Clinical trial NCT03191396
Conditions: Diabetes Diabetes Mellitus, Type 2
Sponsor: Novo Nordisk A/S
Start date: 2017-06-27; Completion date: 2018-08-13
Enrollment: 577 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is conducted in Europe. The aim of the study is to compare the effect of semaglutide subcutaneous (s.c., under the skin) 1.0 mg once-weekly to liraglutide s.c.1.2 mg once-daily on blood sugar levels after 30 weeks of treatment in people with type 2 diabetes. The study will last approximately 9 months (37 weeks). Each participant will have 7 visits at the clinic and 3 phone calls with the study doctor. At the visits, participants will have a number of tests, for example: general health checks, blood samples, heart and eye checks etc. Participants will also fill in some forms about their health and satisfaction with their diabetes treatment.

Detailed description:

Arms: arm 1: Half the study participants are randomised to receive semaglutide arm 2: Half the study participants are randomised to receive liraglutide
Interventions: intervention 1: Semaglutide intervention 2: Liraglutide
Intervention descriptions: intervention 1: Dose gradually increased to 1.0 mg, given s.c. (under the skin), once-weekly for 30 weeks. Participants will remain on their pre-study anti-diabetic drugs (tablets), if any intervention 2: Dose gradually increased to 1.2 mg, given s.c. once-daily for 30 weeks. Participants will remain on their pre-study anti-diabetic drugs, if any

Protocol documents:
Prot_000.pdf: 
Cover Page for Protocol 
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT03191396 
Sponsor trial ID: 
NN9535-4339 
Official title of study: 
Efficacy and safety of semaglutide 1.0 mg once-weekly versus 
liraglutide 1.2 mg once-daily as add-on to 1–3 oral 
anti-diabetic drugs (OADs) in subjects with type 2 diabetes. 
(SUSTAIN 10) 
Document date: 
27 May 2019 
 


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List of contents
Protocol ...............................................................................................................................................
Appendix A - Monitoring of calcitonin.............................................................................................
Appendix B - Adverse events requiring additional data collection................................................
Appendix C - Questionnaire SF-36v2™ and DTSOs......................................................................
Attachment I and II............................................................................................................................
Protocol amendment 1 - FR...............................................................................................................
Protocol amendment 2 - IT................................................................................................................
Protocol amendment 3 - PL...............................................................................................................
Protocol amendment 4 - BG (substantial amendment 1-BG).........................................................
Protocol amendment 5 - BG (substantial amendment 2-BG).........................................................
Protocol amendment 6 - BG (substantial amendment 3-BG).........................................................
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
Semaglutide s.c. Ozempic®
Trial ID: NN9535-4339
Clinical Trial Report
Appendix 16.1.1
27 May 2019
1.0
Final
16.1.1 Protocol and protocol amendments
CONFIDENTIAL
Redacted protocol 
Lncludes redaction of personal identifiable information. 
. 


Protocol
CONFIDENTIAL
Date:
03 February 2017
Novo Nordisk
Trial ID:NN9535-4339
Version:
2.0
UTN:U1111-1190-5868 
Status:
Final
EudraCT no.: 2016-004965-22 
Page:
1 of 96
Protocol
Trial ID: NN9535-4339
SUSTAIN 10 
Efficacy and safety of semaglutide 1.0 mg once-weekly versus 
liraglutide 1.2 mg once-daily as add-on to 1-3 oral anti-diabetic drugs
(OADs) in subjects with type 2 diabetes
Trial phase: 3b
Protocol originator
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol
CONFIDENTIAL
Date:
03 February 2017
Novo Nordisk
Trial ID:NN9535-4339
Version:
2.0
UTN:U1111-1190-5868 
Status:
Final
EudraCT no.: 2016-004965-22 
Page:
2 of 96
Table of Contents
Page
Table of Figures................................................................................................................................................6
Table of Tables..................................................................................................................................................6
List of abbreviations.........................................................................................................................................7
1
Summary....................................................................................................................................................9
2
Flow chart ................................................................................................................................................12
3
Background information and rationale for the trial............................................................................16
3.1
Background information..............................................................................................................16
3.1.1
Type 2 diabetes..........................................................................................................16
3.1.2
Glucagon-like peptide-1 (GLP-1)..............................................................................16
3.1.3
Semaglutide ...............................................................................................................17
3.1.4
Nonclinical data - semaglutide...................................................................................17
3.1.5
Clinical data – semaglutide........................................................................................18
3.1.6
Liraglutide..................................................................................................................20
3.2
Rationale for the trial...................................................................................................................20
4
Objectives and endpoints........................................................................................................................21
4.1
Objectives ....................................................................................................................................21
4.2
Endpoints .....................................................................................................................................21
4.2.1
Primary endpoint........................................................................................................21
4.2.2
Secondary endpoints..................................................................................................21
5
Trial design ..............................................................................................................................................23
5.1
Type of trial .................................................................................................................................23
5.2
Rationale for trial design..............................................................................................................24
5.3
Treatment of subjects...................................................................................................................24
5.3.1
Trial Products/Investigational medicinal Products supplied by Novo Nordisk.........25
5.3.2
Background medication.............................................................................................25
5.4
Injection site.................................................................................................................................26
5.5
Missed dose..................................................................................................................................26
5.6
Treatment after discontinuation of trial product ..........................................................................26
5.7
Rationale for treatment ................................................................................................................26
6
Trial population.......................................................................................................................................27
6.1
Number of subjects......................................................................................................................27
6.2
Inclusion criteria ..........................................................................................................................27
6.3
Exclusion criteria.........................................................................................................................27
6.4
Rescue criteria..............................................................................................................................29
6.5
Criteria for premature discontinuation of trial product................................................................29
6.6
Withdrawal from trial ..................................................................................................................30
6.7
Subject replacement.....................................................................................................................30
6.8
Rationale for trial population.......................................................................................................30
7
Milestones.................................................................................................................................................31
8
Methods and assessments .......................................................................................................................32
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
03 February 2017
Novo Nordisk
Trial ID:NN9535-4339
Version:
2.0
UTN:U1111-1190-5868 
Status:
Final
EudraCT no.: 2016-004965-22 
Page:
3 of 96
8.1
Visit procedures...........................................................................................................................32
8.1.1
Investigator site log....................................................................................................32
8.1.2
Screening, visit 1........................................................................................................32
8.1.3
Fasting visits ..............................................................................................................33
8.1.4
Premature discontinuation of trial product ................................................................33
8.1.5
Withdrawal from trial ................................................................................................34
8.1.6
Investigator assessment..............................................................................................34
8.2
Subject related information/assessments .....................................................................................35
8.2.1
Demography...............................................................................................................35
8.2.2
Diabetes history and diabetes complications .............................................................35
8.2.3
Concomitant illness and medical history...................................................................35
8.2.4
Concomitant medication............................................................................................36
8.2.5
Childbearing potential................................................................................................36
8.2.6
Tobacco use ...............................................................................................................37
8.3
Efficacy assessments....................................................................................................................37
8.3.1
Height, body weight and body mass index................................................................37
8.3.2
Waist circumference ..................................................................................................37
8.3.3
Blood pressure and pulse rate ....................................................................................37
8.3.4
Self-measured plasma glucose (SMPG) ....................................................................38
8.3.5
7-point self-measured plasma glucose profile ...........................................................38
8.4
Safety assessments.......................................................................................................................38
8.4.1
Physical examination.................................................................................................38
8.4.2
Electrocardiogram – 12 lead......................................................................................39
8.4.3
Eye examination ........................................................................................................39
8.4.4
Adverse events...........................................................................................................40
8.4.4.1
Medication error..................................................................................40
8.4.4.2
Adverse events requiring additional data collection ...........................40
8.4.5
Hypoglycaemic episodes ...........................................................................................40
8.5
Laboratory assessments ...............................................................................................................43
8.5.1
Laboratory assessments for efficacy..........................................................................44
8.5.2
Laboratory assessments for safety .............................................................................44
8.6
Other assessments........................................................................................................................45
8.6.1
Subject diary ..............................................................................................................45
8.6.2
Patient reported outcome questionnaires ...................................................................46
8.6.2.1
SF-36v2TM ...........................................................................................46
8.6.2.2
DTSQs.................................................................................................47
8.6.3
Training in the pen-injector .......................................................................................47
8.6.4
Training in blood glucose meter use..........................................................................47
8.7
Subject compliance......................................................................................................................47
9
Trial supplies ...........................................................................................................................................47
9.1
Trial products...............................................................................................................................48
9.2
Labelling......................................................................................................................................48
9.3
Storage .........................................................................................................................................48
9.4
Drug accountability and destruction............................................................................................49
9.5
Auxiliary supplies........................................................................................................................49
10 Interactive web response system............................................................................................................49
11 Randomisation procedure ......................................................................................................................50
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
03 February 2017
Novo Nordisk
Trial ID:NN9535-4339
Version:
2.0
UTN:U1111-1190-5868 
Status:
Final
EudraCT no.: 2016-004965-22 
Page:
4 of 96
12 Adverse events, and technical complaints and pregnancies................................................................50
12.1
Definitions ...................................................................................................................................50
12.1.1
Adverse event ............................................................................................................50
12.1.2
Serious adverse event.................................................................................................52
12.1.3
Non-serious adverse event.........................................................................................53
12.1.4
Medication errors.......................................................................................................53
12.1.5
Adverse events requiring additional data collection..................................................53
12.1.6
Technical complaints.................................................................................................54
12.2
Reporting of adverse events.........................................................................................................54
12.3
Follow-up of adverse events........................................................................................................56
12.4
Technical complaints and technical complaint samples ..............................................................57
12.4.1
Reporting of technical complaints .............................................................................57
12.4.2
Collection, storage and shipment of technical complaint samples ............................58
12.5
Pregnancies..................................................................................................................................58
12.6
Precautions and/or overdose ........................................................................................................60
12.7
Committees related to safety........................................................................................................60
13 Case report forms....................................................................................................................................60
13.1
Corrections to case report forms..................................................................................................61
13.2
Case report form flow..................................................................................................................61
14 Monitoring procedures ...........................................................................................................................62
15 Data management....................................................................................................................................63
16 Computerised systems.............................................................................................................................63
17 Statistical considerations ........................................................................................................................63
17.1
General considerations.................................................................................................................63
17.1.1
Primary estimand.......................................................................................................64
17.1.2
Missing data considerations at week 30.....................................................................64
17.1.3
Confirmatory hypotheses...........................................................................................64
17.1.4
Multiplicity and criteria for confirming hypotheses..................................................65
17.2
Sample size calculation................................................................................................................66
17.3
Data definitions............................................................................................................................67
17.3.1
Data selection.............................................................................................................67
17.3.1.1
Definition of analysis sets ...................................................................67
17.3.1.2
Definition of observation periods........................................................68
17.3.2
Data transformations..................................................................................................69
17.3.3
Definition of baseline.................................................................................................70
17.3.4
Trial completion.........................................................................................................70
17.3.5
Treatment completion................................................................................................70
17.4
Primary endpoint..........................................................................................................................70
17.4.1
Primary analysis.........................................................................................................70
17.4.2
Sensitivity analyses....................................................................................................71
17.4.3
Sensitivity analyses for the primary estimand ...........................................................71
17.4.4
Other sensitivity analyses ..........................................................................................72
17.5
Secondary endpoints....................................................................................................................72
17.5.1
Confirmatory secondary endpoints............................................................................72
17.5.2
Supportive secondary endpoints ................................................................................73
17.5.2.1
Efficacy endpoints...............................................................................73
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
03 February 2017
Novo Nordisk
Trial ID:NN9535-4339
Version:
2.0
UTN:U1111-1190-5868 
Status:
Final
EudraCT no.: 2016-004965-22 
Page:
5 of 96
17.5.2.2
Safety endpoints..................................................................................74
17.6
Health economics and/or PROs ...................................................................................................78
17.7
Interim analysis............................................................................................................................79
18 Ethics........................................................................................................................................................79
18.1
Benefit-risk assessment of the trial..............................................................................................79
18.1.1
Risk and precautions..................................................................................................79
18.1.2
Other safety considerations........................................................................................81
18.1.3
Benefits......................................................................................................................82
18.1.4
Risk and benefit conclusion.......................................................................................82
18.2
Informed consent .........................................................................................................................83
18.3
Data handling...............................................................................................................................83
18.4
Information to subjects during trial..............................................................................................84
18.5
Premature termination of the trial and/or trial site.......................................................................84
19 Protocol compliance................................................................................................................................84
19.1
Protocol deviations ......................................................................................................................84
19.2
Prevention of missing data...........................................................................................................84
20 Audits and inspections ............................................................................................................................85
21 Critical documents ..................................................................................................................................85
22 Responsibilities........................................................................................................................................86
23 Reports and publications........................................................................................................................87
23.1
Communication of results............................................................................................................87
23.1.1
Authorship .................................................................................................................88
23.1.2
Site-specific publication(s) by investigator(s) ...........................................................89
23.2
Investigator access to data and review of results.........................................................................89
24 Retention of clinical trial documentation..............................................................................................89
25 Independent Ethics Committees and regulatory authorities ..............................................................90
26 Indemnity statement ...............................................................................................................................91
27 References................................................................................................................................................92
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
03 February 2017
Novo Nordisk
Trial ID:NN9535-4339
Version:
2.0
UTN:U1111-1190-5868 
Status:
Final
EudraCT no.: 2016-004965-22 
Page:
6 of 96
Table of Figures 
Page
Figure 5–1
Trial design.............................................................................................................................24
Figure 12–1
Reporting of AEs....................................................................................................................55
Figure 17–1
Graphical illustration of the closed testing procedure ............................................................66
Figure 17–2
Novo Nordisk classification of hypoglycaemia......................................................................76
Figure 17–3
ADA classification of hypoglycaemia....................................................................................77
Table of Tables
Page
Table 5–1
Treatment of subjects..............................................................................................................25
Table 9–1
Trial products..........................................................................................................................48
Table 9–2
Storage conditions ..................................................................................................................48
Table 17–1
Assumptions used in the sample size calculation...................................................................67
Table 17–2
Calculated powers for meeting individual hypotheses ...........................................................67
Appendix A
Monitoring of calcitonin
Appendix B
Adverse events requiring additional data collection
Appendix C
Questionnaire SF-36v2™ and DTSOs
Attachment I Globallist of key staff and relevant departments and suppliers 
Attachment IICountry list of key staff and relevant departments
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
03 February 2017
Novo Nordisk
Trial ID:NN9535-4339
Version:
2.0
UTN:U1111-1190-5868 
Status:
Final
EudraCT no.: 2016-004965-22 
Page:
7 of 96
List of abbreviations
AACE
American Association of Clinical Endocrinologists
ADA
American Diabetes Association
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
BG
blood glucose
BMI
body mass index
CRF
case report form
CV
cardio-vascular
DPP-4
ubiquitous dipeptidyl peptidase
DTSQ
Diabetes Treatment Satisfaction Questionnaire, short form
DUN
dispensing unit number
ECG
Electrocardiogram
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
FAS
full analysis set
FSFV
first subject first visit
FPG
fasting plasma glucose
GCP
Good Clinical Practice
GLP-1
glucagon-like peptide-1
GLP-1 RA
glucagon-like peptide-1 receptor agonist
HbA1c
glycosylated haemoglobin
HDL
high-density lipoprotein
IB
Investigator’s Brochure
ICH
International Council on Harmonisation of Technical Requirements  for 
Registration of Pharmaceuticals for Human Use
ICMJE
International Committee of Medical Journal Editors
IEC
independent ethics committee
IWRS
interactive web response system
LDL
low-density lipoprotein
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
03 February 2017
Novo Nordisk
Trial ID:NN9535-4339
Version:
2.0
UTN:U1111-1190-5868 
Status:
Final
EudraCT no.: 2016-004965-22 
Page:
8 of 96
LLOQ
lower limit of qualification
LSFV
last subject first visit
LSLV
last subject last visit
MACE
major adverse cardiovascular events
MAR
missing at random
MCMC
Markov Chain Monte Carlo 
MedDRA
Medical Dictionary for Regulatory Activities
NIMP
non-investigational medicinal product 
NYHA
New York Heart Association
OAD
oral anti-diabetic drug
PG
plasma glucose
PP
per protocol
PRO
patient reported outcome
SAE
serious adverse event
SAS
safety analysis set
s.c.
subcutaneous(ly)
SF-36v2TM
Short Form health survey
SIF
safety information form
SGLT-2
sodium-glucose co-transporter-2
SMPG
self-measured plasma glucose
SU
Sulphonylurea
SUSAR
suspected unexpected serious adverse reaction
T2D
Type 2 diabetes mellitus
UNL
upper normal level
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
03 February 2017
Novo Nordisk
Trial ID:NN9535-4339
Version:
2.0
UTN:U1111-1190-5868 
Status:
Final
EudraCT no.: 2016-004965-22 
Page:
9 of 96
1
Summary
Objective(s) and endpoint(s)
The primary objective
To compare the effect of semaglutide subcutaneous (s.c.) 1.0 mg once-weekly versus liraglutide s.c. 
1.2 mg once-daily on glycaemic control after 30 weeks of treatment in subjects with type 2 diabetes.
The secondary objectives
To compare the effects of semaglutide s.c. 1.0 mg once-weekly versus liraglutide s.c. 1.2 mg 
once-daily after 30 weeks of treatment on body weight, efficacy parameters, safety and tolerability
in subjects with type 2 diabetes. 
Primary endpoint
Change from baseline to week 30 in HbA1c.
Key secondary endpoints
Change from baseline to week 30 in 
!
Body weight (kg)
!
Fasting plasma glucose (FPG) 
!
Systolic and diastolic blood pressure 
Trial design
This is a 30-week, confirmatory, randomised, multicentre, multinational, active-controlled, parallel 
groups, open label, 2-armed trial. 
Subjects with type 2 diabetes inadequately controlled on 1-3 oral anti-diabetic drugs will be 
randomised in a 1:1 manner to receive either semaglutide s.c. 1.0 mg once-weekly or liraglutide s.c. 
1.2 mg once-daily.
The trial includes a treatment period of 30 weeks and a follow-up period of 5 weeks. Total trial 
duration for the individual subjects will be approximately 37 weeks, including a 2-week screening 
period.
Trial population
A planned total number of 576 subjects will be randomised.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
03 February 2017
Novo Nordisk
Trial ID:NN9535-4339
Version:
2.0
UTN:U1111-1190-5868 
Status:
Final
EudraCT no.: 2016-004965-22 
Page:
10 of 96
Key inclusion criteria
!
Male or female, age ≥ 18 years at the time of signing informed consent.
!
Diagnosed with type 2 diabetes mellitus.
!
HbA1c of 7.0-11.0 % (53 - 97 mmol/mol) (both inclusive).
!
Stable daily dose(s) including any of the following anti-diabetic drug(s) or combination 
regimens 90 days prior to the day of screening:
a) Biguanides (metformin ≥ 1500 mg or maximum tolerated dose documented in the 
subject's medical record).
b) Sulphonylureas (≥ half of the maximum approved dose according to local label or 
maximum tolerated dose as documented in subject medical record).
c) SGLT-2 inhibitors (≥ half of the maximum approved dose according to local label or 
maximum tolerated dose as documented in subject medical record).
Key exclusion criteria
!
Family or personal history of multiple endocrine neoplasia type 2 or medullary thyroid 
carcinoma. Family is defined as a first degree relative. 
!
History or presence of pancreatitis (acute or chronic).
!
History of diabetic ketoacidosis.
!
Any of the following: myocardial infarction, stroke, hospitalization for unstable angina or 
transient ischaemic attack within the past 180 days prior to the day of screening. 
!
Subjects presently classified as being in New York Heart Association (NYHA) Class IV.
!
Planned coronary, carotid or peripheral artery revascularisation known on the day of 
screening. 
!
Renal impairment measured as estimated Glomerular Filtration Rate (eGFR) value of < 30 
ml/min/1.73 m2 as defined by KDIGO 2012 classification1.
!
Impaired liver function, defined as ALT ≥ 2.5 times upper normal limit at screening.
!
Proliferative retinopathy or maculopathy requiring acute treatment. Verified by fundus 
photography or dilated fundoscopy performed within the past 90 days prior to 
randomisation.
Key assessments
!
Glucose metabolism (HbA1c, FPG)
!
Body weight 
!
Blood pressure and pulse rate
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
03 February 2017
Novo Nordisk
Trial ID:NN9535-4339
Version:
2.0
UTN:U1111-1190-5868 
Status:
Final
EudraCT no.: 2016-004965-22 
Page:
11 of 96
Trial product(s)
Investigational medicinal products:
!
Test product: Semaglutide 1.34 mg/mL, 1.5 mL PDS290 pre-filled pen-injector ) for s.c.
injection.
!
Reference therapy: Liraglutide 6 mg/mL, 3.0 mL pre-filled pen-injector approved as 
Victoza® for the EU market for s.c. injection.
CONFIDENTIAL


Protocol
UTN:U1111-1190-5868 
Date:
03 February 2017
Status:
Final
Novo Nordisk
Trial ID:NN9535-4339
EudraCT no.: 2016-004965-22 
Version:
2.0
Page:
12 of 96
2
Flow chart
Trial Periods
Protocol 
section
Screening
Randomisation
Treatment
End of treatment
Follow-up
End of treatment 
- Premature 
discontinuation
Follow-up -
Premature 
discontinuation
Visit(V)/Phone contact(P)
V1
V2
P3
V4
V5
V6
V7
P8
V9
P10
V9A
P10A
Timing of visit (weeks)
-2
0
1
4
8
12
16
23
30
35
Visit window (days)
±7
+7
±3
±3
±3
±3
±3
±7
+7
SUBJECT RELATED 
INFO/ASSESMENTS
Informed consent
18.3
X
In/exclusion criteria
6.2, 6.3
X
X
Randomisation
X
Medical history
8.2.3
X
Concomitant illness
8.2.3
X
Concomitant medication
8.2.4
X
X
X
X
X
X
X
X
X
X
X
X
Demography
8.2.1
X
Diabetes history/diabetes 
8.2.2
X
Rescue criteria
6.4
X
X
X
X
X
X
Premature discontinuation criteria
6.5
X
X
X
X
X
X
X
X
Tobacco use
8.2.6
X
EFFICACY
Height
8.3.1
X
Body weight
8.3.1
X
X
X
X
X
X
X
BMI
8.3.1
X
X
X
X
X
X
X
Waist circumference
8.3.2
X
X
X
X


Protocol
UTN:U1111-1190-5868 
Date:
03 February 2017
Status:
Final
Novo Nordisk
Trial ID:NN9535-4339
EudraCT no.: 2016-004965-22 
Version:
2.0
Page:
13 of 96
Trial Periods
Protocol 
section
Screening
Randomisation
Treatment
End of treatment
Follow-up
End of treatment 
- Premature 
discontinuation
Follow-up -
Premature 
discontinuation
Visit(V)/Phone contact(P)
V1
V2
P3
V4
V5
V6
V7
P8
V9
P10
V9A
P10A
Timing of visit (weeks)
-2
0
1
4
8
12
16
23
30
35
Visit window (days)
±7
+7
±3
±3
±3
±3
±3
±7
+7
Blood pressure and pulse rate
8.3.3
X
X
X
X
X
X
X
Fasting plasma glucose
8.5.1
X
X
X
X
X
X
X
HbA1c
8.5.1
X
X
X
X
X
X
X
X
Lipids
8.5.1
X
X
X
X
7-point profile
8.3.5
X
X
X
X
PRO questionnaires
8.6.2
X
X
X
SAFETY
Hypoglycaemic episodes
8.4.5
X
X
X
X
X
X
X
X
X
X
X
ECG
8.4.2
X
X
X
Eye examination
8.4.3
Xa
Xa
Xa
Physical examination
8.4.1
X
X
X
Haematology
8.5.2
X
X
X
X
X
X
Calcitonin
8.5.2
X
X
X
X
Pregnancy testb
8.5.2
X
X
X
X
                                                
a Fundus photography/dilated fundoscopy performed within 90 days prior to randomisation is acceptable if results are available for
evaluation at V2, unless worsening of visual function since last examination.
Fundus photography/dilated fundoscopy must be performed again:
!
at V9 or 5 weeks prior to this. Results should be available at V9.
!
at V9A or within 5 weeks thereafter, and again at or within 5 weeks prior to V9, for subjects who have prematurely discontinued trial product


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Trial Periods
Protocol 
section
Screening
Randomisation
Treatment
End of treatment
Follow-up
End of treatment 
- Premature 
discontinuation
Follow-up -
Premature 
discontinuation
Visit(V)/Phone contact(P)
V1
V2
P3
V4
V5
V6
V7
P8
V9
P10
V9A
P10A
Timing of visit (weeks)
-2
0
1
4
8
12
16
23
30
35
Visit window (days)
±7
+7
±3
±3
±3
±3
±3
±7
+7
Biochemistry
8.5.2
X
X
X
X
X
X
X
Adverse events
12
Xc
X
X
X
X
X
X
X
X
X
X
TRIAL MATERIAL
Dispensing visit
X
X
X
Drug accountability
9.4
X
X
X
X
IWRS call
10
X
X
X
X
X
X
REMINDERS
End of treatment
X
X
End of trial
Xd
Attend visit fasting
8.1.5
X
X
X
X
X
X
X
Schedule of eye examination for next 
visit
8.4.3
X
Xe
Training in trial product and pen 
8.6.3
X
X
                                                                                                                                                                                                                                   
b Only applicable for women of childbearing potential. At V2, urine pregnancy test will be taken. At V1 and V9/V9A, serum pregnancy test will be taken.
c Serious adverse events (SAEs) from screening failures must be transcribed by the investigator into the eCRF
d If premature discontinuation, End of Treatment form must be filled-in when the discontinuation happens and End of Trial form at scheduled visit P10. If a subject completes both the 
treatment and the trial at scheduled time, the End of Treatment form must be filled at V9 and End of Trial form to be filled in at P10. In case of subject withdrawal, both End of Treatment 
form and End of Trial form must be filled-in at the time they withdraw from the trial
e Fundus photography/dilated fundoscopy must be performed again at V9A or within 5 weeks thereafter, and again at or within 5 weeks prior to V9, for subjects who have prematurely 
discontinued trial product


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Trial Periods
Protocol 
section
Screening
Randomisation
Treatment
End of treatment
Follow-up
End of treatment 
- Premature 
discontinuation
Follow-up -
Premature 
discontinuation
Visit(V)/Phone contact(P)
V1
V2
P3
V4
V5
V6
V7
P8
V9
P10
V9A
P10A
Timing of visit (weeks)
-2
0
1
4
8
12
16
23
30
35
Visit window (days)
±7
+7
±3
±3
±3
±3
±3
±7
+7
Handout direction for use 
8.6.3
X
Handout and instruct in diary
8.6.1
X
X
X
X
X
X
X
X
Handout and instruct in BG meter use
8.6.4
X
Handout ID card
8.1.2
X


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3
Background information and rationale for the trial
The trial will be conducted in compliance with this protocol, International Council on 
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use 
(ICH) Good Clinical Practice (GCP)2 and applicable regulatory requirements, and in accordance 
with the Declaration of Helsinki3.
In this document, the term investigator refers to the individual responsible for the overall conduct of 
the clinical trial at a trial site.
3.1
Background information
3.1.1
Type 2 diabetes
Type 2 diabetes (T2D) is a progressive metabolic disease primarily characterised by abnormal 
glucose metabolism. The pathogenesis is not fully understood but seems to be heterogeneous, 
involving environmental, lifestyle, and genetic factors leading to chronic hyperglycaemia caused by 
peripheral tissue insulin resistance, impaired insulin secretion due to abnormal β-cell function and 
abnormal glucose metabolism in the liver4.
Optimal glycaemic control is the treatment goal in subjects with T2D in order to prevent long-term 
complications associated with chronic hyperglycaemia5-8. While an increasing number of agents to 
treat diabetes exist, data collected from 2007−2010 demonstrate that close to 50% of all patients 
treated for their T2D do not achieve the recommended blood glucose target of an HbA1c <7% and 
are thus at increased risk of T2D-related complications9.
3.1.2
Glucagon-like peptide-1 (GLP-1)
GLP-1 is an incretin hormone with a glucose-dependent stimulatory effect on insulin and inhibitory 
effect on glucagon secretion from the pancreatic islets10, 11. Subjects with T2D have a decreased 
incretin effect12-14 , but can respond to the blood glucose lowering effect of GLP-1 when 
administered at supraphysiological levels 15. In addition, supraphysiological levels of GLP-1 reduce 
body weight by lowering energy intake by inducing feelings of satiety and fullness and lowering 
feelings of hunger. GLP-1 is also a neuropeptide produced in the brain and GLP-1 receptors are 
present in several areas of the brain involved in appetite regulation16-18. These mechanisms of action 
make glucagon-like peptide-1 receptor agonists (GLP-1 RAs) an attractive pharmacological 
treatment for T2D19-21.
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3.1.3
Semaglutide
Semaglutide is a potent human GLP-1 RA with a pharmacokinetics profile suitable for once-weekly 
subcutaneous (s.c.) administration. It is structurally similar to liraglutide (Victoza®), an once-daily 
GLP-1 RA developed by Novo Nordisk and approved worldwide for the treatment of T2D. The 
extended half-life of the semaglutide molecule is primarily obtained due to increased albumin
binding, which is facilitated by a large fatty acid derived chemical moiety attached to the lysine in 
position 26. The specific modifications in the molecule are22: 1) a modification in position 8 
(alanine to 2-aminoisobutyric acid) of the peptide backbone to increase stability against dipeptidyl 
peptidase-4 (DPP-4), and a change in position 34 from a lysine to an arginine to limit the options 
for acylation to the one remaining lysine in the sequence; 2) a large hydrophilic spacer between the 
lysine in position 26 and the gamma glutamate whereto the fatty acid is attached; 3) a C18 fatty di-
acid with a terminal acidic group22, 23. The spacer and the fatty acid both contribute to increased 
albumin binding, which slows the degradation of semaglutide in plasma and results in decreased 
renal clearance prolonging the half-life of semaglutide to around 1 week, making it suitable for 
once-weekly s.c. administration.
3.1.4
Nonclinical data - semaglutide
The nonclinical programme for semaglutide was designed according to the ICH M324 guideline to 
support the clinical development. The standard nonclinical data package required to support phase 3 
clinical trials has been completed. In addition, 2-year carcinogenicity studies and a pre- and 
postnatal development toxicity study have been completed.
Semaglutide is generally well tolerated with expected GLP-1 effects on food intake and body 
weight being dose limiting in mice, rats and cynomolgus monkeys. Two potential safety issues have 
been identified and are detailed below.
Thyroid C-cell tumours in rodents
Thyroid C-cell neoplasia was seen in mice and rat 2-year carcinogenicity studies. Proliferative 
C-cell changes in rodents are a known effect following GLP-1 receptor activation by GLP-1 RA. 
The finding in rodents is caused by a non-genotoxic, specific GLP-1 receptor-mediated mechanism 
to which rodents are particularly sensitive. As the GLP-1 receptor is not expressed in the normal 
human thyroid the risk of GLP-1 receptor mediated C-cell changes in humans is considered to be 
low25. C-cell neoplasia corresponds to medullary thyroid carcinoma in humans, which has not been 
reported in the completed phase 3a clinical trials. 
Embryo−foetal development toxicity
In rats, semaglutide adversely affected embryo-foetal development, causing foetal mortality, 
reduced growth, and skeletal and visceral malformations. More specifically, the embryo−foetal 
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development was affected by a GLP-1 receptor-mediated impaired function of the inverted yolk sac 
placenta during a period of gestation when the rat embryo is entirely dependent on the inverted yolk 
sac placenta for its nutrient supply. However, this mechanism is not likely to be of relevance to 
humans due to the fact that in primates, the yolk sac does not invert to fully enclose the embryo. So 
it does not come in direct contact with the uterine wall to form a placenta as it does in rodents. In 
rabbits and cynomolgus monkeys, pregnancy losses and foetal abnormalities were observed at 
exposures below (rabbit) or 3–5 fold above (monkey) the maximum recommended human dose. 
These observations might be either incidental or related to the reduced maternal body weight, but a 
direct effect of semaglutide for subcutaneous administration could not be excluded.
A comprehensive review of results from the nonclinical studies can be found in the current edition 
of semaglutide for subcutaneous administration (NN9535) investigator’s brochure (IB)26, or any 
updates hereof.
3.1.5
Clinical data – semaglutide
More than 4,500 subjects have been exposed to once-weekly s.c. semaglutide in the 16 clinical 
pharmacology trials, the phase 2 trial and the 8 phase 3a trials completed so far (please see the 
current edition of the IB for s.c. administration of semaglutide (NN9535), or any updates thereto for 
details26). 
Clinical pharmacology trials were conducted in healthy subjects, in subjects with T2D, in subjects 
with obesity and in subjects with renal- and hepatic impairment. Semaglutide phase 3a programme 
evaluated the efficacy and safety of semaglutide in a broad T2D population and covered the 
continuum of T2D care. The programme evaluated mono- and combination therapy with anti-
diabetic therapies and compared semaglutide with the most important comparators at the time of 
initiating the phase 3a programme. In addition, the phase 3a programme included a long-term (104-
week) cardiovascular (CV) outcomes trial in a T2D population at high risk of CV events.
Pharmacokinetics
The results from the completed clinical pharmacology trials confirm that semaglutide has 
pharmacokinetic properties compatible with once-weekly administration, with a median time to 
maximum concentration (tmax) of 1−3 days post dosing and a t½ of around 1 week. Overall, the 
pharmacokinetics properties of semaglutide appear comparable between healthy subjects, subjects 
with T2D and subjects with renal failure. 
Results from drug-drug-interaction studies with warfarin, metformin, atorvastatin and digoxin 
indicate that no dose adjustment of the co-administered drugs is warranted when administered 
together with semaglutide. In addition, semaglutide does not decrease the exposure of oral 
contraceptives and hence, is not anticipated to decrease the effectiveness of oral contraceptives.
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Efficacy
Based on results from the clinical pharmacology trials, semaglutide treatment reduced both fasting 
and postprandial glucose compared to placebo, by improving multiple aspects of β-cell function and 
by reducing both fasting and postprandial glucagon concentrations, all in a glucose-dependent 
manner. The weight loss observed with semaglutide was primarily from fat tissue and was 
considered to be explained by lowered appetite, both in the fasting and postprandial state, and 
lowered energy intake. In addition, semaglutide improved control of eating and reduced food 
cravings. Similar to other GLP-1 RA, semaglutide caused a minor delay of early postprandial 
gastric emptying.
Both as monotherapy and as combination therapy, semaglutide significantly reduced glycosylated 
haemoglobin (HbA1c) and body weight in all phase 3a trials when compared with the trial-specific 
comparator, including the active comparators sitagliptin, exenatide ER and insulin glargine. In the 5
global phase 3a trials (3623, 3624, 3625, 3626 and 3627), reductions in HbA1c and body weight of 
up to 1.85%-point and 6.42 kg, respectively, were obtained with semaglutide 1.0 mg. Significantly 
more subjects with semaglutide versus comparators reached the American Diabetes Association 
(ADA) and American Association of Clinical Endocrinologists (AACE)-defined treatment target of 
an HbA1c <7% and ≤6.5%, respectively, and weight loss responses of ≥5% and ≥10%. The superior 
and clinically relevant beneficial effects of semaglutide on glycaemic control as estimated by HbA1c 
were substantiated by improvements in secondary glycaemia-related supportive endpoints27-30.
Safety
Data from the 6 global phase 3a clinical trials (3623, 3624, 3625, 3626, 3627, 3744) showed that the 
safety and tolerability of semaglutide at doses up to 1.0 mg per week and administered for up to 
56 weeks of treatment were consistent with other GLP-1 RAs. The most frequent AEs leading to 
premature treatment discontinuation were nausea, diarrhoea and vomiting. The escalation regimen 
utilized was associated with good tolerability and low numbers of discontinuation due to AEs. 
Hypoglycaemia occurred infrequently in subjects receiving semaglutide and the events were mainly 
non-severe. No episodes of severe hypoglycaemia were observed when semaglutide was used as 
monotherapy. Hypoglycaemic episodes have most frequently been observed when semaglutide is 
combined with sulphonylurea (SU) or insulin. In line with findings for other GLP-1 RAs, an 
increase in pulse rate and serum levels of lipase and amylase has also been observed in subjects 
exposed to semaglutide. As with all protein based pharmaceuticals, subjects treated with 
semaglutide may develop immunogenic and allergic reactions. However, only few subjects 
administered semaglutide experienced allergic reactions and injection site reactions. These have 
mainly been mild and transient of nature; however, more generalised reactions may occur. 
The effect of semaglutide on major adverse cardiovascular events (MACE; CV death, non-fatal 
myocardial infarction and non-fatal stroke) versus placebo was evaluated in a T2D population at 
high risk for CV events, in the CV outcomes trial, SUSTAIN 6 (NN9535-3744)31. The SUSTAIN 6 
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trial achieved its primary objective by showing non-inferiority of semaglutide versus placebo on 
CV outcomes by ruling out an 80% increased risk. Moreover, semaglutide significantly reduced the 
risk of MACEs by 26% vs placebo32.
The overall safety profile of semaglutide in the SUSTAIN 6 trial was consistent with previous 
semaglutide clinical trials. However, in this trial, there was a higher frequency of confirmed events 
of diabetic retinopathy complications in semaglutide-treated subjects compared with placebo.
Further details will soon be available in the semaglutide s.c. (NN9535) IB edition 12.
3.1.6
Liraglutide
The selected active comparator in this trial is liraglutide, an injectable once-daily human GLP-1 RA
developed by Novo Nordisk and approved for the treatment of T2D in the European Union, US and 
Japan under the brand name Victoza®. Victoza® was first approved for marketing in the EU on 30 
Jun 2009. Up until 30 Jun 2016, Victoza® has been approved in 106 countries and launched in 81 
countries worldwide, including the major countries/regions Australia, Brazil, Canada, China, EU, 
Japan, Mexico and the U.S. In the EU, Victoza® is indicated for the treatment of adults with T2D to 
achieve glycaemic control in combination with oral glucose-lowering medicinal products and/or 
basal insulin when these, together with diet and exercise, do not provide adequate glycaemic 
control. For further details, please see the current EU summary of product characteristics (SmPC) 
for Victoza®33.
For an assessment of benefits and risks of the trial (see Section 18.1).
3.2
Rationale for the trial
The current available treatment modalities for T2D are still not satisfactory, as a large proportion of 
patients do not reach their HbA1c treatment targets. Furthermore, there is a segment of patients, who 
either has difficulties adhering to once-daily treatments, or has a wish for more convenient 
treatment regimens such as once-weekly treatments. 
Liraglutide and semaglutide are both human GLP-1 RAs with a prolonged half-life compared to 
native GLP-1, making them suitable for once-daily and once-weekly s.c. injections, respectively. 
Based on the phase 3a results, semaglutide is expected to be marketed with two treatment doses (0.5 
mg and 1.0 mg). Dose-dependent reductions in both HbA1c and body weight were observed in these 
trials with significantly more patient reaching treatment targets of HbA1c < 7% and ≤6.5% with 
semaglutide 1.0 mg compared with semaglutide 0.5 mg. Hence, 1.0 mg is expected to be the most 
frequently used dose when semaglutide is marketed. For liraglutide (Victoza®)), 1.2 mg and 1.8 mg 
are approved treatment doses for treatment of type 2 diabetes. However, in most European countries 
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the 1.2 mg dose of Victoza® is the most commonly used dose34, 35. Therefore, the aim for the current 
trial is to demonstrate the efficacy and safety of once-weekly 1.0 mg semaglutide versus once-daily 
1.2 mg liraglutide 36. 
4
Objectives and endpoints
4.1
Objectives
The primary objective
To compare the effect of semaglutide s.c. 1.0 mg once-weekly versus liraglutide s.c. 1.2 mg 
once-daily on glycaemic control after 30 weeks of treatment in subjects with type 2 diabetes.
The secondary objectives
To compare the effect of semaglutide s.c. 1.0 mg once-weekly versus liraglutide s.c. 1.2 mg 
once-daily after 30 weeks of treatment on body weight, efficacy parameters, safety and tolerability
in subjects with type 2 diabetes. 
4.2
Endpoints
4.2.1
Primary endpoint
Change from baseline to week 30 in HbA1c
4.2.2
Secondary endpoints
Confirmatory secondary endpoints
Change from baseline to week 30 in body weight (kg)
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Supportive secondary endpoints
Supportive secondary efficacy endpoints
Change from baseline to week 30 in: 
!
Fasting plasma glucose (FPG)
!
Self-measured plasma glucose (SMPG), 7 point profile 
–
Mean 7-point profile 
–
Mean post prandial increment (over all meals)
!
Fasting blood lipids (total cholesterol, low-density lipoprotein (LDL)-cholesterol, high-
density lipoprotein (HDL)-cholesterol, triglycerides) 
!
Body Mass Index (BMI)
!
Waist circumference
!
Systolic and diastolic blood pressure
!
Body weight (%)
Subjects who after 30 weeks of treatment achieve: 
!
HbA1c <7.0% (53 mmol/mol), American Diabetes Association (ADA) target 
!
HbA1c ≤6.5% (48 mmol/mol), American Association of Clinical Endocrinologists (AACE) 
target
!
Weight loss ≥3%
!
Weight loss ≥5%
!
Weight loss ≥10%
!
HbA1c <7.0% (53 mmol/mol) without severe or blood glucose confirmed symptomatic 
hypoglycaemia episodes and no weight gain
!
HbA1c reduction ≥1%
!
HbA1c reduction ≥1% and weight loss ≥3%
!
HbA1c reduction ≥1% and weight loss ≥5%
!
HbA1c reduction ≥1% and weight loss ≥10%
Supportive secondary endpoints for selected patient-reported outcomes (PRO)
Change from baseline to week 30 in: 
!
SF-36v2TM Short Form health survey. Total summary scores (physical component and 
mental component) and scores from the 8 domains 
!
Diabetes Treatment Satisfaction Questionnaire (DTSQ). Treatment satisfaction summary 
score (sum of 6 of 8 items) and the 8 items separately upportive secondary safety endpoints
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Supportive secondary safety endpoints
!
Number of treatment-emergent adverse events
!
Number of treatment-emergent severe or blood glucose confirmed symptomatic 
hypoglycaemic episodes
!
Treatment-emergent severe or blood glucose confirmed symptomatic hypoglycaemia 
episodes (yes/no) 
Change from baseline to week 30 in: 
!
Haematology
!
Biochemistry
!
Calcitonin
!
Pulse rate
!
Electrocardiogram (ECG) category 
!
Physical examination category
!
Eye examination category
5
Trial design
5.1
Type of trial
This is a 30-week, confirmatory, randomised, multicentre, multinational, active-controlled, parallel 
groups, open label, 2-armed trial. 
Subjects with T2D inadequately controlled on 1-3 oral anti-diabetic drug(s) (OAD) will be 
randomised in a 1:1 manner to receive either semaglutide s.c. 1.0 mg once-weekly or liraglutide s.c. 
1.2 mg once-daily. The randomisation will be stratified based on subjects background medication of 
SU and sodium-glucose cotransporter-2 (SGLT-2) inhibitors:
!
SU (+/- metformin)
!
SGLT-2 inhibitors (+/- metformin)
!
SU + SGLT-2 inhibitors (+/- metformin)
!
No SU and no SGLT-2 inhibitors (metformin monotherapy)
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Figure 5–1
Trial design
5.2
Rationale for trial design
This trial has been designed as an open-label, two-arm, parallel-group, randomised trial to secure a 
direct comparison between s.c. semaglutide once-weekly and s.c. liraglutide once-daily. The 
treatment period will be 30 weeks to ensure adequate time to compare the full effect of both 
treatments on glycaemic control and body weight. The reason for designing the trial as an open-
label trial is to enable comparison of patient satisfaction with once-weekly versus once-daily 
administration and to limit the number of injections in participating subjects.
The follow-up period is 5 weeks to allow for wash-out of semaglutide. 
5.3
Treatment of subjects
Treatment of subjects is summarised schematically in Table 5–1. 
Semaglutide will be administered once-weekly and liraglutide once-daily, both as s.c. injections. 
After randomisation, all subjects will follow a fixed dose escalation for semaglutide and liraglutide. 
The maintenance dose of 1.0 mg for semaglutide will be reached after an 8-week escalation period. 
This period will consist of 4 doses (4 weeks) of 0.25 mg, followed by 4 doses (4 weeks) of 0.5 mg, 
while the period of maintenance will be 22 weeks. Thus, a total treatment duration of 30 weeks. 
The maintenance daily dose of 1.2 mg for liraglutide will be reached after 1 week of 0.6 mg daily 
dosing. In case of unacceptable gastrointestinal AEs, escalation from 0.6 mg to 1.2 mg of liraglutide 
can be extended over 2 weeks at the discretion of the investigator. 
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Once the maintenance dose of semaglutide (1.0 mg) and liraglutide (1.2 mg) has been reached, 
doses must not be changed during the trial. After the end of the treatment period, there will be a 5-
week follow-up period for safety data collection.
Table 5–1
Treatment of subjects
Trial periods
Screening 
Treatment 
period 1
Treatment 
period 2
Treatment 
period 3
Treatment 
period 4
Follow-
up 
Alias for trial period
Screening
Dose escalation
Dose escalation/ 
Maintenance
Dose escalation/ 
Maintenance
Maintenance
Follow-up
Visits in each period
V1
V2
P3
V4
V5-V9
P10
Duration of each period
2 weeks
1 week
3 weeks
4 weeks
22 weeks
5 weeks
Treatment arm
N
Semaglutide s.c. 
1.0 mg
288
Screening 
Semaglutide 
0.25 mg
Semaglutide  
0.25 mg
Semaglutide
0.5 mg
Semaglutide
1.0 mg
Follow-up 
Liraglutide s.c.  
1.2 mg
288
Screening 
Liraglutide     
0.6 mg
Liraglutide        
1.2 mg
Liraglutide        
1.2 mg
Liraglutide    
1.2 mg
Follow-up 
All subjects on background medication of 1−3 OADs
5.3.1
Trial Products/Investigational medicinal Products supplied by Novo Nordisk 
!
Semaglutide 1.34 mg/mL, 1.5 mL PDS290 pre-filled pen-injector for s.c. injection. 
!
Liraglutide 6 mg/mL, 3.0 mL pre-filled pen-injector approved as Victoza® for the EU 
market for s.c. injection.
5.3.2
Background medication
After screening (V1), subjects must continue their anti-diabetic pre-trial background medication
throughout the entire trial. The background medication must be maintained at the stable, pre-trial 
dose during the entire treatment period unless rescue criteria are met (see Section 6.4 ) or a safety 
concern related to the background medication arises e.g. acute renal impairment on a background of 
metformin or SGLT-2 inhibitors and unacceptable hypoglycaemia on a background of SUs.
All locally available metformin, SGLT-2 inhibitors and SUs are allowed for background 
medication. 
In addition, the background medication: 
1. Is considered to be a non-investigational medicinal product (NIMP) 
2. Will not be supplied by Novo Nordisk A/S. However, the background medication will be 
reimbursed if allowed by the countries regulatory authority or independent ethics committee
(IEC)
3. Should be used in accordance with standard of care or local label in the individual country 
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4. Should not exceed the maximum approved dose in the individual country
5.4
Injection site
Semaglutide and liraglutide are administered s.c. by injections in the thigh, abdomen or upper arm, 
any time of the day and irrespective of meals. Injections should not be administered intravenously 
or intramuscularly. For semaglutide, injections should be administered once weekly on the same 
weekday. For liraglutide, injections should be administered daily and the time of injection is 
recommended to be consistent from one day to another.
5.5
Missed dose
Semaglutide
If a semaglutide dose is missed, it should be administered as soon as noticed, provided the time to 
the next scheduled dose is at least 2 days (48 hours). If a dose is missed and the next scheduled dose 
is less than 2 days (48 hours) away, the subject should not administer the missed dose but rather 
wait for the next scheduled dose. A missed dose should not affect the scheduled dosing day of the 
week.
Liraglutide
If a liraglutide dose is missed, it should be taken as soon as noticed; however, if it is more than 12 
hours since subject should have taken liraglutide, the missed dose should be skipped, and next dose 
should be taken as usual the following day.
5.6
Treatment after discontinuation of trial product
When discontinuing trial products, either at the scheduled end of treatment visit (V9) or if trial 
product is discontinued prematurely, the subject should be switched to a suitable marketed product 
at the discretion of the investigator. The long half-life of semaglutide must be taken into 
consideration when selecting anti-diabetic treatment after discontinuation of trial product. 
5.7
Rationale for treatment
Semaglutide has been developed for s.c. administration. A three dose level escalation of 
semaglutide (0.25, 0.5 and 1.0 mg), has been chosen based on data from the phase 2 dose-finding 
trial (NN9535-1821)22. This regimen has shown a good benefit-risk profile across the phase 3a 
programme26.
Liraglutide is approved for the treatment of T2D in doses of 1.2 mg and 1.8 mg. As the 1.2 mg daily 
dose is currently used as part of standard-of-care in most European countries, a two dose level 
escalation from 0.6 mg to 1.2 mg daily is needed34 35.
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The dose and duration of randomised treatments is considered adequate to collect sufficient data on 
endpoints related to efficacy and safety in accordance with the trial objectives.
6
Trial population
6.1
Number of subjects
Number of subjects planned to be randomised: 576
6.2
Inclusion criteria
For an eligible subject, all inclusion criteria must be answered “yes”. 
1. Informed consent obtained before any trial-related activities. Trial-related activities are any 
procedures that are carried out as part of the trial, including activities to determine suitability 
for the trial.
2. Male or female, age ≥18 years at the time of signing informed consent.
3. Diagnosed with T2D .
4. HbA1c of 7.0-11.0% (53−97 mmol/mol) (both inclusive).
5. Stable daily dose(s) including any of the following anti-diabetic drug(s) or combination 
regimens 90 days prior to the day of screening:
a) Biguanides (metformin ≥1500 mg or maximum tolerated dose documented in the 
subject's medical record).
b) SU (≥ half of the maximum approved dose according to local label or maximum 
tolerated dose as documented in subject medical record).
c) SGLT-2 inhibitors (≥ half of the maximum approved dose according to local label or 
maximum tolerated dose as documented in subject medical record).
6.3
Exclusion criteria
For an eligible subject, all exclusion criteria must be answered “no”. 
1. Known or suspected hypersensitivity to trial product(s) or related products. 
2. Previous participation in this trial. Participation is defined as signed informed consent. 
3. Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing 
potential and not using an adequate contraceptive method (adequate contraceptive measure 
as required by local regulation or practice).
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The following contraceptive measures are considered adequate:
–
Combined estrogen and progestogen containing hormonal contraception associated with 
inhibition of ovulation (oral, intravaginal, transdermal)
–
Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, 
injectable, implantable)
–
Placement of an intrauterine device or intrauterine hormone-releasing system 
–
Bilateral tubal occlusion
–
Barrier methods of contraception (condom or occlusive cap with spermicidal 
foam/gel/film/cream/suppository). (Not applicable for Sweden).
Vasectomised partner (where partner is sole partner of subject) and where vasectomy has 
been confirmed by medical assessment
True sexual abstinence. Sexual abstinence is defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study treatments. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the subject.
For Germany only: Only highly effective methods of birth control are accepted (i.e. one that 
results in less than 1% per year failure rate when used consistently and correctly such as 
implants, injectables, combined oral contraceptives, some intrauterine device), or sexual 
abstinence or vasectomised partner.
4. Participation in any clinical trial of an approved or non-approved investigational medicinal 
product within 90 days before screening.
5. Any condition, which in the investigator’s opinion might jeopardise subject’s safety or 
compliance with the protocol.
6. Family or personal history of multiple endocrine neoplasia type 2 or medullary thyroid 
carcinoma. Family is defined as a first degree relative. 
7. History or presence of pancreatitis (acute or chronic).
8. History of diabetic ketoacidosis.
9. Any of the following: myocardial infarction, stroke, hospitalization for unstable angina or 
transient ischaemic attack within the past 180 days prior to the day of screening. 
10. Subjects presently classified as being in New York Heart Association (NYHA) Class IV.
11. Planned coronary, carotid or peripheral artery revascularisation known on the day of 
screening. 
12. Renal impairment measured as estimated Glomerular Filtration Rate (eGFR) value of <30 
ml/min/1.73 m2 as defined by KDIGO 2012 classification1.
13. Impaired liver function, defined as alanine aminotransferase (ALT) ≥2.5 times upper normal 
limit at screening.
14. Treatment with any medication for the indication of diabetes or obesity other than stated in 
the inclusion criteria within the past 90 days prior to the day of screening. However, short 
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term insulin treatment for a maximum of 14 days and previous insulin treatment for 
gestational diabetes prior to the day of screening is allowed.
15. Proliferative retinopathy or maculopathy requiring acute treatment. Verified by fundus 
photography or dilated fundoscopy performed within the past 90 days prior to 
randomisation.
16. Presence or history of malignant neoplasms within the past 5 years prior to the day of 
screening. Basal and squamous cell skin cancer and any carcinoma in-situ is allowed.
6.4
Rescue criteria
Subjects with persistent and unacceptable hyperglycaemia should be offered treatment 
intensification. If any of the FPG values (including protocol scheduled fasting SMPG) exceed the 
limits outlined below and no intercurrent cause of the hyperglycaemia can be identified, the subject 
must be called in for a confirmatory FPG (at central laboratory):
!
FPG > 13.3 mmol/L (240 mg/dl) from week 8 (V5) to end of week 15 (up until V7)
!
FPG > 11.1 mmol/L (200 mg/dl) from week 16 (V7) to end of treatment
If the confirmatory FPG also exceeds the value described above, the subject should be offered 
rescue medication (i.e. intensification of anti-diabetic background medication and/or initiation of 
new anti-diabetic medication)
It is important for trial integrity that only subjects actually needing treatment intensification (as 
defined above) are started on rescue medication. These subjects should continue to follow the 
protocol-specified visit schedule. Rescue medication should be prescribed at the investigator’s 
discretion as add-on to the randomised treatment and according to ADA/European Association for 
the Study of Diabetes guidelines37, 38 (excluding GLP-1 RAs, DPP-4 inhibitors and amylin 
analogues). Please note, that for subjects randomised to liraglutide, the dose of 1.2 mg must not be 
exceeded and if rescue medication is needed in these subjects, another anti-diabetic agent must be 
added or the dose of existing background therapy increased, at the investigator's discretion. The 
long half-life of semaglutide must be taken into consideration when prescribing rescue medication. 
Considerations regarding rescue medication should be documented in the medical records and 
rescue medication and any changes hereto should be captured on the concomitant medication form 
in the electronic case report form (eCRF) (see Section 8.2.4). Rescue medication is considered to be 
NIMP and will not be provided by Novo Nordisk.
6.5
Criteria for premature discontinuation of trial product 
All efforts should be made to keep the subject on trial product.
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However, the subject may be prematurely discontinued from trial product at the discretion of the 
investigator due to a safety concern.
If so, all efforts must be made to ensure the subjects attend and complete all scheduled visit 
procedures. Subjects should stay in the trial irrespective of lack of adherence to randomised 
treatment, lack of adherence to visit schedule or missing assessments. Only subjects who decline 
any further contact with the site in relation to the trial will be considered as withdrawn from the trial 
(see Section 6.6).
The subject must be prematurely discontinued from trial product, if one of the following applies:
1. Included in the trial in violation of the inclusion and/or exclusion criteria 
2. Safety concern related to trial product or unacceptable intolerability at the discretion of 
the investigator.
3. Pregnancy.
4. Intention of becoming pregnant.
5. Simultaneous participation in another clinical trial of an approved or non-approved.
investigational medicinal product.
6. Calcitonin ≥100 ng/L (see Appendix A).
The primary reason for premature discontinuation of trial product must be specified in the eCRF. If 
a criterion for premature discontinuation of trial product is met, trial product should not be re-
initiated but subjects should continue with the protocol-specified visit schedule.
See Section 8.1.4 for procedures to be performed for subjects discontinuing trial product 
prematurely.
6.6
Withdrawal from trial
The subject may withdraw consent at will at any time. The subject’s request to withdraw from the 
trial must always be respected. Only subjects who withdraw consent should be considered as 
withdrawn from trial.
See Section 8.1.5 for procedures to be performed for subjects withdrawing consent. 
6.7
Subject replacement
Subjects who discontinue trial product prematurely will not be replaced.
6.8
Rationale for trial population 
The trial population will include subjects treated with stable doses of 1−3 OAD(s) (see Section 
5.3.2) for at least 90 days prior to screening. 
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The HbA1c limits 7.0– 11.0% (53–97 mmol/mol) have been chosen to include subjects needing 
intensification of their anti-diabetic medication. FPG and HbA1c will be monitored throughout the 
trial and rescue medication should be initiated in subjects with persistent, unacceptable 
hyperglycaemia according to the investigator. 
Subjects with liver test abnormalities (ALT ≥2.5 × upper normal level ) will be excluded to avoid 
potential confounding of liver safety assessments. As SGLT-2 inhibitors have been associated with 
euglycaemic diabetic ketoacidosis, subjects with a history of diabetic ketoacidosis will also be 
excluded from this trial. 
Overall, the eligibility criteria allow for enrolment of a broad trial population resembling the target 
population in common practice.
7
Milestones
Planned duration of recruitment period (first subject first visit (FSFV) – last subject first visit 
(LSFV): 
20 weeks
Planned date for FSFV: 
27-June-2017
Planned date for last subject last visit (LSLV): 
14-Aug-2018
End of trial is defined as LSLV (trial completion date).
Recruitment
The screening and randomisation rate will be followed closely via the interactive web response 
system (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. All subjects included in the screening period and 
eligible for randomisation can be randomised.
Trial registration
Information of the trial will be disclosed at clinicaltrials.gov and novonordisk-trials.com. According 
to the Novo Nordisk Code of Conduct for Clinical Trial Disclosure39, it will also be disclosed 
according to other applicable requirements such as those of the International Committee of Medical 
Journal Editors (ICMJE)40, the Food and Drug Administration Amendment Act (FDAAA)41,
European Commission Requirements42, 43 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 
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requirements for transparency, some countries require public disclosure of investigator names and 
their affiliations.
Primary Completion Date is the last assessment of the primary endpoint, and is for this protocol 
LSFV + 32 weeks corresponding to V9. If the last subject is withdrawn/dropout early the Primary 
Completion Date is the date when the last subject would have completed V9. The Primary 
Completion Date determines the deadline for results disclosure at Clinicaltrials.gov according to 
FDAAA.
8
Methods and assessments
8.1
Visit procedures
Timing of assessments and procedures are specified in the flow chart (see Section 2). This section 
includes a description of these assessments and procedures. 
Informed consent must be obtained before any trial related activity (see Section 18.3).
8.1.1
Investigator site log 
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.
In addition, the investigator must keep a log of staff and a delegation of task(s) list at the trial site. 
Investigator must sign the log of staff and the delegation of task(s) at the trial site prior to the 
delegation of tasks.
8.1.2
Screening, visit 1
At screening, subjects will be provided with a card stating that they are participating in a trial and 
giving contact address(es) and telephone number(s) of relevant trial site staff. Subjects should be 
instructed to return the card to the investigator at the last trial visit or to destroy the card after the 
last visit.
Each subject will be assigned a unique 6-digit subject number which will remain the same 
throughout the trial. 
Screening failures: For screening failures the screening failure form in the electronic case report 
form (eCRF) must be completed with the reason for not continuing in the trial. Serious adverse 
events (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.
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A screening failure session must be made in the IWRS and 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 if the subject has failed one of the inclusion or exclusion criteria related to 
laboratory parameters.
8.1.3
Fasting visits
The subjects should attend site visits in a fasting state (see Section 2). Fasting is defined as having 
consumed only water within the last 6 hours prior to the visit. 
If the subject does not attend the visit in a fasting state, the subject should be asked to attend a re-
scheduled visit within the visit window to have the fasting assessments performed.
Glucose lowering agents and trial product should not be taken until after blood sampling has been 
performed but other prescribed medication should be taken according to prescription.
8.1.4
Premature discontinuation of trial product
If a subject prematurely discontinues trial product, the investigator must undertake procedures 
described for V9A as soon as possible (preferably the same day), which are similar to those at V9. 
Phone contact 10A should be scheduled at least 5 weeks after the last date on trial product. 
If premature discontinuation of trial product is decided during a scheduled visit, the visit will be 
converted into a V9A and trial procedures must be performed accordingly.
Subjects should continue with the originally scheduled site contacts after P10A and up to and 
including P10. If necessary, in order to retain the subject in the trial, site visits can be replaced by 
phone contacts after P10A. However, all attempts should be made to ensure that V9 is performed as 
a site visit and includes all planned assessments.
In summary, subjects should stay in the trial irrespective of lack of adherence to randomised 
treatment, lack of adherence to visit schedule, missing assessments or premature trial product 
discontinuation for any reason. Only subjects who decline any further contact with the site in 
relation to the trial should be considered as withdrawn from the trial (for withdrawal procedures see 
Section 8.1.5).
The primary reason for premature discontinuation of trial product must be specified in the end-of-
treatment form in the eCRF, and final drug accountability must be performed. A treatment 
discontinuation session must be made in the IWRS at V9A (see Section 10).
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8.1.5
Withdrawal from trial
If a subject withdraws consent, the investigator must aim to undertake the procedures for V9A as 
soon as possible. If a subject has already prematurely discontinued from trial product and 
previously attended V9A and P10A, no further visits should be attended.
For withdrawn subjects the end-of-trial form and end-of-treatment form must be completed, 
including the primary reason for premature discontinuation of trial product, and final drug 
accountability must be performed even if the subject is not able to come to the trial site. 
A premature treatment discontinuation session must be made in the IWRS, if not already done due 
to prior discontinuation from trial product. 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.
8.1.6
Investigator assessment 
Review of diaries, patient reported outcomes questionnaire (PROs), laboratory reports, ECGs, eye
and physical examinations must be documented with the dated signature of the investigator or 
delegated trial staff, either on the front page of the documents and/or in subject's medical record. 
The signed documents must be retained at the trial site as source documentation.
For physical examinations, ECGs, and fundus photography/dilated fundoscopythe evaluations must 
follow the categories:
!
Normal
!
Abnormal
o
Was the result clinically significant (No/Yes)
In case of abnormal clinical significant findings found as a result of screening procedures conducted 
at visit 1 or assessments revealing baseline conditions at visit 2, the investigator or delegate must 
state a comment in the subject’s medical record and record this in the concomitant illness form in 
the eCRF. At subsequent visits, any clinically significant changes or new clinically significant 
findings must be reported as an AE according to Section 12.
Investigator or trial site staff must review the diary and the PROs to ensure that AEs, including 
overall change in health and concomitant medication, are reported. 
If clarification of entries or discrepancies in the diary or the PROs 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.
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Laboratory report values:
For laboratory report values outside the reference range, the investigator must specify whether the 
value is clinically significant or clinically non-significant. All laboratory printouts must be signed 
and dated by the investigator or delegate on the day of evaluation. The signed laboratory report is 
retained at the trial site as source documentation.
8.2
Subject related information/assessments 
8.2.1
Demography
Demography consists of:
!
Date of birth (according to local regulation)
!
Sex
!
Ethnicity (according to local regulation)
!
Race (according to local regulation)
8.2.2
Diabetes history and diabetes complications 
Diabetes history and diabetes complications consist of:
!
Date of diagnosis of T2D
!
Information regarding diabetes complications including date of onset
–
Diabetic retinopathy
–
Diabetic neuropathy
–
Diabetic nephropathy
–
Macroangiopathy (including peripheral vascular disease)
8.2.3
Concomitant illness and medical history
A concomitant illness is any illness that is present at the start of the trial as described in 
Section 8.1.6. Procedures and assessments performed at visit 1 and/or visit 2 (prior to 
randomisation) are considered as screening procedures.
Medical history is a medical event that the subject has experienced in the past. Only relevant 
concomitant illness and medical history as judged by the investigator should be reported. Diabetes 
history and related complications should be reported separately in the diabetes history/complication 
form.
The information collected for concomitant illness and medical history should include diagnosis, 
date of onset and date of resolution or continuation, as applicable.
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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. 
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.
8.2.4
Concomitant medication
A concomitant medication is any medication, other than the trial products, which is taken during 
the trial, including the screening and follow-up periods.
Changes in concomitant medication, including anti-diabetic treatment, must be recorded at each 
visit as they occur. The eCRF should be updated accordingly. GLP-1 RAs, DPP-4 inhibitors and 
amylin analogues must not be pre-prescribed as add-on to the randomised treatment.
The information collected for each concomitant medication includes:
!
Trade name or generic name 
!
Primary indication, start date (only start year is applicable if more than one year) and stop 
date or continuation
!
Total daily dose (only applicable for anti-diabetic medication)
If a change is due to an AE, then this must be reported according to Section 12. If the change 
influences the subject’s eligibility to continue in the trial, the monitor must be informed.
8.2.5
Childbearing potential
It must be recorded in the eCRF whether female subjects are of childbearing potential. 
Pregnancy testing must be performed on female subjects of childbearing potential (see Section 
8.5.2). Female subjects of childbearing potential must be instructed to use adequate contraceptive 
methods (see Section 6.3) throughout the trial and until 5 weeks after end of treatment.
Female of non-childbearing potential is defined as:
!
Female who has undergone a hysterectomy, bilateral oophorectomy or bilateral tubal 
ligation or are postmenopausal (e.g. women above the age of 50, who have been without 
menstrual period for at least 1 year).
!
Other medical reasons preventing childbearing potential
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8.2.6
Tobacco use
Details of tobacco use must be recorded at V1. Smoking is defined as smoking at least one cigarette 
or equivalent daily. 
Smoking status:
!
Never smoked
!
Previous smoker, smoking stop date
!
Current smoker
8.3
Efficacy assessments
8.3.1
Height, body weight and body mass index
Height is measured without shoes in cm and recorded to nearest ½ cm.
Body weight should be measured in kilogram (kg), with one decimal, without shoes and only 
wearing light clothing. 
BMI = body weight (kg)/(height (m) x height (m)) [kg/m2 = lb/in2 x 703] and will be calculated in 
the eCRF every time the weight is measured.
8.3.2
Waist circumference
The waist circumference is defined as the minimal abdominal circumference located midway 
between the lower rib margin and the iliac crest and will be measured using a non-stretchable 
measuring tape. The measurement of waist circumference should be performed and recorded in the 
eCRF to the nearest ½ cm 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. The subject 
should be asked to breathe normally and the measurement should be taken when the subject is 
breathing out gently.
8.3.3
Blood pressure and pulse rate
Systolic and diastolic blood pressure and pulse rate (beats per minute) should be measured in a 
sitting position after the subject has been resting for at least 5 minutes and by using standard clinical 
practice at the trial site. 
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8.3.4
Self-measured plasma glucose (SMPG)
At the screening visit, subjects will be provided with a blood glucose (BG) meter including 
auxiliaries and instructions for use. 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 must be used for the measurements required. 
Subjects should be instructed in how to record the results of the SMPGs in the diaries. The record of 
each SMPG should include date, time and value. All data from the diary must be transcribed into 
the eCRF during or following the contact. 
Occasional review by the investigator of the values stored in the memory of the BG meter and 
correct reporting of these in the diary is advised in order to ensure adequacy of the data reported in 
the trial database.
8.3.5
7-point self-measured plasma glucose profile
The subject will be asked to perform a 7-point SMPG profile, preferably within one week prior to 
site visit according to the flow chart, on days where the subject does not anticipate unusual 
strenuous exercise.
Time points, including date and time, for the 7-point profile: before breakfast, 90 min after start of 
breakfast, before lunch, 90 minutes after start of lunch, before dinner, 90 min after start of dinner 
and at bedtime. For details on how to record SMPG, see Section 8.3.4.
8.4
Safety assessments
8.4.1
Physical examination
A physical examination includes the following:
!
General appearance 
!
Skin
!
Thyroid gland
!
Respiratory system 
!
Cardiovascular system 
!
Gastrointestinal system including mouth
!
Central and peripheral nervous system
!
Lymph node palpation
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8.4.2
Electrocardiogram – 12 lead
A 12-lead ECG must be performed and interpreted locally by the investigator or delegate as 
described in Section 8.1.6.
It is allowed to perform the baseline ECG between the screening visit and the randomisation visit. 
The results must be available prior to randomisation. An ECG performed for any reason unrelated 
to this trial within 7 days prior to the screening visit is acceptable provided no clinical symptoms 
suggestive of cardiac disease have occurred in the meantime.
If the ECG was performed as a part of routine clinical practice on/before the date when the subject 
has signed the informed consent, it must be documented in the medical records that the reason for 
performing the procedure is not related to this trial.
8.4.3
Eye examination
Fundus photography or dilated fundoscopy will be performed as per flow chart (see Section 2) by 
the investigator or according to local practise. Fundoscopy requires pharmacological dilation of 
both pupils. Results of the fundus photography or dilated fundoscopy will be interpreted by the 
investigator (see Section 8.1.6). Relevant findings as a result of the screening procedure must be 
recorded as concomitant illness/medical history or as diabetes history/diabetes complication in 
accordance with Section 8.2.3.
If the fundus photography or dilated fundoscopy has been performed within 90 days prior to 
randomisation, the procedure does not need to be repeated, unless worsening of visual function 
since the last examination. If the subject did not have fundus photography or dilated fundoscopy 
performed within 90 days prior to randomisation, such examination must be performed by the 
investigator or other qualified health care professional according to local practice. The results must 
be available prior to randomisation.
If the applicable fundus photography or dilated fundoscopy was performed before the subject 
signed the informed consent form, it must be documented in the medical records that the reason for 
performing the examination was not related to this trial.
In addition, fundus photography/dilated fundoscopy must be performed at V9 or 5 weeks prior to 
this. Results should be available at V9. In the case of premature discontinuation, fundus 
photography/dilated fundoscopy must be performed both at V9A and at V9. At V9A the 
assessments can be performed in the period between V9A and P10A , but the results should be 
available and reviewed no later than at P10A.
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8.4.4
Adverse events
AEs must be reported in accordance with the procedures outlined in Section 12.
8.4.4.1
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(s) 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.
8.4.4.2
Adverse events requiring additional data collection
For the following AEs additional data collection is required and specific event forms must be 
completed in addition to the AE form:
!
Hypersensitivity reaction
!
Pancreatitis
!
Renal event
!
Hepatic event
!
Diabetic retinopathy
!
Acute gallstone disease
See Appendix B for details about the additional information to report. 
In case any of these events fulfil the criteria for a SAE, please report accordingly (see Section 12).
8.4.5
Hypoglycaemic episodes
Plasma glucose (PG) should always be measured and recorded when a hypoglycaemic episode is 
suspected. 
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All PG values:
!
≤3.9 mmol/L (70 mg/dL) or 
!
>3.9 mmol/L (70 mg/dL) occurring in conjunction with hypoglycaemic symptoms
should be reported in the diary throughout the trial from visit V2 to P10 according to the 
instructions (see Section 8.6.1). All information must be transcribed into the eCRF (hypoglycaemic 
episode form) throughout the trial. For Novo Nordisk classification of hypoglycaemia, see Section 
17.5.2.2.Upon onset of a hypoglycaemic episode the subject is recommended to measure plasma 
glucose every 15 minutes until the SMPG value is >3.9 mmol/L (70 mg/dL) and/or symptoms have 
been resolved in accordance to current guidelines44.
A SMPG value ≤3.9 mmol/L (70 mg/dL) or hypoglycaemic symptoms should be recorded in the 
diary in the hypoglycaemic episode form by the subject. Repeated SMPG measurements and/or 
symptoms, will by default be considered as one hypoglycaemic episode until a succeeding SMPG 
value is >3.9 mmol/dL (70 mg/dL) and/or symptoms have been resolved. One hypoglycaemic 
episode form is to cover these measurement and/or symptoms. 
In case of several low SMPG values within the hypoglycaemic episode, the lowest value is the one 
that will be reported as the SMPG value for the hypoglycaemic episode but the start time of the 
episode will remain as the time for the first SMPG value and/or symptom.
The record should include the following information:
!
Start date and time of the hypoglycaemic episode 
!
Stop date and time of the hypoglycaemic episode (stop time is the first time plasma glucose 
value is >3.9 mmol/L (70 mg/dL) and/or symptoms have been resolved). 
!
If a stop date and time is not reported, a hypoglycaemic episode will cover a period of 
60 minutes.
!
The plasma glucose (PG) level before treating the episode (if available) and any follow up 
measurements. The lowest value measured during the hypoglycaemic episode will be 
reported as the plasma glucose value for the episode, the remaining values will be kept as 
source data in the diary.
!
Whether the episode was symptomatic (Yes/No). A hypoglycaemic episode starting without 
symptoms should be updated to symptomatic if the subject experiences symptoms later 
during the episode.
!
Whether the subject was able to treat him/herself 
!
If the severity of a hypoglycaemic episode aggravates, only one hypoglycaemic episode 
should be reported, reflecting the most severe degree of hypoglycaemia. 
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!
Date-and time of last trial product administration and other anti-diabetic medications prior to 
the episode
!
Date and time of last main meal (not including snacks) prior to the episode
!
Whether the episode occurred in relation to physical activity
!
Change in any concomitant illness
!
Any sign of fever and/or other acute disease 
!
Whether the subject was asleep when the episode occurred
–
If yes, whether the symptoms of the episode woke up the subject.
The answer to the question: "Was the 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. PG 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 concentration44.
If the question "Was the subject able to treat him/herself?" is answered "No", the following 
information should be recorded by the subject:
!
Who assisted in the treatment of the hypoglycaemic episode (i.e. medical person or non-
medical person)?
!
Where the treatment was administered (in clinic/emergency room/hospital or other. If the 
subject was treated in clinic/emergency room/hospital, whether they were transported in an 
ambulance or not)
!
Type of treatment provided by another person (i.e. oral carbohydrates, glucagon, IV glucose 
or other)
!
Were symptoms alleviated after administration of treatment?
!
Factors contributing to the episode (i.e. physical activity, missed meal, diet change, 
medication error (i.e. overdose, mix-up between products, incorrect use of device), 
miscalculation of dose of anti-diabetic medication, other factors not listed or unknown)
!
Did the subject experience seizure?
!
Was the subject unconscious/comatose?
!
Did the subject experience any of the following symptoms (layman term used in the diary is 
specified in brackets if different from the protocol term)?44
–
Autonomic: sweating, trembling, hunger or palpitations (rapid or irregular heart beat)
–
Neuroglycopenic: confusion, drowsiness, speech difficulty, visual disturbances, odd 
behaviour, impaired balance or incoordination (reduced ability to coordinate movement)
–
General malaise: headache or malaise (feeling discomfort/unease)
–
Other symptoms 
The investigator must review the diary for low SMPG values not reported as hypoglycaemic 
episodes. The subject must be questioned whether any of the low values were severe, i.e. whether 
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the subject was able to self-treat or not. If the subject was not able to self-treat, it has to be reported 
as a severe hypoglycaemic episode.
Low SMPG values for non-severe hypoglycaemic episodes not having a hypoglycaemic episode 
form completed within 7 days since the SMPG measurement should be reported on a 
hypoglycaemic episode form with as much information as possible. Novo Nordisk will not query 
for additional data except for the start date, SMPG value and whether the subject was able to self-
treat due to decreased validity of such data45, 46.
The subject must be re-trained in how to report hypoglycaemic episodes if the investigator identifies 
low SMPG values not reported as hypoglycaemic episodes.
If the hypoglycaemic episode fulfils the criteria for an SAE then an AE form and a safety 
information form must also be filled in (see Section 12).
8.5
Laboratory assessments
The laboratory assessments will be performed by a central laboratory. The central laboratory may 
utilise sub-contractors. Descriptions of assay methods, laboratory supplies and procedures for 
collecting, handling, storage and shipping of samples, will be described in the laboratory manual 
provided by the central laboratory.
Subjects will be asked to attend the site visits fasting for samples, except for screening samples (see 
Sections 2 and 8.1.3). Laboratory samples not drawn on the day of the actual visit should preferably 
be drawn on another day within the visit window stated in the flow chart. 
Laboratory results will be sent by the central laboratory to the investigator on an on-going basis and 
the investigator must review all laboratory results for signs of concomitant illness and AEs and 
report these according to this protocol according to Section 8.2.3 and Section 12. The laboratory 
provides results to the trial sites in the units preferred by the trial sites while the results that are 
transferred to the trial database will be in SI units.
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. 
Only laboratory samples specified in the protocol must be sent to the central laboratory for analysis.
All laboratory samples will be destroyed at latest at the completion of the clinical trial report or 
according to local regulations.
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8.5.1
Laboratory assessments for efficacy
Blood samples will be analysed at the central laboratory to determine levels of the following 
efficacy laboratory parameters:
!
Glucose metabolism:
–
HbA1c
–
FPG 
!
Lipids (all fasting):
–
Total cholesterol
–
LDL cholesterol
–
HDL cholesterol
–
Triglycerides
Fasting plasma glucose 
FPG is measured at central laboratory in order to evaluate glycaemic control and subject must 
attend these visits fasting (see Section 8.1.3). 
A central FPG result obtained at the central laboratory of ≤3.9 mmol/L (70 mg/dL) in relation to 
planned fasting visits should not be reported as a hypoglycaemic episode but as a clinical laboratory 
adverse at the discretion of the investigator (see Section 12.1.1).
8.5.2
Laboratory assessments for safety
Blood samples will be drawn and analysed at the central laboratory to determine levels of the 
following laboratory parameters:
Biochemistry:
!
ALT
!
Aspartate aminotransferase (AST)
!
Albumin, bilirubin (total)
!
Alkaline phosphatase
!
Potassium
!
Sodium 
!
Calcium (total) 
!
Amylase
!
Lipase 
!
Calcitonina
!
Creatinine, including eGFR (per CKD-EPI)a
                                                
