Conditions: Diabetes Diabetes Mellitus, Type 2
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 3183
Healthy volunteers: no

Brief summary:
This trial is conducted globally. The aim of the trial is to investigate the cardiovascular safety of oral semaglutide in subjects with type 2 diabetes.

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: semaglutide intervention 2: placebo
Intervention descriptions: intervention 1: For oral use once daily. intervention 2: For oral use once daily.

Protocol document:
Prot_000.pdf: 
Cover Page for Protocol 
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT02692716 
Sponsor trial ID: 
NN9924-4221 
Official title of study: 
PIONEER 6 – Cardiovascular outcomes trial. 
A trial investigating the cardiovascular safety of oral 
semaglutide in subjects with type 2 diabetes 
Document date: 
11 February 2019 
 


Link
Link
Link
Link
Link
Link
Link
List of contents
Protocol ...............................................................................................................................................
Appendix A - Monitoring of calcitonin.............................................................................................
Appendix B - Adverse events requiring additional data collection................................................
Attachment I and II............................................................................................................................
Protocol amendment 1 - DE ..............................................................................................................
Protocol amendment 2 - Global ........................................................................................................
Protocol amendment 3 - Global ........................................................................................................
Date:
Novo Nordisk
Version:
Status:
Oral semaglutide
Trial ID: NN9924 4221
Clinical Trial Report
Appendix 16.1.1
11 February 2019
1.0
Final
16.1.1 Protocol and protocol amendments
CONFIDENTIAL
Redacted protocol 
Lncludes redaction of personal identifiable DQGFRPSDQ\
FRQILGHQWLDOinformation. 
. 


Protocol
Date:
12 February 2016
Novo Nordisk
Trial ID: NN9924-4221
Version:
3.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
1 of 79
Protocol
Trial ID: NN9924-4221
PIONEER 6 – Cardiovascular outcomes
A trial investigating the cardiovascular safety of oral semaglutide in 
subjects with type 2 diabetes
Trial phase: 3a
Protocol originator
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
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
Date:
12 February 2016
Novo Nordisk
Trial ID: NN9924-4221
Version:
3.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
2 of 79
Table of Contents
Page
Table of Contents..............................................................................................................................................2
Table of Figures................................................................................................................................................5
Table of Tables..................................................................................................................................................5
List of abbreviations.........................................................................................................................................6
1
Summary....................................................................................................................................................8
2
Flow chart ................................................................................................................................................10
3
Background information and rationale for the trial............................................................................12
3.1
Background information..............................................................................................................12
3.1.1
Type 2 diabetes and GLP-1........................................................................................12
3.1.2
Oral semaglutide........................................................................................................12
3.1.3
Non-clinical data........................................................................................................13
3.1.3.1
Semaglutide.........................................................................................13
3.1.3.2
SNAC ..................................................................................................14
3.1.4
Clinical data oral semaglutide....................................................................................14
3.1.4.1
Pharmacokinetics ................................................................................14
3.1.4.2
Efficacy ...............................................................................................16
3.1.4.3
Safety...................................................................................................16
3.1.5
Oral semaglutide and cardiovascular risk..................................................................16
3.2
Rationale for the trial...................................................................................................................17
4
Objectives and endpoints........................................................................................................................17
4.1
Objectives ....................................................................................................................................17
4.2
Endpoints .....................................................................................................................................17
5
Trial design ..............................................................................................................................................18
5.1
Type of trial .................................................................................................................................18
5.2
Rationale for trial design..............................................................................................................19
5.3
Treatment of subjects...................................................................................................................20
5.3.1
Missed doses..............................................................................................................20
5.3.2
Dosing instructions ....................................................................................................21
5.3.3
Background medication.............................................................................................21
5.4
Treatment after discontinuation of trial product ..........................................................................22
5.5
Rationale for treatment ................................................................................................................22
6
Trial population.......................................................................................................................................22
6.1
Number of subjects......................................................................................................................22
6.2
Inclusion criteria ..........................................................................................................................22
6.3
Exclusion criteria.........................................................................................................................23
6.4
Composition of overall trial population.......................................................................................24
6.5
Premature discontinuation of trial product ..................................................................................24
6.6
Withdrawal of consent.................................................................................................................25
6.7
Subject replacement.....................................................................................................................25
6.8
Rationale for trial population.......................................................................................................25
CONFIDENTIAL


