Conditions: Diabetes Diabetes Mellitus, Type 2
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 210
Healthy volunteers: no

Brief summary:
This trial is conducted in Asia. The aim of this trial is to compare the efficacy and safety of insulin degludec/liraglutide and insulin degludec both in combination with metformin in Japanese subjects with type 2 diabetes mellitus inadequately controlled with basal or pre-mix/combination insulin therapy and oral anti-diabetic drugs.

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: Insulin degludec/liraglutide intervention 2: Insulin degludec
Intervention descriptions: intervention 1: Injected s.c. / subcutaneously (under the skin) once daily intervention 2: Injected s.c. / subcutaneously (under the skin) once daily

Protocol document:
Prot_000.pdf: 
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CONFIDENTIAL
 
 
 
 
 
Redacted protocol 
Includes redaction of personal identifiable information only. 
 
 
 
. 
 
 


Protocol
CONFIDENTIAL
Date:
02 May 2016
1RYR1RUGLVN
Trial ID: NN9068-4184
Version:
2.0
UTN: U1111-1178-3453 
Status:
Final
EudraCT no.: NA
Page:
1 of 95
Protocol
DUAL™ II Japan
NN9068-4184
A double-blinded trial comparing the efficacy and safety of insulin 
degludec/liraglutide and insulin degludec both in combination with 
metformin in Japanese subjects with type 2 diabetes mellitus inadequately 
controlled with basal or pre-mix/combination insulin therapy
and oral anti-diabetic drugs
Trial phase: 3a
Protocol originator
, Ph.D.
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 No unpublished information contained herein may be 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.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol
CONFIDENTIAL
Date:
02 May 2016
1RYR1RUGLVN
Trial ID: NN9068-4184
Version:
2.0
UTN: U1111-1178-3453 
Status:
Final
EudraCT no.: NA
Page:
2 of 95
Table of Contents
Page
Table of Figures................................................................................................................................................6
Table of Tables..................................................................................................................................................6
List of abbreviations.........................................................................................................................................7
1
Summary..................................................................................................................................................10
1.1
Objectives and endpoints.............................................................................................................10
Primary objective.........................................................................................................................10
Secondary objective.....................................................................................................................10
Primary endpoint..........................................................................................................................10
Key secondary endpoints.............................................................................................................10
1.2
Trial design ..................................................................................................................................10
1.3
Trial population............................................................................................................................10
1.4
Key inclusion criteria...................................................................................................................11
1.5
Key exclusion criteria ..................................................................................................................11
1.6
Assessments.................................................................................................................................12
1.6.1
Key efficacy assessments...........................................................................................12
1.6.2
Key safety assessments..............................................................................................12
1.7
Trial products...............................................................................................................................12
2
Flow chart ................................................................................................................................................13
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
4.1.1
Primary objective.......................................................................................................21
4.1.2
Secondary objective...................................................................................................21
4.2
Endpoints .....................................................................................................................................21
4.2.1
Primary endpoint........................................................................................................21
4.2.2
Secondary endpoints..................................................................................................21
4.2.2.1
Supportive secondary endpoints..........................................................21
5
Trial design ..............................................................................................................................................23
5.1
Type of trial .................................................................................................................................23
5.2
Rationale for trial design..............................................................................................................23
5.3
Treatment of subjects...................................................................................................................24
5.3.1
Insulin degludec/liraglutide .......................................................................................24
5.3.2
Insulin degludec.........................................................................................................24
5.4
Treatment after discontinuation of trial product ..........................................................................25
5.5
Rationale for treatment ................................................................................................................25
6
Trial population.......................................................................................................................................26
6.1
Inclusion criteria ..........................................................................................................................26
6.2
Exclusion criteria.........................................................................................................................27
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
02 May 2016
1RYR1RUGLVN
Trial ID: NN9068-4184
Version:
2.0
UTN: U1111-1178-3453 
Status:
Final
EudraCT no.: NA
Page:
3 of 95
6.3
Withdrawal criteria ......................................................................................................................28
6.4
Subject replacement.....................................................................................................................29
6.5
Rationale for trial population.......................................................................................................29
7
Milestones.................................................................................................................................................30
7.1
Recruitment..................................................................................................................................30
7.2
Trial registration ..........................................................................................................................30
8
Methods and assessments .......................................................................................................................31
8.1
Visit procedures...........................................................................................................................31
8.1.1
Investigator’s assessment...........................................................................................31
8.1.2
Fasting requirements..................................................................................................31
8.1.3
Informed consent process ..........................................................................................31
8.1.4
Screening ...................................................................................................................32
8.1.4.1
Screening failures................................................................................32
8.1.5
Randomisation ...........................................................................................................32
8.1.6
Visits and phone contacts during treatment period....................................................33
8.1.7
End of treatment visit.................................................................................................33
8.1.8
Follow-up phone contact ...........................................................................................33
8.1.9
Unscheduled visits.....................................................................................................33
8.2
Withdrawal from trial ..................................................................................................................34
8.3
Subject related information/assessments .....................................................................................34
8.3.1
Demography...............................................................................................................34
8.3.2
Diabetes history and diabetes complications .............................................................34
8.3.3
Concomitant illness and medical history...................................................................34
8.3.4
Concomitant medication............................................................................................35
8.3.4.1
Metformin............................................................................................35
8.3.5
Tobacco use ...............................................................................................................36
8.4
Efficacy assessments....................................................................................................................36
8.4.1
Self-measured blood glucose (SMBG)......................................................................36
8.4.1.1
9-point self-measured blood glucose (SMBG) profile........................36
8.4.2
Body weight...............................................................................................................37
8.4.3
Waist circumference ..................................................................................................37
8.4.4
Blood pressure ...........................................................................................................38
8.5
Safety assessments.......................................................................................................................38
8.5.1
Adverse events...........................................................................................................38
8.5.1.1
Medication error..................................................................................38
8.5.1.2
Adverse events requiring additional data collection ...........................38
8.5.2
Assessments in case of suspicion of acute pancreatitis..............................................42
8.5.3
Eye Examination........................................................................................................42
8.5.4
Electrocardiogram (ECG)..........................................................................................43
8.5.5
Pulse...........................................................................................................................43
8.5.6
Physical Examination ................................................................................................43
8.5.7
Hypoglycaemic episodes ...........................................................................................44
8.5.8
Suspicion of acute hypersensitivity to trial products .................................................45
8.6
Laboratory assessments ...............................................................................................................46
8.6.1
Laboratory assessments for efficacy..........................................................................46
8.6.1.1
Glucose metabolism............................................................................46
8.6.1.2
Lipids...................................................................................................46
8.6.2
Laboratory assessments for safety .............................................................................47
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
02 May 2016
1RYR1RUGLVN
Trial ID: NN9068-4184
Version:
2.0
UTN: U1111-1178-3453 
Status:
Final
EudraCT no.: NA
Page:
4 of 95
8.6.2.1
Haematology .......................................................................................47
8.6.2.2
Biochemistry .......................................................................................47
8.6.2.3
Hormones ............................................................................................47
8.6.2.4
Pregnancy test .....................................................................................47
8.7
Other assessments........................................................................................................................48
8.7.1
Height ........................................................................................................................48
8.7.2
Body Mass Index .......................................................................................................48
8.7.3
Patient reported outcomes..........................................................................................49
8.7.4
Diaries........................................................................................................................49
8.7.5
Training in the trial product and pen handling...........................................................50
8.8
Subject compliance......................................................................................................................50
9
Trial supplies ...........................................................................................................................................51
9.1
Trial products...............................................................................................................................51
9.2
Metformin....................................................................................................................................51
9.3
Labelling......................................................................................................................................51
9.4
Storage .........................................................................................................................................52
9.5
Drug accountability and destruction............................................................................................52
9.6
Auxiliary supplies........................................................................................................................53
10 Interactive web response system............................................................................................................53
11 Randomisation procedure and breaking of blinded codes..................................................................54
11.1
Randomisation .............................................................................................................................54
11.2
Stratification.................................................................................................................................54
11.3
Breaking of blinded codes ...........................................................................................................54
12 Adverse events, technical complaints and pregnancies .......................................................................55
12.1
Definitions ...................................................................................................................................55
12.1.1
Adverse event ............................................................................................................55
12.1.2
Serious adverse event.................................................................................................56
12.1.3
Non-serious adverse event.........................................................................................57
12.1.4
Medication errors.......................................................................................................57
12.1.5
Adverse events requiring additional data collection..................................................57
12.1.6
Technical complaints.................................................................................................59
12.2
Reporting of adverse events.........................................................................................................59
12.3
Follow-up of adverse events........................................................................................................62
12.4
Technical complaints and technical complaint samples ..............................................................63
12.4.1
Reporting of technical complaints .............................................................................63
12.4.2
Collection, storage and shipment of technical complaint samples ............................63
12.5
Pregnancy.....................................................................................................................................64
12.5.1
Pregnancy in female subjects.....................................................................................64
12.6
Precautions and/or overdose ........................................................................................................65
12.7
Committees related to safety........................................................................................................66
12.7.1
Novo Nordisk safety committee ................................................................................66
12.7.2
Event adjudication committee....................................................................................66
13 Case report forms....................................................................................................................................67
13.1
Corrections to case report forms..................................................................................................68
13.2
Case report form flow..................................................................................................................68
13.2.1
Paper case report form flow.......................................................................................68
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
02 May 2016
1RYR1RUGLVN
Trial ID: NN9068-4184
Version:
2.0
UTN: U1111-1178-3453 
Status:
Final
EudraCT no.: NA
Page:
5 of 95
14 Monitoring procedures ...........................................................................................................................69
15 Data management....................................................................................................................................70
16 Computerised systems.............................................................................................................................70
17 Statistical considerations ........................................................................................................................70
17.1
Sample size calculation................................................................................................................72
17.2
Definition of analysis sets............................................................................................................73
17.3
Primary endpoint..........................................................................................................................73
17.3.1
Sensitivity analysis ....................................................................................................74
17.4
Secondary endpoints....................................................................................................................75
17.4.1
Supportive secondary endpoints ................................................................................75
17.4.1.1
Efficacy endpoints...............................................................................75
17.4.1.2
Safety endpoints..................................................................................76
17.5
Patient reported outcomes............................................................................................................82
18 Ethics........................................................................................................................................................82
18.1
Benefit-risk assessment of the trial..............................................................................................82
18.2
Informed consent .........................................................................................................................84
18.3
Data handling...............................................................................................................................85
18.4
Information to subjects during trial..............................................................................................85
18.5
Premature termination of the trial and/or trial site.......................................................................85
19 Protocol compliance................................................................................................................................86
19.1
Protocol deviations ......................................................................................................................86
19.2
Prevention of missing data...........................................................................................................86
20 Audits and inspections ............................................................................................................................86
21 Critical documents ..................................................................................................................................87
22 Responsibilities........................................................................................................................................87
23 Reports and publications........................................................................................................................88
23.1
Communication of results............................................................................................................89
23.1.1
Authorship .................................................................................................................89
23.1.2
Site-specific publication by investigator....................................................................90
23.2
Investigator access to data and review of results.........................................................................90
24 Retention of clinical trial documentation..............................................................................................90
24.1
Retention of clinical trial documentation.....................................................................................90
25 Institutional Review Boards and regulatory authorities .....................................................................91
25.1
Institutional Review Boards.........................................................................................................91
25.2
Regulatory Authorities.................................................................................................................92
26 Indemnity statement ...............................................................................................................................92
27 References................................................................................................................................................93
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
02 May 2016
1RYR1RUGLVN
Trial ID: NN9068-4184
Version:
2.0
UTN: U1111-1178-3453 
Status:
Final
EudraCT no.: NA
Page:
6 of 95
Table of Figures
Page
Figure 5–1
Trial design.............................................................................................................................23
Figure 12–1
Reporting of adverse events....................................................................................................61
Figure 17–1
Novo Nordisk classification of hypoglycaemia......................................................................78
Figure 17–2
ADA classification of hypoglycaemia....................................................................................79
Table of Tables
Page
Table 8–1
9-point profile (SMBG).........................................................................................................37
Table 9–1
Trial products..........................................................................................................................51
Table 9–2
Storage conditions .................................................................................................................52
Table 12–1
Adverse events requiring completion of specific event forms and/or are subject to event 
adjudication ............................................................................................................................58
Table 12–2
Summary of reporting timelines for adverse events..............................................................60
Table 17–1
Power for various rates of withdrawal and efficacy retention (adjusted treatment 
difference)...............................................................................................................................72
Appendix A: Insulin Titration Guideline
Appendix B: New York Heart Association Criteria for Functional Capacity
Appendix C: 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:
02 May 2016
1RYR1RUGLVN
Trial ID: NN9068-4184
Version:
2.0
UTN: U1111-1178-3453 
Status:
Final
EudraCT no.: NA
Page:
7 of 95
List of abbreviations
ADA
American Diabetes Association
AE
adverse event
α-GI
alpha-glucosidase inhibitor
ALT
alanine aminotransferase 
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
BG
blood glucose
BMI
body mass index
CAS
completer analysis set
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration 
CLAE
clinical laboratory adverse event
CV
coefficient of variation
DFU
direction for use
DUN
dispensing unit number
DPP-4
dipetidyl peptidase-4
DTR-QOL
Diabetes Therapy-Related QOL questionnaire
EAC
event adjudication committee
ECG
electrocardiogram
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
EQ-5D-5L
EuroQol-5D-5L questionnaire
ET
end of treatment
FAS
full analysis set
FPFV
first patient first visit
FPG
fasting plasma glucose
FU
follow-up
GCP
Good Clinical Practice
GLP-1
glucagon-like peptide-1
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
02 May 2016
1RYR1RUGLVN
Trial ID: NN9068-4184
Version:
2.0
UTN: U1111-1178-3453 
Status:
Final
EudraCT no.: NA
Page:
8 of 95
HbA1c
glycosylated haemoglobin
hCG
human chorionic gonadotropin
HDL
high density lipoprotein
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
IDeg
insulin degludec
IDegLira
insulin degludec/liraglutide
IMP
investigational medicinal product
IRB
institutional review board
IWRS
interactive web response system
LDL
low density lipoprotein
LLOQ
lower limit of quantification
LOCF
last observation carried forward
LPFV
last patient first visit
LPLV
last patient last visit
LSMeans
least square means
MEN 2
multiple endocrine neoplasia syndrome type 2 
MI
myocardial infarction
MMRM
mixed model for repeated measurement
MTC
medullary thyroid carcinoma
NYHA
New York Heart Association
OAD
oral anti-diabetic drug
OD
once daily
PMDA
Pharmaceuticals and Medical Devices Agency
PRO
patient reported outcome
SAE
serious adverse event
SAS
safety analysis set
SD
standard deviation
SGLT2i
sodium glucose co-transporter 2 inhibitor
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
02 May 2016
1RYR1RUGLVN
Trial ID: NN9068-4184
Version:
2.0
UTN: U1111-1178-3453 
Status:
Final
EudraCT no.: NA
Page:
9 of 95
SIF
safety information form
SMBG
self-measured blood glucose
SU
sulfonylureas
SUSAR
suspected unexpected serious adverse reaction
T2DM
type 2 diabetes mellitus
TEAE
treatment emergent adverse event
TIA
transient ischemic attack
TMM
Trial Materials Manual
TSH
thyroid stimulating hormone
TZD
thiazolidinedione
T3
triiodothyronine
T4
thyroxine
UNL
upper normal limit
UNR
upper normal range
UTN
Universal Trial Number
VLDL
very low density lipoprotein
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
02 May 2016
1RYR1RUGLVN
Trial ID: NN9068-4184
Version:
2.0
UTN: U1111-1178-3453 
Status:
Final
EudraCT no.: NA
Page:
10 of 95
1
Summary
1.1
Objectives and endpoints
Primary objective 
To confirm the superiority of insulin degludec/liraglutide (IDegLira) vs. insulin degludec (IDeg) in 
controlling glycaemia in Japanese subjects with type 2 diabetes mellitus (T2DM) after 26 weeks of 
treatment.
Secondary objective
To compare the general efficacy and safety of IDegLira and IDeg after 26 weeks of treatment in 
Japanese subjects with T2DM.
Primary endpoint
Change from baseline in glycosylated haemoglobin (HbA1c) after 26 weeks.
Key secondary endpoints
!
Change from baseline in body weight after 26 weeks
!
Change from baseline in fasting plasma glucose (FPG) after 26 weeks
!
Number of treatment emergent severe or blood glucose (BG) confirmed hypoglycaemic 
episodes during 26 weeks of treatment
1.2
Trial design
This is a 26-week randomised, parallel two-arm, double-blinded, multi-centre, treat-to-target trial in 
Japanese subjects with T2DM inadequately controlled with basal insulin or pre-mix/combination
insulin in combination with metformin with or without one of the following oral anti-diabetic drugs 
(OADs): sulphonylureas (SU), glinides, α-glucocidase inhibitors (α-GI), sodium-glucose co-
transporter-2 inhibitors (SGLT2i) or thiazolidinediones (TZD). 
The trial is designed to demonstrate superiority in HbA1c of IDegLira as compared to IDeg with the 
dose capped at 50 units in subjects with T2DM as the maximum dose of IDegLira is 50 dose steps 
(50 units IDeg/1.8 mg liraglutide). 
1.3
Trial population
A total of 210 Japanese subjects with T2DM inadequately controlled on insulin combined with 
metformin with or without one other OAD with HbA1c in the range of 7.5-11.0% (both inclusive),  
and thus in need of treatment intensification to achieve or maintain glycaemic control, are planned 
to be randomised in the trial.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
02 May 2016
1RYR1RUGLVN
Trial ID: NN9068-4184
Version:
2.0
UTN: U1111-1178-3453 
Status:
Final
EudraCT no.: NA
Page:
11 of 95
1.4
Key inclusion criteria
!
Male or female Japanese subjects, age ≥20 years at the time of signing informed consent 
!
T2DM subjects (diagnosed clinically) ≥ 6 months prior to screening
!
HbA1c 7.5-11.0% [58 mmol/mol-97 mmol/mol] (both inclusive) by central laboratory analysis
!
Subjects on stable daily insulin doses for at least 90 days prior to screening administered once or 
twice daily, either as basal insulin (e.g. IDeg, insulin glargine, insulin detemir, NPH insulin) or 
pre-mix/combination insulin (e.g. biphasic insulin aspart, insulin degludec/insulin aspart). Total 
daily insulin dose in the previous 90 days should be within 20-50 units, both inclusive, and on 
the day of screening, but fluctuations of ± 10% within the 90 days prior to screening are 
acceptable. The specified insulin treatment should be administered in combination 
o
with a stable daily dose of metformin within current approved Japanese label for at 
least 90 days prior to screening, 
o
additionally, the anti-diabetic treatment can be with or without a stable daily dose of 
one of the following other OADs: SU, glinides, α-GI, SGLT2i or TZD within current 
approved Japanese label for at least 90 days prior to screening
!
Body Mass Index (BMI) ≥23 kg/m2
1.5
Key exclusion criteria
!
Receipt of any investigational medicinal product (IMP) within 30 days before screening
!
Use of any anti-diabetic drug in a period of 90 days before screening (except pre-
mix/combination or basal insulin, metformin, SU, glinides, α-GI, SGLT2i, or TZD) or 
anticipated change in concomitant medication, which in the investigators opinion could interfere 
with glucose metabolism (e.g. systemic corticosteroids or bolus insulin)
!
Previous treatment with glucagon-like peptide-1 (GLP-1) receptor agonists
!
Treatment with dipetidyl peptidase-4 (DPP-4) inhibitors during the last 90 days prior to 
screening
!
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 IV
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
02 May 2016
1RYR1RUGLVN
Trial ID: NN9068-4184
Version:
2.0
UTN: U1111-1178-3453 
Status:
Final
EudraCT no.: NA
Page:
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1.6
Assessments
1.6.1
Key efficacy assessments
!
HbA1c
!
Body weight 
!
FPG
1.6.2
Key safety assessments
!
Hypoglycaemic episodes
!
Adverse events (AEs)
1.7
Trial products
!
Insulin degludec/liraglutide, 100 units/mL + 3.6 mg/mL, 3 mL pre-filled PDS290 pen injector
!
Insulin degludec, 100 units/mL, 3 mL pre-filled PDS290 pen injector.
CONFIDENTIAL


Protocol
UTN: U1111-1178-3453 
Date:
02 May 2016
Status:
Final
1RYR1RUGLVN
Trial ID: NN9068-4184
EudraCT no.: NA
Version:
2.0
Page:
13 of 95
2
Flow chart
Screening (SC)
Randomisation (RAN)
Site visit (V)
Phone contact (P)1
End of Treatment (ET) 
Follow-up (FU)
SC 
V
RAN
V
P
V
P
V
P
V
P
V
P
V
P
V
P
V
P
ET
V
FU 
P
Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
Time of V or P (week)
- 2
0
0,52
1
1,52
2
2,52
3
3,52
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
Visit window (days)
±1
±1
±1
±1
±1
±1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+3
SUBJECT RELATED
INFO/ASSESSMENTS
Informed consent
x
In/exclusion criteria
x
x
Randomisation3
x
Withdrawal criteria4
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Demography5
x
Diagnosis of diabetes
x
Diabetes treatment history
x
                                                
1 A phone contact may be converted to a site visit.
2 Corresponding to previous visit/contact date plus three days.
3 Randomisation (V2) 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 the screening (V1). 
4 If a subject is withdrawn from the trial, the investigator must aim to undertake procedures similar to those for the end of treatment (V32) as soon as possible and to 
perform the follow-up (P33).
5 Collection of birth date, sex and race.