a In case any calcitonin value at any time of the trial is ≥10 ng/L, the algorithm in Appendix A should be followed
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Haematology:
!
Haemoglobin
!
Haematocrit
!
Erythrocytes
!
Thrombocytes
!
Leucocytes
Pregnancy test (females of childbearing potential):
!
Serum beta-human chorionic gonadotropin (V1, V9/V9A)
!
Urine dip stick (V2)
Pregnancy testing
Females of childbearing potential will have a serum pregnancy test performed at selected visits (see 
Section 2). At the randomisation visit, a urine pregnancy test must be performed prior to 
randomisation.
In case a menstrual period is missed or if pregnancy is suspected at any time during the trial, a urine 
pregnancy test should be performed. The subject should be instructed not to dose trial product 
before pregnancy has been ruled out.
Pregnancy testing will not be required (unless required by local law) for women of non-childbearing 
potential, such as but not limited to women who have undergone a hysterectomy, bilateral 
oophorectomy, bilateral tubal ligation or are postmenopausal (e.g. women above the age of 50, who 
have been without menstrual period for at least 1 year) (see Section 8.2.5).
8.6
Other assessments
8.6.1
Subject diary
At each site visit, the subject will be provided with a new paper diary. Entries in the diaries are only 
to be made by the subject, unless otherwise specified. The diary should be collected at the next site 
visit and retained at the site as source data in accordance with Section 14. However, the last diary 
collecting data from after V9 (End Treatment) will not be returned to the site by the subject, since 
the follow-up visit is a phone contact. 
The diary recordings must be reviewed as described in Section 8.1.6 and transcribed to the eCRF.
                                                                                                                                                                
a Creatinine will be measured using a method traceable to isotope dilution mass spectrometry (IDMS) and eGFR 
calculated using the equation from the Chronic Kidney Disease Epidemiology Collaboration (CKD-Epi) as defined in 
KDIGO{National Kidney Foundation, 2012, KDOQI Clinical Practice Guideline for Diabetes and CKD: 2012 Update}
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The investigator should instruct the subject in recording the following data in the diary:
!
Date, time and dose of first dose of trial product
!
Date and last dose of trial product prior to each visit
!
SMPG 7-point profile
!
Hypoglycaemic episodes
!
Concomitant medication
!
AEs
If hypoglycaemic events are reported at P10 or P10A, related information should be documented in 
the subject’s medical record and will be considered source data. The information must be entered 
into the eCRF.
If a subject prematurely discontinues trial product, diaries should not be dispensed and completed 
by the subject after the follow-up-premature discontinuation visit (P10A). 
8.6.2
Patient reported outcome questionnaires
The following PRO questionnaire will be used in the trial:
!
SF-36v2TM
!
DTSQs
The questionnaires should be completed by the subject as specified in the flow chart (see Section 2),
preferably after conclusion of all fasting related activities but before any other visit-related 
activities. It takes approximately 15 minutes to complete the questionnaires. Subjects should be 
given the opportunity to complete the questionnaires by themselves without interruption. The 
completed questionnaires must be reviewed for potential adverse events and missing data as 
described in Section 8.1.6, while the subject is still at the site. All results from the PROs must be 
transferred into the eCRF. Please refer to Appendix C for details on the PRO questions.
8.6.2.1
SF-36v2TM
The SF-36v2™ questionnaire will be used to assess subjects overall health related quality of life 
and can also be used to estimate quality adjusted life years which is used in cost effectiveness 
calculations. This questionnaire contains 36 items and measures the individual overall health related 
quality of life on 8 domains; physical functioning, role functioning, body pain, general health, 
vitality, social functioning, role emotional and mental health.
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8.6.2.2
DTSQs
The DTSQs questionnaire will be used to assess subject’s treatment satisfaction. This questionnaire 
consists of 8 items and measures the subject’s diabetes treatment (including insulin, tablets and/or 
diet in terms of convenience, flexibility and general feelings regarding treatment).
8.6.3
Training in the pen-injector
An injection pen is used for s.c. administration of semaglutide/liraglutide. The subjects must be 
trained in how to handle the injection pen when handed out the first time. Training must be repeated
at V4 and during the trial at regular intervals according to needs, in order to ensure correct use of 
the injection pen. The training should be done in accordance with the directions for use.
8.6.4
Training in blood glucose meter use
The subjects must be provided with a BG meter and instructed in how to use and handle the BG 
meter, in accordance with the flow chart (see Section 2). The instruction will be repeated as 
necessary during the trial. 
8.7
Subject compliance
Throughout the trial, the investigator will remind the subjects to follow the trial procedures and 
requirements to ensure subject compliance. If a subject is found to be non-compliant, the 
investigator will remind the subject of the importance of following the instructions including taking 
the trial products as prescribed.
Treatment compliance: will be assessed by monitoring of drug accountability. Prior to visits 
where drug accountability is performed the subject will be asked to return all used, partly used and 
unused trial products. The investigator must assess the amount of trial products returned compared 
to what was dispensed at the last dispensing visit and, in case of discrepancies, question the subject.
9
Trial supplies
Trial supplies comprise trial products and auxiliary supplies. Additional details regarding trial 
supplies can be found in the Trial Materials Manual. 
Trial products must not be dispensed to any person not included in the trial. 
Semaglutide must not be used, if it does not appear clear and colourless.
Liraglutide must not be used, if it does not appear clear and colourless or almost colourless.
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9.1
Trial products
The following trial products will be provided by Novo Nordisk A/S, Denmark:
Table 9–1
Trial products
Trial product
Strength
Dosage form
Route of 
administration
Container/delivery 
device
Semaglutide 
1.34 mg/mL 
solution for injection
s.c
1.5 mL pre-filled pen-
injectora
Liraglutide , approved 
as Victoza®
6 mg/mL
solution for injection
s.c
3 mL pre-filled pen-
injectorb
SGLT-2 inhibitors, metformin and SUs are considered background medication (NIMPs) and will 
not be provided by Novo Nordisk.
9.2
Labelling
The trial products will be labelled in accordance with Annex 1347, local regulations and trial 
requirements. Each box will be labelled with a unique dispensing unit number (DUN). Each trial 
site will be supplied with sufficient trial products for the trial on an on-going basis controlled by the 
IWRS. Trial products will be distributed to the trial sites according to enrolment and randomisation. 
9.3
Storage 
Table 9–2
Storage conditions
Trial product
Storage conditions (not-in-use)
In-use conditions
In-use timec
Semaglutide 
1.34 mg/mL
Store in a refrigerator 
(2°C to 8°C)
Protect from light
Do not freeze
Store below 30°C 
Protect from light
Do not freeze
Use within 8 weeks
Liraglutide 6 mg/mL
Store in a refrigerator
(2°C to 8°C )
Protect from light
Do not freeze
Store below 30°C or in a 
refrigerator (2°C to8°C )
Protect from light
Do not freeze
Use within 1 month
The investigator must ensure that trial product is kept under proper storage conditions and record 
and evaluate the temperature. The investigator must inform Novo Nordisk immediately if any trial 
                                                
a Semaglutide 1.34 mg/mL, 1.5 mL pre-filled pen-injector (0.25mg/0.5mg/1.0mg)
b Liraglutide 6 mg/mL, 3.0 mL pre-filled pen-injector (0.6mg/1.2mg/1.8mg)
c In-use time starts when first dose is taken
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product has been stored outside specified conditions (e.g. outside temperature range). Additional 
details regarding handling of temperature deviations can be found in the Trial Materials Manual.
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.
9.4
Drug accountability and destruction
Drug accountability of all trial products received at site is the responsibility of the investigator.
Subjects are instructed to return all used, partly used and unused trial product including empty 
packaging material according to Section 2 (drug accountability). Returned trial product (used/partly 
used and/or unused), expired or damaged trial product can be stored at room temperature and must 
be stored separately from non-allocated trial product.
Non-allocated trial products including expired or damaged products must be accounted as unused at 
the latest at closure of the trial site.
Drug accountability of investigational medicinal products should be performed at pen level.
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.
9.5
Auxiliary supplies
The following auxiliary supplies will be supplied by Novo Nordisk in accordance with the Trial 
Materials Manual:
!
Direction for use for each trial product
!
Needles for pre-filled pen-injectors for trial products
!
BG-meter and related auxiliaries
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. 
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IWRS is used for: 
!
Screening
!
Screening failure
!
Randomisation
!
Stratification (please see Section 5.1)
!
Medication arrival
!
Dispensing
!
Dispensing Verification (when barcode scanner is used)
!
Treatment discontinuation 
!
Completion
!
Drug accountability
!
Data change
A completion session must be performed in IWRS after completion of V9 (and for subjects 
attending V9A).
IWRS user manuals will be provided to each trial site.
11 Randomisation procedure 
This is an open label, two-arm trial. A randomisation session will be performed for all eligible 
subjects by using IWRS. 
At the randomisation visit (V2), eligible subjects will be randomised to one of the two parallel 
treatments groups in a 1:1 manner: 
!
Semaglutide 1.0 mg once-weekly 
!
Liraglutide 1.2 mg once-daily
Randomisation will be stratified based on anti-diabetic background medication at screening (see 
Section 5.1) to ensure a 1:1 distribution of the two treatment arms within each stratum.
12 Adverse events, and 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 
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disease temporally associated with the use of a product, whether or not considered related to the 
product. 
An AE includes:
!
A clinically significant worsening of a concomitant illness.
!
A clinical laboratory adverse event: a clinical laboratory abnormality which is clinically 
significant, i.e. an abnormality that suggests a disease and/or organ toxicity and is of a 
severity that requires active management. Active management includes active treatment or 
further investigations, for example change of medicine dose or more frequent follow-up due 
to the abnormality.
The following should not be reported as AEs:
!
Pre-existing conditions, including those found as a result of screening 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 8.4.5).
The following three definitions are used when assessing an AE:
!
Severity 
–
Mild – no or transient symptoms, no interference with the subject’s daily activities.
–
Moderate – marked symptoms, moderate interference with the subject’s daily activities.
–
Severe – considerable interference with the subject’s daily activities; unacceptable.
!
Causality
Relationship between an AE and the relevant trial product(s):
–
Probable - Good reason and sufficient documentation to assume a causal relationship.
–
Possible - A causal relationship is conceivable and cannot be dismissed.
–
Unlikely - The event is most likely related to aetiology other than the trial product.
!
Final outcome 
–
Recovered/resolved - The subject has fully recovered, or by medical or surgical treatment 
the condition has returned to the level observed at the first trial-related activity after the 
subject signed the informed consent.
–
Recovering/resolving - The condition is improving and the subject is expected to recover 
from the event. This term is only applicable if the subject has completed the trial or has died 
from another AE.
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–
Recovered/resolved with sequelae - The subject has recovered from the condition, but 
with lasting effect due to a disease, injury, treatment or procedure. If a sequela meets an 
SAE criterion, the AE must be reported as an SAE.
–
Not recovered/not resolved - The condition of the subject has not improved and the 
symptoms are unchanged, or the outcome is not known.
–
Fatal - This term is only applicable if the subject died from a condition related to the 
reported AE. Outcomes of other reported AEs in a subject before he/she died should be 
assessed as “recovered/resolved”, “recovering/resolving”, “recovered/resolved with 
sequelae” or “not recovered/not resolved”. An AE with fatal outcome must be reported as 
an SAE.
–
Unknown - This term is only applicable if the subject is lost to follow-up.
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: 
–
Is admitted to a hospital or in-patient, irrespective of the duration of physical stay, or 
–
Stays at the hospital for treatment or observation for more than 24 hours
Medical judgement must always be exercised, and when in doubt, the hospital contact should be 
regarded as a hospitalisation. Hospitalisations for administrative, trial related and social purposes do 
not constitute AEs and should therefore not be reported as AEs or SAEs. Hospital admissions for 
surgical procedures, planned before trial inclusion, are not considered AEs or SAEs.
c. A substantial disruption of a subject’s ability to conduct normal life functions (e.g. following the 
event or clinical investigation the subject has significant, persistent or permanent change, 
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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 adverse events 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. Note: Use of wrong DUN is not considered a medication 
error unless it results in administration of wrong drug.
!
Wrong route of administration, such as intramuscular instead of subcutaneous.
!
Administration of an overdose with the intention to cause harm (e.g. suicide attempt), 
misuse or abuse of trial product.
!
Accidental administration of a lower or higher dose than intended. 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 8.4.4.1).
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. In this trial the following AEs require the completion of 
specific event forms in the eCRF
!
Hypersensitivity reaction
!
Pancreatitis
!
Renal event
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!
Hepatic event
!
Diabetic retinopathy
!
Acute gallstone disease
For details about specific event forms, see Appendix B.
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 follow-up period (P10). The events must be recorded in the applicable eCRF forms in a timely 
manner, see timelines below and Figure 12–1. 
During each contact with the trial site staff, the subject must be asked about AEs and technical 
complaints, for example by asking: “Have you experienced any problems since the last contact?”
All AEs, 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 safety information form (SIF) must be completed in addition to the AE form. If several 
symptoms or diagnoses occur as part of the same clinical picture, one safety information form can 
be used to describe all the SAEs. 
For 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.
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 on the form into the 
eCRF. 
Contact details (fax, telephone, e-mail and address) are provided in the investigator trial master file. 
AE identified
Does the AE require 
a specific event 
form?
AE form < 24 hours
SIF < 5 calendar days
Specific event form 
For SAEs: 
< 14 calendar days
Is the Adverse Event 
serious or non-
serious?
AE form
Non-serious
Serious
No
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 12.1.4 and 12.1.5.
No additional action
AE: Adverse Event   SIF: Safety Information form
Figure 12–1
Reporting of AEs 
Novo Nordisk assessment of AE expectedness: 
Novo Nordisk assessment of expectedness is performed according to the following reference 
documents:
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!
Semaglutide: NN9535 IB, current version26 and any updates thereto
!
Company Core Data Sheet for Victoza® 6 mg/ml ; current versions 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 GCP2. In addition, the 
investigator will be informed of any trial-related SAEs that may warrant a change in any trial 
procedure.
In accordance with regulatory requirements, Novo Nordisk will inform the regulatory authorities, 
including European Medicines Agency (EMA), of trial product-related SUSARs. In addition, Novo 
Nordisk will inform the IECs of trial product-related SUSARs in accordance with local requirement 
and ICH GCP2, 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 
Novo Nordisk, e.g. in the alternative aetiology section on the safety information form. Novo 
Nordisk may need to report this adverse event 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 
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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.
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 investigational medicinal product 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. 
12.4
Technical complaints and technical complaint samples
12.4.1
Reporting of technical complaints 
All technical complaints on any of the following products: 
!
Semaglutide 1.34 mg/mL 1.5 mL prefilled PDS290 pen-injector 
!
Liraglutide 6 mg/mL 3.0 mL pre-filled pen-injector
!
Novo Nordisk needles 
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 and/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 batch or lot number must be 
completed 
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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, or lot number 
and, if available, the DUN. All parts of the DUN should be returned.
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
Pregnancies
Female subjects must be instructed to notify the investigator immediately if they become pregnant 
during the trial. The investigator must report any pregnancy in subjects who have received trial 
product(s).
The investigator must follow the pregnancy until the pregnancy outcome and the newborn infant is 
one month of age.
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:
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Reporting of pregnancy information
Information about the pregnancy and pregnancy outcome/health of the newborn infant(s) has to be 
reported on Maternal Form 1A and 1B, respectively. 
When the pregnancy outcome is abnormal (i.e. congenital anomalies, foetal death including 
spontaneous abortion and/or any anomalies of the foetus observed at gross examination or during 
autopsy), and/or when a congenital anomaly is diagnosed within the first month, further information 
has to be reported for the female subject on Maternal Form 2. In addition, information from the 
male partner has to be reported on the Paternal Form, after an informed consent has been obtained 
from the male partner. 
Initial reporting and follow-up information must be reported within 14 calendar days of the 
investigator’s first knowledge of initial or follow-up information.
Reporting of AE information
The investigator has to report AEs in connection with the pregnancy as well as in the foetus and 
newborn infant(s). The SAEs that must be reported include abnormal outcome, such as foetal death 
(including spontaneous abortion), and congenital anomalies (including those observed at gross 
examination or during autopsy of the foetus), as well as other pregnancy complications fulfilling the 
criteria of an SAE.
Forms and timelines for reporting AEs:
Non-serious AEs: 
!
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.
!
SIF within 5 calendar days of the investigator’s first knowledge of the SAE.
!
SAE follow-up information to the AE form and/or safety information form within 24 
hours of the investigator’s first knowledge of the follow-up information.
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.
                                                
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 safety 
information form
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12.6
Precautions and/or overdose
Overdoses of up to 4 mg of semaglutide in a single dose/in one week have been reported in clinical 
trials. The most commonly reported adverse reaction was nausea, vomiting and headache. 
For liraglutide, overdoses have been reported up to 40 times the recommended maintenance dose
(72 mg). One case of a 10-fold overdose (18 mg daily) given for 7 months has been reported. 
Generally, the patients reported severe nausea, vomiting and diarrhoea, but recovered without 
complications. For more information, please refer to the SmPC for Victoza® 6 mg/ml.
In the event of overdosage, appropriate supportive treatment should be initiated according to 
subject’s clinical signs and symptoms.
12.7
Committees related to safety
Novo Nordisk will constitute an internal semaglutide s.c. safety committee and perform ongoing 
safety surveillance on all reported safety data in the trial. 
13 Case report forms 
Novo Nordisk will provide a system for the electronic case report forms (eCRF). This system and 
support services to the system will be provided by an external supplier.
Ensure that all relevant questions are answered, and that no empty data field exists. If a test or an 
assessment has not been done and will not be available, or if the question is irrelevant (e.g. is not 
applicable), indicate this according to the data entry instructions.
The following will be provided as paper CRFs:
!
Pregnancy forms
!
PRO 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 
!
SIF
!
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 may only be made by drawing a straight line through the 
incorrect data and then writing the correct entry next to the data that was crossed out. Each 
correction must be initialled, dated and explained (if necessary) by the investigator or the 
investigator’s authorized staff.
If corrections are made by the investigator’s delegated staff after the date of the investigator’s 
signature on the affirmation statement, the affirmation statement must be signed and dated again by 
the investigator.
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.
The investigator must ensure that data is recorded as soon as possible after the visit and the phone 
contact. At the end of the trial the investigator must ensure that all remaining data have been entered 
into then 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.
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14 Monitoring procedures 
During the course of the trial, the monitor will visit the trial site to ensure that the protocol is 
adhered to, that all issues have been recorded, to perform source data verification and to monitor 
drug accountability. The first monitoring visit will be performed as soon as possible after FSFV at 
the trial site and no later than 4 weeks after. The monitoring visit intervals will depend on the 
outcome of the remote monitoring of the 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 LSLV 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.
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.
Source data generated by the trial site can be corrected by another person than the person entering 
the source data if accepted by local regulations; any correction must be explained, signed and dated 
by the person making the correction.
The original of the completed diaries and/or PROs must not be removed from the trial site, unless 
they form part of the CRF/eCRF and a copy is kept at the site.
The monitor will ensure that the eCRFs are completed and that paper CRFs are collected.
The following data will be source data verified for screening failures: 
!
Date for obtaining informed consent
!
Reason for screening failure
Monitors will review the subject’s medical records and other source data (e.g. the diaries and PROs)
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.
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15 Data management
Data management is the responsibility of Novo Nordisk. 
Appropriate measures, including encryption of data files containing person identifiable data, will be 
used to ensure confidentiality of subject data, when they are transmitted over open networks. 
Data from central laboratories will be transferred electronically. 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
17.1
General considerations
No interim analyses or other analyses of un-blinded data will be performed before the database is 
locked.
If necessary, a statistical analysis plan may be written in addition to the protocol, including a more 
technical and detailed elaboration of the statistical analyses. The statistical analysis plan will be 
finalised before database lock.
Results from a statistical analysis will be presented by the estimated treatment contrasts at week 30
with associated two-sided 95% confidence intervals and p-values corresponding to two-sided tests 
of no difference if not otherwise specified.
The comparison presented from a statistical analysis will be semaglutide 1.0 mg versus liraglutide 
1.2 mg.
If no statistical analysis is specified, data will be presented using relevant summary statistics.
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Data from all trial sites will be analysed and reported together. 
17.1.1
Primary estimand
To further detail the trial objective an estimand is defined which is a de-jure (efficacy) estimand: 
!
The treatment difference between semaglutide and liraglutide at week 30 for all randomised 
subjects if all subjects completed treatment and did not initiate rescue medication
This primary de-jure estimand is considered clinically relevant as it assesses the glycaemic benefit a 
person with T2D is expected to achieve if initiating and continuing treatment with semaglutide 
compared to liraglutide. Accordingly, only data collected prior to discontinuation of trial product or 
initiation of rescue medication will be used to draw inference. This will avoid confounding from 
rescue medication.
17.1.2
Missing data considerations at week 30
The overall rate of missing data at week 30 is expected to be not more than 10%  based on the rate 
of subjects with measurements of the primary and the confirmatory secondary  endpoints in the s.c. 
semaglutide phase 3a clinical development programme. The frequency and reasons of missing data 
is expected to be similar in the semaglutide and the liraglutide groups.
When estimating the primary estimand, the combined rate of missing data and, subjects 
discontinuing treatment prematurely or initiating rescue medication on top of trial product, is 
expected to be maximum 20%. This is based on the results from the s.c. semaglutide phase 3a 
clinical development programme. Based on these data, premature treatment discontinuation due to 
gastrointestinal adverse events is expected to be low. Other possible reasons for premature 
discontinuing treatment are assumed to be unrelated to treatment and to therefore occur at similar 
rates between the two treatment groups. Thus, overall, the frequency of missing data or data not 
used at week 30 in the primary analysis is expected to be similar between the treatment groups.
To document the extent and reason(s) for missing data, descriptive summaries and graphical 
representation of extent, reason(s) for and pattern of missing data for the primary and secondary 
endpoints will be presented by treatment group. 
17.1.3
Confirmatory hypotheses
The mean treatment difference is defined as μ = (semaglutide minus liraglutide). Three 
confirmatory hypotheses are to be tested:
1. HbA1c non-inferiority of semaglutide 1.0 mg vs. liraglutide 1.2 mg with a non-inferiority 
margin of 0.3
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!
H0: μ ≥0.3%-point against Ha: μ < 0.3%-point
2. Body weight superiority of semaglutide 1.0 mg vs. liraglutide 1.2 mg
!
H0: μ ≥0.0 kg against Ha: μ < 0.0 kg
3. HbA1c superiority of semaglutide 1.0 mg vs.liraglutide 1.2 mg
!
H0: μ ≥0.0%-point against Ha: μ < 0.0%-point
The non-inferiority margin of 0.3 is chosen based on the diabetes guideline48, 49. The effect of 
liraglutide was investigated in various trials including the LEAD programme that included a series 
of six randomised controlled phase 3 trials. In these trials, a substantial and sustained reduction in 
HbA1c was obtained with liraglutide treatment across the continuum of care in patients with type 2 
diabetes50. Based on  the Lead 1 & Lead 4 studies, Liraglutide 1.2 mg showed HbA1c treatment 
difference to placebo of -1.3%51 and -0.9% 52 respectively. Hence, based on these trials, and 
considering the LEAD programme results collectively that assures the effect of liraglutide, the 
chosen non-inferiority margin of 0.3 provides assurance that semaglutide has an effect greater than 
0 with a clinically relevant size.With regards to the constancy assumption, controlled clinical trials 
have consistently established that liraglutide is an effective anti-diabetic drug. Therefore, lack of 
trial sensitivity with liraglutide as comparator is not anticipated to be an issue in this trial.
17.1.4
Multiplicity and criteria for confirming hypotheses
The Type-I error rate for testing the three confirmatory hypotheses related to the HbA1c and body 
weight endpoints will be preserved in the strong sense at an overall alpha (α) level of 2.5% using 
the closed testing procedure described in Bretz et al. The overall α-level of 2.5% is initially 
allocated to the HbA1c non-inferiority test. For this hypothesis, and in general, if a hypothesis is 
confirmed the local α-level (α-local) will be reallocated according to the weight and the direction of 
the edges going from the confirmed hypothesis to the next hypotheses as specified in Figure 17–1. 
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Each of the following hypotheses will be tested at their local α level. This process will be repeated 
until no further hypotheses can be confirmed.
Figure 17–1
Graphical illustration of the closed testing procedure
17.2
Sample size calculation
The sample size calculation will assume a power of 90% for confirming all three confirmatory 
hypotheses (see Section 17.1.3) across efficacy and in-trial assumptions. Please see Table 17–2 for 
calculated powers for efficacy as estimated by the primary analysis for the primary estimand (see 
Section 17.4.1) and for the in-trial effect as estimated by the treatment policy sensitivity analysis 
(see Section 17.4.4)
The sample size assumptions for efficacy based on ‘on-treatment without rescue medication’ data 
and a treatment effect based on in-trial data (see Section 17.3.1.2) together with the standard are 
given in Table 17–1.These are based on the efficacy results and an observed reduction of up to 15% 
in the treatment effect based on in-trial data compared to efficacy based on ‘on-treatment without 
rescue medication’ data in the s.c. semaglutide phase 3a clinical development programme. A similar 
reduction in the in-trial treatment effect compared to efficacy is assumed with liraglutide as 
comparator. 
 = 0
HbA1c (%)
Superiority
 = 0.025
HbA1c (%)
Non-inferiority
 = 0
Body weight (kg)
Superiority
1
1
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Table 17–1
Assumptions used in the sample size calculation
Semaglutide vs. liraglutide
HbA1c
Body weight
Efficacy (treatment difference)
-0.35%
-3.3 kg
In-trial treatment effect (treatment difference)
-0.30 %
-2.38 kg
Standard deviation 
1.1%
4.0 kg
Tests statistics for treatment differences are assumed to follow normal distributions. The sample 
size is calculated using the calcPower function in the R package, gMCP54, using 10,000 simulations. 
All of the three pre-specified confirmatory tests are assumed to be independent. Since some of these 
tests are positively correlated, the assumption of independence is viewed as conservative.
With the above assumptions, allocating 288 subjects to each of the semaglutide and liraglutide 
groups (576 subjects in total) provides at least 90% power to reject all three confirmatory 
hypotheses and thus confirm HbA1c superiority and body weight superiority of semaglutide vs. 
liraglutide across efficacy and in-trial assumptions. Please see Table 17–2.
Table 17–2
Calculated powers for meeting individual hypotheses
Statistical test
HbA1c
non-inferiority
HbA1c superiority
Body weight 
superiority
All
Efficacy power (%)
>99%
97%
>99%
97%
In-trial effect power (%)
>99%
90%
>99%
90%
17.3
Data definitions
17.3.1
Data selection
Subjects and data to be used in an analysis will be selected in a two-step manner:
!
Firstly, subjects will be selected based on the specified analysis set
!
Secondly, data points on the selected subjects from first step will be selected based on the 
specified observation period
17.3.1.1
Definition of analysis sets
The following analysis sets will be defined:
Full analysis set (FAS): includes all randomised subjects. Subjects in the FAS will contribute to 
evaluation “as randomised”.
Safety analysis set (SAS): includes all subjects exposed to at least one dose of trial product. 
Subjects in the SAS will contribute to the evaluation based on the trial product received for the 
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majority of the period they were on treatment. This will be referred to as contributing to the 
evaluation “as treated”.
17.3.1.2
Definition of observation periods
Definition of the observation periods:
In-trial: This observation period represents the time period after randomisation where subjects are 
considered to be in the trial, regardless of discontinuation of trial product or initiation of rescue 
medication. The in-trial observation period starts at randomisation (as registered in IWRS) and ends 
at the date of: 
!
The last direct subject-site contact, which is scheduled to take place 5 weeks after planned 
last dose of trial product at a follow-up visit (phone visit)
!
Withdrawal for subjects who withdraw their informed consent
!
The last subject-investigator contact as defined by the investigator for subjects who are lost 
to follow-up
!
Death for subjects who dies before any of the above
For subjects not randomised but exposed to trial product the in-trial period starts at the date of first 
dose of trial product.
On-treatment: This observation period represents the time period where subjects are considered 
exposed to trial product. The observation period is a sub-set of the in-trial observation period. It 
starts at the date of first dose of trial product. Two slightly different end dates will be needed to 
cover all assessments appropriately according to the flow chart. For AEs including hypoglycaemic 
episodes, the observation period ends at the first date of any of the following:
!
The follow-up visit (P10)
!
The premature discontinuation follow-up visit (P10A)
!
The last date on trial product + 42 days 
!
The end-date for the in-trial observation period
The follow-up visit is scheduled to take place 5 weeks after the last date on trial product 
corresponding to approximately five half-lives of s.c. semaglutide. The visit window for the follow-
up visit is + 7 days, which is the reason for the 42 days specified in the bullet above. Hence, for 
AEs including hypoglycaemic episodes, this period reflects the period in which subjects are 
exposed.
For efficacy and other safety assessments (laboratory assessments, physical examination and vital 
signs) the observation period ends at the last date on trial product with a visit window of + 7 days. 
This ascertainment window corresponds to the dosing interval and will be used to avoid attenuation 
of a potential treatment effect on endpoints for which the effect is reversible shortly after treatment 
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discontinuation. Hence, for those assessments this period reflects the period in which subjects are 
treated. 
On-treatment without rescue medication: This observation period is a sub-set of the on-treatment 
observation period, where subjects are considered treated with trial product, but have not initiated 
rescue medication. Specifically, the period starts at the date of first dose of trial product and ends at 
the first date of any of the following:
!
The last dose of trial product with a visit window of +7 days
!
Initiation of rescue medication
The ’on-treatment without rescue medication’ observation period will be the primary observation 
period for efficacy evaluations. The in-trial observation period will be considered supportive for 
efficacy evaluation. Safety will be evaluated based on the in-trial and the on-treatment observation 
periods unless otherwise specified.
Data points collected outside an observation period will be treated as missing in the analysis. 
Baseline data will always be included in an observation period. Before data are locked for statistical 
analysis, a review of all data will take place. Any decision to exclude either a subject or single 
observations from the statistical analysis is the joint responsibility of the members of the Novo 
Nordisk study group.
Exclusion of data from analyses will be used restrictively and normally no data should be excluded 
from the FAS. The subjects or observations to be excluded, and the reasons for their exclusion will 
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.
17.3.2
Data transformations 
A number of the continuous parameters will be log-transformed prior to statistical analysis. The 
output tables and figures will show the results of the analysis back-transformed to the original scale, 
implying that log-treatment-differences are reported as treatment ratios. Confidence intervals for the 
treatment ratios will be calculated as exponentiated upper and lower limits for log-treatment 
difference confidence intervals. The standard errors of the back-transformed mean and ratio to 
baseline estimates are also provided; these SEs are calculated using the delta-method (first order 
Taylor approximation), whereby the SE on the original scale is calculated as the product of the SE 
on log-scale and the exponentiated estimate of the mean (geometric mean).
Laboratory values below the lower limit of quantification (LLOQ) will be set to ½LLOQ. 
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17.3.3
Definition of baseline
For each assessment, the baseline assessment is defined as the latest available measurement at or 
prior to the randomisation visit (V2). This specifically implies that if a visit 2 assessment is missing 
(whether it was planned or not planned) then the screening assessment (from visit 1), if available, 
will be used as the baseline assessment.
17.3.4
Trial completion
Unless subjects withdraw their informed consent, data collection will continue for the full duration 
of the trial. The full duration of the trial is defined as up to and including the follow-up visit (P10). 
Subjects completing the follow-up visit (P10) will be considered trial completers.
17.3.5
Treatment completion
Treatment period completion is defined as when the subject has received the required treatment, and 
attended the ‘End of Treatment’ (V9).
17.4
Primary endpoint
The primary endpoint is change from baseline to week 30 in HbA1c.
17.4.1
Primary analysis 
The primary estimand will be estimated based on the FAS using post-baseline measurements up to 
and including week 30 from the ’on-treatment without rescue medication’ observation period. 
Imputation of missing data will be handled using multiple imputation assuming that missing data is 
missing at random (MAR). Missing data will be imputed using observed data within the same group 
defined by the randomised treatment (semaglutide/liraglutide). It is hereby assumed that the likely 
values of what the missing data would have been if available are best described by information from 
subjects who receive the same treatment. 
Technically missing values will be imputed as follows:
!
Intermittent missing values are imputed using a Markov Chain Monte Carlo (MCMC) 
method, in order to obtain a monotone missing data pattern. This imputation is done for each 
of the treatment groups separately and 500 copies of the dataset will be generated
!
A sequential regression approach for imputing monotone missing values at planned visits 
will be implemented starting with the first visit after baseline and sequentially continuing to 
the last planned visit at week 30. A model used to impute missing values at each planned 
visit will be fitted for each of the treatment groups using observed data. The model will 
include the SU and SGLT-2 inhibitors anti-diabetic background medication stratification 
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factor ( SU +/- metformin, SGLT-2 inhibitors +/- metformin, SU + SGLT-2 inhibitors +/-
metformin, no SU and no SGLT-2 inhibitors (metformin monotherapy)) as categorical 
effects and the baseline and post-baseline HbA1c values observed prior to the visit in 
question as covariates. 
!
An analysis of covariance (ANCOVA) with treatment and the SU and SGLT-2 inhibitors 
anti-diabetic background medication stratification factor (SU +/- metformin, SGLT-2
inhibitors +/- metformin, SU + SGLT-2 inhibitors +/- metformin, no SU and no SGLT-2
inhibitors (metformin monotherapy)) as categorical effects and baseline HbA1c as a 
covariate will be used to analyse HbA1c values at week 30 for each of the 500 complete data 
sets generated as part of the imputation of missing values. Rubin’s rule will be used to 
combine the analysis results in order to draw inference.
From this analysis, the estimated treatment difference between semaglutide and liraglutide at week 
30 will be presented together with the associated two-sided 95% confidence interval and unadjusted 
two sided p-values.
The one-sided non-inferiority and superiority hypotheses will be confirmed using the overall 
significance level of 2.5% in line with the closed testing procedure in Figure 17–1. Operationally, 
non-inferiority and subsequent superiority will be considered confirmed if the mean treatment 
difference is supporting the corresponding alternative hypothesis and the two-sided p-value  (non-
inferiority H0: u=0.3 vs. Ha: u≠0.3, superiority H0: u=0 vs Ha: u≠0 respectively), from the primary 
analysis of the primary estimand, is strictly below two times its local significance level resulting 
from the closed testing procedure.
17.4.2
Sensitivity analyses
In order to investigate the robustness of the conclusions from the primary analysis and to stress test 
the MAR assumption for missing data tipping point sensitivity analyses will be performed for the 
primary estimand both for the sensitivity of the non-inferiority and the superiority HbA1c
hypotheses.
17.4.3
Sensitivity analyses for the primary estimand
The estimation of the primary estimand will be repeated using the following sensitivity analysis:
!
Tipping-point analysis (pattern mixture model based) based on the FAS using the ’on-
treatment without rescue medication’ observation period. In this analysis, subjects from the 
semaglutide group with missing observations will be given a penalty, i.e., it is assumed that 
subjects with missing observations who are randomised to semaglutide will receive a 
treatment that is less beneficial than subjects with observed values who are randomised to 
semaglutide. The idea is to gradually increase the penalty to evaluate at which level the 
superiority conclusion of the analyses in terms of statistical significance is changed. The 
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tipping point is the penalty level, at which the magnitude of efficacy reduction in subjects 
with missing data creates a shift in the treatment effect of semaglutide from being 
statistically significantly better than liraglutide to being non-statistically significantly better 
for the superiority test and similarly for the non-inferiority test. Technically, this analysis 
will be implemented by replicating the primary analysis including the assumption of MAR 
but subsequently adding increasing penalty values at week 30 to imputed observations in the 
semaglutide group before applying ANCOVA on the 500 complete data sets.
17.4.4
Other sensitivity analyses
The following additional sensitivity analyses are specified:
!
In-trial treatment policy analysis based on the FAS using post-baseline measurements up to 
and including week 30 from the in-trial observation period. Missing data will be imputed 
using the same approach as described for the primary analysis of the primary estimand. 
However the imputation will be done within the same group defined not only by the 
randomised treatment (semaglutide/ liraglutide) but also by the status of treatment 
completion (still on randomised treatment at week 30 yes/no) (4 groups in total). It is hereby 
assumed that the likely values of what the missing data would have been if available are best 
described by information from subjects who at week 30 are similar in terms of randomised 
treatment and treatment completion status. In addition in the imputation step stratification 
factor is not included in the model in order to avoid potential issues with sparse data. This 
analysis could be considered addressing an effectiveness estimand.
!
Per protocol (PP) analysis based on the PP data set using the ‘on-treatment without rescue
medication’ observation period. This analysis will be carried out for non-inferiority testing 
only. The statistical analysis will be the same as the primary analysis for the primary 
estimand.
17.5
Secondary endpoints
17.5.1
Confirmatory secondary endpoints
The confirmatory secondary endpoint is change from baseline to week 30 in body weight (kg). 
The primary estimand will be estimated for body weight using the same approach as described 
in Section 17.4.1. Body weight will be tested for superiority. Baseline and post-baseline body 
weight will be used as covariates instead of HbA1c. 
The one-side hypothesis of superiority will be considered confirmed if the mean treatment 
difference is supporting the corresponding hypothesis and the two-sided p-value from the analysis 
of body weight is strictly below two times its local two-sided significance level resulting from the 
closed testing procedure inFigure 17–1.
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17.5.2
Supportive secondary endpoints
No sensitivity analyses are planned for the supportive secondary endpoints. 
17.5.2.1
Efficacy endpoints
Continuous endpoints
The continuous endpoints are change from baseline to week 30 in: 
!
FPG 
!
SMPG, 7 point profile 
–
Mean 7-point profile 
–
Mean post prandial increment (over all meals)
!
Fasting blood lipids (total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides) 
!
BMI
!
Waist circumference
!
Systolic and diastolic blood pressure 
!
Body weight (%)
The above continuous endpoints will be analysed separately using a similar model approach as for 
the primary endpoint with the associated baseline value as covariates instead of HbA1c for their 
respective analyses.
Fasting lipid profile endpoints will be log-transformed prior to analysis with the associated log-
transformed baseline value as a covariate.
Mean 7-point profile (SMPG) definition
Subjects will be asked to perform SMPG measurements before and 90 minutes after breakfast, 
lunch, dinner, and at bedtime. 
Mean of the 7-point profile is defined as the area under the profile, calculated using the trapezoidal 
method, and divided by the measurement time.
Binary endpoints
The binary endpoints are subjects who after 30 weeks treatment achieve (yes/no):
!
HbA1c < 7.0% (53 mmol/mol), ADA target 
!
HbA1c ≤6.5% (48 mmol/mol), AACE target
!
Weight loss ≥3%
!
Weight loss ≥5%
!
Weight loss ≥ 10%
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!
HbA1c <7.0% (53 mmol/mol) without severe or blood glucose confirmed symptomatic 
hypoglycaemia episodes and no weight gain
!
HbA1c reduction ≥1%
!
HbA1c reduction ≥1% and weight loss ≥3%
!
HbA1c reduction ≥1% and weight loss ≥5%
!
HbA1c reduction ≥1% and weight loss ≥10%
The above 10 endpoints will be analysed for the primary estimand. The analyses for the primary 
estimand for all 10 endpoints will be based on the ’on-treatment without rescue medication’ 
observation period. They will be analysed separately using the same type of logistic regression 
model with treatmentand the SU and SGLT-2 inhibitors anti-diabetic background medication 
stratification factor (SU +/- metformin, SGLT-2 inhibitors +/- metformin, SU + SGLT-2 inhibitors 
+/- metformin, no SU and no SGLT-2 inhibitors (metformin monotherapy)) as categorical effects 
and associated baseline and post-baseline response(s) (i.e. HbA1c responses for HbA1c endpoints, 
body weight responses for weight endpoints and both HbA1c and body weight responses for the 
binary endpoints that combine both parameters) as covariates. 
To account for missing data, the analysis will be made using a sequential multiple imputation 
approach as described below: 
!
Multiple imputed data sets (500) will be created in which missing values for the underlying 
continuous assessments are imputed by treatment group assuming MAR similar to the 
approach described for the primary analysis in Section 17.4.1
!
The binary endpoint will be created for each of the 500 complete data sets
!
Each of the created complete data sets will be analysed with the logistic regression model. 
Estimated odds ratios will be log transformed and inference will be drawn using Rubin’s 
rule55.
The results after applying Rubin’s rule will be back-transformed and described by the odds ratio 
between treatments and the associated 95% confidence interval and p-value for no treatment 
difference.
17.5.2.2
Safety endpoints
The safety endpoints will be evaluated based on SAS using the on-treatment observation period and 
the in-trial observation period unless otherwise stated. 
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Adverse Events
The following endpoint related to AEs is used to support the safety objective;
!
Number of treatment emergent adverse events
A treatment-emergent AE is an event that has onset date (or increase in severity) during the on-
treatment observation period. These will therefore be referred to as ‘on-treatment AEs’ hereafter. 
On-treatment AEs are summarised descriptively 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). These summaries are replicated by outputs including all ‘in-trial’ AEs 
(i.e., AEs with onset date [or increase in severity] during the ‘in-trial’ observation period). AEs with 
onset after the end of the ‘in-trial’ observation period will be reported in a listing. The development 
over time in gastrointestinal AEs will be presented graphically.
The most frequent AEs will be defined as preferred terms that are experienced by at least 5% of the 
subjects in any of the treatment arms. 
All AEs will be coded using the most recent version of the Medical Dictionary for Regulatory 
Activities (MedDRA) coding.
Hypoglycaemic episodes
The following two endpoints related to hypoglycaemic episodes are used to support the safety 
objective:
!
Number of treatment-emergent severe or BG-confirmed symptomatic hypoglycaemic 
episodes 
!
Treatment-emergent severe or BG-confirmed symptomatic hypoglycaemic episodes (yes/no)
Data on treatment-emergent hypoglycaemic episodes are presented in terms of the number of 
subjects with at least one episode, the percentage of subjects with at least one episode (%), the total 
number of episodes and the episode rate per 100 years of exposure. Summaries of treatment-
emergent hypoglycaemic episodes will be presented as an overview including all episodes and 
episodes by severity. 
Classification of Hypoglycaemia: 
Treatment emergent: hypoglycaemic episodes will be defined as treatment emergent if the onset is 
in the on-treatment observation period (see Section 17.3.1.2)
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 17–2) and the ADA classification of hypoglycaemia (see Figure 17–3).
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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) 56. 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 17–2) in addition to the ADA 
classification:
!
Severe or BG confirmed symptomatic hypoglycaemia: An episode that is severe according 
to the ADA classification57 or BG confirmed by a plasma glucose value <3.1 mmol/L 
(56 mg/dL) with symptoms consistent with hypoglycaemia. 
Hypoglycaemic
episode
PG ≤ 3.9 mmol/L 
(70 mg/dL) 
or 
Alleviation of 
symptoms 
or
Seizure, coma or 
fatal 
SMPG
measurement
PG < 3.1 mmol/L
(56 mg/dL)
with symptoms
PG < 3.1 mmol/L
(56 mg/dL)
without
symptoms
Symptomatic BG 
confirmed 
hypoglycaemia
Asymptomatic BG 
confirmed 
hypoglycaemia
Yes
No
Severe or 
BG confirmed 
symptomatic 
hypoglycaemia
BG confirmed 
hypoglycaemia
Severe or BG 
confirmed 
hypoglycaemia
Note: Glucose measurements are performed with capillary blood calibrated to plasma equivalent glucose values
BG: blood glucose  PG: plasma glucose  SMPG: Self-measured plasma glucose  
Subject 
able to 
treat him/
herself
Severe 
hypoglycaemia
(ADA 2013)
Figure 17–2
Novo Nordisk classification of hypoglycaemia
ADA classification57 of hypoglycaemia 
–
Severe hypoglycaemia: An episode requiring assistance of another person to actively 
administer carbohydrate, glucagon, or take other corrective actions. Plasma glucose 
concentrations may not be available during an event, but neurological recovery following 
the return of plasma glucose to normal is considered sufficient evidence that the event was 
induced by a low plasma glucose concentration.
–
Asymptomatic hypoglycaemia: An episode not accompanied by typical symptoms of 
hypoglycaemia, but with a measured plasma glucose concentration ≤ 3.9 mmol/L 
(70 mg/dL).
–
Documented symptomatic hypoglycaemia: An episode during which typical symptoms of 
hypoglycaemia are accompanied by a measured plasma glucose concentration ≤ 3.9 mmol/L 
(70 mg/dL).
–
Pseudo-hypoglycaemia: An episode during which the person with diabetes reports any of 
the typical symptoms of hypoglycaemia with a measured plasma glucose concentration 
> 3.9 mmol/L (70 mg/dL) but approaching that level.
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–
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).
Hypoglycaemic 
episode 
PG ≤ 3.9 mmol/L 
(70 mg/dL) 
or 
Alleviation of 
symptoms 
or
Seizure, coma or 
fatal 
SMPG
measurement
Asymptomatic 
hypoglycaemia
Documented 
symptomatic 
hypoglycaemia
Pseudo-
hypoglycaemia
Probable 
symptomatic 
hypoglycaemia
No
Yes
No measurement 
with symptoms
PG > 3.9 mmol/L 
(70 mg/dL)
with symptoms
PG ≤3.9 mmol/L 
(70 mg/dL)
with symptoms
PG ≤3.9 mmol/L 
(70 mg/dL)
without symptoms
No
Yes
Note: Glucose measurements are performed with capillary blood calibrated to plasma equivalent glucose values
PG: plasma glucose  SMPG: Self-measured plasma glucose  
Subject 
able to 
treat him/
herself
Severe 
hypoglycaemia
(ADA 2013)
Figure 17–3
ADA classification of hypoglycaemia
Number of treatment emergent severe or blood glucose (BG) confirmed symptomatic 
hypoglycaemic episodes
Number of treatment emergent severe or BG confirmed symptomatic hypoglycaemic episodes 
during 35 weeks will be analysed using a negative binomial regression model with a log-link 
function and the logarithm of the time period, from the randomisation and up to the time point in 
which an occurrence of a hypoglycaemic episode is considered treatment emergent as offset 
assuming MAR. The model will include factors for treatment and the SU and SGLT-2 inhibitors
anti-diabetic background medication stratification factor (SU +/- metformin, SGLT-2 inhibitors +/-
metformin, SU + SGLT-2 inhibitors +/- metformin, no SU and no SGLT-2 inhibitors (metformin 
monotherapy)) as categorical factors and baseline HbA1c as covariate. The SAS will be used for the 
analysis.
The results will be described by the rate ratio between treatments and the associated 95% 
confidence interval and p-value for no treatment difference.
Treatment emergent severe or blood glucose confirmed symptomatic hypoglycaemia episodes 
(yes/no)
The binary endpoint indicating whether a subject has no treatment-emergent severe or BG 
confirmed symptomatic hypoglycaemic episodes or at least one will be analysed using a logistic 
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regression model. The model will include factors for treatment and the SU and SGLT-2 inhibitors
anti-diabetic background medication stratification factor (SU +/- metformin, SGLT-2 inhibitors +/-
metformin, SU + SGLT-2 inhibitors +/- metformin, no SU and no SGLT-2 inhibitors (metformin 
monotherapy))as categorical factors and baseline HbA1c as covariate. The SAS will be used for the 
analysis.
The results will be described by the odds ratio between treatments and the associated 95% 
confidence interval and p-value for no treatment difference.
Laboratory assessments
The laboratory assessments supporting the safety objective are change from baseline to week 30 in:
!
Haematology
!
Biochemistry
!
Calcitonin
The above continuous laboratory assessments will be summarised and evaluated by descriptive 
statistics.
In addition amylase and lipase will be analysed separately using an analysis similar to the primary 
analysis of the primary endpoint. However this analysis will be based on SAS using the on-
treatment observation period.
Both analyses will use the associated baseline value as covariates instead of HbA1c. Lipase and 
amylase values will be log-transformed prior to the analysis.
Pulse rate
Change from baseline to week 30 in pulse rate will be analysed separately with the same model 
approach as for amylase and lipase but with the pulse rate value at baseline value as covariates 
instead of HbA1c.
Categorical safety assessments
The categorical assessments supporting the safety objective are change from baseline to week 30 in:
!
ECG category
!
Physical examination category
!
Eye examination category
The above assessments will be summarised descriptively
17.6
Health economics and/or PROs
Change from baseline to week 30 in:
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!
Scores for selected patient reported outcomes:
–
SF-36v2TM : Total summary scores (physical component and mental component) and scores 
from the 8 domains
–
DTSQs: Treatment satisfaction score (sum of 6 of 8 items) and the 8 items separately
The PRO questionnaires, SF-36v2™, DTSQs will be used to evaluate the objective regarding 
Quality of Life. Each of the PRO endpoints will be analysed separately as the other continuous 
efficacy endpoints using a similar model approach as for the primary endpoint with the associated 
baseline value as covariates.
17.7
Interim analysis
No interim analyses will be performed before the database is locked
18 Ethics
18.1
Benefit-risk assessment of the trial
18.1.1
Risk and precautions
The nonclinical safety programme of semaglutide has not revealed any safety issues precluding use 
in humans. 
The sections below describe the risks and precautions associated with semaglutide and liraglutide. 
These are based on findings in nonclinical studies and clinical trials with semaglutide as well as 
other GLP-1 RAs including liraglutide. For each of these risks and precautions, mitigating actions 
have been implemented to minimise the risks for subjects enrolled in this trial. 
Gastrointestinal adverse events 
Consistent with findings with other GLP-1 RAs, the most frequently reported AEs in clinical trials 
with semaglutide and liraglutide have been gastrointestinal disorders (nausea, diarrhoea, vomiting, 
abdominal pain, abdominal distension, constipation, dyspepsia, gastritis, gastro oesophageal reflux 
disease, eructation and flatulence). Clinical trials have indicated that a low starting dose and gradual 
dose escalation mitigates the risk of gastrointestinal AEs. Consequently, a low starting dose and 
dose escalation steps have been implemented in the trial. 
Gallstones
Events of gallstones (cholelithiasis) have been reported from clinical trials both with semaglutide 
and with liraglitide. These events may lead to hospitalisation and removal of the gallbladder. If 
cholelithiasis is suspected appropriate clinical follow-up should be initiated at the investigator’s 
discretion.
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Hypoglycaemia 
Patients treated with semaglutide or liraglutide in combination with a SU or insulin may have an 
increased risk of hypoglycaemia. The risk of hypoglycaemia can be lowered by reducing the dose of 
SU or insulin when initiating treatment with semaglutide/liraglutide.
Allergic reactions and injection site reaction 
As in the case with all protein-based pharmaceuticals, treatment with semaglutide or liraglutide may 
evoke allergic reactions. These may include localized injection site reactions or generalized 
reactions, including urticaria, rash, and pruritus as well as anaphylactic reactions. As a precaution, 
subjects with known or suspected hypersensitivity to trial product(s) or related products will not be 
enrolled in the trial. In addition, subjects will be instructed to contact the site staff as soon as 
possible for further guidance if suspicion of a hypersensitivity reaction to the trial product occurs.
Acute renal impairment 
In subjects treated with GLP-1 RAs, gastrointestinal AEs such as nausea, vomiting and diarrhoea 
may lead to significant dehydration and secondary renal impairment and acute renal failure. 
Subjects with gastrointestinal AEs are recommended to drink plenty of fluids to avoid volume 
depletion. Also, serum creatinine and other markers of kidney function will be monitored 
throughout the trial. SGLT-2 inhibitors, a background medication in this trial, have also been 
associated with volume depletion. It is recommended to monitor renal function and for signs and 
symptoms of fluid loss during therapy. Severe dehydration may be a risk factor for ketoacidosis. 
Impaired renal function may increase the risk of metformin associated lactic acidosis when GLP-1
RAs are co-administered with metformin. As a precaution, serum creatinine will be measured 
regularly. In subjects treated with metformin who experience prolonged or severe nausea and 
vomiting, the investigator should monitor serum creatinine, and if clinically indicated, withhold 
metformin until resolution of renal dysfunction. The use of the background medication should be in 
accordance with the current, approved labels.
Medullary thyroid cancer 
The human relevance of the proliferative C-cell changes found in rodents treated with GLP-1 RAs 
is unknown, but data suggest that rodents are more sensitive to the mode of action of GLP-1 RAs 
for induction of C-cell tumours. However, as a precaution, subjects with a family or personal 
history of multiple endocrine neoplasticity 2 or Medullary thyroid cancer will not be enrolled in the 
trial. During the trial, calcitonin will be measured on V2, V7 and V9, and the guidance for 
investigators on further evaluation and action on elevated calcitonin concentrations is included in 
Appendix A. 
Diabetic retinopathy 
A transient worsening of diabetic retinopathy is a recognised complication in selected patients with 
diabetes after initiation of intensive anti-diabetic treatment58. Risk factors for these events include 
long-standing poor glycaemic control and presence of proliferative retinopathy, and initial large 
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improvements in BG may be an additional aggravating factor. Several studies have, however, 
documented long-term beneficial effects of intensive glycaemic treatment in reducing retinopathy 
progression59 60 even in intensively treated patients who experienced early worsening61. In a 2-year 
cardiovascular outcomes trial with semaglutide, results showed an increased risk of events related to 
diabetic retinopathy in subjects treated with semaglutide compared to placebo, albeit the proportion 
of subjects with an EAC-confirmed event of diabetic retinopathy complications was low 
(semaglutide: 3%; placebo: 1.8%). As a precaution in this trial, all subjects are required to have a 
fundus photography or dilated fundoscopy performed before enrolment into the trial; moreover, 
subjects with proliferative retinopathy or maculopathy requiring acute treatment will be excluded. 
As part of good diabetes management the investigator is encouraged to ensure adequate monitoring 
and treatment of diabetic retinopathy in subjects enrolled into the trial62. 
Acute pancreatitis 
Acute pancreatitis has been reported in subjects treated with GLP-1 RAs, including semaglutide and 
liraglutide. As a precaution, subjects with a history of acute or chronic pancreatitis will not be 
enrolled in the trial. Also, subjects will be informed about the symptoms of acute pancreatitis and 
serum levels of lipase and amylase will be monitored throughout the trial.
Pancreatic cancer 
While patients with T2D have an increased risk of certain types of cancer such as pancreatic cancer 
there is currently no support from nonclinical studies or clinical trials or post marketing data that 
GLP-1-based therapies increase the risk of pancreatic cancer. However, pancreatic cancer has been 
classified as a potential class risk of GLP-1 RAs by EMA. 
Other risks
Patients treated with semaglutide or liraglutide may also experience increased heart rate, increase 
lipase and amylase, fatigue, decreased appetite, headache, upper respiratory tract infections , 
malaise and cholecystitis.
18.1.2
Other safety considerations
Teratogenicity (embryo-foetal development toxicity) 
Please see Section 3.1.4 for information on embryo−foetal development toxicity. As a precaution, 
females who are pregnant, breast-feeding or intend to become pregnant or are of childbearing 
potential and not using an adequate contraceptive method will not be enrolled in the trial. In 
addition, pregnancy tests will be performed according to flowchart in Section 2 and at any time 
during the trial if a menstrual period is missed, or as required by local law. 
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General precautions 
All subjects will be included after a thorough evaluation in regards to in- and exclusion criteria 
defined in order to ensure that subjects are eligible for trial enrolment.
There are also strict glycaemic rescue criteria in place to ensure acceptable glycaemic control 
during the trial (see Section 6.4). If rescue medication is required, it should be in accordance with 
ADA/European Association for the Study of Diabetes37, 38(excluding GLP-1 RAs, DPP-4 inhibitors 
and amylin analogues). 
It is the responsibility of the investigator to ensure the best possible care according to the principles 
outlined in Diabetes Care 2017 Standards of Medical Care in Diabetes62. 
Further details with regards to safety of trial product are described in the current edition of the IB 
for semaglutide (NN9535)26 or any updates thereto. 
Safety information on liraglutide can be found in the current SmPC for Victoza®33
18.1.3
Benefits 
In this trial, subjects will be randomised in a 1:1 manner to either semaglutide s.c 1.0 mg 
once-weekly or liraglutide s.c 1.2 mg once-daily as add-on to their current background medication 
with 1−3 OADs (metformin, SU, SGLT-2 inhibitors). Subjects will therefore be treated with a 
regimen anticipated to be better than the treatment they receive at the time of entry into the trial. 
Based on the results of the phase 3a trials, semaglutide is expected to provide clinically relevant 
improvements in glycaemic control and body weight in subjects with T2D. Similarly, treatment 
with liraglutide is expected to provide significant improvements in glycaemic control.
In addition, it is expected that all subjects will benefit from participation through close contact with 
the study site, with close follow-up of their T2D and a careful medical examination, all of which 
will most likely result in an intensified management of their T2D. 
All subjects in this trial will receive trial products and auxiliary supplies free of charge. 
18.1.4
Risk and benefit conclusion 
The safety profile for semaglutide generated from the clinical and nonclinical development 
programme has not revealed any safety issues that would prohibit administration of semaglutide in 
accordance with the planned clinical trial. The phase 3a results indicate that semaglutide will 
provide clinically relevant improvements in glycaemic control and body weight. 
Liraglutide is already a marketed drug approved for the use in subjects with T2D.
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In conclusion, the potential risk to the subjects in this trial is considered low and acceptable in view 
of the anticipated benefits semaglutide and liraglutide will provide to subjects with T2D.
18.2
Informed consent 
In seeking and documenting informed consent, the investigator must comply with applicable 
regulatory requirement(s) and adhere to ICH GCP2 and the requirements in the Declaration of 
Helsinki3.
Before any trial-related activity, the investigator must give the subject verbal and written 
information about the trial and the procedures involved in a form that the subject can read and 
understand. 
The subjects must be fully informed of their rights and responsibilities while participating in the 
trial as well as possible disadvantages of being treated with the trial products.
The investigator must ensure the subject ample time to come to a decision whether or not to 
participate in the trial. 
A voluntary, signed and personally dated informed consent must be obtained from the subject 
before any trial-related activity. 
The responsibility for seeking informed consent must remain with the investigator, but the 
investigator may delegate the task to a medically qualified person, in accordance with local 
requirements. The written informed consent must be signed and personally dated by the person who 
seeks the informed consent before any trial-related activity.
If information becomes available that may be relevant to the subject’s willingness to continue 
participating in the trial, the investigator must inform the subject in a timely manner, and a revised 
written subject information must be provided and a new informed consent must be obtained.
In order to avoid missing data, the subjects will be informed about the importance of completing the 
trial also if the subjects prematurely discontinue treatment with trial product.
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 visit including follow up 
visits 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.
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If data is used, it will always be in accordance with local regulations and IECs.
18.4
Information to subjects during trial
All written information to subjects must be sent to IEC 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 IECs or a regulatory authority may decide to stop the trial, part of the trial or a 
trial site at any time, but agreement on procedures to be followed must be obtained.
If 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 IECs and provide a detailed written explanation. 
If, after the termination of the trial, the benefit-risk analysis changes, the new evaluation must be 
provided to the IECs in case it has an impact on the planned follow-up of subjects who have 
participated in the trial. If it has an impact, the actions needed to inform and protect the subjects 
should be described.
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. 
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. 
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The subjects will be carefully informed about the trial procedures before signing informed consent, 
so that they know the implications of participating in the trial. 
Close surveillance of subject retention will be performed throughout the trial by Novo Nordisk with 
focus on reasons for premature discontinuation of trial product or withdrawal of consent to secure 
early mitigations in collaboration with the trial sites. 
The investigator will make every effort to ensure that all assessments are performed and data is 
collected. 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 IECs. 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.
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 IECs clearly identifying the documents reviewed as 
follows: protocol, any protocol amendments, subject information/informed consent form, 
any other written information to be provided to the subject and subject recruitment materials
!
List of IEC 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 and SmPC or similar labelling 
!
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
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!
Central laboratory certification and normal ranges
!
Insurance statement, if applicable
!
Financial disclosure form from investigator and sub-investigator(s)
Novo Nordisk will analyse and report data from all sites together if more than one site is involved in 
the trial.
By signing the protocol agreement, each investigator agrees to comply fully with ICH GCP2,
applicable regulatory requirements and the Declaration of Helsinki3. 
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.
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.
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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.
One investigator will be appointed by Novo Nordisk to review and sign the clinical trial report 
(signatory investigator) on behalf of all participating investigators. The signatory investigator will 
be appointed based upon the criteria defined by the International Committee of Medical Journal 
Editors for research publications63
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.
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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 Disclosure39. 
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 Editors 63 (sometimes referred to as the Vancouver 
Criteria).
Novo Nordisk will appoint investigator(s) to prepare publications in collaboration with Novo 
Nordisk. 
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23.1.2
Site-specific publication(s) by investigator(s)
For a multi-centre clinical trial, analyses based on single-site data usually have significant statistical 
limitations and frequently do not provide meaningful information for healthcare professionals or 
subjects, and therefore may not be supported by Novo Nordisk. It is a Novo Nordisk policy that 
such individual reports do not precede the primary manuscript and should always reference the 
primary manuscript of the trial.
Novo Nordisk reserves the right to prior review of such publications. Further to allow for the 
primary manuscript to be published as the first, Novo Nordisk asks for deferment of publication of 
individual site results until the primary manuscript is accepted for publication. As Novo Nordisk 
wants to live up to the industry publication policy, submission of a primary publication will take 
place no later than 18 months after trial completion.
23.2
Investigator access to data and review of results
As owner of the trial database, Novo Nordisk has the discretion to determine who will have access 
to the database. 
Individual investigators will have their own research subjects' data, and will be provided with the 
randomisation code after results are available.
24 Retention of clinical trial documentation
Subject’s medical records must be kept for the maximum period permitted by the hospital, 
institution or private practice.
The investigator must agree to archive the documentation (this includes both electronic and paper-
based records) pertaining to the trial in an archive after completion or discontinuation of the trial if 
not otherwise notified. The investigator should not destroy any documents without prior permission 
from Novo Nordisk. If the investigator cannot archive the documents at the trial site, Novo Nordisk 
can refer the investigator to an independent archive provider that has a system in place to allow only 
the investigator to access the files.
The investigator must be able to access his/her trial documents without involving Novo Nordisk in 
any way. Site-specific CRFs and other subject data (in an electronic readable format or as paper 
copies or prints) will be provided to the investigator before access is revoked to the systems 
supplied by Novo Nordisk. These data must be retained by the trial site. If the provided data (e.g. 
the CD-ROM) is not readable during the entire storage period, the investigator can request a new 
copy. A copy of all data will be stored by Novo Nordisk.
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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 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 Independent Ethics Committees and regulatory authorities
Written approval or favourable opinion must be obtained from IEC prior to commencement of the 
trial.
During the trial, the investigator or Novo Nordisk, as applicable, must promptly report the 
following to the IEC, in accordance with local requirements: updates to Investigator’s Brochure,
unexpected SAEs where a causal relationship cannot be ruled out, protocol amendments according 
to local requirements, deviations to the protocol implemented to eliminate immediate hazards to the 
subjects, new information that may affect adversely the safety of the subjects or the conduct of the
trial (including new 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 IEC.
The investigator must ensure submission of the clinical trial report synopsis to the IEC.
Protocol amendments must not be implemented before approval or favourable opinion according to 
local regulations, unless necessary to eliminate immediate hazards to the subjects.
The investigator must maintain an accurate and complete record of all submissions made to the IEC. 
The records must be filed in the investigator trial master file and copies must be sent to Novo 
Nordisk.
Regulatory Authorities:
Regulatory authorities will receive the clinical trial application, protocol amendments, reports on 
SAEs, and the clinical trial report according to national requirements.
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26 Indemnity statement
Novo Nordisk carries product liability for its products, and liability as assumed under the special 
laws, acts and/or guidelines for conducting clinical trials in any country, unless others have shown 
negligence.
Novo Nordisk assumes no liability in the event of negligence, or any other liability of the sites or 
investigators conducting the trial, or by persons for whom the said site or investigator are 
responsible.
Novo Nordisk accepts liability in accordance with: 
For France only: The French Public Health Code article L 1121-10 (law n° 2004-806 of 9 August 
2004 art. 88 I, IX Journal Officiel of 11 August 2004. The sponsor is responsible for identification 
of the harmful consequences of the biomedical research for the person lending himself thereto and 
for indemnification of his beneficiaries, except in case of proof, incumbent on it, that the prejudice 
is not attributable to his fault of or the fault of any intervening party, without the sponsor's being 
entitled to call on acts by a third party or the voluntary withdrawal of the person who had initially 
consented to cooperating in the research.
For Germany only: German Drug Law dated 24 August 1976 in the version published on 12 Dec 
2005 (BGBI. I S. 3394), last amended by Article 3 of the Law of 04 Apr 2016 (BGBI. I S. 569).
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27 References
1.
National Kidney Foundation. KDOQI Clinical Practice Guideline for Diabetes and CKD: 
2012 Update. Am J Kidney Dis. 2012;60(5):850-86.
2.
International Conference of Harmonisation. ICH Harmonised Tripartite Guideline E6(R1): 
Guideline for Good Clinical Practice. 10 Jun 1996.
3.
World Medical Association. WMA Declaration of Helsinki - Ethical Principles for Medical 
Research Involving Human Subjects. Last amended by the 64th WMA General Assembly, 
Fortaleza, Brazil. October 2013.
4.
DeFronzo RA. Pathogenesis of type 2 diabetes mellitus. Med Clin North Am. 
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UKPDS Group. Intensive blood-glucose control with sulphonylureas or insulin compared 
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Kieffer TJ, Habener JF. The glucagon-like peptides. Endocr Rev. 1999;20(6):876-913.
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Bagger JI, Knop FK, Lund A, Vestergaard H, Holst JJ, Vilsbøll T. Impaired regulation of 
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Nauck M, Stockmann F, Ebert R, Creutzfeldt W. Reduced incretin effect in type 2 (non-
insulin-dependent) diabetes. Diabetologia. 1986;29(1):46-52.
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Nauck MA, Vardarli I, Deacon CF, Holst JJ, Meier JJ. Secretion of glucagon-like peptide-1 
(GLP-1) in type 2 diabetes: what is up, what is down? Diabetologia. 2011;54:10-18.
15.
Hojberg PV, Vilsboll T, Rabol R, Knop FK, Bache M, Krarup T, et al. Four weeks of near-
normalisation of blood glucose improves the insulin response to glucagon-like peptide-1 and 
glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes. Diabetologia. 
2009;52(2):199-207.
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Status:
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16.
Sisley S, Gutierrez-Aguilar R, Scott M, D'Alessio DA, Sandoval DA, Seeley RJ. Neuronal 
GLP1R mediates liraglutide's anorectic but not glucose-lowering effect. J Clin Invest. 
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Secher A, Jelsing J, Baquero AF, Hecksher-Sorensen J, Cowley MA, Dalboge LS. The 
acurate nucleus mediates GLP-1 receptor agnist liraglutide-dependent weight loss. J Clin 
Invest. 2014;124(10):4473-88.
18.
Alvarez E, Martínez MD, Roncero I, Chowen JA, García-Cuartero B, Gispert JD, et al. The 
expression of GLP-1 receptor mRNA and protein allows the effect of GLP-1 on glucose 
metabolism in the human hypothalamus and brainstem. J Neurochem. 2005;92(4):798-806.
19.
Nauck MA, Kleine N, Orskov C, Holst JJ, Willms B, Creutzfeldt W. Normalization of 
fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7-36 amide) in type 2 (non-
insulin-dependent) diabetic patients. Diabetologia. 1993;36(8):741-4.
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Nauck MA. Incretin-based therapies for type 2 diabetes mellitus: properties, functions, and 
clinical implications. Am J Med. 2011;124(1 Suppl):S3-18.
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Toft-Nielsen MB, Damholt MB, Madsbad S, Hilsted LM, Hughes TE, Michelsen BK, et al. 
Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic 
patients. J Clin Endocrinol Metab. 2001;86(8):3717-23.
22.
Nauck MA, Petrie JR, Sesti G, Mannucci E, Courrèges JP, Lindegaard ML, et al. A Phase 2, 
Randomized, Dose-Finding Study of the Novel Once-Weekly Human GLP-1 Analog, 
Semaglutide, Compared With Placebo and Open-Label Liraglutide in Patients With Type 2 
Diabetes. Diabetes Care. 2016;39(2):231-41.
23.
Lau J, Bloch P, Schäffer L, Pettersson I, Spetzler J, Kofoed J, et al. Discovery of the Once-
Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide. J Med Chem. 
2015;58(18):7370-80.
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International Conference of Harmonisation. ICH Harmonised Tripartite Guideline M3(R2). 
Guidance on nonclinical safety studies for the conduct of human clinical trials and 
marketing authorization for pharmaceuticals, Step 4 Version. 11 June 2009.
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Waser B, Blank A, Karamitopoulou E, Perren A, Reubi JC. Glucagon-like-peptide-1 
receptor expression in normal and diseased human thyroid and pancreas. Mod Pathol. 
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26.
Investigator's Brochure for s.c. Semaglutide (NN9535), Edition 11 or any updates hereof. 
2016.
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Sorli C HS, Tsoukas G, Unger J, Derving Karsbol J, Hansen T, Bain S. Efficacy and safety 
of once-weekly semaglutide monotherapy versus placebo in subjects with type 2 diabetes 
(SUSTAIN 1).  ENDO 2016 - 98th Annual Meeting of the Endocrine Society2016.
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Ahmann A, Capehorn M, Charpentier G, Dotta F, Henkel E, Lingvay I, et al. Efficacy and 
safety of once-weekly semaglutide vs exenatide ER after 56 Weeks in subjects with type 2 
diabetes (SUSTAIN 3).  European Association for the Study of Diabetes, 52nd meeting, 
Oral Presentation #1472016.
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Ahrén B, Comas LM, Kumar H, Sargin M, Derving Karsbøl J, Jacobsen SH, et al. Efficacy 
and Safety of Once-weekly Semaglutide vs Sitagliptin as add-on to Metformin and/or 
Thiazolidinediones After 56 Weeks in Subjects With Type 2 Diabetes (SUSTAIN 2).  
European Association for the Study of Diabetes, 52nd meeting, ePoster #7672016.
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Version:
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UTN:U1111-1190-5868 
Status:
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30.
Aroda V, Bain S, Cariou B, Piletic M, Rose L, Axelsen MB, et al. Efficacy and safety of 
once-weekly semaglutide vs once-daily insulin glargine in insulin-naïve subjects with type 2 
diabetes (SUSTAIN 4). Endocrine practice. 2016.
31.
Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, et al. Semaglutide and 
Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2016;375:1834-
44.
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Novo Nordisk A/S. Company Announcement: SUSTAIN 6. 2016.
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EU product information Victoza,  current version and any updates hereof. 
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/001026/h
uman_med_001137.jsp&mid=WC0b01ac058001d124: European Medicines Agency;  [cited 
2017 23-JAN-2017].
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Shyangdan D, Cummins E, Royle P, Waugh N. Liraglutide for the treatment of type 2 
diabetes. Health Technol Assess. 2011;15 Suppl 1:77-86.
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Nice recommendations. https://www.nice.org.uk/guidance/ta203/uptake.
36.
Xue X, Ren Z, Zhang A, Yang Q, Zhang W, Liu F. Efficacy and safety of once-weekly 
glucagon-like peptide-1 receptor agonists compared with exenatide and liraglutide in type 2 
diabetes: a systemic review of randomised controlled trials. Int J Clin Pract. 2016;70(8):649-
56.
37.
Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. 
Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position 
statement of the American Diabetes Association (ADA) and the European Association for 
the Study of Diabetes (EASD). Diabetologia. 2012;55(6):1577-96.
38.
Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. 
Management of hyperglycaemia in type 2 diabetes, 2015: a patient-centred approach. 
Update to a position statement of the American Diabetes Association and the European 
Association for the Study of Diabetes. Diabetologia. 2015;58(3):429-42.
39.
Novo Nordisk A/S. http://www.novonordisk-trials.com/website/content/how-we-disclose-
trial-information.aspx.
40.
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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U.S. Department of Health and Human Services, Food and Drug Administration. Food and 
Drug Administration Amendments Act of 2007.
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The European Parliament and the Council of the European Council. Directive 2001/20/EC 
of the European Parliament and of the Council 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. 01 May 
2001.
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The European Parliament and the Council of the European Council. Regulation (EC) No 
726/2004 of the European Parliament and of the Council of 31 March 2004 laying down 
Community procedures for the authorisation and supervision of medicinal products for 
human and veterinary use and establishing a European Medicines Agency, article 57. 30 
April 2004.
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44.
McAulay V, Deary IJ, Frier BM. Symptoms of hypoglycaemia in people with diabetes. 
Diabet Med. 2001;18(9):690-705.
45.
U.S. Department of Health and Human Services, Food and Drug Administration. Guidance 
for Industry. Patient-Reported Outcome Measures: Use in Medical Product Development to 
Support Labeling Claims. Avaliable from: 
http://www.fda.gov/downloads/Drugs/Guidances/UCM193282.pdf. 2009.
46.
Stull DE, Leidy NK, Parasuraman B, Chassany O. Optimal recall periods for patient-
reported outcomes: challenges and potential solutions. Curr Med Res Opin. 2009;25(4):929-
42.
47.
European Commission. The Rules Governing Medicinal Products in the European Union, 
Volume 4, Annex 13, Investigational Medicinal Products (ENTR/F/2/AM/an D[2010] 
3374). 03 Feb 2010.
48.
U.S.Department of Health and Human Services, Food and Drug Administration, Center for 
Drug Evaluation and Research (CDER). Guidance for Industry, Diabetes Mellitus -
Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. 
December 2008.
49.
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. 2008.
50.
Sethi B, Viswanathan, V., Kumar, A., Chatterjee, S., Chandalia, HB. Liraglutide in Clinical 
Practice: Insights from LEAD Programme. JAPI; 2010. p. 18-22.
51.
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.
52.
Zinman B, Gerich J, Buse JB, Lewin A, Schwartz S, Raskin P, et al. Efficacy and safety of 
the human glucagon-like peptide-1 analog liraglutide in combination with metformin and 
thiazolidinedione in patients with type 2 diabetes (LEAD-4 Met+TZD). Diabetes Care. 
2009;32(7):1224-30.
53.
Bretz F, Posch M, Glimm E, Klinglmueller F, Maurer W, Rohmeyer K. Graphical 
approaches for multiple comparison procedures using weighted Bonferroni, Simes, or 
parametric tests. Biometrical Journal. 2011;53(6):894-913.
54.
Rohmeyer K, Klinglmueller F. gMCP: Graph Based Multiple Test Procedures. R package 
version 0.8-8. 3 Oct 2014.
55.
Little RJA, Rubin DB. Statistical analysis with missing data: New York: John Wiley & 
Sons. 1987.
56.
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.
57.
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.
58.
Dahl-Jørgensen K, Brinchmann-Hansen O, Hanssen KF, Sandvik L, Aagenaes O. Rapid 
tightening of blood glucose control leads to transient deterioration of retinopathy in insulin 
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Date:
03 February 2017
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Version:
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dependent diabetes mellitus: the Oslo study. Br Med J (Clin Res Ed). 1985;290(6471):811-
5.
59.
Turner RC, Holman RR, Stratton IM, Cull CA, Matthews DR, Manley SE, et al. Effect of 
intensive blood-glucose control with metformin on complications in overweight patients 
with type 2 diabetes (UKPDS 34). Lancet. 1998;352(9131):854-65.
60.
The Action to Control Cardiovascular Risk in Diabetes Follow-On (ACCORDION) Eye 
Study Group and the Action to Control Cardiovascular Risk in Diabetes Follow-On 
(ACCORDION) Study Group. Persistent Effects of Intensive Glycemic Control on 
Retinopathy in Type 2 Diabetes in the Action to Control Cardiovascular Risk in Diabetes 
(ACCORD) Follow-On Study. Diabetes Care. 2016;39(7):1089-100.
61.
The Diabetes Control and Complications Trial Research Group. Early worsening of diabetic 
retinopathy in the Diabetes Control and Complications Trial. Arch Ophthalmol. 
1998;116(7):874-86.
62.
Marathe PH, Gao HX, Close KL. American Diabetes Association Standards of Medical 
Care in Diabetes 2017. J Diabetes. 2017.
63.
International Committee of Medical Journal Editors. Recommendations for the Conduct, 
Reporting, Editing and Publication of Scholarly Work in Medical Journals; current version 
available at www.icmje.org.
CONFIDENTIAL


Protocol - Appendix A
CONFIDENTIAL
Date:
03 February 2017
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Trial ID: NN9535-4339
Version:
2.0
UTN: U1111-1190-5868 
Status:
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EudraCT No.:2016-004965-22  
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Appendix A
Monitoring of calcitonin
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties
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This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol - Appendix A
CONFIDENTIAL
Date:
03 February 2017
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Trial ID: NN9535-4339
Version:
2.0
UTN: U1111-1190-5868 
Status:
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1
Background
Treatment with GLP-1 receptor agonists has been shown to be associated with thyroid C-cell 
changes in rodents but not in non-human primates. The human relevance of this finding is 
unknown. However, based on the findings in rodents, monitoring of serum calcitonin (a sensitive 
biomarker for C-cell activation) is currently being performed in clinical trials with semaglutide.
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 A
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03 February 2017
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Trial ID: NN9535-4339
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UTN: U1111-1190-5868 
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2
Calcitonin monitoring
A blood sample will be drawn at pre-specified trial visits for measurement of calcitonin.
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 in the trial.
Calcitonin < 10ng/L
Calcitonin  ≥ 10 ng/L and 
< 50 ng/L
Calcitonin  ≥ 50 ng/L and 
< 100 ng/L
Calcitonin  ≥ 100 ng/L
Evaluation of 
calcitonin results
Calcitonin  ≥ 10 ng/L and 
last measurement in the 
trial
No action
●Investigate potential confounding 
factors
●Continue sampling of calcitonin 
according to protocol
●Refer to thyroid specialist
●Discontinue trial product
●Refer to thyroid specialist
●Refer to thyroid specialist
Figure 1
Flow of calcitonin monitoring
2.1
Calcitonin ≥100 ng/L
Action: The subject must immediately be referred to a thyroid specialist for further evaluation and 
the trial product must be discontinued . The subject should remain in the trial; however, all 
CONFIDENTIAL


Protocol - Appendix A
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Trial ID: NN9535-4339
Version:
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UTN: U1111-1190-5868 
Status:
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medications suspected to relate to this condition must 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 disease 1. All of these patients were diagnosed with medullary thyroid carcinoma (MTC) ,
resulting in a positive predictive value of 100%.
Diagnostic evaluation should include:
!
thyroid ultrasound examination
!
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 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 should be referred to a thyroid specialist for further evaluation. The subject 
should remain in the trial and continuation on trial product should be based on the evaluation done 
by the thyroid specialist. 
Background: These values were found in 8 (0.14%) of the population of 5817 patients with thyroid 
nodular disease 1. 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, and if there are no contraindications, a pentagastrin stimulation test should be done. 
For subjects with positive pentagastrin stimulation test, surgery should be considered.
!
if pentagastrin stimulation test is not available, thyroid ultrasound and fine needle aspiration 
biopsy may add important clinical information about 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 value is from the last sample taken in the trial, the subject should be referred to a thyroid 
specialist for further evaluation.
CONFIDENTIAL


Protocol - Appendix A
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Date:
03 February 2017
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Trial ID: NN9535-4339
Version:
2.0
UTN: U1111-1190-5868 
Status:
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EudraCT No.:2016-004965-22  
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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 disease 1. The predictive value of a C-cell anomaly 
for this calcitonin level was 8.3%. However, the likelihood of having a medullary carcinoma >1 cm 
with calcitonin in this range is extremely low.
For calcitonin values between 10-20 ng/L Costante et al. 1 identified 216 (3.7%) patients. One 
patient out of the 216 had a subsequent basal (unstimulated) calcitonin value 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 CT >10 and <20 
ng/L to allow conclusions 2, 3.
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Protocol - Appendix A
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Date:
03 February 2017
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Trial ID: NN9535-4339
Version:
2.0
UTN: U1111-1190-5868 
Status:
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3
References
1.
Costante G, Meringolo D, Durante C, Bianchi D, Nocera M, Tumino S, et al. Predictive 
value of serum calcitonin levels for preoperative diagnosis of medullary thyroid carcinoma 
in a cohort of 5817 consecutive patients with thyroid nodules. J Clin Endocrinol Metab. 
2007;92(2):450-5.
2.
Scheuba C, Kaserer K, A m, drosten R. Sporadic hypercalcitoninemia: clinica and 
therapeutic consequences. Endocrine Related Cancer. 2009;16(1):243-53.
3.
Verga U, Ferrero S, Vicentini L, Brambilla T, Cirello V, Muzza M, et al. Histopathological 
and molecular studies in patients with goiter and hypercalcitoninemia: reactive or neoplastic 
C-cell hyperplasia? Endocr Relat Cancer. 2007;14(2):393-403.
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
03 February 2017
Novo Nordisk
Trial ID: NN9535-4339
Version:
2.0
UTN:U1111-1190-5868 
Status:
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Appendix B
Adverse events requiring additional data collection
Ann-Sophie Iuel-Brockdorff
Semaglutide Diabetes & Diabetes Outcomes
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties
CONFIDENTIAL
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disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol - Appendix B
CONFIDENTIAL
Date:
03 February 2017
Novo Nordisk
Trial ID: NN9535-4339
Version:
2.0
UTN:U1111-1190-5868 
Status:
Final
EudraCT no.:2016-004965-22  
Page:
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Table of Contents
Table of Contents..............................................................................................................................................2
1
Adverse events requiring additional data collection..............................................................................3
1.1
Hypersensitivity reactions..............................................................................................................3
1.2
Pancreatitis.....................................................................................................................................4
1.3
Renal event ....................................................................................................................................5
1.4
Hepatic event .................................................................................................................................5
1.5
Diabetic retinopathy.......................................................................................................................6
1.6
Acute gallstone disease..................................................................................................................6
2
References..................................................................................................................................................7
CONFIDENTIAL


Protocol - Appendix B
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Date:
03 February 2017
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Trial ID: NN9535-4339
Version:
2.0
UTN:U1111-1190-5868 
Status:
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1
Adverse events requiring additional data collection
For the following AEs, additional data collection is required and specific event forms in eCRF
should be completed in addition to the AE form. 
!
Hypersensitivity reaction
!
Pancreatitis
!
Renal event
!
Hepatic event
!
Diabetic retinopathy
!
Acute gallstone disease
Additional information on a specific form is also required for hypoglycaemic episode and 
medication errors, which is described in the protocol. 
1.1
Hypersensitivity reactions
All events of hypersensitivity reactions must be reported and the following additional information 
should be reported if available:
!
Signs and symptoms associated with the event
!
Time of appearance after administration of trial drug
!
Relevant immunological tests performed
!
Treatment given for the reaction
!
Previous history of similar reactions
!
Risk or confounding factors identified
Assessments in case of suspicion of hypersensitivity reactions:
In case of suspicion of a severe immediate systemic hypersensitivity reaction1 to the trial product, 
the subject must be discontinued from trial product but should remain in the trial. If suspicion of a 
hypersensitivity reaction occurs, the subjects should be instructed to contact the site staff as soon as 
possible for further guidance.
To assist in the diagnostic evaluation it is recommended to draw a blood sample for measurement of 
tryptase (total and/or mature tryptase, local assessment) within 3 hours of onset of the 
hypersensitivity reaction, and if this is achieved, a tryptase sample should also be drawn 2 weeks 
after the event.
Furthermore, a blood sample for assessment of anti-semaglutide IgE antibodies should be drawn 
after 2 weeks and sent to central laboratory. Tryptase concentrations, if available, should be 
included in the specific event form when reporting the AE.
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
03 February 2017
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Trial ID: NN9535-4339
Version:
2.0
UTN:U1111-1190-5868 
Status:
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In case of suspicion of immune complex disease1, the subject must be discontinued from trial 
product but should remain in the trial. It is recommended to draw a blood sample for local 
assessment of complement levels (C3 and C4) to assist in the diagnostic evaluation. Complement 
level results should be included in the specific event form when reporting the AE.
1.2
Pancreatitis
For all confirmed events of pancreatitis the following additional information should be reported if 
available:
!
Signs and symptoms of pancreatitis
!
Specific laboratory test supporting a diagnosis of pancreatitis:
!
Imaging performed and consistency with pancreatic disease
!
Treatment for and complications of the event
!
Relevant risk factors for pancreatic disease
!
Family history of pancreatitis
Assessments in case of suspicion of acute pancreatitis:
Most patients with acute pancreatitis experience severe abdominal pain that is located generally in 
the epigastrium and radiates to the back. The onset of the pain may be swift, reaching maximum 
intensity within 30 min, is frequently unbearable, and characteristically persists for more than 24 
hours without relief2. The pain is often associated with nausea and vomiting. Physical examination 
usually reveals severe upper abdominal tenderness at times associated with guarding.
In general, both amylase and lipase are elevated during the course of acute pancreatitis. The serum 
lipase may remain elevated slightly longer than amylase. The level of the serum amylase and/or 
lipase does not correlate with the severity of acute pancreatitis2. In general, serum lipase is thought 
to be more sensitive and specific than serum amylase in the diagnosis of acute pancreatitis.
In case of suspicion of acute pancreatitis, the trial product should promptly be interrupted (no 
treatment discontinuation call should be made in IWRS before diagnosis of acute pancreatitis is 
confirmed). Appropriate additional examinations should be performed, including measurement of 
amylase and lipase.
The diagnosis of acute pancreatitis requires two of the following three features3:
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
03 February 2017
Novo Nordisk
Trial ID: NN9535-4339
Version:
2.0
UTN:U1111-1190-5868 
Status:
Final
EudraCT no.:2016-004965-22  
Page:
5 of 7
!
abdominal pain consistent with acute pancreatitis (acute onset of a persistent, severe, epigastric 
pain often radiating to the back)
!
serum lipase activity (and/or amylase activity) at least three times greater than the upper normal 
limit
!
characteristic findings of acute pancreatitis on imaging.
1.3
Renal event
If a renal event is observed during the trial, the following additional information should be reported 
if available:
!
Signs and symptoms of renal failure
!
Specific laboratory tests supporting the diagnosis
!
Imaging performed supporting the diagnosis
!
Kidney biopsy results
Risk or confounding factors identified including exposure to nephrotoxic agents
1.4
Hepatic event
!
ALT or AST > 5 × UNL and total bilirubin ≤ 2 × UNL
!
ALT or AST > 3 × UNL and total bilirubin > 2 × UNL*
!
Hepatic event leading to trial product discontinuation
If one of the above events is observed during the trial, the following additional information should
be reported if available:
!
Signs and symptoms associated with the event
!
Risk factors
!
Relevant laboratory test results
!
Diagnostic imaging performed
!
Possible cause(s) of the event
!
Assessments in case of increased levels of aminotransferases
The above mentioned hepatic events should prompt repeat testing (at the central laboratory) 
including ALT, AST, ALP and total bilirubin, and discontinuation of trial product should be 
considered. Thereafter, repeat testing (at the central laboratory) of ALT, AST, ALP and total 
bilirubin should be done regularly until the abnormalities return to normal or baseline state. 
Additional clinical information such as related symptoms, risk factors and contributing conditions 
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
03 February 2017
Novo Nordisk
Trial ID: NN9535-4339
Version:
2.0
UTN:U1111-1190-5868 
Status:
Final
EudraCT no.:2016-004965-22  
Page:
6 of 7
(e.g. viral hepatitis, autoimmune hepatitis, alcoholic hepatitis, hepatobiliary or pancreatic disorders) 
should be gathered to seek a possible cause of the observed laboratory test abnormalities.
*Please note that risk of liver injury defined as ALT or AST > 3 × UNL and total bilirubin > 2 × 
UNL, where no alternative aetiology exits (Hy’s law), should also be reported as a SAE.
1.5
Diabetic retinopathy
If an event of diabetic retinopathy (new onset or worsening of) is observed during the trial the 
following additional information should be reported if available on the diabetic retinopathy form: 
!
Signs and symptoms associated with the event
!
Results of the eye examination 
!
Treatment for and complications of the event
!
Contributing conditions
1.6
Acute gallstone disease
If an event of gallstone is observed during the trial the following additional information should be 
reported if available: 
!
Signs and symptoms of gallstone 
!
Specific laboratory test supporting a diagnosis of gallstone
!
Imaging performed and consistency with  gallstone 
!
Treatment for and complications of the event
!
Relevant risk factors for gallstone 
!
Family history of gallstone
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
03 February 2017
Novo Nordisk
Trial ID: NN9535-4339
Version:
2.0
UTN:U1111-1190-5868 
Status:
Final
EudraCT no.:2016-004965-22  
Page:
7 of 7
2
References
1.
Food and Drug Administration. Guidance for Industry:Immunogenicity Assessment for 
Therapeutic Protein Products. 8/2015 2015.
2.
Banks PA, Freeman ML, Practice Parameters Committee of the American College of 
Gastroenterology. Practice guidelines in acute pancreatitis. Am J Gastroenterol. 
2006;101(10):2379-400.
3.
Banks PA, Bollen TL, Dervenis C, Gooszen HG, Johnson CD, Sarr MG, et al. Classification 
of acute pancreatitis-2012: revision of the Atlanta classification and definitions by 
international consensus. Gut. 2013;62(1):102-11.
4.
National Cancer Institute. Common Terminology Criteria for Adverse Events v4.03 (NIH 
publication # 09-7473). http://evsncinihgov/ftp1/CTCAE/CTCAE_403_2010-06-
14_QuickReference_5x7pdf. 2010.
CONFIDENTIAL


Protocol - Appendix C
CONFIDENTIAL
Date:
03 February 2017
Novo Nordisk
Trial ID: NN9535-4339
Version:
2.0
UTN: U1111-1190-5868 
Status:
Final
EudraCT No.:2016-004965-22  
Page:
2 of 9
SF-36v2® Health Survey ! 2016 QualityMetric Incorporated and Medical Outcomes Trust.  All rights reserved.
SF-36® is a registered trademark of Medical Outcomes Trust.
(SF-36v2® Health Survey Standard, United States (English))
Appendix C
SF-36v2TM and DTSQ
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
CONFIDENTIAL
Date:
03 February 2017
Novo Nordisk
Trial ID: NN9535-4339
Version:
2.0
UTN: U1111-1190-5868 
Status:
Final
EudraCT No.:2016-004965-22  
Page:
3 of 9
SF-36v2® Health Survey ! 2016 QualityMetric Incorporated and Medical Outcomes Trust.  All rights reserved.
SF-36® is a registered trademark of Medical Outcomes Trust.
(SF-36v2® Health Survey Standard, United States (English))
Your Health and Well-Being
This survey asks for your views about your health.  This information will help 
keep track of how you feel and how well you are able to do your usual 
activities. Thank you for completing this survey!
For each of the following questions, please mark an 
in the one box that best 
describes your answer.
1.
In general, would you say your health is:
Excellent
Very good
Good
Fair
Poor
 
 

 
 
  
1
  
2
  
3
  
4
  
5
2.
Compared to one year ago, how would you rate your health in general 
now?
Much better 
now than one 
year ago
Somewhat
better
now than one 
year ago
About the
same as
one year ago
Somewhat
worse
now than one
year ago
Much worse 
now than one 
year ago
 
 
 
 
 
  
1
  
2
  
3
  
4
  
5
CONFIDENTIAL


Protocol - Appendix C
CONFIDENTIAL
Date:
03 February 2017
Novo Nordisk
Trial ID: NN9535-4339
Version:
2.0
UTN: U1111-1190-5868 
Status:
Final
EudraCT No.:2016-004965-22  
Page:
4 of 9
SF-36v2® Health Survey ! 2016 QualityMetric Incorporated and Medical Outcomes Trust.  All rights reserved.
SF-36® is a registered trademark of Medical Outcomes Trust.
(SF-36v2® Health Survey Standard, United States (English))
3.
The following questions are about activities you might do during a typical 
day.  Does your health now limit you in these activities?  If so, how much? 
Yes,
limited
a lot
Yes,
limited
a little
No, not 
limited
at all
  
a
Vigorous activities, such as running, lifting 
heavy objects, participating in strenuous sports.......................
1..............
2..............
3
b
Moderate activities, such as moving a table, pushing 
a vacuum cleaner, bowling, or playing golf.............................
1..............
2..............
3
c
Lifting or carrying groceries ....................................................
1..............
2..............
3
d
Climbing several flights of stairs .............................................
1..............
2..............
3
e
Climbing one flight of stairs ....................................................
1..............
2..............
3
f
Bending, kneeling, or stooping ................................................
1..............
2..............
3
g
Walking more than a mile........................................................
1..............
2..............
3
h
Walking several hundred yards................................................
1..............
2..............
3
i
Walking one hundred yards .....................................................
1..............
2..............
3
j
Bathing or dressing yourself ....................................................
1..............
2..............
3
CONFIDENTIAL


Protocol - Appendix C
CONFIDENTIAL
Date:
03 February 2017
Novo Nordisk
Trial ID: NN9535-4339
Version:
2.0
UTN: U1111-1190-5868 
Status:
Final
EudraCT No.:2016-004965-22  
Page:
5 of 9
SF-36v2® Health Survey ! 2016 QualityMetric Incorporated and Medical Outcomes Trust.  All rights reserved.
SF-36® is a registered trademark of Medical Outcomes Trust.
(SF-36v2® Health Survey Standard, United States (English))
4.
During the past 4 weeks, how much of the time have you had any of the 
following problems with your work or other regular daily activities as a 
result of your physical health?
All of
the time
Most of
the time
Some of
the time
A little of
the time
None of
the time
     
a
Cut down on the amount of
time you spent on work or 
other activities.................................
1 .............
2 .............
3 ..............
4.............
5
b
Accomplished less than you 
would like........................................
1 .............
2 .............
3 ..............
4.............
5
c
Were limited in the kind of 
work or other activities....................
1 .............
2 .............
3 ..............
4.............
5
d
Had difficulty performing the
work or other activities (for 
example, it took extra effort)...........
1 .............
2 .............
3 ..............
4.............
5
5.
During the past 4 weeks, how much of the time have you had any of the 
following problems with your work or other regular daily activities as a 
result of any emotional problems (such as feeling depressed or anxious)?
All of
the time
Most of
the time
Some of
the time
A little of
the time
None of
the time
     
a
Cut down on the amount of
time you spent on work or 
other activities.................................
1 .............
2 .............
3 ..............
4.............
5
b
Accomplished less than you 
would like........................................
1 .............
2 .............
3 ..............
4.............
5
c
Did work or other activities
less carefully than usual ..................
1 .............
2 .............
3 ..............
4.............
5
CONFIDENTIAL


Protocol - Appendix C
CONFIDENTIAL
Date:
03 February 2017
Novo Nordisk
Trial ID: NN9535-4339
Version:
2.0
UTN: U1111-1190-5868 
Status:
Final
EudraCT No.:2016-004965-22  
Page:
6 of 9
SF-36v2® Health Survey ! 2016 QualityMetric Incorporated and Medical Outcomes Trust.  All rights reserved.
SF-36® is a registered trademark of Medical Outcomes Trust.
(SF-36v2® Health Survey Standard, United States (English))
6.
During the past 4 weeks, to what extent has your physical health or 
emotional problems interfered with your normal social activities with 
family, friends, neighbors, or groups?
Not at all
Slightly
Moderately
Quite a bit
Extremely
 
 
 
 
 
  
1
  
2
  
3
  
4
  
5
7.
How much bodily pain have you had during the past 4 weeks?
None
Very mild
Mild
Moderate
Severe
Very severe
 
     
  
1
  
2
  
3
  
4
  
5
  
6
8.
During the past 4 weeks, how much did pain interfere with your normal 
work (including both work outside the home and housework)?
Not at all
A little bit
Moderately
Quite a bit
Extremely
 
 
 
 
 
  
1
  
2
  
3
  
4
  
5
CONFIDENTIAL


Protocol - Appendix C
CONFIDENTIAL
Date:
03 February 2017
Novo Nordisk
Trial ID: NN9535-4339
Version:
2.0
UTN: U1111-1190-5868 
Status:
Final
EudraCT No.:2016-004965-22  
Page:
7 of 9
SF-36v2® Health Survey ! 2016 QualityMetric Incorporated and Medical Outcomes Trust.  All rights reserved.
SF-36® is a registered trademark of Medical Outcomes Trust.
(SF-36v2® Health Survey Standard, United States (English))
9.
These questions are about how you feel and how things have been with you 
during the past 4 weeks.  For each question, please give the one answer that 
comes closest to the way you have been feeling.  How much of the time 
during the past 4 weeks…
10. During the past 4 weeks, how much of the time has your physical health or 
emotional problems interfered with your social activities (like visiting with 
friends, relatives, etc.)?
All of
the time
Most of
the time
Some of
the time
A little of
the time
None of
the time
 
 
 
 
 
  
1
  
2
  
3
  
4
  
5
All of
the time
Most of
the time
Some of
the time
A little of
the time
None of
the time
     
a
Did you feel full of life?..................
1 .............
2 .............
3 ..............
4.............
5
b
Have you been very nervous? .........
1 .............
2 .............
3 ..............
4.............
5
c
Have you felt so down in the
dumps that nothing could 
cheer you up? ..................................
1 .............
2 .............
3 ..............
4.............
5
d
Have you felt calm and  
peaceful?..........................................
1 .............
2 .............
3 ..............
4.............
5
e
Did you have a lot of energy? .........
1 .............
2 .............
3 ..............
4.............
5
f
Have you felt downhearted  
and depressed?.................................
1 .............
2 .............
3 ..............
4.............
5
g
Did you feel worn out?....................
1 .............
2 .............
3 ..............
4.............
5
h
Have you been happy? ....................
1 .............
2 .............
3 ..............
4.............
5
i
Did you feel tired?...........................
1 .............
2 .............
3 ..............
4.............
5
CONFIDENTIAL


Protocol - Appendix C
CONFIDENTIAL
Date:
03 February 2017
Novo Nordisk
Trial ID: NN9535-4339
Version:
2.0
UTN: U1111-1190-5868 
Status:
Final
EudraCT No.:2016-004965-22  
Page:
8 of 9
SF-36v2® Health Survey ! 2016 QualityMetric Incorporated and Medical Outcomes Trust.  All rights reserved.
SF-36® is a registered trademark of Medical Outcomes Trust.
(SF-36v2® Health Survey Standard, United States (English))
11. How TRUE or FALSE is each of the following statements for you?
Definitely 
true
Mostly 
true
Don’t 
know
Mostly 
false
Definitely
false

 


a
I seem to get sick a little
easier than other people...................
1 .............
2 .............
3..............
4 .............
5
b
I am as healthy as 
anybody I know...............................
1 .............
2 .............
3..............
4 .............
5
c
I expect my health to 
get worse .........................................
1 .............
2 .............
3..............
4 .............
5
d
My health is excellent .....................
1 .............
2 .............
3..............
4 .............
5
Thank you for completing these questions!
CONFIDENTIAL


Protocol - Appendix C
CONFIDENTIAL
Date:
03 February 2017
Novo Nordisk
Trial ID: NN9535-4339
Version:
2.0
UTN: U1111-1190-5868 
Status:
Final
EudraCT No.:2016-004965-22  
Page:
9 of 9
FOR USE by Novo Nordisk A/S in study NN9535-4339 under licence HPR 1971
DTSQs © Prof Clare Bradley 9/93 Standard UK English (rev. 7/94)
Health Psychology Research, Dept of Psychology, Royal Holloway, University of London, Egham, Surrey, TW20 0EX, UK.
Diabetes Treatment Satisfaction Questionnaire: DTSQs
The following questions are concerned with the treatment for your diabetes (including 
insulin, tablets and/or diet) and your experience over the past few weeks.  Please answer 
each question by circling a number on each of the scales.
1.
How satisfied are you with your current treatment?
very satisfied
6
5
4
3
2
1
0
very dissatisfied
2.
How often have you felt that your blood sugars have been unacceptably high recently?
most of the time
6
5
4
3
2
1
0
none of the time
3.
How often have you felt that your blood sugars have been unacceptably low recently?
most of the time
6
5
4
3
2
1
0
none of the time
4.
How convenient have you been finding your treatment to be recently?
very convenient
6
5
4
3
2
1
0
very inconvenient
5.
How flexible have you been finding your treatment to be recently?
very flexible
6
5
4
3
2
1
0
very inflexible
6.
How satisfied are you with your understanding of your diabetes?
very satisfied
6
5
4
3
2
1
0
very dissatisfied
7.
Would you recommend this form of treatment to someone else with your kind of diabetes?
Yes, I would definitely 
recommend the 
treatment
6
5
4
3
2
1
0
No, I would definitely 
not recommend the 
treatment
8.
How satisfied would you be to continue with your present form of treatment?
very satisfied
6
5
4
3
2
1
0
very dissatisfied
Please make sure that you have circled one number on each of the scales.
CONFIDENTIAL


End Text – UK/English - Version 1.0 of 23-Sep-2011
Endtext_TS1.0_eng-GBori.doc
There are no more questions.
Thank you for carefully answering all the questions.
Please check that you have answered all the questions and 
once you are done, hand the questionnaire to the study 
coordinator.
Thank you very much for your help.
CONFIDENTIAL


Global and country key Novo Nordisk staff
Attachments I and II (if applicable) to the protocol are located in the Trial Master File.
Content: Global key staff and Country key staff
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
Semaglutide s.c. Ozempic®
Trial ID: NN9535-4339
Clinical Trial Report
Appendix 16.1.1
27 May 2019
1.0
Final
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
18 May 2017
Novo Nordisk
Trial ID: NN9535-4339
Version:
1.0-Fr
UTN:U1111-1190-5868
Status:
Final
EudraCT No.:2016-004965-22
Page:
1 of 4
Protocol Amendment
no 1-Fr
to Protocol, final version 2.0
dated 03 february 2017
Trial ID:NN9535-4339
SUSTAIN 10 
Efficacy and safety of semaglutide 1.0 mg once-weekly versus 
liraglutide 1.2 mg once-daily as add-on to 1-3 oral anti-diabetic drugs 
(OADs) in subjects with type 2 diabetes
Trial phase: 3b
Applicable to France 
Amendment originator:
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol Amendment
CONFIDENTIAL
Date:
18 May 2017
Novo Nordisk
Trial ID: NN9535-4339
Version:
1.0-Fr
UTN:U1111-1190-5868
Status:
Final
EudraCT No.:2016-004965-22
Page:
2 of 4
Table of Contents   
Page
Table of Contents........................................................................................................................................2
Table of Tables............................................................................................................................................2
1
Introduction including rationale for the protocol amendment...........................................................3
2
Changes ................................................................................................................................................3
2.1
Page 30, Section 6.8 Rationale for trial population.....................................................................3
2.2
Page 48, Section 9.3 Storage .....................................................................................................3
Table of Tables   
Page
Table 9–2
Storage conditions ..............................................................................................................3
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
18 May 2017
Novo Nordisk
Trial ID: NN9535-4339
Version:
1.0-Fr
UTN:U1111-1190-5868
Status:
Final
EudraCT No.:2016-004965-22
Page:
3 of 4
1
Introduction including rationale for the protocol amendment
Following the submission of the NN9535-4339 on the 22 March 2017, the French Health Authority 
requested the changes below to be included in the protocol: 
-
The IMPD to be modified in order to comply with the European guidance 
CPMP/QWP/159/96 corr for the in-use shelf life limited to 4 weeks at a temperature below 
30 °C consequently the protocol is updated with an in-use period for semaglutide drug 
product of 28 days
-
The protocol to be modified in order to specify that the trial will include patients with type 2 
diabetes in whom treatment with diet and physical exercise alone should have been 
attempted and deemed not sufficient to achieve glycaemic control and who subsequently are 
treated with stable doses of 1-3 OAD(s). 
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
2
Changes
2.1
Page 30, Section 6.8 Rationale for trial population
The trial population will include subjects in whom treatment with diet and physical exercise alone 
should have been attempted and deemed not sufficient to achieve glycaemic control, and who 
subsequently are treated with stable doses of 1−3 OAD(s) (see Section 5.3.2) for at least 90 days 
prior to screening.
2.2
Page 48, Section 9.3 Storage
Table 9–2
Storage conditions
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
18 May 2017
Novo Nordisk
Trial ID: NN9535-4339
Version:
1.0-Fr
UTN:U1111-1190-5868
Status:
Final
EudraCT No.:2016-004965-22
Page:
4 of 4
Trial product
Storage conditions (not-
in-use)
In-use conditions
In-use time1
Semaglutide 
1.34 mg/mL
Store in a refrigerator 
(2°C to 8°C) 
Store below 30°C 
Protect from light
Use within 8 weeks 28 
days
Liraglutide 6 
mg/mL
Store in a refrigerator
(2°C to 8°C )
Store below 30°C or in 
a refrigerator (2°C 
to8°C )
Use within 1 month
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
13 June 2017
Novo Nordisk
Trial ID: NN9535-4339
Version:
1.0-It
UTN:U1111-1190-5868
Status:
Final
EudraCT No.:2016-004965-22
Page:
1 of 3
Protocol Amendment
No. 2-IT
to Protocol, final version 2.0
dated 03 february 2017
Trial ID:NN9535-4339
SUSTAIN 10 
Efficacy and safety of semaglutide 1.0 mg once-weekly versus 
liraglutide 1.2 mg once-daily as add-on to 1-3 oral anti-diabetic drugs 
(OADs) in subjects with type 2 diabetes
Trial phase: 3b
Applicable to Italy
Amendment originator:
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol Amendment
CONFIDENTIAL
Date:
13 June 2017
Novo Nordisk
Trial ID: NN9535-4339
Version:
1.0-It
UTN:U1111-1190-5868
Status:
Final
EudraCT No.:2016-004965-22
Page:
2 of 3
Table of Contents   
Page
Table of Contents........................................................................................................................................2
1
Introduction including rationale for the protocol amendment...........................................................3
2
Changes ................................................................................................................................................3
2.1
Page 30, Section 6.8 Rationale for trial population.....................................................................3
2.2
Page 81, Section 18.1.2 Other safety considerations ..................................................................3
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
13 June 2017
Novo Nordisk
Trial ID: NN9535-4339
Version:
1.0-It
UTN:U1111-1190-5868
Status:
Final
EudraCT No.:2016-004965-22
Page:
3 of 3
1
Introduction including rationale for the protocol amendment
Following the submission of the NN9535-4339 trial on the 10 Mar 2017, the Italian Health 
Authority (AIFA) requested further clarifications regarding information about diet and the level of 
physical activity based on the SmPC for liraglutide. In the Smpc, it is stated that liraglutide can be 
used in combination with other oral anti-diabetic drugs (OADs) and /or basal insulin if these drugs, 
associated to diet and physical activity, are not sufficient to guarantee an adequate glycaemic 
control.
Subjects in this trial are required to be treated with stable doses of pre-defined anti-diabetic 
medications and should therefore have exhausted the option of diet and physical exercise only. 
However, to ensure that diet and exercise has been attempted before pharmacological therapy is 
initiated and that lifestyle modification is recommended as adjunct therapy to all subjects with type 
2 diabetes, the following will be added to Sections 6.8 and 18.1.2 of the trial protocol.
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
2
Changes
2.1
Page 30, Section 6.8 Rationale for trial population
The trial population will include subjects in whom treatment with diet and physical exercise alone 
should have been attempted and deemed not sufficient to achieve glycaemic control, and who 
subsequently are treated with stable doses of 1−3 OAD(s) (see Section 5.3.2) for at least 90 days 
prior to screening.
2.2
Page 81, Section 18.1.2 Other safety considerations
It is the responsibility of the investigator to ensure the best possible care according to the principles 
outlined in Diabetes Care 2017 Standards of Medical Care in Diabetes62. This includes guidance on 
lifestyle modification as adjunct to therapy as per current local practice.
62. Marathe PH, Gao HX, Close KL. American Diabetes Association Standards of Medical Care in Diabetes 2017. J 
Diabetes. 2017.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
27 June 2017
Novo Nordisk
Trial ID: NN9535-4339
Version:
1.0-Pl
UTN:U1111-1190-5868
Status:
Final
EudraCT No.:2016-004965-22
Page:
1 of 3
Protocol Amendment
No. 3-PL
to Protocol, final version 2.0
dated 03 february 2017
Trial ID:NN9535-4339
SUSTAIN 10 
Efficacy and safety of semaglutide 1.0 mg once-weekly versus 
liraglutide 1.2 mg once-daily as add-on to 1-3 oral anti-diabetic drugs 
(OADs) in subjects with type 2 diabetes
Trial phase: 3b
Applicable to Poland
Amendment originator:
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol Amendment
CONFIDENTIAL
Date:
27 June 2017
Novo Nordisk
Trial ID: NN9535-4339
Version:
1.0-Pl
UTN:U1111-1190-5868
Status:
Final
EudraCT No.:2016-004965-22
Page:
2 of 3
Table of Contents   
Page
Table of Contents........................................................................................................................................2
1
Introduction including rationale for the protocol amendment...........................................................3
2
Changes ................................................................................................................................................3
2.1
Section 26 Indemnity statement.................................................................................................3
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
27 June 2017
Novo Nordisk
Trial ID: NN9535-4339
Version:
1.0-Pl
UTN:U1111-1190-5868
Status:
Final
EudraCT No.:2016-004965-22
Page:
3 of 3
1
Introduction including rationale for the protocol amendment
Based on local regulations, below indemnity statement is added to section 26.
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
2
Changes
2.1
Section 26 Indemnity statement
Novo Nordisk accepts liability in accordance with:
For Poland only:
Novo Nordisk carries liability for the Trial exclusively in the scope defined by the applicable laws 
and in particular by the Civil Code and the Pharmaceutical Law dated 6 September 2001 (uniform 
version Journal of Laws of 2008 No. 45 item 271 with amendments). In order to support potential
claims for liability attributable to the Trial, Novo Nordisk and Investigator are covered by the 
Insurance Policy issued according to applicable Polish law.
CONFIDENTIAL


Local Substantial Amendment
CONFIDENTIAL
Date:
10 July 2017
Novo Nordisk
Trial ID: NN9535-4339
Version:
1.0
UTN: U1111-1190-5868
Status:
Final
EudraCT No.: 2016-004965-22
Page:
1 of 3
  Local Substantial Amendment
no 1.0_BG
Trial ID: 9535-4339
SUSTAIN 10 
Efficacy and safety of semaglutide 1.0 mg once-weekly versus liraglutide 1.2 mg once-daily as 
add-on to 1-3 oral anti-diabetic drugs (OADs) in subjects with type 2 diabetes 
Trial phase: 3b
Applicable to Bulgaria
Amendment originator:
Name: 
Department: 
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.


Local Substantial Amendment
CONFIDENTIAL
Date:
10 July 2017
Novo Nordisk
Trial ID: NN9535-4339
Version:
1.0
UTN: U1111-1190-5868
Status:
Final
EudraCT No.: 2016-004965-22
Page:
2 of 3
Table of Contents   
Page
Table of Contents........................................................................................................................................2
1
Changes ................................................................................................................................................3
CONFIDENTIAL


Local Substantial Amendment
CONFIDENTIAL
Date:
10 July 2017
Novo Nordisk
Trial ID: NN9535-4339
Version:
1.0
UTN: U1111-1190-5868
Status:
Final
EudraCT No.: 2016-004965-22
Page:
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1
Changes
This is an amendment to patients’ material ”Overview of visit activities in the SUSTAIN 10 study”. 
A mistake has been identified in the master of the document “Overview of visit activities in the 
SUSTAIN 10 study”, version 2.0, dated 08-Feb-2017 - a physical exam icon was present at visit 2, 
however according to the protocol there is no physical exam at visit 2. The master document was 
updated to version 3.0, dated 03-July-2017. The local translation of this document was changed in 
accordance with the master document and version updated.
CONFIDENTIAL


Local Substantial Amendment
CONFIDENTIAL
Date:
11 April 2018
Novo Nordisk
Trial ID: NN9535-4339
Version:
1.0
UTN: U1111-1190-5868
Status:
Final
EudraCT No.: 2016-004965-22
Page:
1 of 3
  Local Substantial Amendment
no 2.0_BG
Trial ID: 9535-4339
SUSTAIN 10 
Efficacy and safety of semaglutide 1.0 mg once-weekly versus liraglutide 1.2 mg once-daily as 
add-on to 1-3 oral anti-diabetic drugs (OADs) in subjects with type 2 diabetes 
Trial phase: 3b
Applicable to Bulgaria
Amendment originator:
Name: 
Department: 
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.


Local Substantial Amendment
CONFIDENTIAL
Date:
11 April 2018
Novo Nordisk
Trial ID: NN9535-4339
Version:
1.0
UTN: U1111-1190-5868
Status:
Final
EudraCT No.: 2016-004965-22
Page:
2 of 3
Table of Contents   
Page
Table of Contents........................................................................................................................................2
1
Changes ................................................................................................................................................3
CONFIDENTIAL


Local Substantial Amendment
CONFIDENTIAL
Date:
11 April 2018
Novo Nordisk
Trial ID: NN9535-4339
Version:
1.0
UTN: U1111-1190-5868
Status:
Final
EudraCT No.: 2016-004965-22
Page:
3 of 3
1
Changes
IB for Semaglutide (subcutaneous administration) updated to new edition 13, version 1.0, dated 08 
March 2018 and this update is considered as Substantial amendment due to change in Reference 
Safety Information (RSI).
CONFIDENTIAL


Local Substantial Amendment
CONFIDENTIAL
Date:
11 May 2018
Novo Nordisk
Trial ID: NN9535-4339
Version:
1.0
UTN: U1111-1190-5868
Status:
Final
EudraCT No.: 2016-004965-22
Page:
1 of 3
  Local Substantial Amendment
no 3.0_BG
Trial ID: 9535-4339
SUSTAIN 10 
Efficacy and safety of semaglutide 1.0 mg once-weekly versus liraglutide 1.2 mg once-daily as 
add-on to 1-3 oral anti-diabetic drugs (OADs) in subjects with type 2 diabetes 
Trial phase: 3b
Applicable to Bulgaria
Amendment originator:
Name: 
Department: 
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.


Local Substantial Amendment
CONFIDENTIAL
Date:
11 May 2018
Novo Nordisk
Trial ID: NN9535-4339
Version:
1.0
UTN: U1111-1190-5868
Status:
Final
EudraCT No.: 2016-004965-22
Page:
2 of 3
Table of Contents   
Page
Table of Contents........................................................................................................................................2
1
Changes ................................................................................................................................................3
CONFIDENTIAL


Local Substantial Amendment
CONFIDENTIAL
Date:
11 May 2018
Novo Nordisk
Trial ID: NN9535-4339
Version:
1.0
UTN: U1111-1190-5868
Status:
Final
EudraCT No.: 2016-004965-22
Page:
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1
Changes
The RSI section in IB Liraglutide (Victoza®), edition 20, dated 05 April 2018 has been changed to 
reflect the requirements set forth by the new Clinical Trial Facilitation Group (CTFG) guidance on 
the Reference safety information (RSI).
Going forward, the RSI contained in the IB section RSI will be used for assessment of expectedness 
of serious adverse reactions instead of the CCDS as included now in the protocol for NN9535-4339 
section 12.
CONFIDENTIAL

SAP_001.pdf: 
Cover Page for Statistical Analysis Plan 
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT03191396 
Sponsor trial ID: 
NN9535-4339 
Official title of study: 
Efficacy and safety of semaglutide 1.0 mg once-weekly versus 
liraglutide 1.2 mg once-daily as add-on to 1–3 oral 
anti-diabetic drugs (OADs) in subjects with type 2 diabetes. 
(SUSTAIN 10) 
Document date: 
27 May 2019 
 


Link
List of contents
Statistical analysis plan......................................................................................................................
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
Semaglutide s.c. Ozempic®
Trial ID: NN9535-4339
Clinical Trial Report
Appendix 16.1.9
27 May 2019
1.0
Final
16.1.9 Documentation of statistical methods
CONFIDENTIAL
Redacted VWDWLVWLFDODQDO\VLVSODQ 
Includes redaction of personal identifiable information only. 
. 


Statistical Analysis Plan
CONFIDENTIAL
Date:
28 August 2018
Novo Nordisk
Trial ID: nn9535-4339
Version:
1.0
UTN: U1111-1190-5868
Status:
Final
EudraCT No.: 2016-004965-22
Page:
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Statistical Analysis Plan
Trial ID: NN9535-4339
SUSTAIN 10
Efficacy and safety of semaglutide 1.0 mg once-weekly versus 
liraglutide 1.2 mg once-daily as add-on to 1-3 oral anti-
diabetic drugs (OADs) in subjects with type 2 diabetes
Trial phase: 3b
Author:
, Statistician
Biostatistics Semaglutide s.c.
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
28 August 2018
Novo Nordisk
Trial ID: nn9535-4339
Version:
1.0
UTN: U1111-1190-5868
Status:
Final
EudraCT No.: 2016-004965-22
Page:
2 of 23
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 .....................................................................................................................5
2.1
General considerations ..............................................................................................................5
2.1.1
Primary estimand.....................................................................................................5
2.1.2
Missing data considerations at week 30....................................................................5
2.1.3
Confirmatory hypotheses .........................................................................................6
2.1.4
Multiplicity and criteria for confirming hypotheses ..................................................7
2.2
Sample size calculation .............................................................................................................7
2.3
Data definitions.........................................................................................................................8
2.3.1
Data selection ..........................................................................................................8
2.3.1.1
Definition of analysis sets...................................................................9
2.3.1.2
Definition of observation periods........................................................9
2.3.2
Data transformations..............................................................................................11
2.3.3
Definition of baseline.............................................................................................11
2.3.4
Trial completion ....................................................................................................11
2.3.5
Treatment completion ............................................................................................11
2.4
Primary endpoint.....................................................................................................................12
2.4.1
Primary analysis ....................................................................................................12
2.4.2
Sensitivity analyses................................................................................................13
2.4.3
Sensitivity analyses for the primary estimand.........................................................13
2.4.4
Other sensitivity analyses.......................................................................................13
2.5
Secondary endpoints ...............................................................................................................14
2.5.1
Confirmatory secondary endpoints.........................................................................14
2.5.2
Supportive secondary endpoints .............................................................................14
2.5.2.1
Efficacy endpoints............................................................................14
2.5.2.2
Safety endpoints...............................................................................16
2.6
Health economics and/or PROs ...............................................................................................21
2.7
Interim analysis.......................................................................................................................21
3
Changes to the statistical analyses planned in the protocol..............................................................22
4
References ..........................................................................................................................................23
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
28 August 2018
Novo Nordisk
Trial ID: nn9535-4339
Version:
1.0
UTN: U1111-1190-5868
Status:
Final
EudraCT No.: 2016-004965-22
Page:
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List of abbreviations
AE
adverse event
ANCOVA
analysis of covariance
BMI
body mass index
FAS
full analysis set
MedDRA
Medical Dictionary for Regulatory Activities
PP
per protocol
SAS
safety analysis set
SAP
statistical analysis plan
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
28 August 2018
Novo Nordisk
Trial ID: nn9535-4339
Version:
1.0
UTN: U1111-1190-5868
Status:
Final
EudraCT No.: 2016-004965-22
Page:
4 of 23
1
Introduction
1.1
Trial information
This is a 30-week, confirmatory, randomised, multicentre, multinational, active-controlled, parallel 
groups, open label, 2-armed trial.
The primary objective
To compare the effect of semaglutide s.c. 1.0 mg once-weekly versus liraglutide s.c. 1.2 mg 
once-daily on glycaemic control after 30 weeks of treatment in subjects with type 2 diabetes.
The secondary objectives
To compare the effect of semaglutide s.c. 1.0 mg once-weekly versus liraglutide s.c. 1.2 mg 
once-daily after 30 weeks of treatment on body weight, efficacy parameters, safety and tolerability 
in subjects with type 2 diabetes. 
Trial design
Subjects with T2D inadequately controlled on 1-3 oral anti-diabetic drug(s) (OAD) will be 
randomised in a 1:1 manner to receive either semaglutide s.c. 1.0 mg once-weekly or liraglutide s.c. 
1.2 mg once-daily. The randomisation will be stratified based on subjects background medication of 
SU and sodium-glucose cotransporter-2 (SGLT-2) inhibitors:
!
SU (+/- metformin)
!
SGLT-2 inhibitors (+/- metformin)
!
SU + SGLT-2 inhibitors (+/- metformin)
!
No SU and no SGLT-2 inhibitors (metformin monotherapy)
See protocol for trial NN9535-4339 for further details.
1.2
Scope of the statistical analysis plan
This SAP is based on the protocol “SUSTAIN 10: Efficacy and safety of semaglutide 1.0 mg once-
weekly versus liraglutide 1.2 mg once-daily as add-on to 1-3 oral anti-diabetic drugs (OADs) in 
subjects with type 2 diabetes”, version 2.0.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
28 August 2018
Novo Nordisk
Trial ID: nn9535-4339
Version:
1.0
UTN: U1111-1190-5868
Status:
Final
EudraCT No.: 2016-004965-22
Page:
5 of 23
2
Statistical considerations
2.1
General considerations
No interim analyses or other analyses of un-blinded data will be performed before the database is 
locked.
If necessary, a statistical analysis plan may be written in addition to the protocol, including a more 
technical and detailed elaboration of the statistical analyses. The statistical analysis plan will be 
finalised before database lock.
Results from a statistical analysis will be presented by the estimated treatment contrasts at week 30 
with associated two-sided 95% confidence intervals and p-values corresponding to two-sided tests 
of no difference if not otherwise specified.
The comparison presented from a statistical analysis will be semaglutide 1.0 mg versus liraglutide 
1.2 mg.
If no statistical analysis is specified, data will be presented using relevant summary statistics.
Data from all trial sites will be analysed and reported together. 
2.1.1
Primary estimand
To further detail the trial objective an estimand is defined which is a de-jure (efficacy) estimand: 
!
The treatment difference between semaglutide and liraglutide at week 30 for all randomised 
subjects if all subjects completed treatment and did not initiate rescue medication
This primary de-jure estimand is considered clinically relevant as it assesses the glycaemic benefit a 
person with T2D is expected to achieve if initiating and continuing treatment with semaglutide 
compared to liraglutide. Accordingly, only data collected prior to discontinuation of trial product or 
initiation of rescue medication will be used to draw inference. This will avoid confounding from 
rescue medication.
2.1.2
Missing data considerations at week 30
The overall rate of missing data at week 30 is expected to be not more than 10%  based on the rate 
of subjects with measurements of the primary and the confirmatory secondary endpoints in the s.c. 
semaglutide phase 3a clinical development programme. The frequency and reasons of missing data 
is expected to be similar in the semaglutide and the liraglutide groups.
When estimating the primary estimand, the combined rate of missing data and, subjects 
discontinuing treatment prematurely or initiating rescue medication on top of trial product, is 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
28 August 2018
Novo Nordisk
Trial ID: nn9535-4339
Version:
1.0
UTN: U1111-1190-5868
Status:
Final
EudraCT No.: 2016-004965-22
Page:
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expected to be maximum 20%. This is based on the results from the s.c. semaglutide phase 3a 
clinical development programme. Based on these data, premature treatment discontinuation due to 
gastrointestinal adverse events is expected to be low. Other possible reasons for premature 
discontinuing treatment are assumed to be unrelated to treatment and to therefore occur at similar 
rates between the two treatment groups. Thus, overall, the frequency of missing data or data not 
used at week 30 in the primary analysis is expected to be similar between the treatment groups.
To document the extent and reason(s) for missing data, descriptive summaries and graphical 
representation of extent, reason(s) for and pattern of missing data for the primary and secondary 
endpoints will be presented by treatment group. 
2.1.3
Confirmatory hypotheses
The mean treatment difference is defined as μ = (semaglutide minus liraglutide). Three 
confirmatory hypotheses are to be tested:
1. HbA1c non-inferiority of semaglutide 1.0 mg vs. liraglutide 1.2 mg with a non-inferiority 
margin of 0.3
!
H0: μ ≥ 0.3%-point against Ha: μ < 0.3%-point
2. Body weight superiority of semaglutide 1.0 mg vs. liraglutide 1.2 mg
!
H0: μ ≥ 0.0 kg against Ha: μ < 0.0 kg
3. HbA1c superiority of semaglutide 1.0 mg vs.liraglutide 1.2 mg
!
H0: μ ≥ 0.0%-point against Ha: μ < 0.0%-point
The non-inferiority margin of 0.3 is chosen based on the diabetes guideline1, 2. The effect of 
liraglutide was investigated in various trials including the LEAD programme that included a series 
of six randomised controlled phase 3 trials. In these trials, a substantial and sustained reduction in 
HbA1c was obtained with liraglutide treatment across the continuum of care in patients with type 2 
diabetes3. Based on  the Lead 1 & Lead 4 studies, Liraglutide 1.2 mg showed HbA1c treatment 
difference to placebo of -1.3%4 and -0.9%5 respectively. Hence, based on these trials, and 
considering the LEAD programme results collectively that assures the effect of liraglutide, the 
chosen non-inferiority margin of 0.3 provides assurance that semaglutide has an effect greater than 
0 with a clinically relevant size. With regards to the constancy assumption, controlled clinical trials 
have consistently established that liraglutide is an effective anti-diabetic drug. Therefore, lack of 
trial sensitivity with liraglutide as comparator is not anticipated to be an issue in this trial.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
28 August 2018
Novo Nordisk
Trial ID: nn9535-4339
Version:
1.0
UTN: U1111-1190-5868
Status:
Final
EudraCT No.: 2016-004965-22
Page:
7 of 23
2.1.4
Multiplicity and criteria for confirming hypotheses
The Type-I error rate for testing the three confirmatory hypotheses related to the HbA1c and body 
weight endpoints will be preserved in the strong sense at an overall alpha (α) level of 2.5% (one-
sided), corresponding to a two-sided 5% level hierarchical test, using the closed testing procedure 
described in Bretz et al. The overall α-level of 2.5% is initially allocated to the HbA1c non-
inferiority test. For this hypothesis, and in general, if a hypothesis is confirmed the local α-level (α-
local) will be reallocated according to the weight and the direction of the edges going from the 
confirmed hypothesis to the next hypotheses as specified in Figure 2–1. 
Each of the following hypotheses will be tested at their local α level. This process will be repeated 
until no further hypotheses can be confirmed.
Figure 2–1
Graphical illustration of the closed testing procedure
2.2
Sample size calculation
The sample size calculation will assume a power of 90% for confirming all three confirmatory 
hypotheses (see Section 2.1.3) across efficacy and in-trial assumptions. Please see Table 2–2 for 
calculated powers for efficacy as estimated by the primary analysis for the primary estimand (see 
Section 2.4.1) and for the in-trial effect as estimated by the treatment policy sensitivity analysis (see 
Section 2.4.4)
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
28 August 2018
Novo Nordisk
Trial ID: nn9535-4339
Version:
1.0
UTN: U1111-1190-5868
Status:
Final
EudraCT No.: 2016-004965-22
Page:
8 of 23
The sample size assumptions for efficacy based on ‘on-treatment without rescue medication’ data 
and a treatment effect based on in-trial data (see Section 2.4.2) together with the standard are given 
in Table 2–1.These are based on the efficacy results and an observed reduction of up to 15% in the 
treatment effect based on in-trial data compared to efficacy based on ‘on-treatment without rescue 
medication’ data in the s.c. semaglutide phase 3a clinical development programme. A similar 
reduction in the in-trial treatment effect compared to efficacy is assumed with liraglutide as 
comparator. 
Table 2–1
Assumptions used in the sample size calculation
Semaglutide vs. liraglutide
HbA1c 
Body weight 
Efficacy (treatment difference)
-0.35%
-3.3 kg
In-trial treatment effect (treatment difference)
-0.30 %
-2.38 kg
Standard deviation 
1.1%
4.0 kg
Tests statistics for treatment differences are assumed to follow normal distributions. The sample 
size is calculated using the calcPower function in the R package, gMCP6, using 10,000 simulations. 
All of the three pre-specified confirmatory tests are assumed to be independent. Since some of these 
tests are positively correlated, the assumption of independence is viewed as conservative.
With the above assumptions, allocating 288 subjects to each of the semaglutide and liraglutide 
groups (576 subjects in total) provides at least 90% power to reject all three confirmatory 
hypotheses and thus confirm HbA1c superiority and body weight superiority of semaglutide vs. 
liraglutide across efficacy and in-trial assumptions. Please see Table 2–2.
Table 2–2
Calculated powers for meeting individual hypotheses
Statistical test
HbA1c
non-inferiority
HbA1c superiority
Body weight 
superiority
All
Efficacy power (%)
>99%
97%
>99%
97%
In-trial effect power (%)
>99%
90%
>99%
90%
2.3
Data definitions
2.3.1
Data selection
Subjects and data to be used in an analysis will be selected in a two-step manner:
!
Firstly, subjects will be selected based on the specified analysis set
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
28 August 2018
Novo Nordisk
Trial ID: nn9535-4339
Version:
1.0
UTN: U1111-1190-5868
Status:
Final
EudraCT No.: 2016-004965-22
Page:
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!
Secondly, data points on the selected subjects from first step will be selected based on the 
specified observation period
2.3.1.1
Definition of analysis sets
The following analysis sets will be defined:
Full analysis set (FAS): includes all randomised subjects. Subjects in the FAS will contribute to 
evaluation “as randomised”.
Safety analysis set (SAS): includes all subjects exposed to at least one dose of trial product. 
Subjects in the SAS will contribute to the evaluation based on the trial product received for the 
majority of the period they were on treatment. This will be referred to as contributing to the 
evaluation “as treated”.
Per protocol (PP) analysis set: includes all subjects in the FAS who fulfil the following criteria:
!
Have not violated any inclusion criteria
!
Have not fulfilled any exclusion criteria
!
Have a non-missing HbA1c measurement at screening and/or randomisation
!
Have a treatment duration of at least 16 weeks
!
Have at least one non-missing HbA1c measurement at or after week 16
Subjects in the PP analysis set will contribute to the analysis “as treated” as defined for the SAS.
2.3.1.2
Definition of observation periods
Definition of the observation periods:
In-trial: This observation period represents the time period after randomisation where subjects are 
considered to be in the trial, regardless of discontinuation of trial product or initiation of rescue 
medication. The in-trial observation period starts at randomisation (as registered in IWRS) and ends 
at the date of: 
!
The last direct subject-site contact, which is scheduled to take place 5 weeks after planned last 
dose of trial product at a follow-up visit (phone visit) 
!
Withdrawal for subjects who withdraw their informed consent
!
The last subject-investigator contact as defined by the investigator for subjects who are lost to 
follow-up
!
Death for subjects who dies before any of the above
For subjects not randomised but exposed to trial product the in-trial period starts at the date of first 
dose of trial product.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
28 August 2018
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Trial ID: nn9535-4339
Version:
1.0
UTN: U1111-1190-5868
Status:
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EudraCT No.: 2016-004965-22
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On-treatment: This observation period represents the time period where subjects are considered 
exposed to trial product. The observation period is a sub-set of the in-trial observation period. It 
starts at the date of first dose of trial product. Two slightly different end dates will be needed to 
cover all assessments appropriately according to the flow chart. For AEs including hypoglycaemic 
episodes, the observation period ends at the first date of any of the following:
!
The follow-up visit (P10)
!
The premature discontinuation follow-up visit (P10A)
!
The last date on trial product + 42 days 
!
The end-date for the in-trial observation period
The follow-up visit is scheduled to take place 5 weeks after the last date on trial product 
corresponding to approximately five half-lives of s.c. semaglutide. The visit window for the follow-
up visit is + 7 days, which is the reason for the 42 days specified in the bullet above. Hence, for 
AEs including hypoglycaemic episodes, this period reflects the period in which subjects are 
exposed.
For efficacy and other safety assessments (laboratory assessments, physical examination and vital 
signs) the observation period ends at the last date on trial product with a visit window of + 7 days. 
This ascertainment window corresponds to the dosing interval and will be used to avoid attenuation 
of a potential treatment effect on endpoints for which the effect is reversible shortly after treatment 
discontinuation. Hence, for those assessments this period reflects the period in which subjects are 
treated. 
On-treatment without rescue medication: This observation period is a sub-set of the on-treatment 
observation period, where subjects are considered treated with trial product, but have not initiated 
rescue medication. Specifically, the period starts at the date of first dose of trial product and ends at 
the first date of any of the following:
!
The last dose of trial product with a visit window of +7 days
!
Initiation of rescue medication
The ’on-treatment without rescue medication’ observation period will be the primary observation 
period for efficacy evaluations. The in-trial observation period will be considered supportive for 
efficacy evaluation. Safety will be evaluated based on the in-trial and the on-treatment observation 
periods unless otherwise specified.
Data points collected outside an observation period will be treated as missing in the analysis. 
Baseline data will always be included in an observation period. Before data are locked for statistical 
analysis, a review of all data will take place. Any decision to exclude either a subject or single 
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Statistical Analysis Plan
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Date:
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Trial ID: nn9535-4339
Version:
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UTN: U1111-1190-5868
Status:
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observations from the statistical analysis is the joint responsibility of the members of the Novo 
Nordisk study group.
Exclusion of data from analyses will be used restrictively and normally no data should be excluded 
from the FAS. The subjects or observations to be excluded, and the reasons for their exclusion will 
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.
2.3.2
Data transformations
A number of the continuous parameters will be log-transformed prior to statistical analysis. The 
output tables and figures will show the results of the analysis back-transformed to the original scale, 
implying that log-treatment-differences are reported as treatment ratios. Confidence intervals for the 
treatment ratios will be calculated as exponentiated upper and lower limits for log-treatment 
difference confidence intervals. The standard errors of the back-transformed mean and ratio to 
baseline estimates are also provided; these SEs are calculated using the delta-method (first order 
Taylor approximation), whereby the SE on the original scale is calculated as the product of the SE 
on log-scale and the exponentiated estimate of the mean (geometric mean).
Moreover, a number of binary endpoints will be analysed using a logistic regression. From this 
analysis, the estimated odds will be presented, calculated as the exponentiated estimate of the log-
odds. The standard errors for the estimated odds are calculated as the standard error of the estimated 
log-odds times the estimated odds by using the delta method.
Laboratory values below the lower limit of quantification (LLOQ) will be set to ½LLOQ. 
2.3.3
Definition of baseline
For each assessment, the baseline assessment is defined as the latest available measurement at or 
prior to the randomisation visit (V2). This specifically implies that if a visit 2 assessment is missing 
(whether it was planned or not planned) then the screening assessment (from visit 1), if available, 
will be used as the baseline assessment.
2.3.4
Trial completion
Unless subjects withdraw their informed consent, data collection will continue for the full duration 
of the trial. The full duration of the trial is defined as up to and including the follow-up visit (P10). 
Subjects completing the follow-up visit (P10) will be considered trial completers.
2.3.5
Treatment completion
Treatment period completion is defined as when the subject has received the required treatment, and 
attended the ‘End of Treatment’ (V9).
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Statistical Analysis Plan
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Date:
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Trial ID: nn9535-4339
Version:
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UTN: U1111-1190-5868
Status:
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2.4
Primary endpoint
The primary endpoint is change from baseline to week 30 in HbA1c.
2.4.1
Primary analysis 
The primary estimand will be estimated based on the FAS using post-baseline measurements up to 
and including week 30 from the ’on-treatment without rescue medication’ observation period. 
Imputation of missing data will be handled using multiple imputation assuming that missing data is 
missing at random (MAR). Missing data will be imputed using observed data within the same group 
defined by the randomised treatment (semaglutide/liraglutide). It is hereby assumed that the likely 
values of what the missing data would have been if available are best described by information from 
subjects who receive the same treatment. 
Technically, missing values will be imputed as follows:
!
Intermittent missing values are imputed using a Markov Chain Monte Carlo (MCMC) method, 
in order to obtain a monotone missing data pattern. This imputation is done for each of the 
treatment groups separately and 500 copies of the dataset will be generated
!
A sequential regression approach for imputing monotone missing values at planned visits will 
be implemented starting with the first visit after baseline and sequentially continuing to the last 
planned visit at week 30. A model used to impute missing values at each planned visit will be 
fitted for each of the treatment groups using observed and imputed data. The model will include 
the SU and SGLT-2 inhibitors anti-diabetic background medication stratification factor ( SU +/-
metformin, SGLT-2 inhibitors +/- metformin, SU + SGLT-2 inhibitors +/- metformin, no SU 
and no SGLT-2 inhibitors (metformin monotherapy)) as categorical effects and the baseline and 
post-baseline HbA1c values observed prior to the visit in question as covariates. 
!
An analysis of covariance (ANCOVA) with treatment and the SU and SGLT-2 inhibitors anti-
diabetic background medication stratification factor (SU +/- metformin, SGLT-2 inhibitors +/-
metformin, SU + SGLT-2 inhibitors +/- metformin, no SU and no SGLT-2 inhibitors 
(metformin monotherapy)) as categorical effects and baseline HbA1c as a covariate will be used 
to analyse HbA1c values at week 30 for each of the 500 complete data sets generated as part of 
the imputation of missing values. Rubin’s rule will be used to combine the analysis results in 
order to draw inference.
From this analysis, the estimated treatment difference between semaglutide and liraglutide at week 
30 will be presented together with the associated two-sided 95% confidence interval and unadjusted 
two sided p-values.
The one-sided non-inferiority and superiority hypotheses will be confirmed using the overall 
significance level of 2.5% in line with the closed testing procedure in Figure 2–1. Operationally, 
non-inferiority and subsequent superiority will be considered confirmed if the mean treatment 
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Statistical Analysis Plan
CONFIDENTIAL
Date:
28 August 2018
Novo Nordisk
Trial ID: nn9535-4339
Version:
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UTN: U1111-1190-5868
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difference is supporting the corresponding alternative hypothesis and the two-sided p-value  (non-
inferiority H0: u=0.3 vs. Ha: u≠0.3, superiority H0: u=0 vs Ha: u≠0 respectively), from the primary 
analysis of the primary estimand, is strictly below two times its local significance level resulting 
from the closed testing procedure.
2.4.2
Sensitivity analyses
In order to investigate the robustness of the conclusions from the primary analysis and to stress test 
the MAR assumption for missing data tipping point sensitivity analyses will be performed for the 
primary estimand both for the sensitivity of the non-inferiority and the superiority HbA1c
hypotheses. No tipping point analysis will be performed on the non-inferiority test if the superiority 
test is confirmed.
2.4.3
Sensitivity analyses for the primary estimand
The estimation of the primary estimand will be repeated using the following sensitivity analysis:
!
Tipping-point analysis (pattern mixture model based) based on the FAS using the ’on-treatment 
without rescue medication’ observation period. In this analysis, subjects from the semaglutide 
group with missing observations will be given a penalty, i.e., it is assumed that subjects with 
missing observations who are randomised to semaglutide will receive a treatment that is less 
beneficial than subjects with observed values who are randomised to semaglutide. The idea is to 
gradually increase the penalty to evaluate at which level the superiority conclusion of the 
analyses in terms of statistical significance is changed. The tipping point is the penalty level, at 
which the magnitude of efficacy reduction in subjects with missing data creates a shift in the 
treatment effect of semaglutide from being statistically significantly better than liraglutide to 
being non-statistically significantly better for the superiority test and similarly for the non-
inferiority test. Technically, this analysis will be implemented by replicating the primary 
analysis including the assumption of MAR but subsequently adding increasing penalty values at 
week 30 to imputed observations in the semaglutide group before applying ANCOVA on the 
500 complete data sets.
2.4.4
Other sensitivity analyses
The following additional sensitivity analyses are specified:
!
Retrieved dropout analysis based on the FAS using post-baseline measurements up to and 
including week 30 from the in-trial observation period. Missing data will be imputed using the 
same approach as described for the primary analysis of the primary estimand. However the 
imputation will be done within the same group defined not only by the randomised treatment 
(semaglutide/ liraglutide) but also by the status of treatment completion (still on randomised 
treatment at week 30 yes/no) (4 groups in total). It is hereby assumed that the likely values of 
what the missing data would have been if available are best described by information from 
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Statistical Analysis Plan
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Date:
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Trial ID: nn9535-4339
Version:
1.0
UTN: U1111-1190-5868
Status:
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subjects who at week 30 are similar in terms of randomised treatment and treatment completion 
status. In addition in the imputation step stratification factor is not included in the model in 
order to avoid potential issues with sparse data. The ANCOVA performed in the analysis step 
will include the same categorical effects and covariates as the primary analysis. This analysis 
could be considered addressing an effectiveness estimand. This analysis will be carried out for 
the superiority test only.
!
Per protocol (PP) analysis based on the PP data set using the ‘on-treatment without rescue 
medication’ observation period. This analysis will be carried out for non-inferiority testing only. 
The statistical analysis will be the same as the primary analysis for the primary estimand.
2.5
Secondary endpoints
2.5.1
Confirmatory secondary endpoints
The confirmatory secondary endpoint is change from baseline to week 30 in body weight (kg). 
The primary estimand will be estimated for body weight using the same approach as described 
in Section 2.4.1. Body weight will be tested for superiority. Baseline and post-baseline body weight 
will be used as covariates instead of HbA1c. 
The one-side hypothesis of superiority will be considered confirmed if the mean treatment 
difference is supporting the corresponding hypothesis and the two-sided p-value from the analysis 
of body weight is strictly below two times its local two-sided significance level resulting from the 
closed testing procedure in Figure 2–1.
The tipping point sensitivity analysis pre-specified to evaluate the robustness of the conclusions 
from the primary analysis of HbA1c will also be performed to evaluate the robustness of the
conclusion from the body weight superiority test. In addition, the retrieved dropout sensitivity 
analysis will also be performed for body weight.
2.5.2
Supportive secondary endpoints
No sensitivity analyses are planned for the supportive secondary endpoints. 
2.5.2.1
Efficacy endpoints
Continuous endpoints
The continuous endpoints are change from baseline to week 30 in: 
!
FPG 
!
SMPG, 7 point profile 
-
Mean 7-point profile 
-
Mean post prandial increment (over all meals)
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
28 August 2018
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Trial ID: nn9535-4339
Version:
1.0
UTN: U1111-1190-5868
Status:
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!
Fasting blood lipids (total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides) 
!
BMI
!
Waist circumference
!
Systolic and diastolic blood pressure 
!
Body weight (%)
The above continuous endpoints will be analysed separately using a similar model approach as for 
the primary endpoint with the associated baseline value as covariates instead of HbA1c for their 
respective analyses.
Fasting lipid profile endpoints will be log-transformed prior to analysis with the associated log-
transformed baseline value as a covariate.
Mean 7-point profile (SMPG) definition
Subjects will be asked to perform SMPG measurements before and 90 minutes after breakfast, 
lunch, dinner, and at bedtime. 
Mean of the 7-point profile is defined as the area under the profile, calculated using the trapezoidal 
method, and divided by the measurement time.
Binary endpoints
The binary endpoints are subjects who after 30 weeks treatment achieve (yes/no):
!
HbA1c < 7.0% (53 mmol/mol), ADA target 
!
HbA1c ≤ 6.5% (48 mmol/mol), AACE target
!
Weight loss ≥ 3%
!
Weight loss ≥ 5%
!
Weight loss ≥ 10%
!
HbA1c <7.0% (53 mmol/mol) without severe or blood glucose confirmed symptomatic 
hypoglycaemia episodes and no weight gain
!
HbA1c reduction ≥ 1%
!
HbA1c reduction ≥ 1% and weight loss ≥ 3%
!
HbA1c reduction ≥ 1% and weight loss ≥ 5%
!
HbA1c reduction ≥ 1% and weight loss ≥ 10%
The above 10 endpoints will be analysed for the primary estimand. The analyses for the primary 
estimand for all 10 endpoints will be based on the ’on-treatment without rescue medication’ 
observation period. They will be analysed separately using the same type of logistic regression 
model with treatment and the SU and SGLT-2 inhibitors anti-diabetic background medication 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
28 August 2018
Novo Nordisk
Trial ID: nn9535-4339
Version:
1.0
UTN: U1111-1190-5868
Status:
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EudraCT No.: 2016-004965-22
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stratification factor (SU +/- metformin, SGLT-2 inhibitors +/- metformin, SU + SGLT-2 inhibitors 
+/- metformin, no SU and no SGLT-2 inhibitors (metformin monotherapy)) as categorical effects 
and associated baseline and post-baseline response(s) (i.e. HbA1c responses for HbA1c endpoints, 
body weight responses for weight endpoints and both HbA1c and body weight responses for the 
binary endpoints that combine both parameters) as covariates. 
To account for missing data, the analysis will be made using a sequential multiple imputation 
approach as described below: 
!
Multiple imputed data sets (500) will be created in which missing values for the underlying 
continuous assessments are imputed by treatment group assuming MAR similar to the approach 
described for the primary analysis in Section 2.4.1
!
The binary endpoint will be created for each of the 500 complete data sets
!
Each of the created complete data sets will be analysed with the logistic regression model. 
Estimated odds ratios will be log transformed and inference will be drawn using Rubin’s rule7.
The results after applying Rubin’s rule will be back-transformed and described by the odds ratio 
between treatments and the associated 95% confidence interval and p-value for no treatment 
difference.
2.5.2.2
Safety endpoints
The safety endpoints will be evaluated based on SAS using the on-treatment observation period and 
the in-trial observation period unless otherwise stated. 
Adverse Events
The following endpoint related to AEs is used to support the safety objective;
!
Number of treatment emergent adverse events
A treatment-emergent AE is an event that has onset date (or increase in severity) during the on-
treatment observation period. These will therefore be referred to as ‘on-treatment AEs’ hereafter. 
On-treatment AEs are summarised descriptively 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). These summaries are replicated by outputs including all ‘in-trial’ AEs 
(i.e., AEs with onset date [or increase in severity] during the ‘in-trial’ observation period). AEs with 
onset after the end of the ‘in-trial’ observation period will be reported in a listing. The development 
over time in gastrointestinal AEs will be presented graphically.
The most frequent AEs will be defined as preferred terms that are experienced by at least 5% of the 
subjects in any of the treatment arms. 
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Statistical Analysis Plan
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Trial ID: nn9535-4339
Version:
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All AEs will be coded using the most recent version of the Medical Dictionary for Regulatory 
Activities (MedDRA) coding.
Hypoglycaemic episodes
The following two endpoints related to hypoglycaemic episodes are used to support the safety 
objective:
!
Number of treatment-emergent severe or BG-confirmed symptomatic hypoglycaemic episodes 
!
Treatment-emergent severe or BG-confirmed symptomatic hypoglycaemic episodes (yes/no)
Data on treatment-emergent hypoglycaemic episodes are presented in terms of the number of 
subjects with at least one episode, the percentage of subjects with at least one episode (%), the total 
number of episodes and the episode rate per 100 years of exposure. Summaries of treatment-
emergent hypoglycaemic episodes will be presented as an overview including all episodes and 
episodes by severity. 
Classification of Hypoglycaemia: 
Treatment emergent: hypoglycaemic episodes will be defined as treatment emergent if the onset is 
in the on-treatment observation period (see Section 2.3.1.2)
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 2–2) and the ADA classification of hypoglycaemia (see Figure 2–3).
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) 8. 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 2–2) in addition to the ADA 
classification:
-
Severe or BG confirmed symptomatic hypoglycaemia: An episode that is severe according 
to the ADA classification9 or BG confirmed by a plasma glucose value <3.1 mmol/L 
(56 mg/dL) with symptoms consistent with hypoglycaemia. 
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Statistical Analysis Plan
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Trial ID: nn9535-4339
Version:
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Hypoglycaemic
episode
PG ≤ 3.9 mmol/L 
(70 mg/dL) 
or 
Alleviation of 
symptoms 
or
Seizure, coma or 
fatal 
SMPG
measurement
PG < 3.1 mmol/L
(56 mg/dL)
with symptoms
PG < 3.1 mmol/L
(56 mg/dL)
without
symptoms
Symptomatic BG 
confirmed 
hypoglycaemia
Asymptomatic BG 
confirmed 
hypoglycaemia
Yes
No
Severe or 
BG confirmed 
symptomatic 
hypoglycaemia
BG confirmed 
hypoglycaemia
Severe or BG 
confirmed 
hypoglycaemia
Note: Glucose measurements are performed with capillary blood calibrated to plasma equivalent glucose values
BG: blood glucose  PG: plasma glucose  SMPG: Self-measured plasma glucose  
Subject 
able to 
treat him/
herself
Severe 
hypoglycaemia
(ADA 2013)
Figure 2–2
Novo Nordisk classification of hypoglycaemia
ADA classification9 of hypoglycaemia 
- Severe hypoglycaemia: An episode requiring assistance of another person to actively administer 
carbohydrate, glucagon, or take other corrective actions. Plasma glucose concentrations may not be 
available during an event, but neurological recovery following the return of plasma glucose to 
normal is considered sufficient evidence that the event was induced by a low plasma glucose 
concentration.
- Asymptomatic hypoglycaemia: An episode not accompanied by typical symptoms of 
hypoglycaemia, but with a measured plasma glucose concentration ≤ 3.9 mmol/L (70 mg/dL).
- Documented symptomatic hypoglycaemia: An episode during which typical symptoms of 
hypoglycaemia are accompanied by a measured plasma glucose concentration ≤ 3.9 mmol/L 
(70 mg/dL).
- Pseudo-hypoglycaemia: An episode during which the person with diabetes reports any of the 
typical symptoms of hypoglycaemia with a measured plasma glucose concentration > 3.9 mmol/L 
(70 mg/dL) but approaching that level.
- Probable symptomatic hypoglycaemia: An episode during which symptoms of hypoglycaemia are 
not accompanied by a plasma glucose determination but that was presumably caused by a plasma 
glucose concentration ≤3.9 mmol/L (70 mg/dL).
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Statistical Analysis Plan
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Trial ID: nn9535-4339
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Hypoglycaemic 
episode 
PG ≤ 3.9 mmol/L 
(70 mg/dL) 
or 
Alleviation of 
symptoms 
or
Seizure, coma or 
fatal 
SMPG
measurement
Asymptomatic 
hypoglycaemia
Documented 
symptomatic 
hypoglycaemia
Pseudo-
hypoglycaemia
Probable 
symptomatic 
hypoglycaemia
No
Yes
No measurement 
with symptoms
PG > 3.9 mmol/L 
(70 mg/dL)
with symptoms
PG ≤3.9 mmol/L 
(70 mg/dL)
with symptoms
PG ≤3.9 mmol/L 
(70 mg/dL)
without symptoms
No
Yes
Note: Glucose measurements are performed with capillary blood calibrated to plasma equivalent glucose values
PG: plasma glucose  SMPG: Self-measured plasma glucose  
Subject 
able to 
treat him/
herself
Severe 
hypoglycaemia
(ADA 2013)
Figure 2–3
ADA classification of hypoglycaemia
Number of treatment emergent severe or blood glucose (BG) confirmed symptomatic 
hypoglycaemic episodes
Number of treatment emergent severe or BG confirmed symptomatic hypoglycaemic episodes 
during 35 weeks will be analysed using a negative binomial regression model with a log -link 
function and the logarithm of the time period, from the randomisation and up to the time point in 
which an occurrence of a hypoglycaemic episode is considered treatment emergent as offset 
assuming MAR. The model will include factors for treatment and the SU and SGLT-2 inhibitors 
anti-diabetic background medication stratification factor (SU +/- metformin, SGLT-2 inhibitors +/-
metformin, SU + SGLT-2 inhibitors +/- metformin, no SU and no SGLT-2 inhibitors (metformin 
monotherapy)) as categorical factors and baseline HbA1c as covariate. In case of convergence 
issues, due to sparse data, the stratification factor will be omitted from the model. The SAS will be 
used for the analysis.
The results will be described by the rate ratio between treatments and the associated 95% 
confidence interval and p-value for no treatment difference.
Treatment emergent severe or blood glucose confirmed symptomatic hypoglycaemia episodes 
(yes/no)
The binary endpoint indicating whether a subject has no treatment-emergent severe or BG 
confirmed symptomatic hypoglycaemic episodes or at least one will be analysed using a logistic 
regression model. The model will include factors for treatment and the SU and SGLT-2 inhibitors 
anti-diabetic background medication stratification factor (SU +/- metformin, SGLT-2 inhibitors +/-
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
28 August 2018
Novo Nordisk
Trial ID: nn9535-4339
Version:
1.0
UTN: U1111-1190-5868
Status:
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EudraCT No.: 2016-004965-22
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metformin, SU + SGLT-2 inhibitors +/- metformin, no SU and no SGLT-2 inhibitors (metformin 
monotherapy)) as categorical factors and baseline HbA1c as covariate. In case of convergence 
issues, due to sparse data, the stratification factor will be omitted from the model. The SAS will be 
used for the analysis.
The results will be described by the odds ratio between treatments and the associated 95% 
confidence interval and p-value for no treatment difference.
Laboratory assessments
The laboratory assessments supporting the safety objective are change from baseline to week 30 in:
!
Haematology
!
Biochemistry
!
Calcitonin
The above continuous laboratory assessments will be summarised and evaluated by descriptive 
statistics.
In addition amylase and lipase will be analysed separately using an analysis similar to the primary 
analysis of the primary endpoint. However this analysis will be based on SAS using the on-
treatment observation period.
Both analyses will use the associated log-transformed baseline value as covariates instead of HbA1c. 
Lipase and amylase values will be log-transformed prior to the analysis.
Pulse rate
Change from baseline to week 30 in pulse rate will be analysed separately with the same model 
approach as for amylase and lipase, but with the pulse rate (not log-transformed) value at baseline 
as covariate.
Categorical safety assessments
The categorical assessments supporting the safety objective are change from baseline to week 30 in:
!
ECG category
!
Physical examination category
!
Eye examination category
The above assessments will be summarised descriptively
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Statistical Analysis Plan
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Trial ID: nn9535-4339
Version:
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2.6
Health economics and/or PROs
Change from baseline to week 30 in:
!
Scores for selected patient reported outcomes:
-
SF-36v2TM (standard version): Total summary scores (physical component and mental 
component) and scores from the 8 domains
-
DTSQs: Treatment satisfaction score (sum of 6 of 8 items) and the 8 items separately
The PRO questionnaires, SF-36v2™, DTSQs will be used to evaluate the objective regarding 
Quality of Life. Each of the PRO endpoints will be analysed separately as the other continuous 
efficacy endpoints using a similar model approach as for the primary endpoint with the associated 
baseline value as covariates.
2.7
Interim analysis
No interim analyses will be performed before the database is locked.
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Statistical Analysis Plan
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Date:
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Trial ID: nn9535-4339
Version:
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3
Changes to the statistical analyses planned in the protocol
The changes to the statistical analyses planned in the protocol in described in Table 3–1 below.
Table 3–1
Overview of changes
Change to planned statistical analyses
Rationale for change
Addition of PP analysis set
The PP analysis set was not pre-specified in the protocol 
so details have been provided in this SAP. 
Sensitivity analysis on body weight: 
Retrieved drop-out analysis and tipping 
point analysis
The sensitivity analyses to be conducted to test the 
robustness of the results of the confirmatory superiority 
hypothesis on body weight were not pre-specified in the 
protocol so details have been provided in this SAP. 
Wording on analysis on pulse rate
Clarification of that pulse rate should not be log-
transformed prior to analysis
Stratification factor in hypoglycaemic 
episode analyses
For both the negative binomial model and the logistic 
regression model for analysing hypoglycaemic episodes, 
it has been specified that the stratification factor will be 
omitted as a covariate in case of convergence issues due 
to few hypoglycaemic episodes.
Wording on retrieved drop-out analysis 
on body weight
Per new preferred terminology, this is no longer called an 
‘in-trial’ analysis, but rather a retrieved drop-out analysis. 
Wording on analyses of amylase and 
lipase
Clarification of that baseline values of amylase and lipase 
should be log-transformed before being used as 
covariates in the analyses.
Clarification of retrieved drop-out 
analysis
Clarification of that the covariates to be used in the 
ANCOVA step of the retrieved drop-out analysis, is the 
same ones as for the primary analysis. 
Clarification that the retrieved drop-out analysis will only 
be conducted to test the robustness of the superiority 
hypotheses.
Clarification of overall alpha level in 
testing approach
It has been clarified that the overall alpha level of 2.5% is 
one-sided, corresponding to a 5% two-sided alpha level.
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Statistical Analysis Plan
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4
References
1.
U.S.Department of Health and Human Services, Food and Drug Administration, Center for 
Drug Evaluation and Research (CDER). Guidance for Industry, Diabetes Mellitus -
Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. 
December 2008.
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