Protocol
Date:
12 February 2016
Novo Nordisk
Trial ID: NN9924-4221
Version:
3.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
3 of 79
6.8.1
Determining subject’s eligibility................................................................................25
6.8.2
Microalbuminuria and proteinuria.............................................................................26
6.8.3
Glomerular filtration rate, estimated (eGFR).............................................................26
7
Milestones.................................................................................................................................................26
8
Methods and assessments .......................................................................................................................27
8.1
Visit procedures...........................................................................................................................27
8.1.1
Informed consent .......................................................................................................28
8.1.2
In/exclusion criteria ...................................................................................................28
8.1.3
Screening ...................................................................................................................28
8.1.4
Demography...............................................................................................................29
8.1.5
Tobacco use ...............................................................................................................29
8.1.6
Physical examination.................................................................................................29
8.1.7
Pregnancy test............................................................................................................30
8.1.8
Concomitant illness and medical history...................................................................31
8.1.9
Concomitant medication............................................................................................31
8.1.10
Body measurements (height and body weight)..........................................................32
8.1.11
Vital signs ..................................................................................................................32
8.1.12
Electrocardiogram......................................................................................................32
8.1.13
Randomisation, dispensing of trial product and drug accountability.........................33
8.1.14
Blood sampling..........................................................................................................33
8.1.15
Hand out and instruct in BG meter use......................................................................35
8.1.16
Adverse events and technical complaints ..................................................................35
8.1.16.1
Hypoglycaemic episodes.....................................................................36
8.1.16.2
Medication errors ................................................................................36
8.1.17
End of trial .................................................................................................................36
8.2
Other assessments........................................................................................................................36
8.2.1
Assessments in case of suspicion of acute pancreatitis..............................................36
8.2.2
Assessments in case of suspicion of hypersensitivity reactions to the trial 
product .......................................................................................................................37
8.2.3
Assessments in case of increased levels of aminotransferases ..................................38
8.3
Treatment compliance..................................................................................................................38
8.4
Trial adherence ............................................................................................................................38
9
Trial supplies ...........................................................................................................................................40
9.1
Trial products...............................................................................................................................40
9.2
Labelling......................................................................................................................................40
9.3
Storage .........................................................................................................................................41
9.4
Drug accountability and destruction............................................................................................41
9.5
Auxiliary supplies........................................................................................................................41
10 Interactive voice/web response system ..................................................................................................42
11 Randomisation procedure and breaking of blinded codes..................................................................43
11.1
Breaking of blinded codes ...........................................................................................................43
12 Adverse events, technical complaints and pregnancies .......................................................................43
12.1
Definitions ...................................................................................................................................43
12.1.1
Adverse event ............................................................................................................43
12.1.2
Serious adverse event.................................................................................................45
CONFIDENTIAL


Protocol
Date:
12 February 2016
Novo Nordisk
Trial ID: NN9924-4221
Version:
3.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
4 of 79
12.1.3
Non-serious adverse event.........................................................................................46
12.1.4
Adverse events requiring additional data collection..................................................46
12.1.5
Technical complaint...................................................................................................47
12.2
Reporting of adverse events.........................................................................................................47
12.3
Follow-up of adverse events........................................................................................................50
12.4
Technical complaints and technical complaint samples ..............................................................51
12.4.1
Reporting of technical complaints .............................................................................51
12.4.2
Collection, storage and shipment of technical complaint samples ............................51
12.5
Pregnancies..................................................................................................................................52
12.6
Precautions and/or overdose ........................................................................................................52
12.7
Committees related to safety........................................................................................................53
12.7.1
Novo Nordisk safety committee ................................................................................53
12.7.2
Data monitoring committee .......................................................................................53
12.7.3
Event adjudication committee....................................................................................53
13 Case report forms....................................................................................................................................56
14 Monitoring procedures ...........................................................................................................................57
15 Data management....................................................................................................................................58
16 Computerised systems.............................................................................................................................58
17 Statistical considerations ........................................................................................................................59
17.1
Sample size calculation................................................................................................................60
17.2
Definition of analysis sets............................................................................................................61
17.3
Primary endpoint..........................................................................................................................61
17.3.1
Sensitivity analysis ....................................................................................................62
17.4
Secondary endpoints....................................................................................................................63
17.4.1
Confirmatory secondary endpoint..............................................................................63
17.4.2
Safety endpoints.........................................................................................................63
17.4.3
Efficacy endpoints .....................................................................................................64
18 Ethics........................................................................................................................................................64
18.1
Benefit–risk assessment of the trial .............................................................................................65
18.2
Data handling...............................................................................................................................67
18.3
Information to subject during trial...............................................................................................68
18.4
Premature termination of the trial and/or trial site.......................................................................68
19 Protocol compliance................................................................................................................................68
20 Audits and inspections ............................................................................................................................69
21 Critical documents ..................................................................................................................................69
22 Responsibilities........................................................................................................................................70
23 Reports and publications........................................................................................................................71
23.1
Communication of results............................................................................................................72
23.1.1
Authorship .................................................................................................................73
23.1.2
Site-specific publication(s) by investigator(s) ...........................................................73
23.2
Investigator access to data and review of results.........................................................................73
24 Retention of clinical trial documentation and human biospecimens..................................................73
CONFIDENTIAL


Protocol
Date:
12 February 2016
Novo Nordisk
Trial ID: NN9924-4221
Version:
3.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
5 of 79
24.1
Retention of clinical trial documentation.....................................................................................73
24.2
Retention of human biospecimens...............................................................................................74
25 Institutional Review Boards/Independent Ethics Committees and regulatory authorities..............74
26 Indemnity statement ...............................................................................................................................75
27 References................................................................................................................................................77
Appendix A – Calcitonin monitoring
Appendix B – Adverse events requiring additional data collection
Attachment I – Global list of key staff and relevant departments and suppliers
Attachment II – Country list of key staff and relevant departments, if applicable for the individual 
country
Table of Figures
Page
Figure 5–1
Trial design.............................................................................................................................19
Figure 12–1
Initial reporting of AEs...........................................................................................................49
Table of Tables
Page
Table 5–1
Treatment of subjects..............................................................................................................20
Table 6–1
Measurement of albuminuria..................................................................................................26
Table 9–1
Investigational medicinal products.........................................................................................40
Table 9–2
Storage conditions for trial products.......................................................................................41
Table 12–1
Adverse events for adjudication .............................................................................................55
Table 17–1
Expected trial duration according to event rates.....................................................................60
CONFIDENTIAL


Protocol
Date:
12 February 2016
Novo Nordisk
Trial ID: NN9924-4221
Version:
3.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
6 of 79
List of abbreviations
ADA
American Diabetes Association
AE
adverse event
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
AUC
area under the curve
BG
blood glucose
CRF
case report form
CRO
contract research organisation
DMC
data monitoring committee
DPP-4
dipeptidyl peptidase-4
DUN
dispensing unit number
EAC
event adjudication committee
ECG
electrocardiogram
eCRF
electronic case report form
eGFR
glomerular filtration rate, estimated 
EMA
European Medicines Agency
FAS
full analysis set
FDA
U.S. Food and Drug Administration
FPG
fasting plasma glucose
FSFV
first subject first visit
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
HR
hazard ratio
IB
Investigator’s Brochure


Protocol
Date:
12 February 2016
Novo Nordisk
Trial ID: NN9924-4221
Version:
3.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
7 of 79
IEC
independent ethics committee
IRB
institutional review board
ITT
intention-to-treat
IV/WRS
interactive voice/web response system
LDL
low density lipoprotein
LLoQ
lower limit of quantification 
LSFV
last subject first visit
LSLV
last subject last visit
MACE
major adverse cardiovascular event
MedDRA
Medical Dictionary for Regulatory Activities
MEN 2
multiple endocrine neoplasia type 2
MTC
medullary thyroid carcinoma
NYHA
New York Heart Association
PYO
patient years of observation time
SAE
serious adverse event
SAP
statistical analysis plan
s.c.
subcutaneous(ly)
SDV
source data verification
SGLT2
sodium-glucose cotransporter-2
SMPG
self-measured plasma glucose
SNAC
sodium N-(8-(2-hydroxybenzoyl) amino) caprylate
SUSAR
suspected unexpected serious adverse reaction
T2D
type 2 diabetes
TIA
transient ischaemic attack 
TMM
Trial Materials Manual
UTN
Universal Trial Number


Protocol
Date:
12 February 2016
Novo Nordisk
Trial ID: NN9924-4221
Version:
3.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
8 of 79
1
Summary
Objectives and endpoints:
The primary objective is to confirm that treatment with oral semaglutide does not result in an 
unacceptable increase in cardiovascular risk compared to placebo (rule out 80% excess risk) in 
subjects with type 2 diabetes at high risk of cardiovascular events. 
The primary endpoint is time from randomisation to first occurrence of a major adverse 
cardiovascular event (MACE) composite endpoint consisting of: cardiovascular death, non-fatal 
myocardial infarction or non-fatal stroke.
The secondary objectives are to compare the efficacy and safety of oral semaglutide versus 
placebo in subjects with type 2 diabetes at high risk of cardiovascular events.
Key secondary endpoints:
!
Time from randomisation to first occurrence of an expanded composite cardiovascular 
endpoint consisting of: cardiovascular death, non-fatal myocardial infarction, non-fatal 
stroke, unstable angina requiring hospitalisation or hospitalisation for heart failure
!
Time from randomisation to first occurrence of each of the individual components in the 
expanded composite cardiovascular endpoint
!
Time from randomisation to first occurrence of a composite endpoint consisting of: all-cause 
death, non-fatal myocardial infarction or non-fatal stroke
For the primary and the key secondary endpoints, maximum treatment duration is dependent on 
event rates and is estimated to be no longer than 19 months.
Trial design:
This trial is a randomised, double-blind, placebo-controlled trial to assess the cardiovascular safety 
of oral semaglutide versus placebo when added to standard of care in subjects with type 2 diabetes 
at high risk of cardiovascular events. Subjects will be randomised 1:1 to receive either oral 
semaglutide or placebo. The trial will be event-driven and will be continued until at least 122 first 
MACEs confirmed by adjudication have accrued. The treatment period for each subject is estimated 
to be between 12 and 19 months, depending on the time-point of recruitment and the accrual of first 
MACEs confirmed by adjudication. 
Trial population:
Number of subjects planned to be randomised is 3,176


Protocol
Date:
12 February 2016
Novo Nordisk
Trial ID: NN9924-4221
Version:
3.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
9 of 79
Key inclusion criteria: 
!
Male or female diagnosed with type 2 diabetes
!
Age ≥50 years at screening and presence of cardiovascular disease, or age ≥60 years at 
screening and presence of at least one cardiovascular risk factor
Key exclusion criteria:
!
Current or previous (within 90 days prior to screening) treatment with any GLP-1 receptor 
agonist, DPP-4 inhibitor or pramlintide
!
Family or personal history of multiple endocrine neoplasia type 2 (MEN 2) or medullary 
thyroid carcinoma (MTC)
!
History of pancreatitis (acute or chronic)
!
History of major surgical procedures involving the stomach potentially affecting absorption 
of trial product (e.g. subtotal and total gastrectomy, sleeve gastrectomy, gastric bypass 
surgery)
!
Subjects presently classified as being in New York Heart Association (NYHA) Class IV
heart failure
!
Planned coronary, carotid or peripheral artery revascularisation known on the day of 
screening
!
Any of the following: myocardial infarction, stroke or hospitalisation for unstable angina or 
transient ischaemic attack within the past 60 days prior to screening
!
Chronic or intermittent hemodialysis or peritoneal dialysis or severe renal impairment 
(corresponding to eGFR <30 mL/min/1.73 m2)
!
History or presence of malignant neoplasms within the last 5 years (except basal and 
squamous cell skin cancer and carcinoma in situ)
Key assessments:
!
Adverse events
Trial products:
!
Semaglutide 3 mg tablet
!
Semaglutide 7 mg tablet
!
Semaglutide 14 mg tablet
!
Placebo tablet


Protocol
UTN: U1111-1173-0750
Date:
12 February 2016
Status:
Final
Novo Nordisk
Trial ID: NN9924-4221
EudraCT No.: 2015-003563-10
Version:
3.0
Page:
10 of 79
2
Flow chart
Trial Periods
Scree-
ning
Ran-
domi-
sation
Treatment
End of 
treat-
ment
Follow-
up
Visit (V) Phone (P)
V1
V2
P3
V4
V5
V6
P72
V8
P92
V10
P112
V12
P132
V14
P152
V16
V171
P181
Timing of visit (weeks after V2)
Up to -2
0
2
4
8
14
20
26
32
38
44
50
56
62
69
76
83
88
Visit window (days)
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+3
Informed consent
X
In/exclusion criteria
X
Demography, tobacco use
X
Physical examination
X
X
Pregnancy test, urine dipsticks3
X
X
Concomitant illness, medical 
history
X
Concomitant medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
Body weight
X
X
X
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
Electrocardiogram
X
X
X
X
Blood sampling
X
X
X
X
X
X
X
X
X
X
HbA1c
X
X
X
X
X
X
X
X
X
Fasting plasma glucose
X
X
X
X
X
X
Lipids
X
X
X
X
Biochemistry
X
X
X
X
X
X
X
X
X
X
Haematology
X
X
X
X
X
X
X
X
X
X
Hormones
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Technical complaints
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


Protocol
UTN: U1111-1173-0750
Date:
12 February 2016
Status:
Final
Novo Nordisk
Trial ID: NN9924-4221
EudraCT No.: 2015-003563-10
Version:
3.0
Page:
11 of 79
Trial Periods
Scree-
ning
Ran-
domi-
sation
Treatment
End of 
treat-
ment
Follow-
up
Visit (V) Phone (P)
V1
V2
P3
V4
V5
V6
P72
V8
P92
V10
P112
V12
P132
V14
P152
V16
V171
P181
Timing of visit (weeks after V2)
Up to -2
0
2
4
8
14
20
26
32
38
44
50
56
62
69
76
83
88
Visit window (days)
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+3
IV/WRS call
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Randomisation
X
Dispensing of trial product
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Drug accountability
X
X
X
X
X
X
X
X
X
X
X
X
X
X
REMINDERS
Handout ID card
X
Handout and instruct in BG 
meter use
X
Attend visit fasting
X
X
X
X
X
X
End of trial 
X
1 V17 (End of treatment) and P18 (Follow-up) are applicable for all randomised subjects. P18 can be conducted over the telephone. For a subject who discontinued trial 
product prematurely (i.e. more than 5 weeks prior to the anticipated V17), V17 can be postponed to the point when P18 is otherwise due.
2 Dispensing visit (i.e. a combination of dispensing trial product and collecting relevant information over the telephone. If the subject provides the required information to 
site staff when collecting trial product, the telephone contact can be omitted).
3 For women of childbearing potential only. In addition to the planned assessment at screening and end-of-treatment, urine dipstick pregnancy test should be performed at 
site at any time during the trial if a menstrual period is missed, or if pregnancy is suspected, or as required by local law.


Protocol
Date:
12 February 2016
Novo Nordisk
Trial ID: NN9924-4221
Version:
3.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
12 of 79
3
Background information and rationale for the trial
The trial will be conducted in compliance with this protocol, ICH GCP1 and applicable regulatory 
requirements, and in accordance with the Declaration of Helsinki.2
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 and GLP-1
Type 2 diabetes (T2D) is a progressive metabolic disease primarily characterised by abnormal 
glucose metabolism. The pathogenesis is heterogeneous, and characterised by chronic 
hyperglycaemia caused by peripheral tissue insulin resistance, impaired insulin secretion due to 
abnormal beta-cell function and abnormal glucose metabolism in the liver3.
Glucagon-like peptide-1 (GLP-1) is an incretin hormone with a glucose-dependent stimulatory 
effect on insulin- and inhibitory effect on glucagon secretion from the pancreatic islets4,5. Subjects 
with T2D have a decreased incretin effect6-9. However, the insulinotropic action of GLP-1 and thus, 
the ability to lower blood glucose (BG) levels, is preserved when GLP-1 is administered at supra 
physiological levels10. In addition, supra physiological levels of GLP-1 lower body weight due to 
decreased energy intake induced by reduced appetite11. These mechanisms of action make GLP-1 
an attractive pharmacological treatment for T2D12-14.
3.1.2
Oral semaglutide
Semaglutide is a long-acting GLP-1 receptor agonist (GLP-1 RA) structurally similar to liraglutide 
(Victoza®), a once-daily GLP-1 RA developed by Novo Nordisk and approved worldwide for the 
treatment of T2D. Compared to human native GLP-1, which has a very short half-life, the 
semaglutide molecule has three minor but important modifications ensuring protraction of its 
action: amino acid substitutions at position 8 (alanine to alfa-aminoisobutyric acid, a synthetic 
amino acid) and position 34 (lysine to arginine), and acylation of the peptide backbone with a 
spacer and C-18 fatty di-acid chain to lysine in position 2615. The fatty di-acid side chain and the 
spacer mediate strong binding to albumin, thereby reducing renal clearance. The amino acid 
substitution at position 8 makes semaglutide less susceptible to degradation by dipeptidyl peptidase-
4 (DPP-4). The change in position 34 from a lysine to an arginine is included to have only one 
lysine in the sequence where to a spacer can be attached.
Semaglutide is in development for oral once-daily treatment of T2D. As the bioavailability of 
GLP-1 RAs is very low when administered orally, semaglutide has been co-formulated with the 
absorption enhancing excipient sodium N-(8-(2-hydroxybenzoyl) amino) caprylate (SNAC) based 
on the 
 concept developed by 
 in order to increase 


Protocol
Date:
12 February 2016
Novo Nordisk
Trial ID: NN9924-4221
Version:
3.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
13 of 79
bioavailability. When semaglutide is co-formulated with SNAC, SNAC has the capacity to augment 
the absorption of semaglutide across the gastrointestinal epithelium. The absorption enhancement 
by SNAC is dose, size and time-dependent and is believed to take place in close proximity of the 
tablet in the stomach. The absorption process is hampered if dosed with food, liquid or in the 
presence of significant stomach content. Throughout this document oral semaglutide will refer to 
the drug product, that is, semaglutide co-formulated with 300 mg SNAC. 
Novo Nordisk is currently also developing semaglutide for once-weekly subcutaneous (s.c.) 
administration in subjects with T2D.
3.1.3
Non-clinical data
3.1.3.1
Semaglutide
The non-clinical programme for semaglutide was designed according to the ICH M3 guideline to 
support the clinical development. The standard non-clinical 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 was generally well 
tolerated in animals (mice, rats and cynomolgus monkeys). Two potential safety issues have been 
identified and these are detailed below.
Thyroid C-cell tumours in rodents
Treatment-related non-genotoxic proliferative changes in the thyroid C-cells of mice and rats were 
observed in 2-year carcinogenicity studies with semaglutide; thyroid hyperplasia was preceded by 
an increase in serum calcitonin. C-cell changes have not been observed in long-term studies in non-
human primate. The observed pattern of effects in mice and rats and lack of these effects in the non-
human primate and in man suggest that the mechanism by which semaglutide acts on the thyroid C-
cells in rodents is the same as has been demonstrated for other GLP-1 RAs, including liraglutide. 
According to this mechanism, C-cell hyperplasia is mediated by the GLP-1 receptor and is not 
associated with RET (re-arranged during transfection) gene activation and rodents appear to be 
particularly sensitive, whereas humans are not. The relevance for human subjects is currently 
unknown, but considered to be low16.
Embryo−foetal development toxicity
Semaglutide caused embryo-foetal development toxicity in the rat through a GLP-1 receptor 
mediated effect on the inverted yolk sac placenta leading to impaired nutrient supply to the 
developing embryo. Primates do not have an inverted yolk sac placenta which makes this 
mechanism unlikely to be of relevance to humans and cynomolgus monkeys. In the developmental 
toxicity studies in cynomolgus monkey, a marked pharmacology mediated maternal body weight 
loss coincided with increased early foetal loss; however, there was no indication of a teratogenic 


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potential of semaglutide in this species. These data suggest an important species-dependent 
mechanism, whereby semaglutide is teratogenic in rats but not in primates.
A review of results from the non-clinical studies can be found in the current edition of the 
investigator’s brochure (IB) for s.c. semaglutide (NN9535)17, and the current edition of the IB for 
oral administration of semaglutide (NN9924)18, or any updates to these documents.
3.1.3.2
SNAC
SNAC was developed as an absorption enhancing excipient for the oral route of administration. The 
non-clinical programme to support clinical phase 3 development and marketing authorisation 
application submission has been conducted including a 26-week carcinogenicity study in transgenic 
rasH2 mice and a 2-year carcinogenicity study in Sprague-Dawley rats.
 
 
 
 
 
The carcinogenicity studies demonstrated that SNAC was not carcinogenic to the transgenic rasH2 
mouse or the Sprague-Dawley rat. The doses tested covered plasma exposures (area under the curve 
(AUC)) of 2-fold in the mouse and up to 44-fold in the rat when compared to the mean human 
exposure following a clinical dose of 300 mg SNAC/day.
A review of results from the non-clinical studies can be found in the current edition of the IB for 
oral administration of semaglutide (NN9924)18, or any updates thereto.
3.1.4
Clinical data oral semaglutide
A comprehensive clinical pharmacology programme including 12 trials has been completed, as well 
as a 26-week phase 2 dose-finding trial involving more than 600 subjects with T2D.
For details on the individual trials, please see the current edition of the IB for oral administration of 
semaglutide (NN9924)18, or any updates thereto.
3.1.4.1
Pharmacokinetics
In single dose trials, oral semaglutide has demonstrated a long mean terminal half-life (t½) ranging 
from 153 to 161 hours (~1 week) and a median time to reach maximum observed concentration 
(tmax) ranging from 1 to 2 hours in healthy subjects. 


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In multiple-dose pharmacokinetics trials, the exposure to oral semaglutide increased with increasing 
dose. Overall, the pharmacokinetic properties of semaglutide appeared similar in healthy subjects 
and in subjects with T2D.
Exposure of semaglutide exhibits a substantially greater dose-to-dose variation following oral 
administration compared to s.c. administration. However, when administered orally once-daily the 
pharmacokinetic properties of semaglutide, i.e. low clearance and long half-life, will limit the 
variation in steady state plasma exposure.
Data obtained following investigation of different dosing conditions for oral semaglutide have 
demonstrated that subjects should take the oral semaglutide tablet in the morning in a fasting state 
and at least 30 minutes before the first meal of the day. The tablet should be taken with up to half a 
glass of water (i.e. 120mL/4 fluid oz).
 
 
 
 
 
 
 
 
 
 
 
 
 
In subjects with mild to severe hepatic impairment, the exposure to semaglutide appeared to be 
unaffected by the degree of hepatic impairment, whereas the exposure to SNAC (in terms of both 
AUC and Cmax) was increased for subjects with hepatic impairment as compared to subjects with 
normal hepatic function.
All tablets of oral semaglutide contain 300 mg of SNAC. SNAC is rapidly absorbed with a median 
tmax ranging from 0.35−0.5 hours in healthy subjects and from 0.52−1.43 hours in subjects with 
T2D. It is extensively metabolized and no accumulation of SNAC has been observed in clinical 
trials. 


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3.1.4.2
Efficacy
The efficacy of oral semaglutide in adult subjects with T2D was investigated in a 26-week phase 2 
dose-finding trial. In this trial, placebo or one of the following doses of oral semaglutide were 
administered once daily: 2.5, 5, 10, 20 and 40 mg.
Results from the trial showed that oral semaglutide effectively lowered glycosylated haemoglobin 
(HbA1c) and body weight. Placebo-adjusted reductions in HbA1c were dose-dependent and 
statistically significant for all oral semaglutide treatment arms at week 26 (range: -0.40% to -
1.59%). Placebo-adjusted reductions in body weight were dose-dependent and statistically 
significant for oral semaglutide treatment doses of 10 mg and above at week 26 (range: -3.61 to -
6.98 kg). 
3.1.4.3
Safety
In the clinical trials completed so far, no unexpected safety findings have been identified for oral 
semaglutide administered up to 40 mg once daily. Consistent with other GLP-1 RAs, common 
adverse events (AEs) included nausea and vomiting, most of them of mild to moderate severity. In 
line with findings for other GLP-1 RAs, an increase in heart rate and serum levels of lipase and 
amylase has also been observed in subjects exposed to oral semaglutide.
In addition to the 13 completed clinical trials with oral semaglutide, SNAC has been investigated in 
the programme of orally administrated heparin in combination with SNAC (heparin/SNAC). The 
heparin/SNAC programme 
 included 29 phase 1 trials (SNAC doses 
ranged from 0.172-10.5 g). In three of these trials SNAC alone was investigated (to a maximum 
dose of 10.5 g). The studies covered formulation development, food effect, hepatic and renal 
impairment, age-effect and drug-drug interaction. The programme also included a total of three 
phase 2 and 3 trials in which the effects of orally delivered heparin solution (with >1.5 g SNAC 
three times a day) were investigated. The overall safety profile of oral semaglutide and 
heparin/SNAC indicates that SNAC is safe and well-tolerated.
For further details please see the current edition of the IB for oral administration of semaglutide 
(NN9924)18, or any updates thereto.
3.1.5
Oral semaglutide and cardiovascular risk
Based on the nonclinical and clinical data obtained with semaglutide dosed either orally or 
subcutaneously to date, no adverse safety signals have been identified that indicate an increased risk 
of cardiovascular events. In addition, although an increase in heart rate has been observed as a class 
effect for GLP-1 RAs, the extensive amount of clinical data from marketed products have not 
indicated that this drug class increases risk of cardiovascular events. In support, findings from the 
recently completed ELIXA™trial confirmed that treatment with the once daily injectable GLP-1 
RA lixisenatide does not increase the risk of MACE as compared to placebo. This trial is the first 


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cardiovascular outcomes trial within the GLP-1 RA drug class to report and several others 
(including SUSTAIN™6 investigating the cardiovascular safety of s.c. semaglutide) are ongoing. 
The absorption enhancer SNAC used in the formulation of oral semaglutide is an excipient with no 
discernable systemic or pharmacodynamic effects. