
additional data 
collection and/or 
events requiring 
adjudication 
Definitions
Rationale
Event Adjudication 
Committee
the following three diagnostic criteria of 
acute renal failure:
!
Increase in serum creatinine ≥ 0.3 
mg/dL within 48 hours
!
Increase in serum creatinine to ≥ 1.5 
times baseline within 7 days
!
Urine volume < 0.5mL/kg/h for 6 
hours
been associated with 
dehydration/volume depletion. 
Severe dehydration/volume 
depletion per se can be 
associated with development of 
renal impairment and acute 
renal failure. Therefore renal 
impairment and acute renal 
failure are followed closely.  
2
Medical Events of Special Interest (MESI)
MESIs
Definitions
Rationale
Event 
Adjudication 
Committee
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.
Administration of an accidental 
overdose i.e. a dose which may lead 
to significant health consequences, as 
judged by the investigator, 
irrespective of whether the SAE 
criteria are fulfilled or not.
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
3
Reference
1 
Hicks KA, Hung HMJ, Mahaffey KW, Mehran R, Nissen SE, Strockbridge NL et al. Standardized 
Definitions for Cardiovascular and Stroke End Point Events in Clinical Trials (DRAFT).  20 Aug 2014. 
CONFIDENTIAL


Protocol - Appendix-D
CONFIDENTIAL
Date:
02 Oct 2015
Novo Nordisk
Trial ID: NN9068-4183
Version:
3.0
UTN: U1111-1170-1332
Status:
Final
EudraCT No.: N/A
Page:
1 of 4
Appendix D
Monitoring of Calcitonin
Trial ID: NN9068-4183
DUAL™ I Japan
A trial comparing the efficacy and safety of insulin degludec/liraglutide, insulin 
degludec and liraglutide in Japanese subjects with type 2 diabetes mellitus
Trial phase: 3a
Protocol originator
Insulin & Diabetes Outcomes, Clinical Operations
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
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


Protocol - Appendix-D
CONFIDENTIAL
Date:
02 Oct 2015
Novo Nordisk
Trial ID: NN9068-4183
Version:
3.0
UTN: U1111-1170-1332
Status:
Final
EudraCT No.: N/A
Page:
2 of 4
1
Background
Treatment with GLP-1 receptor agonists has shown to be associated with thyroid C-cell changes in 
rodents but not in non-human primates. The human relevance of this finding is unknown. However, 
based on the findings in rodents, monitoring of serum calcitonin (a sensitive biomarker for C-cell 
activation) is currently being performed in clinical trials with liraglutide and insulin 
degludec/liraglutide (IDegLira).
While there is general agreement on the clinical interpretation of substantially elevated calcitonin 
levels (>100 ng/L) as likely indicative of C-cell neoplasia, the interpretation of values between 
upper normal range (5.0 and 8.4 ng/L for women and men, respectively) and 100 ng/L is less clear 
with regards to indication of disease. 
There are several known confounding factors affecting calcitonin levels, e.g.:
!
renal dysfunction
!
smoking
!
autoimmune thyroiditis
!
several drug classes (e.g. proton pump inhibitors, beta-blockers, H2-blockers and 
glucocorticoids)
Physiology of C-cell activation in various clinical conditions and in different patient populations 
(i.e. with various co-morbidities) is poorly understood. There may be various clinical conditions not 
identified so far which mildly or moderately affect calcitonin secretion by C-cells.
2
Calcitonin monitoring
A blood sample will be drawn at pre-specified trial visits for measurement of calcitonin. Subjects 
with a calcitonin value ≥ 50 ng/L at screening cannot be randomised according to protocol section 
6.3 and further if the calcitonin value is measured to be ≥ 50 ng/L during the treatment period, the 
subjects must be withdrawn according to section 6.4 in the protocol. 
In case a subject has a calcitonin value ≥ 10 ng/L the algorithm outlined in Figure 1 and described 
below should be followed. The algorithm applies for all calcitonin values including screening 
values.
CONFIDENTIAL


Protocol - Appendix-D
CONFIDENTIAL
Date:
02 Oct 2015
Novo Nordisk
Trial ID: NN9068-4183
Version:
3.0
UTN: U1111-1170-1332
Status:
Final
EudraCT No.: N/A
Page:
3 of 4
Figure 1
Flow of calcitonin monitoring
2.1
Calcitonin ≥ 100 ng/L  
Action: The subject (even if a screen failure) must immediately be referred to a thyroid specialist 
for further evaluation and the subject must be withdrawn from the trial. All medications suspected 
to relate to this condition should be discontinued. 
Background: These values were found in 9 (0.15%) of a population of 5817 patients with thyroid 
nodular disease1. All of these patients were diagnosed with MTC resulting in a positive predictive 
value of 100%.
Diagnostic evaluation should include: 
!
thyroid ultrasound
!
fine needle aspiration of any nodules >1 cm 
!
potentially surgery with neck dissection
In case a subject is diagnosed with MTC, it is common clinical practice to explore the family 
history of MTC or MEN2 and perform a genetic test for RET proto-oncogene mutation.
2.2
Calcitonin ≥ 50 and < 100 ng/L
Action: The subject (even if a screen failure) should be referred to a thyroid specialist for further 
evaluation and the subject must be withdrawn from the trial. All medications suspected to relate to 
this condition should be discontinued.
CONFIDENTIAL


Protocol - Appendix-D
CONFIDENTIAL
Date:
02 Oct 2015
Novo Nordisk
Trial ID: NN9068-4183
Version:
3.0
UTN: U1111-1170-1332
Status:
Final
EudraCT No.: N/A
Page:
4 of 4
Background: These values were found in 8 (0.14%) of the population of 5817 patients with thyroid 
nodular disease1. Two of these subjects were diagnosed with MTC and two were diagnosed with C-
cell hyperplasia, resulting in a positive predictive value of a C-cell anomaly of 50%.
Diagnostic evaluation should include: 
!
thyroid ultrasound examination 
!
if available no contraindication, a pentagastrin stimulation test. Subjects with positive 
pentagastrin stimulation tests should be considered to undergo surgery 
!
if pentagastrin is not available, thyroid ultrasound and fine needle aspiration biopsy may add 
important clinical information informing the need for surgery.
2.3
Calcitonin ≥ 10 and <50 ng/L
Action: The subject can continue in the trial on trial product. Continue sampling of calcitonin 
according to the protocol. If the subject is a screen failure or if the value is from the last sample 
taken in the trial, the subject should be referred to a thyroid specialist for further evaluation.
Background: Calcitonin values from 20-50 ng/L were found in up to 1% of subjects of the 
population of 5817 patients with thyroid nodular disease1. The predictive value of a C-cell anomaly 
for this calcitonin level was 8.3%. However, the likelihood of having a medullary carcinoma >1 cm 
with calcitonin in this range is extremely low.
For calcitonin values 10-20 ng/L Costante et al1 identified 216 (3.7%) patients. One patient out of 
the 216 had a subsequent basal (unstimulated) calcitonin of 33 ng/L, and had C-cell hyperplasia at 
surgery. Two other studies used a cut-off of CT > 10 ng/L to screen for C-cell disease, but they do 
not provide sufficient information on patients with basal CT >10 and <20 ng/L to allow 
conclusions2 3.
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 
Scheuba C, Kaserer K, Moritz A, Drosten R, Vierhapper H, Bieglmayer C et al. 
Sporadic hypercalcitoninemia: clinical and therapeutic consequences. Endocrine-Related Cancer 
2009 2009; 16(1):243-253.
3 
Verga U, Ferrero S, Vicentini L, Brambilla T, Cirello V, Muzza M et al. 
Histopathological and molecular studies in patients with goiter and hypercalcitoninemia: reactive or 
neoplastic C-cell hyperplasia? Endocr Relat Cancer 2007; 14(2):393-403.
CONFIDENTIAL


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: NN9068-4183
Clinical Trial Report
Appendix 16.1.1
01 June 2018
1.0
Final
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
02 October 2015
Novo Nordisk
Trial ID: NN9068-4183
Version:
1.0
UTN: U1111-1170-1332 
Status:
Final
EudraCT No.: N/A
Page:
1 of 5
Protocol Amendment
No 1
to Protocol, final version 2.0
dated 15 July 2015
DUAL™ I Japan
Trial ID:NN9068-4183
A trial comparing the efficacy and safety of insulin degludec/liraglutide, insulin 
degludec and liraglutide in Japanese subjects with type 2 diabetes mellitus
Trial phase: 3a
Applicable to Japan
Amendment originator:
ClinOps2, Insulin & Diabetes Outcomes
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.
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


Protocol Amendment
CONFIDENTIAL
Date:
02 October 2015
Novo Nordisk
Trial ID: NN9068-4183
Version:
1.0
UTN: U1111-1170-1332 
Status:
Final
EudraCT No.: N/A
Page:
2 of 5
Table of Contents   
Page
Table of Contents..............................................................................................................................................2
Table of Figures.................................................................................................. Error! Bookmark not defined.
Table of Tables.................................................................................................... Error! Bookmark not defined.
1
Introduction including rationale for the protocol amendment.............................................................3
2
Changes......................................................................................................................................................4
2.1
Section 6.3 – Exclusion Criteria 16 corrected for consistency throughout protocol......................4
2.2
Section 6.4 – Withdrawal Criteria 5 modified to align with excl. criterion 7................................4
2.3
Section 8.2.2 – Concomitant Medication – definition changed.....................................................5
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
02 October 2015
Novo Nordisk
Trial ID: NN9068-4183
Version:
1.0
UTN: U1111-1170-1332 
Status:
Final
EudraCT No.: N/A
Page:
3 of 5
1
Introduction including rationale for the protocol amendment
It has been identified, that the protocol exclusion criterion 16 was not consistent with the text in 
other sections of the protocol which is why, it’s deemed necessary to correct this error. While
amending the above inconsistency, two minor corrections were made in order to improve clarity 
and quality of the protocol.
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
02 October 2015
Novo Nordisk
Trial ID: NN9068-4183
Version:
1.0
UTN: U1111-1170-1332 
Status:
Final
EudraCT No.: N/A
Page:
4 of 5
2
Changes
The following changes listed in section 2.1-2.3 have been made:
2.1
Section 6.3 – Exclusion Criteria 16 corrected for consistency throughout protocol
2.1.1 Change:
16. Proliferative retinopathy or maculopathy requiring acute treatment as verified by fundoscopy or 
fundus photography performed within 90 days prior to randomisation screening.
2.1.2 Rationale:
The exclusion criterion was not phrased as intended by mistake. Importantly it should be allowed to 
perform the eye examination at the screening (Visit 1) or in the period between Visit 1 and Visit 2 
(randomisation), as long as results are available prior to randomising a subject into the trial. This is 
in accordance with the protocol Section 2: Flow Chart; foot note 8 & Section 8.4.7 stating the 
following:
Section 2: Flow chart footnote 8:
”Eye examination (fundoscopy/fundus photography) obtained within 90 days prior to Visit 2 as part 
of routine practise may replace the screening assessment if results are available for evaluation at 
Visit 2.”
Section 8.4.7 Eye Examination
”Fundoscopy/fundus photography performed within 90 days prior to Visit 2 is acceptable. If a 
funduscopy/fundus photography has been performed prior to the screening visit (Visit 1) the 
procedure does not need to be repeated, unless worsening of visual function since the last 
examination has been noted.”
2.2
Section 6.4 – Withdrawal Criteria 5 modified to align with excl. criterion 7
2.2.1 Change:
5. Initiation of any systemic treatment with products which in the investigator's opinion could 
interfere with subjects weight, or glucose or lipid metabolism (e.g. systemic corticosteroids)
2.2.2 Rationale
The reason for adding this is in order to align with and exclusion criterion 7, stating the following:
“7. Anticipated initiation or change in concomitant medications in excess of 14 days known to 
affect weight or glucose metabolism.”
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
02 October 2015
Novo Nordisk
Trial ID: NN9068-4183
Version:
1.0
UTN: U1111-1170-1332 
Status:
Final
EudraCT No.: N/A
Page:
5 of 5
2.3
Section 8.2.2 – Concomitant Medication – definition changed.
2.3.1 Change:
A concomitant medication is any medication, other than the trial products and OADs, which is 
taken during the trial, including screening and follow-up periods.
2.3.2 Rationale:
The reason for deleting the ‘including screening’ is, that text is redundant, since in the paragraph
below the following is stated:
“Details of any concomitant medication must be recorded at Visit 1.”
Further, ’and the follow up periods’ will be deleted in order to avoid confusion, since in fact it is not 
intended to record any concomitant medication in the follow-up period, please refer to the last 
paragraph of section 8.2.2 stating as follows:
”Concomitant medication and anti-diabetic therapy initiated at end of treatment visit (Visit 54) and 
at the follow up visit (Visit 55) should not be recorded in the eCRF.”
CONFIDENTIAL