Protocol
UTN: U1111-1178-3453 
Date:
02 May 2016
Status:
Final
1RYR1RUGLVN
Trial ID: NN9068-4184
EudraCT no.: NA
Version:
2.0
Page:
14 of 95
Screening (SC)
Randomisation (RAN)
Site visit (V)
Phone contact (P)1
End of Treatment (ET) 
Follow-up (FU)
SC 
V
RAN
V
P
V
P
V
P
V
P
V
P
V
P
V
P
V
P
ET
V
FU 
P
Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
Time of V or P (week)
- 2
0
0,52
1
1,52
2
2,52
3
3,52
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
Visit window (days)
±1
±1
±1
±1
±1
±1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+3
Family history of diabetes
x
Diabetes complications
x
Concomitant illness
x
Medical history
x
Concomitant medication
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Tobacco use
x
EFFICACY
Pre-breakfast SMBG6
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
9-point SMBG profile7
x
x
x
Body weight
x
x
x
x
x
Waist circumference
x
x
x
x
Blood pressure (systolic and diastolic) 
x
x
x
x
x
HbA1c
x
x
x
x
x
x
x
x
Fasting plasma glucose
x
x
x
x
x
x
x
                                                
6 Daily pre-breakfast SMBG should be recorded. Anti-diabetic medication should be withheld until after the SMBG measurement.
7 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 has not been anticipating
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. 


Protocol
UTN: U1111-1178-3453 
Date:
02 May 2016
Status:
Final
1RYR1RUGLVN
Trial ID: NN9068-4184
EudraCT no.: NA
Version:
2.0
Page:
15 of 95
Screening (SC)
Randomisation (RAN)
Site visit (V)
Phone contact (P)1
End of Treatment (ET) 
Follow-up (FU)
SC 
V
RAN
V
P
V
P
V
P
V
P
V
P
V
P
V
P
V
P
ET
V
FU 
P
Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
Time of V or P (week)
- 2
0
0,52
1
1,52
2
2,52
3
3,52
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
Visit window (days)
±1
±1
±1
±1
±1
±1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+3
Lipids    
x
x
x
x
SAFETY
Adverse events
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Technical complaints
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Eye examination8
x
x
ECG9
x
x
Pulse
x
x
x
x
x
Physical examination
x
x
Hypoglycaemic episodes
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Haematology 
x
x
x
Biochemistry 
x
x
x
Calcitonin
x
x
x
                                                
8 Eye examination will be performed as fundoscopy/fundus photography. If performed within 90 days prior to randomisation (V2) as part of routine practice, it may 
replace the screening assessment, if results are available for evaluation at V2. Eye examination obtained within 14 days prior to end of treatment (V32) is acceptable, if 
results are available for evaluation at V32.
9 ECG obtained within 14 days prior to randomisation (V2), as part of routine practice, may replace the screening assessment and ECG obtained within 14 days prior to 
end of treatment (V32) is acceptable, if results are available for evaluation at the respective visits.


Protocol
UTN: U1111-1178-3453 
Date:
02 May 2016
Status:
Final
1RYR1RUGLVN
Trial ID: NN9068-4184
EudraCT no.: NA
Version:
2.0
Page:
16 of 95
Screening (SC)
Randomisation (RAN)
Site visit (V)
Phone contact (P)1
End of Treatment (ET) 
Follow-up (FU)
SC 
V
RAN
V
P
V
P
V
P
V
P
V
P
V
P
V
P
V
P
ET
V
FU 
P
Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
Time of V or P (week)
- 2
0
0,52
1
1,52
2
2,52
3
3,52
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
Visit window (days)
±1
±1
±1
±1
±1
±1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+3
Pregnancy test10
x
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
x
OTHER ASSESSMENTS
Height
x
DTR-QOL11
x
x
x
EQ-5D-5L11
x
x
x
TRIAL MATERIAL
IWRS session
x
x
x
x
x
x
x
x
Dispensing visit
x
x
x
x
x
x
Drug accountability (IWRS)
x
x
x
x
x
x
x
REMINDERS
Attend visit fasting12
x
x
x
x
x
x
x
Discontinue OADs except for metformin
x
                                                
10 For females of childbearing potential: A serum pregnancy test must be performed at screening (V1) and at end of treatment (V32). Urine pregnancy test should be 
performed at site if a menstrual period is missed, or if pregnancy is suspected, indicated by (x). 
11 PRO questionnaires should be completed by subject and reviewed by investigator.
12 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 as usual. If a subject attend site visit in a non-fasting condition, blood sampling should be re-scheduled, preferably within the 
visit window.


Protocol
UTN: U1111-1178-3453 
Date:
02 May 2016
Status:
Final
1RYR1RUGLVN
Trial ID: NN9068-4184
EudraCT no.: NA
Version:
2.0
Page:
17 of 95
Screening (SC)
Randomisation (RAN)
Site visit (V)
Phone contact (P)1
End of Treatment (ET) 
Follow-up (FU)
SC 
V
RAN
V
P
V
P
V
P
V
P
V
P
V
P
V
P
V
P
ET
V
FU 
P
Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
Time of V or P (week)
- 2
0
0,52
1
1,52
2
2,52
3
3,52
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
Visit window (days)
±1
±1
±1
±1
±1
±1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+3
Handout ID card
x
Handout directions for use of trial 
product13
x
(x)
(x)
(x)
(x)
(x)
Training in trial product and pen 
handling14
x
(x)
x
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
Handout and instruct in BG meter use
x
Handout and instruct in diary
x
x
x
x
x
x
x
x
x
x
Collection of diary15
x
x
x
x
x
x
x
x
x
x
Instruction in titration algorithm
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Make appointment for eye examination 
x
End of treatment
x
End of trial16
x
Sign of casebook
x
                                                
13 Handout direction for use only in case needed by subject during trial is indicated by (x).
14 Training in trial product and pen handling should be performed at randomisation (V2) and one week after (V4). At other site visits and at phone contacts training will 
be at the investigator’s discretion based on subject needs, indicated by (x).
15 Diary data collected from end of treatment (V32) to follow-up (P33) will be collected per phone as notes written down by the investigator based on an interview. 
16 Due to the long half-life of insulin degludec, the follow-up (P33) procedures should be undertaken minimum 7 days after end of treatment (V32).


Protocol
CONFIDENTIAL
Date:
02 May 2016
1RYR1RUGLVN
Trial ID: NN9068-4184
Version:
2.0
UTN: U1111-1178-3453 
Status:
Final
EudraCT no.: NA
Page:
18 of 95
3
Background information and rationale for the trial
The trial will be conducted in compliance with this protocol, International Conference on 
Harmonisation Good Clinical Practice Guideline (ICH GCP)1 and applicable regulatory 
requirements, and in accordance with the Declaration of Helsinki2.
In this document, the term investigator refers to the individual responsible for the overall conduct of 
the clinical trial at a trial site.
3.1
Background information
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 diabetes3, 4.
Given the progressive nature of T2DM, current anti-diabetic therapies with OADs and insulin often 
fail to provide sustained glycaemic control. The successful outcome of recent global trials 
combining basal insulin and GLP-1 treatment as separate injections has led to the inclusion of this 
treatment combination in the most recent guidelines from the Japanese Diabetes Society, the 
American Diabetes Association and in the European Association for the Study of Diabetes position 
statement on management of hyperglycaemia in T2DM5-7.
Treatment guidance from the Japanese Diabetes Society suggests a stepwise approach comprising 
lifestyle changes followed by pharmacological intervention7. Initial OAD monotherapy is 
recommended, escalated with combination therapy with OADs combined with insulin, or GLP-1 
receptor agonists, and combination of insulin and GLP-1 receptor. 
Insulin degludec (IDeg)
IDeg is a long-acting basal insulin, marketed with the brandname Tresiba®, which has been 
approved in Japan, US, EU, and several other countries.
For more details on IDeg, see the current Investigator’s Brochure (IB)8 and any updates hereof as 
well as the latest Japanese approved labelling for Tresiba®.
Liraglutide 
Liraglutide is an analogue native (human) 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®.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
02 May 2016
1RYR1RUGLVN
Trial ID: NN9068-4184
Version:
2.0
UTN: U1111-1178-3453 
Status:
Final
EudraCT no.: NA
Page:
19 of 95
For more details on liraglutide, please see the current IB 9 and any updates hereof as well as latest 
Japanese approved labelling for Victoza®.
Insulin degludec/liraglutide (IDegLira)
IDegLira is a basal insulin (IDeg) and GLP-1 receptor agonist (liraglutide) combination solution for 
subcutaneous injection for treatment of T2DM with once daily use 10. The combination brings
complimentary effects of the two compounds (IDeg and liraglutide) on fasting  and postprandial 
(liraglutide) glycaemic control. The addition of liraglutide to IDeg 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 in EU among others. Marketing authorisation has been granted in several 
countries, e.g. in Switzerland and in EU. IDegLira is not approved in Japan.
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 an assessment of benefits and risks of the trial, see 
section 18.1.
For more information, see the current IB version of IDegLira11, IDeg8 and liraglutide9 or any 
updates hereof.
3.2
Rationale for the trial
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. 
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
02 May 2016
1RYR1RUGLVN
Trial ID: NN9068-4184
Version:
2.0
UTN: U1111-1178-3453 
Status:
Final
EudraCT no.: NA
Page:
20 of 95
Both IDeg and liraglutide are on the market in Japan. The present confirmatory trial (NN9068-4184 
DUAL™ II Japan) in Japanese subjects with T2DM treated with insulin and OAD aims to confirm 
efficacy and safety of once daily treatment with IDegLira, as compared to treatment with once daily 
IDeg. To establish the contribution of the monocomponents in a combination product, and as the 
maximum daily dose of IDegLira is 50 dose steps (50 units of IDeg/1.8 mg of liraglutide); the IDeg 
dose in the comparator arm is capped at 50 units. Given that the trial is double-blinded, any 
difference between the two treatment arms will be attributable to the liraglutide component in 
IDegLira. 
NN9068-4184 DUAL™ II Japan is a part of the Japanese IDegLira development programme, which 
also includes trials NN9068-4183 DUAL™ I Japan testing IDegLira against the monocomponents 
in OAD experienced T2DM subjects. In the three arm trial NN9068-4183 DUAL™ I Japan,
IDegLira is tested against freely titrated IDeg and a maximum dose of 1.8 mg liraglutide, 
respectively, and safety and efficacy data of IDegLira combined with 6 different OADs will be 
collected in that trial. As such, the present trial in insulin experienced subjects with T2DM will 
together with NN9068-4183 be used for registration of IDegLira in Japan as agreed with the 
Pharmaceuticals and Medical Devices Agency (PMDA).
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
02 May 2016
1RYR1RUGLVN
Trial ID: NN9068-4184
Version:
2.0
UTN: U1111-1178-3453 
Status:
Final
EudraCT no.: NA
Page:
21 of 95
4
Objectives and endpoints
4.1
Objectives
4.1.1
Primary objective 
To confirm the superiority of IDegLira vs. IDeg in controlling glycaemia in Japanese subjects with 
T2DM after 26 weeks of treatment.
4.1.2
Secondary objective
To compare the general efficacy and safety of IDegLira and IDeg after 26 weeks of treatment in 
Japanese subjects with T2DM.
4.2
Endpoints
4.2.1
Primary endpoint
Change from baseline in HbA1c after 26 weeks.
4.2.2
Secondary endpoints
4.2.2.1
Supportive secondary endpoints
Supportive secondary efficacy endpoints:
!
Daily insulin dose after 26 weeks
!
Change from baseline in body weight after 26 weeks*
!
Responder after 26 weeks (yes/no):
o
HbA1c < 7.0% 
o
HbA1c < 7.0% and without weight gain
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 without weight gain 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 without weight gain 
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 without weight gain and without treatment emergent severe or BG 
confirmed symptomatic hypoglycaemic episodes during the last 12 weeks of 
treatment 
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
02 May 2016
1RYR1RUGLVN
Trial ID: NN9068-4184
Version:
2.0
UTN: U1111-1178-3453 
Status:
Final
EudraCT no.: NA
Page:
22 of 95
!
Change from baseline after 26 weeks in: 
o
FPG*
o
Waist circumference
o
Blood pressure (systolic and diastolic)
o
Self-measured blood glucose (SMBG) 9-point profile
-
9-point profile (individual points in the profile)
-
Mean of the 9-point profile
-
Mean of postprandial plasma glucose increments (from before meal to 90 
min after breakfast, lunch and dinner). The mean increment over all meals 
will be derived as the mean of all available meal increments
!
Lipid profile after 26 weeks of treatment
Supportive secondary safety endpoints:
!
Number of treatment emergent adverse events (TEAE) during 26 weeks of treatment
!
Number of treatment emergent severe or BG confirmed hypoglycaemic episodes during 26 
weeks of treatment*
!
Number of treatment emergent severe or BG confirmed symptomatic hypoglycaemic episodes 
during 26 weeks of treatment
!
Number of treatment emergent hypoglycaemic episodes according to ADA definition during 26 
weeks of treatment
!
Number of treatment emergent nocturnal severe or BG confirmed symptomatic hypoglycaemic 
episodes during 26 weeks of treatment
!
Change from baseline in clinical evaluation after 26 weeks of treatment:
o
Physical examination
o
Fundoscopy or fundus photography
o
Electrocardiogram (ECG)
o
Pulse
!
Change from baseline in laboratory assessments after 26 weeks of treatment:
o
Biochemistry (including amylase and lipase)
o
Haematology
o
Calcitonin
Supportive secondary patient reported outcome endpoints:
!
Change from baseline in patient reported outcomes (PROs) after 26 weeks of treatment:
o
Diabetes Therapy-Related QOL (DTR-QOL) questionnaire
o
EuroQol-5D (EQ-5D-5L) questionnaire
Key supportive secondary endpoints prospectively selected for disclosure (e.g. clinicaltrials.gov) 
are marked with an asterisk (*).
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
02 May 2016
1RYR1RUGLVN
Trial ID: NN9068-4184
Version:
2.0
UTN: U1111-1178-3453 
Status:
Final
EudraCT no.: NA
Page:
23 of 95
5
Trial design
5.1
Type of trial
This is a 26-week randomised, parallel two-arm, double-blinded, multi-centre, treat-to-target trial in 
Japanese subjects with T2DM inadequately controlled with basal insulin or pre-mix/combination
insulin, combined with metformin with or without one of the following OADs: SU, glinides, α-GI, 
SGLT2i or TZD, hereafter collectively referred to as other OADs. 
Inadequately controlled diabetes will be defined as HbA1c level of 7.5-11.0 % both inclusive. A 
total of 210 subjects will be randomised in a 1:1 manner using an interactive web response system
(IWRS) to either IDegLira once daily or IDeg once daily both in combination with metformin, see
Figure 5–1. To ensure an even proportion of subjects on pre-trial basal or pre-mix/combination
insulin in each treatment arm, the randomisation will be stratified with regards to these two different 
pre-trial insulin therapies combined with metformin with or without one other OAD (see section 
11.2).
The duration of the trial from screening to follow-up will be approximately 29 weeks with a 
screening period of 2 weeks, a treatment duration of 26 weeks, and 1 week of follow-up. The trial
will include a screening visit (V1) at which the eligibility of the subjects are assessed followed by a 
randomisation visit (V2), an end of treatment (ET) visit (V32) and a follow-up contact (P33) at end 
of trial (week 27).
Figure 5–1
Trial design
5.2
Rationale for trial design
Based on prior experience from IDegLira trials, the treatment duration of 26 weeks is sufficient to 
reach a stable HbA1c level and to obtain sufficient data for efficacy and safety evaluation.
The current trial is designed to demonstrate superiority in HbA1c of IDegLira as compared to IDeg 
in subjects with T2DM. To enable an evaluation of the contribution of the liraglutide component of 
IDegLira to glycaemic control and secondary endpoints, the maximum dose of IDeg in the IDeg 
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arm is set to 50 units, i.e. equivalent to the maximum dose of the IDeg component in IDegLira (50 
units of IDeg/1.8 mg of liraglutide).
Two types of insulin are allowed pre-trial (basal and pre-mix/combination insulin), since these may 
reflect different states of disease progression, the randomisation will be stratified with regards to 
pre-trial insulin therapy (see section 11.2).
The treat-to-target approach is used in both arms and has been chosen in order to ensure optimal 
titration based on pre-breakfast SMBG values and thereby to obtain improved HbA1c results.
5.3
Treatment of subjects
Subjects with T2DM treated with 20 to 50 units of basal insulin or pre-mix/combination insulin 
given once or twice daily in combination with metformin with or without one other OAD are 
eligible for the trial. Apart from metformin, all other OADs will be discontinued at randomisation. 
Moreover, basal insulin or pre-mix/combination insulin will be discontinued at randomisation in 
favour of either IDegLira or IDeg. No other anti-diabetic treatment, or treatment which in the 
investigators opinion could interfere with weight, glucose or lipid metabolism should be initiated 
between screening and ET. 
Hence, IDegLira and IDeg will be given as add-on to metformin therapy. The trial drugs will be 
double-blinded and should be injected subcutaneously once daily in the thigh, upper arm (deltoid 
region) or abdomen. Dosing can be done at any time of the day independent of meals, but should be 
approximately at the same time of the day throughout the trial for the individual subject. The 
injection area chosen should remain unchanged throughout the trial, although rotation within the 
area is recommended. Both trial drugs will be provided in a prefilled device. Titration should be 
performed twice weekly for both treatment arms (see Appendix A). 
5.3.1
Insulin degludec/liraglutide
The recommended start dose of IDegLira is 10 dose steps (10 units IDeg/0.36 mg liraglutide), with 
the option of choosing up to 16 dose steps (16 units IDeg/0.6 mg liraglutide) at the investigator’s 
discretion. The 0.36 mg of liraglutide contained in the recommended starting dose almost 
corresponds to the approved starting dose (0.3 mg) of Victoza® in Japan. IDegLira will be titrated
twice weekly according to a predefined titration algorithm to a maximum of 50 dose steps (50 units 
insulin degludec/1.8 mg liraglutide) aiming to reach a FPG target between 4.0 mmol/L (72 mg/dL)
and 5.0 mmol/L (90 mg/dL). 
5.3.2
Insulin degludec
The recommended starting dose of IDeg is 10 units, with the option of choosing up to 16 units at the 
investigator’s discretion. IDeg will be titrated  twice weekly according to a predefined titration 
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algorithm with a maximum dose of 50 units of IDeg aiming to reach a FPG target between 4.0 
mmol/L (72 mg/dL) and 5.0 mmol/L (90 mg/dL). 
5.4
Treatment after discontinuation of trial product
When discontinuing trial products, either at the scheduled ET visit or if a subject is withdrawn, the 
subject should be recommended a suitable marketed product at the discretion of the investigator.
5.5
Rationale for treatment
IDegLira will be investigated to demonstrate efficacy and safety, when administered to insulin 
experienced subjects with T2DM, inadequately controlled on a stable dose of insulin combined with 
metformin with or without one other OAD. This is in line with clinical practice to escalate treatment 
in this setting with the initiation of a GLP-1 receptor agonist, basal insulin or a combination of basal 
insulin and a GLP-1 receptor agonist, such as IDegLira. 
Pre-trial insulin and OAD treatment should be in accordance with current Japanese approved 
labelling. Subjects should be on at least 90 days of stable treatment (insulin and OADs) defined as 
unchanged medication and unchanged dose. To reduce the risk of hypoglycaemia all other OADs 
apart from metformin will be discontinued at randomisation. After randomisation metformin 
treatment should remain unchanged during the trial, however in case of safety concerns the dose 
may be reduced at the discretion of the investigator. To avoid impact on trial objectives, no other 
treatments affecting weight, glucose or lipid should be used, and certain drugs should not be used 
before the trial (see exclusion criteria no. 5, 6 and 7).
IDeg capped at a maximum dose of 50 units per day have been included as comparator in order to 
assess the additional effect of the liraglutide component in IDegLira as compared to treatment with 
IDeg alone at a similar dose.
For further information regarding dosing and treatment refer to Appendix A.
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6
Trial population
Number of subjects
Planned number of subjects to be randomised: 210.
Expected number of subjects to complete the trial: 179.
6.1
Inclusion criteria
For an eligible subject, all inclusion criteria must be answered “yes”. 
1. Informed consent obtained before any trial-related activities. Trial-related activities are any 
procedures that are carried out as part of the trial, including activities to determine suitability 
for the trial.
2. Male or female Japanese subjects ≥20 years of age at the time of signed informed consent.
3. Type 2 diabetes mellitus subjects (diagnosed clinically) ≥ 6 months prior to screening.
4. HbA1c 7.5-11.0% [58 mmol/mol-97 mmol/mol] (both inclusive) by central laboratory 
analysis.
5. Subjects on stable daily insulin doses for at least 90 days prior to screening administered 
once or twice daily according to current Japanese label, either as basal insulin (e.g. IDeg, 
insulin glargine, insulin detemir, NPH insulin), or pre-mix/combination insulin (e.g. 
biphasic insulin aspart, insulin degludec/insulin aspart). Total daily insulin dose in the 
previous 90 days should be within 20-50 units, both inclusive, and on the day of screening, 
but fluctuations of ± 10% within the 90 days prior to screening are acceptable. The specified 
insulin treatment should be administered in combination
o
with a stable daily dose of metformin within current approved Japanese label for at 
least 90 days prior to screening, 
o
additionally, the anti-diabetic treatment can be with or without a stable daily dose of 
one of the following other oral anti-diabetic drugs: sulphonylureas (SU), glinides, α-
glucocidase inhibitors (α-GI), sodium-glucose co-transporter-2 inhibitors (SGLT2i)
or thiazolidinediones (TZD) within current approved Japanese label for at least 90 
days prior to screening. 
6. Body Mass Index (BMI) ≥23 kg/m2.
Rational for inclusion criteria:
!
Criterion 1 is applied through an ethical consideration, in accordance with the GCP 1
!
Criterion 2 is applied to exclude minors through an ethical consideration. Subjects aged 65 year 
or older are included in accordance with the ICH guideline: Studies in support of special 
populations: Geriatrics12
!
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. HbA1c range 
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(7.5-11.0 %) is chosen to include subjects whose glycaemic control is not adequate on pre-trial 
treatment and intensification 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. 
!
Criterion 5 is applied to ensure that the subject's glycaemic control is stabilised at 
randomisation. 90 days of unchanged pre-trial treatment are required.
!
Criterion 6 is chosen in order to ensure a population allowing for exploring the full dose range 
of IDegLira, and to minimize the individual impact of any weight loss that may be associated 
with IDegLira treatment.
6.2
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 (IMP) within 30 days before screening.
5. Use of any anti-diabetic drug in a period of 90 days before screening (except pre-
mix/combination insulin or basal insulin, metformin, sulphonylureas (SU), glinides, α-
glucocidase inhibitors (α-GI), sodium-glucose co-transporter-2 inhibitors (SGLT2i), or 
thiazolidinediones (TZD) or anticipated change in concomitant medication, which in the 
investigators opinion could interfere with glucose metabolism (e.g. systemic corticosteroids 
or bolus insulin).
6. Previous treatment with glucagon-like peptide-1 (GLP-1) receptor agonist.
7. Treatment with dipetidyl peptidase-4 (DPP-4) inhibitors during the last 90 days prior to 
screening.
8. Impaired liver function, defined as alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) ≥2.5 times upper limit of normal (UNL).
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).
12. Personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine 
neoplasia syndrome type 2 (MEN 2).
13. Subjects presently classified as being in New York Heart Association (NYHA) Class IV.
14. Within the past 180 days have had any of the following: myocardial infarction (MI), stroke 
or hospitalisation for unstable angina and/or transient ischemic attack (TIA) prior to 
screening.
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15. Inadequately treated blood pressure as defined as Class 2 hypertension or higher (Systolic ≥
160 mmHg or diastolic ≥100 mmHg) in accordance with National High Blood Pressure 
Education Program, 7th Joint National Committee and European Societies of 
Hypertension/Cardiology 2013 guidelines13.
16. Proliferative retinopathy or maculopathy requiring acute treatment as verified by 
fundoscopy or fundus photography performed within 90 days prior to randomisation.
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. 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, 8-18 are chosen to ensure the safety of the subjects
!
Criterion 2 is chosen in order to exclude subjects who were previously judged as ineligible, 
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
6.3
Withdrawal criteria
The subject may withdraw consent at will at any time. The subject’s decision to withdraw from the 
trial must always be respected. See section 8.2 for procedures to be performed for subjects 
withdrawing consent. 
The subject may also be withdrawn from treatment at any time at the discretion of the investigator 
due to a safety concern. 
The subject must be withdrawn from the trial treatment if the following applies: 
1. Included in the trial in violation of the inclusion and/or exclusion criteria and/or randomised 
in error.
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 subject’s weight, or 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 diagnosed with acute pancreatitis (see section 8.5.2).
8. Simultaneous participation in another clinical trial of an approved or non-approved IMP.
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9. If the pre-breakfast self-measured blood glucose (SMBG) values taken on three consecutive 
days or if any of the fasting plasma glucose (FPG) samples analysed by the central 
laboratory exceeds the limit of:
o
15.0 mmol/L (270 mg/dL) from baseline to week 6 
o
13.3 mmol/L (240 mg/dL) from week 7 to week 12 
o
11.1 mmol/l (200 mg/dL) from  week 13 to week 26
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.
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
6.4
Subject replacement
Withdrawn subjects will not be replaced.
6.5
Rationale for trial population 
Subjects with T2DM treated with insulin, but in need of treatment intensification to achieve or 
maintain glycaemic control is the target population for inclusion in the trial.
More specifically Japanese subjects with T2DM inadequately controlled on once or twice daily 
basal or pre-mix/combination insulin with metformin with or without one other OAD with HbA1c in 
the range of 7.5-11.0% (both inclusive), and eligibility for treatment intensification based on the 
investigators discretion, will be randomised to treatment. The rationale for this specific trial 
population is to ensure inclusion of subjects reflecting a population of insulin treated T2DM 
subjects that require additional treatment, which will allow for exploration of the higher dose range 
of IDegLira in order to substantiate the superior effect of IDegLira compared to IDeg. Additionally, 
a lower limit of BMI (≥ 23 kg/m2) will minimize the individual impact of weight loss that has been 
observed in global trials with IDegLira.
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Only serious concomitant conditions (i.e. NYHA class 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.
7
Milestones
Planned duration of recruitment period (first patient first visit (FPFV) – last patient first visit
(LPFV):16 weeks.
End of trial is defined as last patient last visit (LPLV).
7.1
Recruitment
Recruitment will be done according to agreements with the individual investigational sites. 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 via the IWRS in order to estimate 
when to stop screening. All investigators will be notified immediately when the recruitment period 
ends, after which no further subjects may be screened and the IWRS will be closed for further 
screening.
7.2
Trial registration
Information of the trial will be disclosed at clinicaltrials.gov, novonordisk-trials.com and at the
Clinical Trials Information/JapicCTI site (clinicaltrials.jp). According to the Novo Nordisk Code of 
Conduct for Clinical Trial Disclosure14, it will also be disclosed according to other applicable 
requirements such as those of the International Committee of Medical Journal Editors 15, the Food 
and Drug Administration Amendment Act16, European Commission Requirements17, 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
The following sections describe the assessments and procedures as well as how to record the results. 
These are also included in the flow chart (see section 2).
8.1
Visit procedures
It is the responsibility of the investigator to ensure that all site visits and phone contacts including 
procedures occur according to the flow chart. A phone contact may be converted to a site visit, if 
needed, while a site visit cannot be converted to a phone contact.
8.1.1
Investigator’s assessment
Review of diaries, PROs, laboratory reports, ECGs, eye examination (fundoscopy/fundus
photography), physical examination etc. must be documented with the investigator’s dated signature 
either on the front page of the documents and/or in the subject’s medical record. The signed 
documents must be retained at the investigator site as source documentation.
If clarification of entries or discrepancies in the diary or PRO is needed, the subject must be 
questioned and a conclusion made in the subject's medical record. Care must be taken not to bias 
the subject.
At screening visit (V1) any abnormal clinically significant findings (laboratory reports, ECGs, eye 
examination, physical examination etc.) must be recorded in the medical history/concomitant illness 
form in the electronic case report form (eCRF). At subsequent visits’ any clinically significant 
change or new clinically significant finding must be reported as an AE according to section 12.2.
8.1.2
Fasting requirements
The subject should attend some visits fasting. Fasting is defined as at least 8 hours prior to visit 
without food and drink intake, except for water. Trial product and metformin should be withheld on 
the day of the visit until blood sampling has been performed. Other prescribed concomitant 
medication can be taken as usual.
If the subject attends a fasting visit in a non-fasting condition, blood sampling should be 
rescheduled, preferably within the visit window. 
8.1.3
Informed consent process
Informed consent must be obtained before any trial-related activity, see section 18.2. Accordingly, 
before any screening (V1) procedure takes place, the investigator must provide the subject with 
verbal and written information about the trial. The date of informed consent must be transcribed to 
the eCRF. 
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8.1.4
Screening
Screening will be carried out by using IWRS (see section 10). Each subject will be assigned a 
unique 6-digit subject number which will remain the same throughout the trial. 
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 or to destroy the card after the last trial visit.
The investigator must keep a subject screening log, a subject identification code list and a subject 
enrolment log. Only subjects who have signed the informed consent form should be included on the 
logs. The subject screening log and subject enrolment log may be combined in one log.
All inclusion and exclusion criteria must be reviewed and if any criteria cannot be assessed e.g. 
criteria related to results from blood sampling performed at screening or if the eye examination is 
missing, the investigator must ensure these are obtained for assessment of eligibility prior to the 
randomisation of the subject. 
8.1.4.1
Screening failures
For screening failures the screening failure form in the eCRF must be completed with the reason for 
not continuing in the trial. Serious adverse events (SAEs) from screening failures must be 
transcribed by the investigator into the eCRF. Follow-up on 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-screening is NOT allowed if the subject has failed one of the inclusion or exclusion criteria; this 
includes re-sampling (unless samples are lost or unsuitable for analysis e.g. haemolysed).
8.1.5
Randomisation
Randomisation should NOT take place more than 14 calendar days after screening (V1). 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. 
At randomisation (V2), the subject will be supplied with trial product, receive training in trial 
product and pen handling, and given directions for use verbally and in writing. For further 
information on trial product please see section 9. The subject should take the first dose of trial 
product on the day of randomisation (V2) or the day after. The date and first dose of trial product 
should be recorded in the diary and the eCRF. In case a starting dose of more than 10 dose steps or 
units is selected, the reason for dose selection should be recorded. Pre-trial insulin and other OADs 
than metformin should be discontinued.
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Randomisation of subjects and allocation of trial product will be done using the IWRS (see sections 
10 and 11).
8.1.6
Visits and phone contacts during treatment period
If a site visit/phone contact for some reason is not performed at the scheduled time point, the 
investigator should ensure that the site visit/phone contact is performed as soon as possible and aim 
to schedule within the visit window. Date of visit and visit window is calculated in relation to the 
randomisation visit (V2).
8.1.7
End of treatment visit
At ET (V32), 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 recommended a suitable marketed product at and after ET. 
Anti-diabetic treatment initiated at or after ET (V32) and at the FU (P33) should not be recorded in 
the eCRF.
8.1.8
Follow-up phone contact
The FU phone contact (P33) should be scheduled at least 7-10 days after ET (V32). The end of trial 
form must be completed in the eCRF.
8.1.9
Unscheduled visits
Unscheduled visits can be performed at any time at the discretion of the investigator. An 
unscheduled visit should be performed if:
!
Additional laboratory samples are needed due to an AE requiring special forms in the eCRF (see 
section 8.5.1.2)
!
A blood re-sampling (out of visit window) related to a specific visit is needed. Only if scheduled
blood sample could not be analysed
!
Confirmatory FPG test for withdrawal criteria evaluation
For the above an unscheduled visit form must be completed in the eCRF, indicating the reason for 
the visit. 
An unscheduled visit form should not be completed if the subject attends the trial site for a blood re-
sampling within the visit window. Also, if only additional trial product dispensing or auxiliary 
supply is needed, no unscheduled visit form should be completed, but an additional dispensing 
session should be made in the IWRS.
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8.2
Withdrawal from trial
If a subject withdraws consent, the investigator must aim to undertake procedures similar to those at 
ET (V32) as soon as possible. If the subject agrees, the FU contact (P33) must be performed at least 
7 days after discontinuation of trial product.
The end of trial form must be completed, and final drug accountability must be performed even if 
the subject is not able to come to the trial site. A withdrawal session must be made in the IWRS. 
When all data has been monitored and all queries have been resolved the case book must be signed. 
Although a subject is not obliged to give his/her reason(s) for withdrawing consent, 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 withdrawing consent must be specified in 
the end of trial form in the eCRF.
8.3
Subject related information/assessments 
8.3.1
Demography
Demography will be recorded at screening and consists of:
!
Date of birth 
!
Sex
!
Race
8.3.2
Diabetes history and diabetes complications 
Diabetes history and diabetes complications should be recorded in the eCRF at screening (V1). The 
following should be recorded in the diabetes history/diabetes complications form:
!
Date of diagnosis of diabetes
!
Diabetes complications (i.e. diabetic retinopathy/neuropathy/nephropathy and macro angiopathy 
(including peripheral vascular disease)
The following should be recorded in the family history form:
!
Family history of diabetes
8.3.3
Concomitant illness and medical history
A concomitant illness is any illness that is present at the start of the trial (i.e. at V1) or found as a 
result of a screening procedure. Concomitant illness includes any pre-planned procedures, surgery 
and any intermittent illness (e.g. allergies) that may not be apparent at the time of screening. T2DM 
and diabetes complications should not be recorded as concomitant illness. 
Any change to a concomitant illness should be recorded during the trial. A clinically significant 
worsening of a concomitant illness must be reported as an AE. 
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Medical history is a medical event that the subject has experienced in the past. Only relevant 
medical history related to the evaluation of this trial should be reported at the investigator’s 
discretion.
The information collected for concomitant illness and medical history should include diagnosis, 
date of onset and date of resolution or continuation, as applicable. It should be recorded at screening 
(V1) in the eCRF at the medical history/concomitant illness form.
It must be possible to verify the subject’s medical history in source documents such as subject’s 
medical record. If a subject is not from the investigators own practice; the investigator must make 
reasonable effort to obtain a copy of subject’s medical record from relevant party e.g. primary 
physician. The investigator must document any attempt to obtain external medical information by 
noting the date(s) when information was requested and who has been contacted.
8.3.4
Concomitant medication
A concomitant medication is any medication, other than the trial product, which is taken during 
the trial. Anti-diabetic treatment (diabetes treatment history, i.e. pre-trial insulin and OADs) taken 
in the time between screening (V1) and randomisation (V2) will also be regarded as concomitant 
medication.
Details of any concomitant medication must be recorded at screening (V1) in the eCRF. Changes in 
concomitant medication must also be recorded at each visit as they occur until ET (V32). 
The information collected for each concomitant medication includes trade name or generic name,
dose (only for pre-trial insulin), 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 initiated at ET (V32) and at the FU (P33) should not be recorded in the 
eCRF.
8.3.4.1
Metformin
Metformin and its dosing information should be recorded at the concomitant specific drug 
metformin form in the eCRF.
The metformin treatment should be kept unchanged unless changed for safety reasons. In case of 
change in total daily dose, it must be reported at the concomitant specific drug metformin form in 
the eCRF. The information collected for metformin includes trade name or generic name, dose, start 
date and stop date or continuation. 
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8.3.5
Tobacco use
Details of tobacco use must be recorded at screening (V1). Smoking is defined as smoking at least 
one cigarette or equivalent daily.
Smoking status:
!
Never smoked
!
Previous smoker
!
Current smoker
8.4
Efficacy assessments
8.4.1
Self-measured blood glucose (SMBG)
At screening (V1), subjects will be provided with a BG meter to be used for daily pre-breakfast 
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 BG 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. 
Only the BG meter provided by Novo Nordisk should be used for the measurements required in the 
protocol. 
Subjects should be instructed how to record the SMBGs in the diaries. The record of each pre-
breakfast SMBG should include date and value. All data from the diary must be transcribed into the 
eCRF during or following the contact with site. If obtained via phone and a discrepancy is detected
later on, the values in the eCRF should be corrected.
For SMBG values that meet the definition of a hypoglycaemic episode (see section 8.5.7), relevant 
information must be registered in the subject diary and a hypoglycaemic episode form must be 
completed in the eCRF.
8.4.1.1
9-point self-measured blood glucose (SMBG) profile
Subjects will be instructed to perform a 9-point SMBG profile three times during the trial and 
record it in the diary. The 9-point SMBG profiles should include date and value in addition to actual 
clock time of each measurement. As for daily SMBGs, the data from the diary must be transcribed 
into the eCRF. The measurements should take place preferably within the week prior to the site visit 
on days where the subject does not anticipate unusual strenuous exercise.
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Date:
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The points of SMBG measurements starts with a pre-breakfast SMBG on day 1 and ends with a pre-
breakfast SMBG on the following day as listed in Table 8–1 below.
Table 8–1
9-point profile (SMBG)
Time point
Day 1
The following day 
Pre-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.
∀ 
Trial product and metformin should be withheld until after the pre-breakfast SMBG measurements 
have been performed. Other prescribed concomitant medication can be taken as usual.
8.4.2
Body weight
Body weight should be measured (kilogram [kg], with one decimal) without shoes and only wearing 
light clothing and recorded in the eCRF. Preferably the same equipment should be used throughout 
the trial.
8.4.3
Waist circumference
The waist circumference is the minimal abdominal circumferences located midway between the 
lower rib margin and the iliac crest.
Waist circumference must be performed and recorded in the eCRF. The waist circumferences will 
be measured in cm using a non-stretchable measuring tape. It should be recorded to the nearest ½ 
cm preferably using the same measuring tape throughout the trial.
The waist circumference 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. 
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8.4.4
Blood pressure
Blood pressure (systolic and diastolic) should be measured after the subject has been resting for at 
least 5 minutes in a sitting position. It is recommended to use the same arm and preferably the same 
equipment throughout the trial.
At screening (V1) 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 6.2). 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.
8.5
Safety assessments
8.5.1
Adverse events
All AEs must be collected and reported from the first trial-related activity, after the subject has 
signed the informed consent, to FU (P33). Information on AEs occurring between ET (V32) and FU 
(P33) must be collected and recorded in the eCRF. Procedures for reporting are outlined in section 
12.2.
Mind that a clinically significant worsening of a concomitant illness (section 8.3.3) must also be 
reported as an AE.
8.5.1.1
Medication error
If a medication error is observed during the trial, the following information is required and a 
specific event form must be completed in the eCRF in addition to the AE form: 
!
Trial product involved 
!
Classification of medication error
!
Whether the subject experienced any hypoglycaemic episode and/or AE(s) as a result of the 
medication error 
!
Suspected primary reason for the medication error 
For definition of medication errors, see section 12.1.4.
8.5.1.2
Adverse events requiring additional data collection
For the following AEs additional data collection is required and specific event forms must be 
completed in the eCRF in addition to the AE form by the investigator. 
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Date:
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UTN: U1111-1178-3453 
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The events of concern are:
!
Fatal events
!
Cardiovascular events
!
Thyroid disease
!
Neoplasm
!
Renal failure
!
Pancreatitis
In case any of these events fulfil the criteria for a SAE, please report accordingly, see section 12.2.
Further details of AEs requiring additional data collection in the eCRF can be found in Appendix C.
Cardiovascular events
Acute coronary syndrome
All types of MI 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 moreover 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
!
Treatment given for the condition
!
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
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Date:
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Heart failure requiring hospitalisation
If an event of heart failure requiring hospitalisation (admission to an in-patient unit or a visit to an 
emergency department that results in at least a 24 hour stay) is observed during the trial, this must 
be recorded as an SAE and in addition on a specific cardiovascular event form in the eCRF. The 
following information must be reported if available:
!
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
Thyroid disease
If an event of thyroid disease, including any thyroid neoplasms, is observed during the trial, this 
must be recorded as an AE and on a specific thyroid disease event form in the eCRF. The following 
information must be reported if available:
!
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
!
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
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Date:
02 May 2016
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Version:
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UTN: U1111-1178-3453 
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!
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 with the event
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 
!
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
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Date:
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Version:
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8.5.2
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 be interrupted until pancreatitis is ruled out. Appropriate examinations must be 
performed, including measurement of amylase and lipase. Subjects diagnosed with acute 
pancreatitis must be withdrawn from trial treatment. 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/magnetic resonance 
imaging
If acute pancreatitis is ruled out, trial product should be re-initiated at the discretion of the 
investigator. The investigator should consider the last dose of trial product and moreover 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.
8.5.3
Eye Examination
Eye examination (fundoscopy/fundus photography) must be performed by the investigator or a local 
ophthalmologist or an optometrist 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 randomisation (V2) is 
acceptable and does not need to be repeated, unless worsening of visual function since the last 
examination has been noted. The investigator must 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 reasons for performing the procedure was 
not related to this trial.
Eye examination performed within a period of 14 days before ET (V32) is acceptable if results are 
available at the ET visit.
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Protocol
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Date:
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Version:
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8.5.4
Electrocardiogram (ECG)
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)
ECG obtained as part of routine practise may replace the screening assessment, if results are 
available for evaluation at the randomisation visit and if obtained within 14 days prior to 
randomisation (V2). The ECG must be done at randomisation (V2) at the latest. 
ECG obtained within 14 days before ET (V32) is acceptable, if results are available for evaluation 
at the ET visit.
8.5.5
Pulse
Pulse (beats per minute) should be measured after resting at least 5 minutes in a sitting position and 
recorded in the eCRF. 
8.5.6
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)
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Version:
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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 8.3.3. Findings not present at 
screening must be reported as AE according to section 12.2.
8.5.7
Hypoglycaemic episodes
Plasma glucose should always be measured and recorded when a hypoglycaemic episode is 
suspected. 
All plasma glucose values:
!
≤ 3.9 mmol/L (70 mg/dL) or 
!
> 3.9 mmol/L (70 mg/dL) when they occur in conjunction with hypoglycaemic symptoms 
should be recorded by the subject. These must be transcribed into the eCRF (hypoglycaemic 
episode form) throughout the trial from randomisation (V2) to FU (P33). 
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 concentration19.
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Date:
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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)
!
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 
Oral carbohydrates should not be given if the subject is unconscious.
A hypoglycaemic episode form must be filled in for each hypoglycaemic episode. If the 
hypoglycaemic episode fulfils the criteria for an SAE then an AE form and a safety information 
form (SIF) must also be filled in, see section 12.2.
Information on AEs and hypoglycaemic episodes occurring between ET (V32) and FU (P33) must 
be collected and recorded in the eCRF.
8.5.8
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. 
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Date:
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Blood sampling should be performed at least 7 days after but no later than 4 weeks 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.
8.6
Laboratory assessments
All laboratory samples will be analysed by a central laboratory contracted by Novo Nordisk. The 
central laboratory will provide all laboratory supplies for the sampling and transportation of all 
blood samples taken during the trial.
Description of assay methods and a 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. Information regarding laboratory materials such as tubes and labels are also described. 
Samples will be coded in order to keep subject’s identity anonymous.
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 the laboratory results for 
concomitant illnesses and AEs and report these according to section 12.2 and document it on the 
reports by date and signature.
8.6.1
Laboratory assessments for efficacy
Except from screening (V1), blood samples will be drawn in a fasting state (see section 8.1.2)
according to flow chart (see section 2). They will be analysed to determine levels of the below 
efficacy laboratory parameters.
8.6.1.1
Glucose metabolism
!
HbA1c
!
FPG
8.6.1.2
Lipids
!
Cholesterol (total)
!
LDL cholesterol
!
VLDL cholesterol
!
HDL cholesterol
!
Triglycerides
!
Free fatty acids
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Protocol
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Date:
02 May 2016
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Version:
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UTN: U1111-1178-3453 
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8.6.2
Laboratory assessments for safety
Except from screening (V1), blood samples will be drawn in a fasting state (see section 8.1.2). They 
will be analysed to determine levels of the below safety laboratory parameters.
8.6.2.1
Haematology
!
Haemoglobin
!
Haematocrit
!
Thrombocytes
!
Erythrocytes
!
Leucocytes
!
Differential count (eosinophils, neutrophils, basophils, monocytes and lymphocytes)
8.6.2.2
Biochemistry
!
Creatinine
!
eGFR value will be calculated using the serum creatinine result and the CKD-EPI formula by 
the central laboratory
!
ALT
!
AST
!
Alkaline phosphatase
!
Sodium
!
Potassium
!
Albumin
!
Bilirubin (total)
!
Urea
!
Creatine kinase
!
Calcium (total)
!
Calcium, ionized (albumin corrected)
!
Lipase
!
Amylase
8.6.2.3
Hormones
!
Calcitonin, if ≥10 ng/L, see Appendix D for monitoring of calcitonin.
8.6.2.4
Pregnancy test
!
Human serum chorionic gonadotrophin (hCG)
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Pregnancy testing must be performed on female subjects of childbearing potential. Female subjects 
of childbearing potential must be instructed to use adequate contraceptive methods throughout the 
trial and until 7-10 days after ET (V32).
Females of childbearing potential must have a serum pregnancy test (beta-human chorionic 
gonadotropin [beta-hCG]) performed at screening (V1) before entering the trial and at ET (V32).
Urine pregnancy tests will be performed at the site during the trial for females of childbearing 
potential if a menstrual period is missed or if pregnancy is suspected.
If subject reports missing menstrual period, the subject will have a urine-stick pregnancy test 
performed as soon as possible.
Pregnancy test will not be required for women of non-childbearing potential. 
Female of non-childbearing potential is defined as:
o
Female who has undergone a hysterectomy, bilateral oophorectomy or bilateral tubal 
ligation 
o
Postmenopausal defined as women above 50 years with no menses for 12 months 
and without an alternative medical cause
o
Other medical reasons preventing childbearing potential 
Non-childbearing potential reasons must be recorded at the medical history/concomitant illness 
form in the eCRF.
8.7
Other assessments
8.7.1
Height
Height should be measured without shoes in centimetres (cm) and recorded in the eCRF to nearest 
½ cm. Height measured at screening (V1) will only be used for calculation of BMI.
8.7.2
Body Mass Index
BMI will be calculated at screening (V1) for assessment of eligibility (section 6.1).
The BMI will be calculated by the eCRF once body weight and height is entered at screening (V1).
It is calculated as follows:
BMI (kg/m2) = body weight (kg)/(height [m] × height [m])
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8.7.3
Patient reported outcomes
The following PRO questionnaires must be completed by the subject:
!
DTR-QOL21
!
EQ-5D-5L22
The investigator is only allowed to fill in the headings of the questionnaires and is not allowed to 
influence the subject in answering. 
The investigator should check for empty fields in the questionnaires when returned by the subject. 
Review of the questionnaires must be documented either on the documents and/or in the subject’s 
medical record.
If clarification of entries or discrepancies in the questionnaires is needed, the subject must be 
questioned and a conclusion made in the subject’s medical record. Care must be taken not to bias 
the subject. All responses to the questionnaires must be transcribed into the eCRF. 
8.7.4
Diaries
At each site visit the subjects will be provided with a new diary. The diary must be collected at the 
next site visit, and retained at the site as source data. However, after ET (V32), the diary data at the 
FU contact (P33) will be collected per phone. Consequently, source data from the FU contact (P33) 
will be the notes written by the investigator in the subject’s medical record and based on an 
interview.
The investigator is only allowed to record the following data in the diary: 
!
Subject number
!
Site contact details
!
Time and date of next visit or phone contact
!
Prescribed dose of trial product
!
Prescribed metformin treatment
!
Prescribed diabetes treatment at V32
!
Doses and values from SMBG measurements from previous diary, if required to complete next 
dose adjustment
!
Review signature and date
The subject must record the following information in the diary: 
!
Date and value of the daily pre-breakfast SMBG (see section 8.4.1)
!
Date, actual clock time and value of the 9-point profile SMBG prior to V2, V18 and V32 (see 
section 8.4.1.1)
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!
Date and dose of trial product each day
o
Time for the first and the last trial product dose taken when randomised and at ET, 
respectively
!
Hypoglycaemic episodes (see section 8.5.7)
!
Medical issues
!
Changes to concomitant medication (see section 8.3.4)
!
Changes in  total daily dose of metformin (see section 8.3.4.1)
If the subject is not able to complete the diary and need assistance from a third party to complete the 
diary, this must be stated in the subject’s medical records. 
Based on the values from the SMBG measurements, the investigator/subject will assess whether 
trial product dose needs adjustment according to the titration guideline (Appendix A). 
The diary must be reviewed by the investigator to ensure that AEs, including medical issues and 
concomitant medication, are reported (see section 8.3.4, 8.5.1 and 12.2). In addition, the 
investigator must ensure that the SMBG measurements are reported as hypoglycaemic episodes if 
required (see section 8.5.7).
The investigator or delegated staff should transcribe the diary data to the eCRF as soon as possible, 
preferable within 24 hours after each site visit/phone contact. Safety data from the diaries must be 
handled according to the timelines described in Figure 12–1. If data is obtained via phone and a 
discrepancy is later detected, the values in the eCRF should be corrected according to the diary.  
Review of the diary must be documented either on the document and/or in the subject’s medical 
record. If clarification of entries or discrepancies in the diary is needed, the subject must be 
questioned and a conclusion made in the subject’s medical record. Care must be taken not to bias 
the subject.
8.7.5
Training in the trial product and pen handling
The subjects must be trained in how to handle the trial product when handed out the first time at 
randomisation (V2) and one week after (V4) to ensure sufficient training. Moreover, directions for 
use (DFU) will be dispensed. Training must be repeated during the trial as needed. 
8.8
Subject compliance
Throughout the trial, the investigator will remind the subjects to follow the trial procedures and 
requirements to ensure subject compliance. If a subject is found to be non-compliant, the 
investigator must remind the subject of the importance of following the instructions given including 
taking the trial products as prescribed.
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The investigator should assess the compliance of the subject at each visit based on a review of 
glycaemic control, adherence of the visit schedule, completion of the subject diary including SMBG
measurements.
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 used by any person not included in the trial. IDegLira and IDeg must not 
be used, if it does not appear clear and colourless. 
9.1
Trial products
The following trial products will be provided by Novo Nordisk:
Table 9–1
Trial 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
3 mL pre-filled 
PDS290
pen injector
Insulin degludec
100 units/mL
IDegLira and IDeg are visually identical.
The trial products will be dispensed to each subject according to the treatment group they have been 
randomised to. The IWRS will allocate trial product (DUNs) to the subject at the randomisation 
visit and at each dispensing visit (see section 10).
9.2
Metformin
Metformin will not be supplied by Novo Nordisk. 
9.3
Labelling
The trial products will be labelled in accordance with Annex 1323, local regulations and trial 
requirements.
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Each trial site will be supplied with sufficient trial products for the trial on an on-going basis 
controlled by the IWRS. Dispensing unit numbers (DUNs) will be distributed to the trial sites 
according to screening 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 (V2). 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, see section 2).
9.4
Storage 
Table 9–2
Storage conditions
Trial product
Storage conditions
(not-in-use)
In-use conditions
In-use time*
Insulin degludec/ liraglutide 
Store in a refrigerator (2°C 
– 8°C)
Do not freeze
Protect from light
Do not store above 30°C
Do not freeze
Protect from light
Use within 3 
weeks 
Insulin degludec
*In-use time starts when the first dose is taken or product is taken out of the refrigerator at subject’s residence
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. Additional details regarding handling of temperature deviations can 
be found in the TMM.
Trial product that has been stored improperly must not be dispensed to any subject before it has 
been evaluated and approved for further use by Novo Nordisk. The investigator must take 
appropriate action to ensure correct storage.
9.5
Drug accountability and destruction
Drug accountability of all trial products received at site is the responsibility of the investigator.
Returned trial product (used/partly used and unused), expired and damaged trial product can be 
stored at room temperature and must be stored separately from non-allocated trial product.
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Non-allocated trial products including expired or damaged products must be accounted as unused at 
the latest at closure of the trial site. 
The trial products must be accounted for at pen level and either recorded as used/partly used, 
unused or lost. Returned pens must be sent for destruction, thus may not be re-allocated to new 
subjects.
Destruction of trial products can be performed on an on-going basis and will be done according to 
local procedures after accountability is finalised and reconciled by the monitor. Destruction of 
products must be documented in the IWRS.
9.6
Auxiliary supplies
The following will be provided by Novo Nordisk in accordance with and specified in the TMM:
!
DFU for the PDS290 pen injector
!
Needles (no longer than 8 mm) for the PDS290 pen injector
!
BG meters and BG meter auxiliaries
!
Glucose for treating a hypoglycaemia
Only needles provided by Novo Nordisk must be used for administration of trial product. 
10
Interactive web response system
A trial-specific 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 is used for: 
!
Screening
!
Screening failure
!
Randomisation
!
Stratification
!
Medication arrival
!
Dispensing
!
Withdrawal
!
Completion
!
Code break
!
Drug accountability
!
Data change
IWRS user manuals will be provided to each trial site.
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It is important that only DUNs allocated by the IWRS are dispensed to the subject. By doing this it 
will ensure that; 
o
The right trial product is dispensed to the right subject 
o
Needed stock is available at a site for the subjects 
o
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. 
11 Randomisation procedure and breaking of blinded codes
11.1
Randomisation
Eligible screened subjects will be randomised via the IWRS into two treatment arms in a 1:1 
manner.
11.2
Stratification
To ensure an even proportion of subjects on pre-trial basal or pre-mix/combination insulin in each 
treatment arm, the randomisation will be stratified as in the following with regards to these two 
different pre-trial insulin therapies combined with metformin with or without one other OAD:
!
metformin + basal insulin
!
metformin + basal insulin + one other OAD 
!
metformin + pre-mix/combination insulin  
!
metformin + pre-mix/combination insulin + one other OAD
11.3
Breaking of blinded codes
The IWRS will notify Novo Nordisk (monitor and the Global Safety department) immediately after 
the code is broken.
The code for a particular subject may be broken in a medical emergency if knowing the actual 
treatment would influence the treatment of the subject. Whenever a code is broken the person 
breaking the code must print the Code Break Confirmation Notification generated by the IWRS, 
record the reason, and sign and date the document.
When the code is broken, the treatment allocation will be accessible to the investigator and the 
Novo Nordisk Global Safety department. If IWRS is not accessible at the time of code break the 
IWRS helpdesk should be contacted. Contact details are listed in Attachment I.
If the code has been broken, the subject must be withdrawn and a withdrawal session must be 
completed in IWRS.  
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12 Adverse events, technical complaints and pregnancies
12.1
Definitions
12.1.1
Adverse event 
An AE is any untoward medical occurrence in a subject administered a medicinal product, and 
which does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom or disease temporally associated with the use of a product, whether or not 
considered related to the product. 
An AE includes:
!
A clinically significant worsening of a concomitant illness.
!
A 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 or other trial procedures 
performed before exposure to trial product (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 8.5.7.
The following three definitions are used when assessing an AE:
!
Severity 
o
Mild – no or transient symptoms, no interference with the subject’s daily activities.
o
Moderate – marked symptoms, moderate interference with the subject’s daily 
activities.
o
Severe – considerable interference with the subject’s daily activities; unacceptable.
!
Causality 
Relationship between an AE and the relevant trial product(s): 
o
Probable - Good reason and sufficient documentation to assume a causal 
relationship.
o
Possible - A causal relationship is conceivable and cannot be dismissed.
o
Unlikely - The event is most likely related to aetiology other than the trial product.
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!
Final outcome
o
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.
o
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.
o
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.
o
Not recovered/not resolved - The condition of the subject has not improved and the 
symptoms are unchanged, or the outcome is not known.
o
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.
o
Unknown - This term is only applicable if the subject is lost to follow-up.
12.1.2
Serious adverse event
A SAE is an experience that at any dose results in any of the following:
!
Death.
!
A life-threateninga experience.
!
In-patient hospitalisationb or prolongation of existing hospitalisation.
!
A persistent or significant disability or incapacityc.
!
A congenital anomaly or birth defect.
!
Important medical events that may not result in death, be life threateninga or require 
hospitalisationb may be considered an SAE when - based on appropriate medical judgement -
they may jeopardise the subject and may require medical or surgical intervention to prevent one 
of the outcomes listed in the definition of SAEd. 
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
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Medical judgement must always be exercised, and when in doubt, the hospital contact should be 
regarded as a hospitalisation. Hospitalisations for administrative, trial-related and social purposes 
do not constitute AEs and should therefore not be reported as AEs or SAEs. Hospital admissions for 
surgical procedures, planned before trial inclusion, are not considered AEs or SAEs.
c. A substantial disruption of a subject’s ability to conduct normal life functions (e.g. following the 
event or clinical investigation the subject has significant, persistent or permanent change, 
impairment, damage or disruption in his/her body function or structure, physical activity and/or 
quality of life).
d. For example intensive treatment in an emergency room or at home of allergic bronchospasm, 
blood dyscrasia or convulsions that do not result in hospitalisation or development of drug 
dependency or drug abuse.
The following AEs must always be reported as an SAE using the important medical event criterion 
if no other seriousness criteria are applicable:
!
Suspicion of transmission of infectious agents via the trial product 
!
Risk of liver injury defined as ALT or AST > 3 x UNL and total bilirubin > 2 x UNL, where no 
alternative aetiology exists (Hy's law).
12.1.3
Non-serious adverse event
A non-serious AE is any AE which does not fulfil the definition of an SAE.
12.1.4
Medication errors
A medication error concerning trial products is defined as:
!
Administration of wrong drug or use of wrong device.
!
Use of wrong DUN is not considered a medication error.
!
Wrong route of administration, such as intramuscular instead of subcutaneous
!
Administration of an overdose with the intention to cause harm (e.g. suicide attempt), misuse or 
abuse of trial product.
!
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.
Medication errors must be reported on an AE form and a specific event form, see section 8.5.1.1.
12.1.5
Adverse events requiring additional data collection
AEs requiring additional data collection are AEs where the additional data will benefit the 
evaluation of the safety of the trial product.
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Some events in this trial will be adjudicated by an independent external committee as described in 
section 12.7.2.
Table 12–1 lists AEs that require completion of specific event forms in the eCRFs and/or are 
subject to event adjudication.
Table 12–1
Adverse events requiring completion of specific event forms and/or are subject 
to event adjudication
Event
Specific event 
form
Event 
adjudication
Fatal event
No
Yes
Acute coronary syndrome (MI or hospitalisation for 
unstable angina)
Yes
Yes
Cerebrovascular event (stroke or TIA)
Yes
Yes
Heart failure (requiring hospitalisation)
Yes
Yes, all cases of 
heart failure 
requiring 
hospitalisation, 
defined as an 
admission to an 
inpatient unit or a 
visit to an 
emergency 
department that 
results in at least 
a 24 hour stay, 
will be 
adjudicated
Thyroid disease (including thyroid neoplasm)
Yes
Yes, (only if 
thyroid neoplasm 
or resulting in 
thyroidectomy)
Neoplasm (excluding thyroid neoplasm)
Yes
Yes
Renal failure
Yes
No
Pancreatitis
Yes
Yes
Medication error (see section 12.1.4)
Yes
No
For details about specific event forms, see section 8.5.1.2 and Appendix C.
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12.1.6
Technical complaints
A technical complaint is any written, electronic, or oral communication that alleges product 
(medicine or device) defects. The technical complaint may be associated with an AE, but does not 
concern the AE itself.
Examples of technical complaints:
!
The physical or chemical appearance of trial products (e.g. discoloration, particles or 
contamination)
!
All packaging material including labelling
!
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 (P33), see flowchart in section 2. The events must be recorded 
in the applicable eCRF forms in a timely manner, see timelines below, Table 12–2 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, observed by the investigator or subject, must be reported by the investigator and evaluated. 
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 SIF must be completed in addition to the AE form. If several symptoms or diagnoses 
occur as part of the same clinical picture, one SIF 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.
For all non-serious AEs, the applicable forms should be signed when the event is resolved or at the 
end of the trial at the latest.
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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 SIF within 5 calendar days of the investigator’s
first knowledge of the SAE. Both forms must be signed within 7 calendar days from the date the 
information was entered in the eCRF. 
!
For SAEs requiring reporting on a specific event form: In addition to the above the specific 
event form within 14 calendar days from the investigator’s first knowledge of the AE.
!
For non-serious AEs: The AE form within 14 calendar days of the investigators first 
knowledge of the AE.
!
For non-serious AEs requiring 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: The adjudication form within 14 calendar days of the investigator’s 
first knowledge of the AE, see section 12.7.2.
Table 12–2
Summary of reporting timelines for adverse events
Event Type / Form
AE Form1
SIF1
Specific event 
form1
Adjudication 
form1
SAE
24 hours2
5 days2
Non-serious AE
14 days
Non-serious AE with 
additional data collection
14 days
14 days
14 days3
SAE with additional data 
collection
24 hours2
5 days2
14 days
14 days3
1All days are calendar days
2Forms must be signed within 7 days
3If qualifying for adjudication
If the eCRF is unavailable, the concerned AE information must be reported on a paper AE form 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 into the eCRF. 
Contact details (fax, telephone, e-mail and address) are provided in the investigator trial master file. 
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AE identified
Does the AE require 
a specific event 
form?
Is the AE category 
for adjudication 
and/or is the 
outcome fatal?
AE form < 24 hours
SIF < 5 calendar days
Specific event form
< 14 calendar days
Is the AE serious or 
non-serious?
AE form
< 14 calender days
Adjudication form
< 14 calendar days
Source data < 4 weeks
Non-serious
Serious
No
Yes
Yes
Queries and follow-up 
requests to be resolved 
< 14 calendar days
Timelines are for the completion of forms from the time of 
investigator’s awareness.
AEs requiring specific event forms are descibed in Section 8.5
AEs for adjudication are described in Section 12.1.5
No additional action
No additional action
No
AE: Adverse Event
SIF: Safety Information form 
Figure 12–1
Reporting of adverse events 
Novo Nordisk assessment of AE expectedness: 
Novo Nordisk assessment of expectedness is performed according to the following reference 
documents:
!
IDegLira; current version of the company core data sheet and any updates thereto.
!
IDeg; current version of the company core data sheet and any updates thereto.
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 ICH GCP1. In addition, the 
investigator will be informed of any trial-related SAEs that may warrant a change in any trial 
procedure.
In accordance with regulatory requirements, Novo Nordisk will inform the regulatory authorities of 
trial product-related SUSARs. In addition, Novo Nordisk will inform the institutional review boards 
(IRBs) of trial product-related SUSARs in accordance with local requirement and ICH GCP1, unless 
locally this is an obligation of the investigator.
Novo Nordisk products used as concomitant medication:
If an AE is considered to have a causal relationship with a Novo Nordisk marketed product used as 
concomitant medication in the trial, it is important that the suspected relationship is reported to 
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Novo Nordisk, e.g. in the alternative aetiology section on the SIF. Novo Nordisk may need to report 
this AE to relevant regulatory authorities.
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 
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 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 recording of the worst case severity and seriousness of an 
event is kept throughout the trial. A worsening of an unresolved AE must be reported as follow-up
with re-assessment of severity and/or seriousness of the event.
Queries or follow-up requests from Novo Nordisk must be responded to within 14 calendar days
from the date of receipt of the request, unless otherwise specified in the follow-up request.
SAEs after end of trial: If the investigator becomes aware of an SAE with a suspected causal 
relationship to the IMP occurring to a subject after the subject has ended the trial, the investigator 
should report this SAE within the same timelines as for SAEs during the trial. 
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12.4
Technical complaints and technical complaint samples
12.4.1
Reporting of technical complaints 
All technical complaints on any of the following products:
!
IDegLira, 100 units/mL + 3.6 mg/mL, 3 mL prefilled PDS290 pen injector
!
IDeg (Tresiba®), 100 units/mL, 3 mL prefilled PDS290 pen injector
!
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.
The investigator must assess whether the technical complaint is related to any AEs or SAEs.
Technical complaints must be reported on a separate technical complaint form:
!
One technical complaint form must be completed for each affected DUN 
!
If DUN is not available, a technical complaint form for each code or lot number 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 copy of the technical complaint form must be included 
in the shipment of the sample. If several samples are returned in one shipment, the individual 
sample and the corresponding technical complaint form must be clearly separated.
The investigator must ensure that the technical complaint sample contains the batch, code or lot 
number and, if available, the DUN. All parts of the DUN should be returned.
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If the technical complaint sample is unobtainable, the investigator must specify on the technical 
complaint form why it is unobtainable. 
Storage of the technical complaint sample must be done in accordance with the conditions 
prescribed for the product.
12.5
Pregnancy
12.5.1
Pregnancy 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 the 
newborn infant is one month of age.
The investigator must report information about the pregnancy, pregnancy outcome, and health of 
the newborn infant(s), as well as AEs in connection with the pregnancy, and AEs in the foetus and 
newborn infant.
The following must be collected and reported by the investigator to Novo Nordisk - electronically 
(e.g. in PDF format), or by fax or courier:
1. Reporting of pregnancy information
Information about the pregnancy and pregnancy outcome/health of the newborn infant(s) has to 
be reported on Maternal Form 1A and 1B, respectively. 
When the pregnancy outcome is abnormal (i.e. congenital anomalies, foetal death including 
spontaneous abortion and/or any anomalies of the foetus observed at gross examination or 
during autopsy), and/or when a congenital anomaly is diagnosed within the first month, further 
information has to be reported for the female subject on Maternal Form 2. In addition, 
information from the male partner has to be reported on the Paternal Form, after an informed 
consent has been obtained from the male partner. 
Initial reporting and follow-up information must be reported within 14 calendar days of the 
investigator’s first knowledge of initial or follow-up information.
2. Reporting of AE information
The investigator has to report AEs in connection with the pregnancy as well as in the foetus and 
newborn infant(s). The SAEs that must be reported include abnormal outcome, such as foetal 
death (including spontaneous abortion), and congenital anomalies (including those observed at 
gross examination or during autopsy of the foetus), as well as other pregnancy complications 
fulfilling the criteria of an SAE.
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Forms and timelines for reporting AEs:
Non-serious AEs: 
!
AE forma within 14 calendar days of the investigator’s first knowledge of the initial or follow-
up information to the non-serious AE.
SAEs: 
!
AE forma within 24 hours of the investigator’s first knowledge of the SAE.
!
Paper SIF within 5 calendar days of the investigator’s first knowledge of the SAE.
!
SAE follow-up information to the AE form and/or SIF within 24 hours of the investigator’s 
first knowledge of the follow-up information.
a 
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. If the AE occurred in the foetus or newborn infant, the AE 
can only be reported on paper AE and SIF.
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 BG 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 
subcutaneously 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 
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reported included severe nausea and severe vomiting. None of the reports included severe 
hypoglycaemia. All patients recovered without complications.
When initiating treatment with IDegLira, the subject may in some cases experience loss of 
fluids/dehydration, due to vomiting, nausea or diarrhoea. It is important to avoid dehydration by 
drinking plenty of fluids.
For more information, see the current IB version of IDegLira11, IDeg8 and liraglutide9 or any 
updates hereof.
12.7
Committees related to safety
12.7.1
Novo Nordisk safety committee
Novo Nordisk will constitute an internal IDegLira safety committee to perform ongoing safety 
surveillance. The IDegLira safety committee will be informed about the results of continuous on-
going safety surveillance activities for IDegLira and may recommend unblinding of any data for 
further analysis. In this case an independent ad hoc group will be established in order to maintain 
the blinding of the trial personnel.
12.7.2
Event adjudication committee
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 AEs for adjudication are listed in Table 12–1. A full list of AEs for adjudication and rationales 
for adjudicating these can be found in Appendix C.
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, 
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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. In addition the specific 
adjudication form should be completed within 14 calendar days of the investigator’s first 
knowledge of the AE, and all relevant predefined documents provided within 4 weeks according to 
instructions in the event adjudication site manual.
The assessment made by the EAC will be included in the clinical trial report as well as the 
assessments made by the investigator. However, the adjudication made by the event adjudication 
committee, given its independent analysis of each event, will be attributed with greater importance 
of the two. 
13 Case report forms 
Novo Nordisk will provide a system for the eCRFs. This system and support services to the system 
will be provided by an external supplier.
Ensure that all relevant questions are answered, and that no empty data field exists. If a test or an 
assessment has not been done and will not be available, or if the question is irrelevant (e.g. is not 
applicable), indicate this according to the data entry instructions.
The following will be provided as paper CRFs:
!
Pregnancy forms
The following will be provided as paper CRFs to be used when access to the eCRF is revoked or if 
the eCRF is unavailable:
!
AE forms 
!
SIFs
!
Technical complaint forms (also to be used to report complaints that are not subject related (e.g. 
discovered at trial site before allocation) 
On the paper CRF forms print legibly, using a ballpoint pen. Ensure that all questions are answered, 
and that no empty data blocks exist. Ensure that no information is recorded outside the data blocks. 
If a test/assessment has not been done and will not be available, indicate this by writing “ND” (not 
done) in the appropriate answer field in the CRF. If the question is irrelevant (e.g. is not applicable) 
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indicate this by writing “NA” (not applicable) in the appropriate answer field. Further guidance can 
be obtained from the instructions in the CRF.
The investigator must ensure that all information is consistent with the source documentation. By 
electronically signing the case book in the eCRF, the investigator confirms that the information in 
the eCRF and related forms is complete and correct.
13.1
Corrections to case report forms 
Corrections to the eCRF data may be made by the investigator or the investigator’s 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.
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 LPLV 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.
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14 Monitoring procedures 
During the course of the trial, the monitor will visit the trial site to ensure that the protocol is 
adhered to, that all issues have been recorded, to perform source data verification and to monitor 
drug accountability. The first monitoring visit will be performed as soon as possible after FPFV 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 until LPLV at the trial site.
The monitor must be given direct access to all source documents (original documents, data and 
records). Direct access includes permission to examine, analyse, verify and reproduce any record(s) 
and report(s) that are important to the evaluation of the trial. If the electronic medical record does 
not have a visible audit trail, the investigator must provide the monitor with signed and dated 
printouts. In addition the relevant trial site staff should be available for discussions at monitoring 
visits and between monitoring visits (e.g. by telephone).
All data must be verifiable in source documentation other than the eCRF, except age and BMI 
which are calculated by the eCRF.
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 
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Monitors will review the subject’s medical records and other source data (e.g. the diaries) to ensure 
consistency and/or identify omissions compared to the eCRF. 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.
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. 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.
17 Statistical considerations
Novo Nordisk will analyse and report data from all sites together.
All analyses of efficacy and safety endpoints will be based on the full analysis set (FAS). All 
efficacy endpoints will be summarised using the FAS and safety endpoints will be summarised 
using the safety analysis set (SAS). 
The impact of protocol deviations and outliers may be investigated further in sensitivity analyses if 
deemed relevant.
Unless otherwise specified, all continuous measurements will be summarised descriptively at each 
visit by treatment using observed data. After 26 weeks of treatment, descriptive statistics will be 
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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, pre-trial anti-diabetic treatment (metformin 
+ basal insulin, metformin + one other OAD + basal insulin, metformin + pre-mix/combination
insulin, metformin + one other OAD + pre-mix/combination insulin) 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 guidance24
endpoints will be assessed at frequent visits. If an assessment has been made both at screening (V1) 
and randomisation (V2), and if not otherwise specified, the value from the randomisation visit will 
be used as the baseline value. If the value measured at the randomisation visit is missing and the 
assessment also has been made at screening, then the screening value will be used as the baseline 
value.
Missing values (including intermittent missing values) will be imputed using the LOCF method. 
Subjects without data after randomisation will be included by carrying forward their baseline value. 
LOCF has been a standard approach in diabetes trials for many years, and was used as the primary 
analysis in both IDegLira and IDeg phase 3 trials. LOCF is considered to be an appropriate method 
in the context of treat-to-target trials, where subjects after withdrawal typically continue their 
therapy using commercially available insulin. In previous treat-to-target 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
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17.1
Sample size calculation
The primary objective of this trial is to confirm the superiority of insulin IDegLira versus IDeg in 
controlling glycaemia in Japanese subjects with T2DM. The primary endpoint is the change from 
baseline in HbA1c after 26 weeks.
Formally, let D be the mean difference (IDegLira - IDeg ) in change from baseline in HbA1c . 
Superiority will thus be considered confirmed if the upper bound of the two-sided 95% confidence 
interval for D is strictly below 0.0%. Equivalently, if the p-value for the two-sided test of
H0: D = 0 against HA : D ≠ 0,
is less than 5% and D < 0, where D is the mean treatment difference. This is equivalent to using a 
one-sided test of size 2.5%, which means that the type 1 error rate is controlled at 2.5%.
The sample size is determined using a t-statistic under the assumptions of a two-sided test of size 
5%, a mean treatment difference of 0.45% for the completers, a retained effect of 0.2% for the 15% 
withdrawals and a standard deviation of 1.0%. Superiority will be investigated on the FAS. The 
above assumptions are based on experience from the phase 3a development programmes for 
IDegLira and IDeg. From these assumptions and based on a 1:1 randomisation the sample size is set 
to 105 subjects per treatment arm; in total 210 subjects will be randomized. This will ensure a 
nominal power of at least 84.5% (see Table 17–1).
Table 17–1
Power for various rates of withdrawal and efficacy retention (adjusted 
treatment difference)
Withdrawal rate
Eff.ret.(%)
5%
10%
15%
20%
0.00
86.9% (0.428)
83.2% (0.405)
78.8% (0.383)
73.8% (0.360)
0.10
87.7% (0.433)
84.9% (0.415)
81.8% (0.398)
78.2% (0.380)
0.15
88.0% (0.435)
85.7% (0.420)
83.2% (0.405)
80.3% (0.390)
0.20
88.4% (0.438)
86.5% (0.425)
84.5% (0.413)
82.2% (0.400)
Considering 0% efficacy retention as the most conservative approach for the anticipated 15% of 
subjects discontinuing randomised treatment, for the multiple imputation sensitivity analysis, the 
expected treatment difference is reduced to 0.38% for the superiority test. A total of 105 subjects 
per treatment arm will then yield a superiority power of at least 78.8%.
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17.2
Definition of analysis sets
The following analysis sets are defined in accordance with the ICH-E9 guidance25:
!
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 principle 
and subjects will contribute to the evaluation “as randomised”
!
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 CAS 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 
be documented and signed by those responsible before database lock. The subjects and observations 
excluded from analysis sets, and the reason for this, will be described in the clinical trial report.
17.3
Primary endpoint
The primary endpoint is defined as change from baseline in HbA1c after 26 weeks of treatment.
The change from baseline in HbA1c after 26 weeks of treatment will be analysed using an 
ANCOVA model with treatment, pre-trial anti-diabetic treatment (metformin + basal insulin, 
metformin + one other OAD + basal insulin, metformin + pre-mix/combination insulin, metformin 
+ one other OAD + pre-mix/combination insulin) as fixed factors and baseline HbA1c as covariate. 
Missing values after 26 weeks of treatment will be imputed applying LOCF using HbA1c values at 
and after baseline. 
Superiority of IDegLira vs. IDeg will be considered as confirmed if the 95% confidence interval for 
the mean treatment difference for change from baseline in HbA1c lies entirely below 0.0%; 
equivalent to a one-sided test with significance level of 2.5%. Conclusion of superiority will be 
based on FAS.
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17.3.1
Sensitivity analysis
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 anti-diabetic 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 intention-to-treat scenario will be applied.
The imputation in the IDegLira arm will be based on IDeg values. It will be done as follows:
!
In the first step intermittent missing values are imputed using a Markov Chain Monte Carlo 
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 anti-diabetic treatment as fixed factors, and baseline HbA1c as covariates 
is fitted to the change in HbA1c from baseline to 4 weeks (V10) 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 
anti-diabetic treatment and HbA1c at baseline.
!
In the third step, for each of the 1000 copies of the dataset, missing HbA1c values at 8 weeks 
(V14) 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 26 weeks (V32)
!
For each of the complete data sets, the change from baseline to 26 weeks is analysed using an 
analysis of variance model with treatment and pre-trial anti-diabetic 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 rule26. 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 clinical trial report.
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17.4
Secondary endpoints
17.4.1
Supportive secondary endpoints
17.4.1.1
Efficacy endpoints
Insulin dose after 26 weeks of treatment
The actual daily dose after 26 weeks of treatment will be analysed using the standard ANCOVA 
model including treatment and pre-trial anti-diabetic treatment as fixed factors and baseline HbA1c 
value and baseline insulin dose as covariates.
Responder after 26 weeks of treatment 
Two dichotomous endpoints (responder/non-responder) will be defined based on whether a subject 
has met a specific target level after 26 weeks of treatment:
!
HbA1c < 7.0% 
!
HbA1c ≤ 6.5% 
Analysis of each of the two responder endpoints will be based on a logistic regression model with 
treatment and pre-trial anti-diabetic treatment as fixed factors and baseline HbA1c values as a 
covariate.
HbA1c responder endpoints without weight gain after 26 weeks of treatment
Responder for HbA1c without weight gain after 26 weeks of treatment will be defined as HbA1c  < 
7.0% or ≤ 6.5% at ET 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 anti-diabetic treatment as fixed factors and baseline HbA1c and baseline body weight values 
as covariates.
HbA1c responder endpoints without hypoglycaemic episodes
Responder for HbA1c without hypoglycaemic episodes after 26 weeks of treatment will be defined 
as HbA1c  < 7.0% or ≤ 6.5% at ET 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 
anti-diabetic treatment as fixed factors and baseline HbA1c values as a covariate.
HbA1c responder endpoints without hypoglycaemic episodes and weight gain
Responder for HbA1c without hypoglycaemic episodes and weight gain after 26 weeks of treatment 
will be defined as HbA1c  < 7.0% or ≤ 6.5% at ET, without treatment emergent severe 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 anti-diabetic
treatment as fixed factors and baseline HbA1c and body weight values as covariates.
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Fasting plasma glucose (FPG)
Change from baseline in FPG after 26 weeks of treatment will be analysed using the standard 
ANCOVA model.
Waist circumference
Change from baseline in waist circumference after 26 weeks of treatment will be analysed using the 
standard ANCOVA model.
Blood pressure (systolic and diastolic)
Change from baseline in blood pressure after 26 weeks of treatment will be analysed using the 
standard ANCOVA model.
Self-measured blood glucose (SMBG) 9-point profile
The following six endpoints from the 9-point profile will be defined:
!
9-point profile (individual SMBG values) [One endpoint]
!
Mean of the 9-point profile, defined as the area under the profile (calculated using the 
trapezoidal method) divided by the measurement time [One endpoint]
!
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 [Four endpoints]
A linear mixed effect model will be fitted to the 9-point SMBG profile data. The model will include 
treatment, pre-trial anti-diabetic treatment, time, the interaction between treatment and time and the 
interaction between pre-trial anti-diabetic treatment and time as fixed factors and subject as random 
effect. From the model mean profile by treatment and relevant treatment differences will be 
estimated and explored.
Change from baseline after 26 weeks of treatment in mean of the 9-point profile and post-prandial 
increment endpoints will be analysed separately using the standard ANCOVA model.
Lipids
Total cholesterol, low density lipoprotein cholesterol (LDL cholesterol), high density lipoprotein 
cholesterol (HDL cholesterol), very low density lipoprotein cholesterol (VLDL cholesterol), 
triglycerides, and free fatty acids after 26 weeks of treatment will be analysed separately by using 
the standard ANCOVA model. In these statistical analyses the endpoint will be log-transformed and 
so will the baseline covariate.
17.4.1.2
Safety endpoints
Adverse events
AEs will be coded using the most recent version of the Medical Dictionary for Regulatory 
Activities.
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A TEAE is defined as an event that has onset date on or after the first day of exposure to 
randomised treatment and no later than 7 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.
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).
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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)27. Therefore, Novo Nordisk has included hypoglycaemia with plasma glucose
levels below this cut-off point in the definition of BG confirmed hypoglycaemia.
Novo Nordisk uses the following classification (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 classification19 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 
classification19 or BG confirmed by a plasma glucose value < 3.1 mmol/L (56 mg/dL) with or 
without symptoms consistent with hypoglycaemia. 
Figure 17–1
Novo Nordisk classification of hypoglycaemia
ADA classification19 of hypoglycaemia 
!
Severe hypoglycaemia: An episode requiring assistance of another person to actively administer 
carbohydrate, glucagon, or take other corrective actions. plasma glucose concentrations may not 
be available during an event, but neurological recovery following the return of plasma glucose
to normal is considered sufficient evidence that the event was induced by a low plasma glucose
concentration.
!
Asymptomatic hypoglycaemia: An episode not accompanied by typical symptoms of 
hypoglycaemia, but with a measured plasma glucose concentration ≤ 3.9 mmol/L (70 mg/dL).
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!
Documented symptomatic hypoglycaemia: An episode during which typical symptoms of 
hypoglycaemia are accompanied by a measured plasma glucose concentration ≤ 3.9 mmol/L (70 
mg/dL).
!
Pseudo-hypoglycaemia: An episode during which the person with diabetes reports any of the 
typical symptoms of hypoglycaemia with a measured plasma glucose concentration > 3.9 
mmol/L (70 mg/dL) but approaching that level.
!
Probable symptomatic hypoglycaemia: An episode during which symptoms of hypoglycaemia 
are not accompanied by a plasma glucose determination but that was presumably caused by a 
plasma glucose concentration ≤ 3.9 mmol/L (70 mg/dL).
Figure 17–2
ADA classification of hypoglycaemia
Data on treatment emergent hypoglycaemic episodes are presented in terms of the number of 
subjects with at least one event (N), the percentage of subjects with at least one event (%), the 
number of events (E) and the event rate per 100 years (R).
Separate summaries are made for severe or BG confirmed hypoglycaemic episodes, severe or BG 
confirmed symptomatic hypoglycaemic episodes, , nocturnal severe or BG confirmed symptomatic 
hypoglycaemic episodes  and the ADA classification of hypoglycaemia.
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The number of hypoglycaemic episodes during 26 weeks of treatment will be analysed separately 
for each endpoint using a negative binominal regression model with a log-link function and the 
logarithm of the time period in which a hypoglycaemic episode is considered treatment emergent as 
offset. The model will include treatment and pre-trial anti-diabetic treatment as fixed factor. 
Clinical evaluations (physical examination, eye examination and ECG)
Eye examination (fundoscopy/fundus photography) and ECG findings will be summarised 
descriptively, including:
!
summaries for each visit
!
shift table from baseline to after 26 weeks of treatment
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 AEs.
Pulse
Change from baseline in pulse after 26 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 26 weeks of treatment
!
Proportion of subjects with measurements outside reference range by treatment and week
Laboratory values will be presented graphically as box plots by treatment and week. For each 
laboratory parameter, individual values outside the reference ranges (abnormal values) will be 
listed.
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). 
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The following criteria are defined for tabulations:
Persistent (all post baseline measurements)
!
From < UNR to persistently ≥ UNR
!
From < UNR to persistently ≥ 1.5 UNR
!
From < UNR to persistently ≥ 20 ng/L
!
From < UNR to persistently ≥ 50 ng/L
!
From < 20 ng/L to persistently ≥ 20 ng/L
!
From < 50 ng/L to persistently ≥ 50 ng/L
Incidental (at least one post baseline measurements)
!
From < UNR to ≥ UNR
!
From < UNR to ≥ 1.5 UNR
!
From < UNR to ≥ 20 ng/L
!
From < UNR to ≥ 50 ng/L
!
From < 20 ng/L to ≥ 20 ng/L
!
From < 50 ng/L to ≥ 50 ng/L
The distribution of all calcitonin measurements across treatment groups and time will be shown 
with histograms and corresponding cumulative plots for actual levels of calcitonin and change from 
baseline. The plots will be presented by treatment group (using ET 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 ≥ lower limit of quantification (LLOQ), minimum, Q25, median, Q75 and 
maximum. Summaries will be presented for all subjects and by gender.
Longitudinal changes for subjects with calcitonin levels ≥ 20 ng/L will be plotted (longitudinal 
plots). The plots will be done by treatment and gender. They will be done for subjects in the 
persistent and incidental categories, separately.
A listing of subjects with at least one post baseline value ≥ 20 ng/L will be done. The listing will 
include age, gender, calcitonin measurements over time and AE history (including preferred term, 
onset and stop dates).
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17.5
Patient reported outcomes
The following questionnaires will be used to compare PROs between treatments:
!
DTR-QOL questionnaire
!
EQ-5D-5L questionnaire
The questionnaires will be summarised descriptively by visit and treatment. 
For the DTR-QOL questionnaire change from baseline in the following scores will be analysed 
separately using the standard ANCOVA:
!
Domain QOL scores
o
Burden on social activities and daily activities
o
Anxiety and dissatisfaction with treatment
o
Hypoglycemia
o
Satisfaction with treatment
!
Total QOL score
For the EQ-5D-5L questionnaire change from baseline in QOL and VAS scores will analysed 
separately using the standard ANCOVA.
Quality Adjusted Life Years will be evaluated in a separate report by the Novo Nordisk Health 
Economics and Outcomes Research department.
18 Ethics
18.1
Benefit-risk assessment of the trial
The trial will be conducted in compliance with ICH GCP 1 and applicable regulatory requirements, 
and in accordance with the Declaration of Helsinki 2. All subjects will be included after an
evaluation in regards to inclusion/exclusion criteria defined in order to ensure that subjects are 
eligible for participating in the trial. Randomised subjects will be treated with IDegLira or IDeg in 
combination with metformin. Such regimen is anticipated to be equal to or better than basal insulin 
or pre-mix/combination insulin combined with metformin with or without one other OAD as 
received by subjects before 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 trial participation.
Both trial products are marketed 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.
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The trial products 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 products 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 levels28-32.
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 Japan10. In addition, these 
subjects may benefit from the effect of treatment on weight previously demonstrated for 
liraglutide28-32.
The most common side effect of all available insulin products is hypoglycaemic episodes. IDeg is a 
basal insulin preparation with a long acting effect. So, recovery from a hypoglycaemic episode may 
be delayed as for other long acting insulin’s.
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 
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 MEN 2. 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 of serum 
calcitonin or thyroid ultrasound will mitigate human risk of thyroid C-cell tumours. 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 
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human exposure at the maximum recommended human dose of 1.8 mg/day. The US Victoza®
Prescribing Information includes the Pregnancy Category C (US Food and Drug Administration
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 trial products generated from the clinical and nonclinical development 
programme has not revealed any safety issues that would prohibit administration 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 
IB version of IDeglira11, liraglutide9 and IDeg8 and in the current version of the Japanese approved 
labelling for Vicoza® and Tresiba®.
When treatment with trial product ends, the subject and investigator will decide on the best 
available treatment. Novo Nordisk will not offer investigational drugs after the end of trial 
treatment.
18.2
Informed consent 
In seeking and documenting informed consent, the investigator must comply with applicable 
regulatory requirement(s) and adhere to ICH GCP 1 and the requirements in the Declaration of 
Helsinki2.
Before any trial-related activity, the investigator must give the subject verbal and written 
information about the trial and the procedures involved in a form that the subject can read and 
understand. 
The subjects must be fully informed of their rights and responsibilities while participating in the 
trial as well as possible disadvantages of being treated with the trial products.
The investigator must ensure that the subject has ample time to come to a decision whether or not to 
participate in the trial and before obtaining a voluntary, signed and personally dated informed 
consent from the subject.
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.
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If information becomes available that may be relevant to the subject’s willingness to continue 
participating in the trial, the investigator must inform the subject in a timely manner, and a revised 
written subject information must be provided and a new informed consent must be obtained.
In this trial additional informed consent must be obtained if: 
!
A female subject becomes pregnant during the trial, the male partner should be asked to sign a 
separate informed consent form if an abnormality is found in the foetus or new-born infant.
18.3
Data handling
If the subject withdraws from the trial or is lost to follow-up, then the subject’s data will be handled 
as follows:
!
Data already collected and any data collected at the end of trial will be retained by Novo 
Nordisk, entered into the database and used for the clinical 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.
18.4
Information to subjects during trial
The subject may receive information provided to the site by Novo Nordisk, an example of this may 
be a “thank you for your participation letter” after completion of the trial. Further the subject may 
receive letters during 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.
18.5
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 the 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, a 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
19.1
Protocol deviations
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 trial database. 
Documentation on protocol deviations must be kept in the investigator trial master file and sponsor 
trial master file.
19.2
Prevention of missing data
The importance of subject retention will be addressed by Novo Nordisk in the training and 
communication with the trial sites. Moreover, the subjects will be carefully informed about the trial 
procedures by the investigator before signing informed consent, so that they know the implications 
of participating in the trial (see 8.1.3).
The investigator will make every effort to ensure that all assessments are performed and data are 
collected. If missing data does occur the reason will be collected via the protocol deviation process, 
see section 19.1 Novo Nordisk will monitor protocol deviations on an on-going basis throughout the 
trial followed by appropriate actions (e.g. re-training of site staff).
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, written notification from Novo Nordisk
must be received and the following documents must be available to Novo Nordisk:
!
Regulatory approval and/or acknowledgement of notification as required 
!
Approval/favourable opinion from IRBs clearly identifying the documents reviewed as follows: 
protocol, any protocol amendments, subject information/informed consent form, any other 
written information to be provided to the subject and subject recruitment materials
!
List of IRB members and/or constitution (or a general assurance number/statement of 
compliance)
!
Curricula vitae of investigator and sub-investigator(s) (current, dated and signed - must include 
documented GCP training or a certificate)
!
Signed receipt of IB
!
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 agreement, each investigator agrees to comply fully with ICH GCP 1
applicable regulatory requirements and the Declaration of Helsinki2.
By signing the protocol agreement, 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 and must ensure adequate 
supervision of the conduct of the trial at the trial 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 and documented 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.
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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 must be kept in a secure locked facility, so no unauthorized persons can get access to the 
data. 
The investigator will take all necessary technical and organisational safety measures to prevent 
accidental or wrongful destruction, loss or deterioration of data. The investigator will prevent any 
unauthorised access to data or any other processing of data against applicable law. The investigator 
must be able to provide the necessary information or otherwise demonstrate to Novo Nordisk that 
such technical and organisational safety measures have been taken.
During any period of unavailability, the investigator must delegate responsibility for medical care of 
subjects to a specific qualified physician who will be readily available to subjects during that time.
If the investigator is no longer able to fulfil the role as investigator (e.g. if he/she moves or retires), 
a new investigator will be appointed in consultation with Novo Nordisk. 
The investigator and other site personnel must have sufficient English skills according to their 
assigned task(s).
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.
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One investigator will be appointed by Novo Nordisk to review and sign the clinical trial report
(signatory investigator).
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 Disclosure14.
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 Editors33 (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 International Committee of Medical Journal Editors authorship 
criteria to be named authors on publications. 
23.1.2
Site-specific publication by investigator
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.
24 Retention of clinical trial documentation
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.
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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 at least 20 years 
after discontinuation of the marketing authorisation, termination of the trial or cancellation of the 
research project whichever is longest.
The files from the trial site/institution must be retained for 15 years after end of trial as defined in 
Section 7, 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.  
25 Institutional Review Boards and regulatory authorities
25.1
Institutional Review Boards 
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 IB, 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.
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25.2
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. 
Guideline for Good Clinical Practice E6(R1), Step 4. 10 June 1996.
2.
World Medical Association. Declaration of Helsinki. Ethical Principles for Medical 
Research Involving Human Subjects. Last amended by the 64th WMA General Assembly, 
Fortaleza, Brazil. October 2013.
3.
The effect of intensive treatment of diabetes on the development and progression of long-
term complications in insulin-dependent diabetes mellitus. The Diabetes Control and 
Complications Trial Research Group. N Engl J Med. 1993;329(14):977-86.
4.
Intensive blood-glucose control with sulphonylureas or insulin compared with conventional 
treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK 
Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352(9131):837-53.
5.
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):140-9.
6.
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):2228-34.
7.
Japan Diabetes Society. Treatment guideline from the Japanese Diabetes Society. 2015.
8.
Novo Nordisk A/S. Investigator´s Brochure, insulin degludec (11th edition). December 
2015.
9.
Novo Nordisk A/S. Investigator´s Brochure, Liraglutide (16th edition). August 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(11):885-93.
11.
Novo Nordisk A/S. Investigator´s Brochure, insulin degludec/liraglutide (8th edition). 
December 2015.
12.
International Conference on Harmonisation, 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. March 1994.
13.
Krakoff LR, Gillespie RL, Ferdinand KC, Fergus IV, Akinboboye O, Williams KA, et al. 
2014 hypertension recommendations from the eighth joint national committee panel 
members raise concerns for elderly black and female populations. J Am Coll Cardiol. 
2014;64(4):394-402.
14.
Novo Nordisk A/S. http://www.novonordisk-trials.com/website/content/how-we-disclose-
trial-information.aspx.
15.
De Angelis C, Drazen JM, Frizelle FA, Haug C, Hoey J, Horton R, et al. Clinical trial 
registration: a statement from the International Committee of Medical Journal Editors. N 
Engl J Med. 2004;351(12):1250-1.
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16.
U.S. Department of Health and Human Services, Food and Drug Administration. Food and 
Drug Administration Amendments Act of 2007. 27 September 2007.
17.
The European Parliament and the Council of the European Council. 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. 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 2004 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. 2004.
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. Diabetes Care. 2013;36(5):1384-95.
20.
McAulay V, Deary IJ, Frier BM. Symptoms of hypoglycaemia in people with diabetes. 
Diabet Med. 2001;18(9):690-705.
21.
Ishii H. Development and psychometric validation of the Diabetes Therapy-Related QOL 
(DTR-QOL) questionnaire. J Med Econ. 2012;15(3):556-63.
22.
Oppe M, Devlin NJ, van Hout B, Krabbe PF, de Charro F. A program of methodological 
research to arrive at the new international EQ-5D-5L valuation protocol. Value Health. 
2014;17(4):445-53.
23.
Ethical considerations for clinical trials on medicinal products conducted with the paediatric 
population - Recommendations of the adhoc group for the development of implementing 
guidelines for Directive 2001/20/EC relating to good clinical practice in the conduct of 
clinical trials on medicinal products for human use.: European Commission, ad hoc group 
for the development of implementing guidelines for Directive 2001/20/EC; 2014 2008 2014.
24.
U.S. Department of Health and Human Services, Food and Drug Administration. Guidance 
for Industry. Diabetes Mellitus: Developing Drugs and Therapeutic Biologics for Treatment 
and Prevention, Draft Guidance. February 2008.
25.
International Conference on Harmonisation. ICH Harmonised Tripartite Guideline. 
Statistical principles for clinical trials E9. International Conference on Harmonisation E9 
Expert Working Group. September 1998.
26.
Little RJA, Rubin DB. Statistical analysis with missing data: New York: John Wiley & 
Sons. 1987.
27.
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):777-81.
28.
Buse JB, Rosenstock J, Sesti G, Schmidt WE, Montanya E, Brett JH, 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(9683):39-47.
29.
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 
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randomised, 52-week, phase III, double-blind, parallel-treatment trial. Lancet. 
2009;373(9662):473-81.
30.
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):268-78.
31.
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):2046-55.
32.
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 Obesity & Metabolism. 
2012;14(10):944-50.
33.
International Committee of Medical Journal Editors. Recommendations for the Conduct, 
Reporting, Editing and Publication of Scholarly Work in Medical Journals; current version 
available at www.icmje.org.
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Appendix A
Insulin Titration Guideline
Trial ID: NN9068-4184
DUAL™ II Japan
A double-blinded trial comparing the efficacy and safety of insulin 
degludec/liraglutide and insulin degludec both in combination with 
metformin in Japanese subjects with type 2 diabetes mellitus inadequately 
controlled with basal or pre-mix/combination insulin therapy 
and oral anti-diabetic drugs 
Trial Phase: 3a
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol - Appendix 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..................................................................................................................................4
2.1
Injection area..................................................................................................................................4
2.2
Time of injection............................................................................................................................4
3
Initiation and titration ..............................................................................................................................5
3.1
Initiation of IDegLira.....................................................................................................................5
3.2
Initiation of IDeg ...........................................................................................................................5
3.3
Titration of IDegLira and IDeg......................................................................................................5
3.4
Deviations from the algorithm.......................................................................................................6
4
Data collection ...........................................................................................................................................7
5
Review procedure......................................................................................................................................8
6
References..................................................................................................................................................9
List of in-text tables
Page
Table 1
Twice weekly titration on fixed days (Tue/Fri) .............................................................................5
Table 2
     Twice weekly adjusted titration................................................................................................6
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1
Introduction
The goal of insulin therapy is to achieve near normoglycaemia, i.e. to reach a pre-defined HbA1c
level with a low rate of hypoglycaemic episodes and as little weight gain as possible. Several trials 
have shown that this is difficult to achieve, unless plasma glucose 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 plasma glucose levels.
It is recognised that treatments differ between different regions and countries. Likewise, specific 
titration guidelines may not be applicable in certain clinical situations. It is important that other 
information, such as symptoms of hypo/hyperglycaemia, previous response to dose adjustments, 
other glucose measurements and other indicators of the subject’s level of glycaemic control, is 
taken into consideration when decisions on dosing are made. The investigator should always use his 
clinical judgement to avoid safety hazards. The investigator is responsible for the treatment of the 
subjects and can therefore overrule the guideline.
To optimise and maintain glycaemic control, the investigator should, throughout the trial be at least 
in weekly contact with the subjects to assist the subjects in adjusting insulin doses and to ensure the 
subject’s welfare.
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2
Treatment regimens
At randomisation all subjects will be randomised in a 1:1 manner into two parallel treatment 
groups:
!
IDegLira once daily
!
IDeg once daily
First dosing should take place on the day of randomisation (V2) or on the day following 
randomisation.
Maximum dose for IDegLira is 50 dose steps.
Maximum dose for IDeg is 50 units.
There are no minimum doses for IDegLira or IDeg.
2.1
Injection area
Both IDegLira and IDeg should be injected subcutaneously into the thigh, upper arm (deltoid 
region) or the abdomen. 
The injection site should remain the same throughout the trial. Rotation of injection sites within a 
given region is recommended.
2.2
Time of injection
Dosing time can be anytime of the day, but should be approximately on the same time each dosing 
day throughout the trial.
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3
Initiation and titration
3.1
Initiation of IDegLira 
The recommended start dose of IDegLira is 10 dose steps (10 units of IDeg and 0.36 mg liraglutide) 
daily, with the option of choosing up to 16 dose steps (16 units IDeg/0.6 mg liraglutide) at the 
investigator’s discretion.
3.2
Initiation of IDeg
The recommended start dose of IDeg is 10 units, with the option of choosing up to 16 units at the 
investigator’s discretion.
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 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), according to a predefined titration algorithm described in Table 1. The 
investigator will support titration at all contacts. 
Table 1
Twice weekly titration on fixed days (Tue/Fri)
Sun
Mon
Tue
Wed
Thu
Fri
Sat
SMBG
X1
X1
X1
X2
X2
X2
X2
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 2.
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Table 2
     Twice weekly adjusted titration 
Mean pre-breakfast SMBG values
Dose adjustment
mmol/L
mg/dL
Dose steps/units
< 4.0
< 72
-2
4.0-5.0
72-90
0
> 5.0
> 90
+2
If one or more SMBGs values are missing, the adjustment should be performed on the remaining 
SMBG value(s).
3.4
Deviations 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.
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4
Data collection
The following data should be entered into the eCRF within 24 hours (on weekdays) after a site 
visit/phone contact:
!
Pre-breakfast SMBG values measured since last visit/phone contact
!
Doses of IDegLira or IDeg taken before and after titration
!
Reasons for deviation from the titration algorithms, if applicable
!
Hypoglycaemic episodes
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5
Review procedure
Surveillance of titration data will be performed centrally by Novo Nordisk in an unbiased manner. It 
is important that data regarding dose titration is entered into the eCRF within 24 hours (on 
weekdays). If delays occur, action cannot be taken in due time before the subject’s next site 
visit/phone contact. The aim is to reduce the time periods in which a subject may receive 
suboptimal treatment.
The data listed in section 4 will be reviewed by Novo Nordisk within 24 hours (on weekdays). The 
reviewer may contact the investigator to get clarification regarding the reason for deviation or to 
request entry of missing data.
When the investigator receives an inquiry, a response should be received at Novo Nordisk within 24 
hours (on weekdays). 
During the trial HbA1c will be monitored by Novo Nordisk for additional surveillance of the 
glycaemic control. Novo Nordisk may be in contact with sites (visit or phone contact) to discuss 
progress in glycaemic control and titration of individual subjects based on SMBGs and HbA1c. This 
will be done in an unbiased and whenever possible in a blinded manner.
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6
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.
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Protocol - Appendix B
CONFIDENTIAL
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Appendix B
New York Heart Association Criteria for Functional Capacity
Trial ID: NN9068-4184
DUAL™ II Japan
A double-blinded trial comparing the efficacy and safety of insulin 
degludec/liraglutide and insulin degludec both in combination with 
metformin in Japanese subjects with type 2 diabetes mellitus inadequately 
controlled with basal or pre-mix/combination insulin therapy 
and oral anti-diabetic drugs 
Trial Phase: 3a
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol - Appendix B
CONFIDENTIAL
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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


– AProtocol - Appendix Cppendix C
CONFIDENTIAL
Date:
02 May 2016
1RYR1RUGLVN
Trial ID: NN9068-4184
Version:
2.0
UTN: U1111-1178-3453 
Status:
Final
EudraCT No.: NA
Page:
1 of 5
Appendix C
Events with additional data collection 
and events requiring adjudication 
Trial ID: NN9068-4184
DUALTM II Japan
A double-blinded trial comparing the efficacy and safety of insulin 
degludec/liraglutide and insulin degludec both in combination with 
metformin in Japanese subjects with type 2 diabetes mellitus inadequately 
controlled with basal or pre-mix/combination insulin therapy 
and oral anti-diabetic drugs 
Trial phase: 3a
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol - Appendix C
UTN: U1111-1178-3453  
Date:
02 May 2016
Status:
Final
1RYR1RUGLVN
Trial ID: NN9068-4184
EudraCT No.: NA
Version:
2.0
Page:
2 of 5
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 U.S Food and Drug Administration 
(FDA) guidance document1 requests that 
Sponsors demonstrate the cardiovascular 
safety profile of any new therapy for type 2 
diabetes in order to ensure, that the new 
therapy does not increase the cardiovascular 
risk to an unacceptable extent.
All events will be 
adjudicated
Acute coronary syndrome:
!
MI
!
Hospitalisation 
for unstable 
angina
All types of 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 TIA)
Stroke (ischaemic, haemorrhagic or undetermined) is 
defined as an acute episode of neurological 
dysfunction, caused by focal or global brain, spinal 
cord, or retinal vascular injury.
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 document1requests that 
Sponsors demonstrate the cardiovascular 
safety profile of any new therapy for type 2 
diabetes in order to ensure, that the new 
therapy does not increase the cardiovascular 
risk to an unacceptable extent.
All events will be 
adjudicated


Protocol - Appendix C
UTN: U1111-1178-3453  
Date:
02 May 2016
Status:
Final
1RYR1RUGLVN
Trial ID: NN9068-4184
EudraCT No.: NA
Version:
2.0
Page:
3 of 5
Events with additional 
data collection and/or 
events requiring 
adjudication 
Definitions
Rationale
Event Adjudication 
Committee
Heart failure requiring 
hospital admission
Clinical manifestations of a new episode or worsening 
of existing heart failure requiring admission.
An FDA guidance document1 requests that 
Sponsors demonstrate the cardiovascular 
safety profile of any new therapy for type 2 
diabetes in order to ensure, that the new 
therapy does not increase the cardiovascular 
risk to an unacceptable extent.
All cases of heart 
failure requiring 
hospitalisation,
defined as an 
admission to an 
inpatient unit or a visit 
to an emergency 
department that results 
in at least a 24 hour 
stay, will be 
adjudicated
Thyroid disease
All disorders of thyroid gland (incl. thyroid neoplasms) 
must be reported.
Please refer to the protocol for further details on the 
assessments.
Thyroid C-cells carcinogenicity has been 
reported in rats and mice treated with GLP-1 
receptor agonists in non-clinical studies.
All thyroid neoplasms 
will be adjudicated.
Thyroid disorders 
which require 
thyroidectomy 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 a thyroid disease and should not be 
reported as a Neoplasm)
Neoplasm is an event we follow closely for 
GLP-1 analogues due to non-clinical findings 
in rats and mice treated with GLP-1 agonists.
All neoplasm events, 
irrespective of 
malignancy stage, will 
be adjudicated


Protocol - Appendix C
UTN: U1111-1178-3453  
Date:
02 May 2016
Status:
Final
1RYR1RUGLVN
Trial ID: NN9068-4184
EudraCT No.: NA
Version:
2.0
Page:
4 of 5
Events with additional 
data collection and/or 
events requiring 
adjudication 
Definitions
Rationale
Event Adjudication 
Committee
Renal failure
!
All events of renal failure should be reported, 
including events fulfilling one of the following 
three diagnostic criteria, fulfilling the diagnosis 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 < 0.5 mL/kg/h for 6 hours
The liraglutide component in IDegLira has 
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.
No adjudication 
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 and/or 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 agonists has been 
associated with acute pancreatitis. 
Pancreatitis (including necrotising 
pancreatitis) is an identified risk according to 
the Company Core Data Sheet (CCDS) for 
liraglutide, a component of IDegLira. Novo 
Nordisk therefore monitors these events 
closely.
All events will be 
adjudicated


Protocol - Appendix C
CONFIDENTIAL
Date:
02 May 2016
1RYR1RUGLVN
Trial ID: NN9068-4184
Version:
2.0
UTN: U1111-1178-3453  
Status:
Final
EudraCT No.: NA
Page:
5 of 5
2
References
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.
2. The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for 
Diagnosis of Diseases of the Heart and Great Vessels. 9th ed. Boston, Mass: Little, Brown 
& Co;1994:253-256.
CONFIDENTIAL


Protocol - Appendix D
CONFIDENTIAL
Date:
02 May 2016
1RYR1RUGLVN
Trial ID: NN9068-4184
Version:
2.0
UTN: U1111-1178-3453 
Status:
Final
EudraCT No.: NA
Page:
1 of 5
Appendix D
Monitoring of calcitonin
Trial ID: NN9068-4184
DUALTM II Japan
A double-blinded trial comparing the efficacy and safety of insulin 
degludec/liraglutide and insulin degludec both in combination with 
metformin in Japanese subjects with type 2 diabetes mellitus inadequately 
controlled with basal or pre-mix/combination insulin therapy
and oral anti-diabetic drugs 
Trial phase: 3a
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol - Appendix D
CONFIDENTIAL
Date:
02 May 2016
1RYR1RUGLVN
Trial ID: NN9068-4184
Version:
2.0
UTN: U1111-1178-3453 
Status:
Final
EudraCT No.: NA
Page:
2 of 5
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 where liraglutide is included as in this trial 
where it is a component of the trial product, IDegLira.
While there is general agreement on the clinical interpretation of substantially elevated calcitonin 
levels (greater than 100 ng/L) as likely indicative of C-cell neoplasia, the interpretation of values 
between upper normal range (5.0 and 8.4 ng/L for women and men, respectively) and 100 ng/L 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.
CONFIDENTIAL


Protocol - Appendix D
CONFIDENTIAL
Date:
02 May 2016
1RYR1RUGLVN
Trial ID: NN9068-4184
Version:
2.0
UTN: U1111-1178-3453 
Status:
Final
EudraCT No.: NA
Page:
3 of 5
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 cannot be randomised according to exclusion criteria of this trial. 
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.
Figure 1
Flow of calcitonin monitoring
CONFIDENTIAL


Protocol - Appendix D
CONFIDENTIAL
Date:
02 May 2016
1RYR1RUGLVN
Trial ID: NN9068-4184
Version:
2.0
UTN: U1111-1178-3453 
Status:
Final
EudraCT No.: NA
Page:
4 of 5
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 withdrawn from the trial. All medications suspected to relate to this 
condition should be discontinued until diagnosis has been established. 
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 (medullary thyroid cancer)
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 (multiple endocrine neoplasia type 2) 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. 
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 
CONFIDENTIAL


Protocol - Appendix D
CONFIDENTIAL
Date:
02 May 2016
1RYR1RUGLVN
Trial ID: NN9068-4184
Version:
2.0
UTN: U1111-1178-3453 
Status:
Final
EudraCT No.: NA
Page:
5 of 5
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 calcitonin > 10 ng/L to screen for C-cell disease, but 
they do not provide sufficient information on patients with basal calcitonin >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


Protocol Amendment
CONFIDENTIAL
Date:
30 June 2016
1RYR1RUGLVN
Trial ID: NN9068-4184
Version:
1.0
UTN: U1111-1178-3453 
Status:
Final
EudraCT No.: N/A
Page:
1 of 4
Protocol Amendment
No 1
to Protocol, final version 2.0
dated 02 May 2016
DUAL™ II Japan
Trial ID:NN9068-4184
A double-blinded trial comparing the efficacy and safety of insulin 
degludec/liraglutide and insulin degludec both in combination with metformin in 
Japanese subjects with type 2 diabetes mellitus inadequately controlled with basal or 
pre-mix/combination insulin therapy 
and oral anti-diabetic drugs 
Trial phase: 3a
Applicable to Japan
Amendment originator:
, PhD
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.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol Amendment
CONFIDENTIAL
Date:
30 June 2016
1RYR1RUGLVN
Trial ID: NN9068-4184
Version:
1.0
UTN: U1111-1178-3453 
Status:
Final
EudraCT No.: N/A
Page:
2 of 4
Table of Contents   
Page
Table of Contents..............................................................................................................................................2
1
Introduction including rationale for the protocol amendment.............................................................3
2
Changes......................................................................................................................................................4
2.1
Section 5.3.1– PMDA request for added text is implemented.......................................................4
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
30 June 2016
1RYR1RUGLVN
Trial ID: NN9068-4184
Version:
1.0
UTN: U1111-1178-3453 
Status:
Final
EudraCT No.: N/A
Page:
3 of 4
1
Introduction including rationale for the protocol amendment
An inquiry to protocol section 5.3.1 have been received from PMDA concerning that the
recommended start dose of IDegLira is 10 dose steps (10 units IDeg/0.36 mg liraglutide), with the 
option of choosing up to 16 dose steps (16 units IDeg/0.6 mg liraglutide), at the investigator’s 
discretion, but the 16 dose steps correspond a starting dose of 0.6 mg liraglutide which is not an 
approved starting dose of Victoza in Japan. Accordinly, PMDA request additional text in section 
5.3.1 to cover that consideration of patient safety is at the investigators discretion when starting at 
16 dose steps corresponding to 0.6 mg liraglutide.
PMDA inquiry was as follows:
There is an explanation about the starting dose of IDegLira in protocol section 5.3.1, ‘The 
recommended start dose of IDegLira is 10 dose steps (10 units IDeg/0.36 mg liraglutide), with the 
option of choosing up to 16 dose steps (16 units IDeg/0.6 mg liraglutide) at the investigator’s 
discretion. The 0.36 mg of liraglutide contained in the recommended starting dose almost 
corresponds to the approved starting dose (0.3 mg) of Victoza® in Japan.’
PMDA request for added text was as follows:
With regard to the starting dose of 16 dose steps, please consider adding the explanation in the 
protocol such as ‘The 0.6 mg of liraglutide contained in the starting 16 dose steps is different from 
the approved starting dose of Victoza® in Japan, however in consideration of each subject’s safety 
status including the possibility of hypoglycaemia or hyperglycaemia up to 16 dose steps can be 
chosen at the investigator’s discretion’.:.
We have applied according to PMDA request in this amendment No 1 to protocol version 2.0
In this protocol amendment:
!
Any new text is written in italics.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
30 June 2016
1RYR1RUGLVN
Trial ID: NN9068-4184
Version:
1.0
UTN: U1111-1178-3453 
Status:
Final
EudraCT No.: N/A
Page:
4 of 4
2
Changes
The following changes in section 5.3.1 have been made:
2.1
Section 5.3.1– PMDA request for added text is implemented
2.1.1 Change:
The recommended start dose of IDegLira is 10 dose steps (10 units IDeg/0.36 mg liraglutide), with 
the option of choosing up to 16 dose steps (16 units IDeg/0.6 mg liraglutide) at the investigator’s 
discretion. The 0.36 mg of liraglutide contained in the recommended starting dose almost 
corresponds to the approved starting dose (0.3 mg) of Victoza® in Japan. The 0.6 mg of liraglutide 
contained in the starting 16 dose steps is different from the approved starting dose of Victoza® in 
Japan, however in consideration of each subject’s safety status, including the possibility of 
hypoglycaemia or hyperglycaemia, up to 16 dose steps can be chosen at the investigator’s 
discretion. IDegLira will be titrated twice weekly according to a predefined titration algorithm to a 
maximum of 50 dose steps (50 units insulin degludec/1.8 mg liraglutide) aiming to reach a FPG 
target between 4.0 mmol/L (72 mg/dL) and 5.0 mmol/L (90 mg/dL). 
2.1.2 Rationale:
The starting dose of liraglutide could potentially be 0.6 mg (at the discretion of the investigator) 
which is not an approved starting dose of Victoza in Japan. So PMDA request it further stated that 
consideration in relation to subject safety is at the discretion of the investigator when choosing up to 
16 dose steps (16 units IDeg/0.6 mg liraglutide) as the starting dose.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
14 December 2016
1RYR1RUGLVN
Trial ID: NN9068-4184
Version:
1.0
UTN: U1111-1178-3453
Status:
Final
EudraCT No.: NA
Page:
1 of 8
Protocol Amendment
No 2
to Protocol, final version 3.0
dated 08 Sep 2016
Trial ID: NN9068-4184
A double-blinded trial comparing the efficacy and safety of insulin degludec/liraglutide and 
insulin degludec both in combination with metformin in Japanese subjects with type 2 
diabetes mellitus inadequately controlled with basal or pre-mix/combination insulin therapy 
and oral anti-diabetic drugs
Trial phase: 3a
Applicable to Japan
Amendment originator:
, PharmD
TrialOps 2, Insulin & Devices
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol Amendment
CONFIDENTIAL
Date:
14 December 2016
1RYR1RUGLVN
Trial ID: NN9068-4184
Version:
1.0
UTN: U1111-1178-3453
Status:
Final
EudraCT No.: NA
Page:
2 of 8
Table of Contents   
Page
Table of Contents..............................................................................................................................................2
1
Introduction including rationale for the protocol amendment.............................................................3
1.1
Eligibility criteria update ...............................................................................................................3
1.1.1
Medical rationale for why the suggested changes do not challenge the integrity 
of the trial.....................................................................................................................3
1.2
Recruitment extension ...................................................................................................................4
2
Changes......................................................................................................................................................4
1 
Summary......................................................................................................................4
1.4 
Key inclusion criteria ............................................................................4
1.5 
Key exclusion criteria............................................................................5
5 
Trial design ..................................................................................................................5
5.5 
Rationale for treatment..........................................................................5
6 
Trial population............................................................................................................6
6.1 
Inclusion criteria....................................................................................6
6.2 
Exclusion criteria...................................................................................7
7 
Milestones....................................................................................................................8
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
14 December 2016
1RYR1RUGLVN
Trial ID: NN9068-4184
Version:
1.0
UTN: U1111-1178-3453
Status:
Final
EudraCT No.: NA
Page:
3 of 8
1
Introduction including rationale for the protocol amendment
1.1
Eligibility criteria update
The trial population is insulin-treated type 2 diabetes mellitus subjects. Originally these were
required to have a 90-day stable treatment of anti-diabetic drugs; insulin (pre-mix/combination 
insulin or basal insulin) and oral anti-diabetic drugs (OADs) (metformin, sulphonylureas [SU], 
glinides, α-glucocidase inhibitors [α-GI], sodium-glucose co-transporter-2 inhibitors [SGLT2i], or 
thiazolidinediones [TZD]) prior to screening. Moreover, the pre-trial insulin fluctuation should not 
be greater than 10% over the 90-day stable pre-trial insulin treatment. Additionally the subjects 
were required to be naïve to glucacon-like peptide-1 (GLP-1) receptor agonist treatment, and not 
have been treated with dipetidyl peptidase-4 (DPP-4) inhibitors for 90 days prior to screening. 
These treatment criteria were set in place to avoid bias and minimize the risk of carry-over effect 
while preserving the overall aim of the trial.
These criteria have, however, been considered to be over restrictive in Japanese clinical practice and 
due to seriously low recruitment rate, it has been decided to reduce the required period on stable 
treatment to 60 days. The same reduction from 90 to 60 days has been imposed on the period where 
DPP-4 inhibitors are not allowed. Correspondingly, it has been decided to include subjects 
previously treated with, but not currently on GLP-1 receptor agonists for at least 60 days.
Furthermore, to maintain the integrity of the trial additional requirements are set in place if GLP-1 
receptor agonists have been discontinued previously (i.e. 60 days or more before screening). 
Additionally, to more closely mirror the target population in Japanese clinical practice, the pre-trial 
insulin fluctuation rate has been allowed to be up to 20%. All changes are set in place because of 
seriously low recruitment rates discovered during the trial, which are deemed to be due to over
restrictive criteria in Japanese clinical practice.
1.1.1
Medical rationale for why the suggested changes do not challenge the integrity of 
the trial
The pre-screen period on stable treatment is changed from 90 to 60 days (inclusion criterion #5, 
exclusion criteria [EC] #6 and #7), in line with the Japanese DUAL I trial. Furthermore, the allowed 
fluctuation for pre-trial insulin dose is changed from 10 % to 20 %, still ensuring a stable pre-trial 
insulin treatment, but allowing for somewhat greater fluctuations (inclusion criterion #5). Both of 
these changes will make the identification of the subjects less cumbersome, while it is not judged to 
affect risk of carry-over effect in the beginning of the trial. Therefore the subjects will still be in a 
stable condition at start of investigational treatment. Furthermore, safety of subjects is not likely to 
be affected by this change.
The less strict approach to GLP-1 receptor agonists (EC #6) is set in place to better reflect Japanese
clinical practice where GLP-1 receptor agonists are often used in shorter periods. Due to the overall 
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
14 December 2016
1RYR1RUGLVN
Trial ID: NN9068-4184
Version:
1.0
UTN: U1111-1178-3453
Status:
Final
EudraCT No.: NA
Page:
4 of 8
aim of the trial, which is to examine the additional effect of liraglutide in insulin 
degludec/liraglutide (IDegLira) as compared to insulin degludec (IDeg), it is judged unethical to 
include subjects in whom previous GLP-1 receptor agonists therapy were discontinued due to safety 
concerns and/or tolerability issues. If we include patients who discontinued due to lack of efficacy 
we will jeopardize the overall aim of the trial. Initial versions of trial synopsis, trial outline, and 
protocol secured the overall aim by excluding previous treatment with GLP-1 receptor agonists or 
DPP-4 inhibitors completely – and moving forward with a more relaxed set of inclusion criteria the 
protocol must be very clear on how we ensure not to include subjects previously failing or showing 
intolerance towards GLP-1 receptor agonists. To minimize carry-over effect of incretin-based 
treatments neither GLP-1 receptor agonists nor DPP-4 inhibitors should have been used in the 
previous 60 days.
1.2
Recruitment extension
Given the massive challenges to identify the trial population, the recruitment period is extended 
with 8 weeks (i.e. in total 24 weeks) in order to allow sufficient time for recruitment.
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
2
Changes
1 
Summary
1.4 
Key inclusion criteria
!
Male or female Japanese subjects, age ≥ 20 years at the time of signing informed consent T2DM 
subjects (diagnosed clinically) ≥ 6 months prior to screening
!
HbA1c 7.5-11.0% [58 mmol/mol-97 mmol/mol] (both inclusive) by central laboratory analysis
!
Subjects on stable daily insulin doses for at least 60 90 days prior to screening administered 
once or twice daily, either as basal insulin (e.g. IDeg, insulin glargine, insulin detemir, NPH 
insulin) or pre-mix/combination insulin (e.g. biphasic insulin aspart, insulin degludec/insulin 
aspart). Total daily insulin dose in the previous 60 90 days should be within 20-50 units, both 
inclusive, and on the day of screening, but fluctuations of ± 2010% within the 60 90 days prior 
to screening are acceptable. The specified insulin treatment should be administered in 
combination 
o
with a stable daily dose of metformin within current approved Japanese label for 
at least 60 90 days prior to screening, 
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
14 December 2016
1RYR1RUGLVN
Trial ID: NN9068-4184
Version:
1.0
UTN: U1111-1178-3453
Status:
Final
EudraCT No.: NA
Page:
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o
additionally, the anti-diabetic treatment can be with or without a stable daily dose 
of one of the following other OADs: SU, glinides, α-GI, SGLT2i or TZD within 
current approved Japanese label for at least 60 90 days prior to screening 
!
Body Mass Index (BMI) ≥ 23 kg/m2
1.5 
Key exclusion criteria
!
Receipt of any investigational medicinal product (IMP) within 30 days before screening
!
Use of any anti-diabetic drug in a period of 60 90 days before screening (except pre-
mix/combination or basal insulin, metformin, SU, glinides, α-GI, SGLT2i, or TZD) or 
anticipated change in concomitant medication, which in the investigators opinion could interfere 
with glucose metabolism (e.g. systemic corticosteroids or bolus insulin)
!
Treatment with glucagon-like peptide-1 (GLP-1) receptor agonist during the last 60 days prior 
to screening and furthermore, the discontinuation of GLP-1 receptor agonist at any point in 
time must not have been due to safety concerns, tolerability issues or lack of efficacy, as judged 
by the investigator Previous treatment with glucagon-like peptide-1 (GLP-1) receptor agonists
!
Treatment with dipetidyl peptidase-4 (DPP-4) inhibitors during the last 60 90 days prior to 
screening
!
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 IV
5 
Trial design
5.5 
Rationale for treatment
Pre-trial insulin and OAD treatment should be in accordance with current Japanese approved 
labelling. Subjects should be on at least 60 90 days of stable treatment (insulin and OADs) defined
as unchanged medication and unchanged dose. To reduce the risk of hypoglycaemia all other OADs 
apart from metformin will be discontinued at randomisation. After randomisation metformin 
treatment should remain unchanged during the trial, however in case of safety concerns the dose 
may be reduced at the discretion of the investigator. To avoid impact on trial objectives, no other 
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
14 December 2016
1RYR1RUGLVN
Trial ID: NN9068-4184
Version:
1.0
UTN: U1111-1178-3453
Status:
Final
EudraCT No.: NA
Page:
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treatments affecting weight, glucose or lipid should be used, and certain drugs should not be used 
before the trial (see exclusion criteria no. 5, 6 and 7).
6 
Trial population
6.1 
Inclusion criteria
For an eligible subject, all inclusion criteria must be answered “yes”. 
1. Informed consent obtained before any trial-related activities. Trial-related activities are any 
procedures that are carried out as part of the trial, including activities to determine suitability for 
the trial.
2. Male or female Japanese subjects ≥ 20 years of age at the time of signed informed consent.
3. Type 2 diabetes mellitus subjects (diagnosed clinically) ≥ 6 months prior to screening.
4. HbA1c 7.5-11.0% [58 mmol/mol-97 mmol/mol] (both inclusive) by central laboratory analysis.
5. Subjects on stable daily insulin doses for at least 60 90 days prior to screening administered 
once or twice daily according to current Japanese label, either as basal insulin (e.g. IDeg, insulin 
glargine, insulin detemir, NPH insulin), or pre-mix/combination insulin (e.g. biphasic insulin 
aspart, insulin degludec/insulin aspart). Total daily insulin dose in the previous 60 90 days 
should be within 20-50 units, both inclusive, and on the day of screening, but fluctuations of ± 
2010% within the 60 90 days prior to screening are acceptable. The specified insulin treatment 
should be administered in combination
o
with a stable daily dose of metformin within current approved Japanese label for 
at least 60 90 days prior to screening, 
o
additionally, the anti-diabetic treatment can be with or without a stable daily dose 
of one of the following other oral anti-diabetic drugs: sulphonylureas (SU), 
glinides, α-glucocidase inhibitors (α-GI), sodium-glucose co-transporter-2 
inhibitors (SGLT2i) or thiazolidinediones (TZD) within current approved 
Japanese label for at least 60 90 days prior to screening. 
6. Body Mass Index (BMI) ≥ 23 kg/m2.
Rational for inclusion criteria:
!
Criterion 1 is applied through an ethical consideration, in accordance with the GCP 1
!
Criterion 2 is applied to exclude minors through an ethical consideration. Subjects aged 65 year 
or older are included in accordance with the ICH guideline: Studies in support of special 
populations: Geriatrics12
!
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. HbA1c 
range (7.5-11.0 %) is chosen to include subjects whose glycaemic control is not adequate on 
pre-trial treatment and intensification is considered possible. The upper limit of HbA1c is 
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
14 December 2016
1RYR1RUGLVN
Trial ID: NN9068-4184
Version:
1.0
UTN: U1111-1178-3453
Status:
Final
EudraCT No.: NA
Page:
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chosen in order to exclude subjects with unacceptable glycaemic control who need a more 
intensive therapy.
!
Criterion 5 is applied to ensure that the subject's glycaemic control is stabilised at 
randomisation. 60 90 days of unchanged pre-trial treatment are required.
!
Criterion 6 is chosen in order to ensure a population allowing for exploring the full dose range 
of IDegLira, and to minimize the individual impact of any weight loss that may be associated 
with IDegLira treatment.
6.2 
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 (IMP) within 30 days before screening.
5. Use of any anti-diabetic drug in a period of 60 90 days before screening (except pre-
mix/combination insulin or basal insulin, metformin, sulphonylureas (SU), glinides, α-
glucocidase inhibitors (α-GI), sodium-glucose co-transporter-2 inhibitors (SGLT2i), or 
thiazolidinediones (TZD) or anticipated change in concomitant medication, which in the 
investigators opinion could interfere with glucose metabolism (e.g. systemic corticosteroids or 
bolus insulin).
6. Treatment with glucagon-like peptide-1 (GLP-1) receptor agonist during the last 60 days prior 
to screening and furthermore, the discontinuation of GLP-1 receptor agonist at any point in 
time must not have been due to safety concerns, tolerability issues or lack of efficacy, as judged 
by the investigator. Previous treatment with glucagon-like peptide-1 (GLP-1) receptor agonist.
7. Treatment with dipetidyl peptidase-4 (DPP-4) inhibitors during the last 60 90 days prior to 
screening.
8. Impaired liver function, defined as alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) ≥ 2.5 times upper limit of normal (UNL).
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).
12. Personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine 
neoplasia syndrome type 2 (MEN 2).
13. Subjects presently classified as being in New York Heart Association (NYHA) Class IV.
14. Within the past 180 days have had any of the following: myocardial infarction (MI), stroke or 
hospitalisation for unstable angina and/or transient ischemic attack (TIA) prior to screening.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
14 December 2016
1RYR1RUGLVN
Trial ID: NN9068-4184
Version:
1.0
UTN: U1111-1178-3453
Status:
Final
EudraCT No.: NA
Page:
8 of 8
15. Inadequately treated blood pressure as defined as Class 2 hypertension or higher (Systolic ≥ 160 
mmHg or diastolic ≥ 100 mmHg) in accordance with National High Blood Pressure Education 
Program, 7th Joint National Committee and European Societies of Hypertension/Cardiology 
2013 guidelines13.
16. Proliferative retinopathy or maculopathy requiring acute treatment as verified by fundoscopy or 
fundus photography performed within 90 days prior to randomisation.
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. Any condition that in the opinion of the investigator might jeopardise subject’s safety or 
compliance with the protocol.
7 
Milestones
Planned duration of recruitment period (first patient first visit (FPFV) – last patient first visit 
(LPFV): 2416 weeks.
End of trial is defined as last patient last visit (LPLV).
CONFIDENTIAL


Global and country key Novo Nordisk staff
Attachments I and II (if applicable) to the protocol are located in the Trial Master File.
Content: Global key staff and Country key staff
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CONFIDENTIAL

SAP_001.pdf: 
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CONFIDENTIAL
Redacted VWDWLVWLFDODQDO\VLVSODQ 
Includes redaction of personal identifiable information only. 
. 


Statistical Analysis Plan
CONFIDENTIAL
Date:
08 December 2017
Novo Nordisk
Trial ID: NN9068-4184
Version:
1.0
UTN: U1111-1178-3453
Status:
Final
EudraCT No.: NA
Page:
1 of 14
Statistical Analysis Plan
Trial ID: NN9068-4184
DUALTM II Japan - Insulin degludec/liraglutide (IDegLira) vs. insulin degludec 
(IDeg) therapy 
A clinical trial comparing efficacy and safety of
insulin degludec/liraglutide (IDegLira) versus insulin degludec (IDeg) 
therapy in subjects with type 2 diabetes mellitus
Author:
Biostatistics IDegLira
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
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.


Statistical Analysis Plan
CONFIDENTIAL
Date:
08 December 2017
Novo Nordisk
Trial ID: NN9068-4184
Version:
1.0
UTN: U1111-1178-3453
Status:
Final
EudraCT No.: NA
Page:
2 of 14
Table of contents
Page
Table of contents.........................................................................................................................................2
List of abbreviations ...................................................................................................................................3
1
Introduction .........................................................................................................................................4
1.1
Trial information.......................................................................................................................4
1.2
Scope of the statistical analysis plan..........................................................................................4
2
Statistical considerations .....................................................................................................................4
2.1
Sample size calculation .............................................................................................................5
2.2
Definition of analysis sets..........................................................................................................5
2.3
Primary endpoint.......................................................................................................................6
2.3.1
Sensitivity analysis ..................................................................................................6
2.4
Secondary endpoints .................................................................................................................8
2.4.1
Supportive secondary endpoints ...............................................................................8
2.4.1.1
Efficacy endpoints..............................................................................8
2.4.1.2
Safety endpoints...............................................................................10
2.4.2
Patient reported outcomes ......................................................................................13
3
Changes to the statistical analyses planned in the protocol..............................................................13
4
References ..........................................................................................................................................13
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
08 December 2017
Novo Nordisk
Trial ID: NN9068-4184
Version:
1.0
UTN: U1111-1178-3453
Status:
Final
EudraCT No.: NA
Page:
3 of 14
List of abbreviations
ADA
American Diabetes Association
AE
adverse event
ANCOVA
analysis of covariance 
BG
blood glucose
CAS
completer analysis set
CTR
clinical trial report
ECG
electrocardiogram
ET
End of treatment
FAS
full analysis set
FDA
U.S. Food and Drug Administration
FPG
fasting plasma glucose
HbA1c
glycosylated haemoglobin
HDL
high density lipoprotein
IDegLira
insulin degludec/liraglutide
IDeg
insulin degludec
ITT
intention-to-treat 
LDL
low density lipoprotein
LLOQ
lower limit of quantification
LOCF
Last Observation Carried Forward 
PRO
patient reported outcome
SAE
serious adverse event
SAP
statistical analysis plan
SAS
safety analysis set
SD 
standard deviation 
SMPG
self-measured plasma glucose 
T2DM
type 2 diabetes mellitus
TEAEs
treatment emergent adverse events 
UTN
Universal Trial Number
VLDL
very low density lipoprotein
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
08 December 2017
Novo Nordisk
Trial ID: NN9068-4184
Version:
1.0
UTN: U1111-1178-3453
Status:
Final
EudraCT No.: NA
Page:
4 of 14
1
Introduction
1.1
Trial information
This phase 3 trial is a 26-week randomised, parallel two-arm, double-blinded, multi-centre, treat-to-
target trial in Japanese subjects with T2DM inadequately controlled with basal insulin or pre-
mix/combination insulin, combined with metformin with or without one of the following OADs: 
SU, glinides, α-GI, SGLT2i or TZD, hereafter collectively referred to as other OADs. The trial is 
comparing efficacy and safety of insulin degludec/liraglutide (IDegLira) versus insulin degludec 
(IDeg) both in combination with Metformin. For further details please see the protocol.
1.2
Scope of the statistical analysis plan
This Statistical Analysis Plan (SAP) is based on Final Protocol version 4.0 (15-Dec-2016).
The scope of this SAP is to specify the statistical analysis for change from baseline in body weight 
after 26 weeks of treatment and add sensitivity analysis for change from baseline in HbA1cafter 26 
weeks of treatment due to protocol amendment 2 during recruitment of subjects. Furthermore, some 
errors have been corrected. For further details on the changes see section 3.
2
Statistical considerations
Novo Nordisk will analyse and report data from all sites together.
All analyses of efficacy and safety endpoints will be based on the full analysis set (FAS). All 
efficacy endpoints will be summarised using the FAS and safety endpoints will be summarised 
using the safety analysis set (SAS). 
The impact of protocol deviations and outliers may be investigated further in the sensitivity 
analyses if deemed relevant.
Unless otherwise specified, all continuous measurements will be summarised descriptively at each 
visit by treatment using observed data. After 26 weeks of treatment, descriptive statistics will be 
presented based both on observed and last observation carried forward (LOCF) imputed data. 
Endpoints that are analysed untransformed and endpoints that are not formally analysed are 
summarised by the arithmetic mean, standard deviation (SD), median, and minimum and maximum 
values. 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.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
08 December 2017
Novo Nordisk
Trial ID: NN9068-4184
Version:
1.0
UTN: U1111-1178-3453
Status:
Final
EudraCT No.: NA
Page:
5 of 14
A standard analysis of covariance (ANCOVA) model will be applied for the continuous primary 
and secondary endpoints. The model includes treatment, pre-trial anti-diabetic treatment (metformin 
+ basal insulin, metformin + one other OAD + basal insulin, metformin + pre-mix/combination 
insulin, metformin + one other OAD + pre-mix/combination insulin) 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 guidance
endpoints will be assessed at frequent visits. If an assessment was made both at screening (V1) and 
randomisation (V2), and if not otherwise specified, the value from the randomisation visit will be 
used as the baseline value. If the value measured at the randomisation visit is missing and the 
assessment also has been made at screening, then the screening value was 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 3 trials. LOCF is considered to be an appropriate method 
in the context of treat-to-target trials, where subjects after withdrawal typically continue their 
therapy using commercially available insulin. In previous treat-to-target 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
2.1
Sample size calculation
Sample size calculations are described in the protocol section 17.1 and will not further be described
here.
2.2
Definition of analysis sets
The following analysis sets are defined in accordance with the ICH-E9 guidance1:
!
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
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
08 December 2017
Novo Nordisk
Trial ID: NN9068-4184
Version:
1.0
UTN: U1111-1178-3453
Status:
Final
EudraCT No.: NA
Page:
6 of 14
documented. The statistical evaluation of the FAS will follow the intention-to-treat principle 
and subjects will contribute to the evaluation “as randomised”
!
Safety Analysis Set (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”
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 
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.
2.3
Primary endpoint
The primary endpoint is defined as change from baseline in HbA1c after 26 weeks of treatment.
The change from baseline in HbA1c after 26 weeks of treatment will be analysed using an 
ANCOVA model with treatment, pre-trial anti-diabetic treatment (metformin + basal insulin, 
metformin + one other OAD + basal insulin, metformin + pre-mix/combination insulin, metformin 
+ one other OAD + pre-mix/combination insulin) as fixed factors and baseline HbA1c as covariate. 
Missing values after 26 weeks of treatment will be imputed applying LOCF using HbA1c values at 
and after baseline. 
Superiority of IDegLira vs. IDeg will be considered as confirmed if the 95% confidence interval for 
the mean treatment difference for change from baseline in HbA1c lies entirely below 0.0%; 
equivalent to a one-sided test with significance level of 2.5%. Conclusion of superiority will be 
based on FAS.
2.3.1
Sensitivity analysis
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 anti-diabetic 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.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
08 December 2017
Novo Nordisk
Trial ID: NN9068-4184
Version:
1.0
UTN: U1111-1178-3453
Status:
Final
EudraCT No.: NA
Page:
7 of 14
Further, a pattern mixture model approach, mimicking an intention-to-treat scenario will be applied. 
The imputation in the IDegLira arm will be based on IDeg values. It will be done as follows:
!
In the first step intermittent missing values are imputed using a Markov Chain Monte Carlo
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 anti-diabetic treatment as fixed factors, and baseline HbA1c as covariates
is fitted to the change in HbA1c from baseline to 4 weeks (V10) 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
anti-diabetic treatment and HbA1c at baseline.
!
In the third step, for each of the 1000 copies of the dataset, missing HbA1c values at 8 weeks
(V14) 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 26 weeks (V32)
!
For each of the complete data sets, the change from baseline to 26 weeks is analysed using an
analysis of variance model with treatment and pre-trial anti-diabetic treatment as fixed factors
and baseline HbA1c value as a covariate.
The estimates and standard deviations for datasets are pooled to one estimate and associated 
standard deviation using Rubin’s rule3. From these pooled estimates the confidence interval for the 
treatment differences and the associated p-value are calculated. 
The results of the 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 clinical trial report.
Additional sensitivity analysis will be performed comparing the treatment difference in subjects 
recruited by one set of criteria compared to ones recruited with updated set of criteria, in order to
evaluate the impact of protocol amendment 2 (08-Sep-2016) implemented during recruitment of 
subjects. 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
08 December 2017
Novo Nordisk
Trial ID: NN9068-4184
Version:
1.0
UTN: U1111-1178-3453
Status:
Final
EudraCT No.: NA
Page:
8 of 14
2.4
Secondary endpoints
2.4.1
Supportive secondary endpoints
2.4.1.1
Efficacy endpoints
Insulin dose after 26 weeks of treatment
The actual daily dose after 26 weeks of treatment will be analysed using the standard ANCOVA 
model including treatment and pre-trial anti-diabetic treatment as fixed factors and baseline HbA1c
value and baseline insulin dose as covariates.
Body weight
The change from baseline in body weight after 26 weeks of treatment will be analysed using the 
standard ANCOVA model with treatment and pre-trial anti-diabetic treatment as fixed factors and 
baseline body weight as covariate. Missing values after 26 weeks of treatment will be imputed 
applying LOCF using body weight values at and after baseline.
Responder after 26 weeks of treatment 
Two dichotomous endpoints (responder/non-responder) will be defined based on whether a subject 
has met a specific target level after 26 weeks of treatment:
!
HbA1c < 7.0%
!
HbA1c ≤ 6.5%
Analysis of each of the two responder endpoints will be based on a logistic regression model with 
treatment and pre-trial anti-diabetic treatment as fixed factors and baseline HbA1c values as a 
covariate.
HbA1c responder endpoints without weight gain after 26 weeks of treatment
Responder for HbA1c without weight gain after 26 weeks of treatment will be defined as HbA1c
<7.0% or ≤ 6.5% at ET 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 anti-diabetic treatment as fixed factors and baseline HbA1c and baseline body weight 
values as covariates.
HbA1c responder endpoints without hypoglycaemic episodes
Responder for HbA1c without hypoglycaemic episodes after 26 weeks of treatment will be defined 
as HbA1c  < 7.0% or ≤ 6.5% at ET 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 
anti-diabetic treatment as fixed factors and baseline HbA1c values as a covariate.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
08 December 2017
Novo Nordisk
Trial ID: NN9068-4184
Version:
1.0
UTN: U1111-1178-3453
Status:
Final
EudraCT No.: NA
Page:
9 of 14
HbA1c responder endpoints without hypoglycaemic episodes and weight gain
Responder for HbA1c without hypoglycaemic episodes and weight gain after 26 weeks of treatment 
will be defined as HbA1c  < 7.0% or ≤ 6.5% at ET, without treatment emergent severe 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 anti-diabetic 
treatment as fixed factors and baseline HbA1c and body weight values as covariates.
Fasting plasma glucose (FPG)
Change from baseline in FPG after 26 weeks of treatment will be analysed using the standard 
ANCOVA model.
Waist circumference
Change from baseline in waist circumference after 26 weeks of treatment will be analysed using the 
standard ANCOVA model.
Blood pressure (systolic and diastolic)
Change from baseline in blood pressure after 26 weeks of treatment will be analysed using the 
standard ANCOVA model.
Self-measured blood glucose (SMBG) 9-point profile
The following six endpoints from the 9-point profile will be defined:
!
9-point profile (individual SMBG values) [One endpoint]
!
Mean of the 9-point profile, defined as the area under the profile (calculated using the
trapezoidal method) divided by the measurement time [One endpoint]
!
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 [Four endpoints]
A linear mixed effect model will be fitted to the 9-point SMBG profile data. The model will include 
treatment, pre-trial anti-diabetic treatment, time, the interaction between treatment and time and the 
interaction between pre-trial anti-diabetic treatment and time as fixed factors and subject as random 
effect. From the model mean profile by treatment and relevant treatment differences will be 
estimated and explored.
Change from baseline after 26 weeks of treatment in mean of the 9-point profile and post-prandial 
increment endpoints will be analysed separately using the standard ANCOVA model.
Lipids 
Total cholesterol, low density lipoprotein cholesterol (LDL cholesterol), high density lipoprotein 
cholesterol (HDL cholesterol), very low density lipoprotein cholesterol (VLDL cholesterol), 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
08 December 2017
Novo Nordisk
Trial ID: NN9068-4184
Version:
1.0
UTN: U1111-1178-3453
Status:
Final
EudraCT No.: NA
Page:
10 of 14
triglycerides, and free fatty acids after 26 weeks of treatment will be analysed separately by using 
the standard ANCOVA model. In these statistical analyses the endpoint will be log-transformed and 
so will the baseline covariate.
2.4.1.2
Safety endpoints
Adverse events
AEs will be coded using the most recent version of the Medical Dictionary for Regulatory 
Activities.
A TEAE is defined as an event that has onset date on or after the first day of exposure to 
randomised treatment and no later than 7 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.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
08 December 2017
Novo Nordisk
Trial ID: NN9068-4184
Version:
1.0
UTN: U1111-1178-3453
Status:
Final
EudraCT No.: NA
Page:
11 of 14
Hypoglycaemic events
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 hypoglycaemic episodes during 26 weeks of treatment will be analysed separately 
for each endpoint using a negative binominal regression model with a log-link function and the 
logarithm of the time period in which a hypoglycaemic episode is considered treatment emergent as 
offset. The model will include treatment and pre-trial anti-diabetic treatment as fixed factor. 
Clinical evaluations (physical examination, eye examination and ECG)
Eye examination (fundoscopy/fundus photography) and ECG findings will be summarised 
descriptively, including:
!
summaries for each visit
!
shift table from baseline to after 26 weeks of treatment
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 AEs.
Pulse
Change from baseline in pulse after 26 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 26 weeks of treatment
!
Proportion of subjects with measurements outside reference range by treatment and week
Laboratory values will be presented graphically as box plots by treatment and week. For each 
laboratory parameter, individual values outside the reference ranges (abnormal values) will be 
listed.
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.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
08 December 2017
Novo Nordisk
Trial ID: NN9068-4184
Version:
1.0
UTN: U1111-1178-3453
Status:
Final
EudraCT No.: NA
Page:
12 of 14
Calcitonin will be displayed in terms of the number of subjects (N), the percentage of subjects (%) 
and the incidence rate per 100 years of exposure (R). 
The following criteria are defined for tabulations:
Persistent (all post baseline measurements)
!
From < UNR to persistently ≥ UNR
!
From < UNR to persistently ≥ 1.5 UNR
!
From < UNR to persistently ≥ 20 ng/L
!
From < UNR to persistently ≥ 50 ng/L
!
From < 20 ng/L to persistently ≥ 20 ng/L
!
From < 50 ng/L to persistently ≥ 50 ng/L
Incidental (at least one post baseline measurements)
!
From < UNR to ≥ UNR
!
From < UNR to ≥ 1.5 UNR
!
From < UNR to ≥ 20 ng/L
!
From < UNR to ≥ 50 ng/L
!
From < 20 ng/L to ≥ 20 ng/L
!
From < 50 ng/L to ≥ 50 ng/L
The distribution of all calcitonin measurements across treatment groups and time will be shown 
with box plots and corresponding cumulative plots for actual levels of calcitonin and change from 
baseline. The plots will be presented by treatment group (using ET 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 ≥ lower limit of quantification (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).
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
08 December 2017
Novo Nordisk
Trial ID: NN9068-4184
Version:
1.0
UTN: U1111-1178-3453
Status:
Final
EudraCT No.: NA
Page:
13 of 14
2.4.2
Patient reported outcomes
The following questionnaires will be used to compare PROs between treatments:
!
DTR-QOL questionnaire
!
EQ-5D-5L questionnaire
The questionnaires will be summarised descriptively by visit and treatment. 
For the DTR-QOL questionnaire change from baseline in the following scores will be analysed 
separately using the standard ANCOVA:
!
Domain QOL scores
!
Burden on social activities and daily activities
!
Anxiety and dissatisfaction with treatment
!
Hypoglycemia
!
Satisfaction with treatment
!
Total QOL score
For the EQ-5D-5L questionnaire change from baseline in QOL and VAS scores will analysed 
separately using the standard ANCOVA.
Quality Adjusted Life Years will be evaluated in a separate report by the Novo Nordisk Health 
Economics and Outcomes Research department.
3
Changes to the statistical analyses planned in the protocol
Corrections have been made to the supportive secondary endpoints. The description of analysis of 
change from baseline in body weight after 26 weeks of treatment has accidently been left out of 
protocol, however listed in the endpoint section of the protocol. 
Additional sensitivity analysis for change from baseline in HbA1c has been added to further 
evaluate the impact of protocol amendment 2 (08-Sep-2016) implemented during recruitment of 
subjects for this trial. In this amendment inclusion and exclusion criteria was changed, therefore a 
sensitivity analysis comparing treatment difference in subjects recruited by one set of criteria will 
be compared to ones recruited with updated set of criteria. 
Box plots have replaced the planned histograms for calcitonin.
4
References
1. International Conference on Harmonisation. ICH Harmonised Tripartite Guideline. Statistical
principles for clinical trials E9. International Conference on Harmonisation E9 Expert Working
Group. September 1998.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
08 December 2017
Novo Nordisk
Trial ID: NN9068-4184
Version:
1.0
UTN: U1111-1178-3453
Status:
Final
EudraCT No.: NA
Page:
14 of 14
2. O'Kelly M, Ratitch B. Clinical trials with missing data : a guide for practitioners. 2014.
3. Little RJA, Rubin D.B. Statistical analysis with missing data. New York: John Wiley & Sons,
1987.
CONFIDENTIAL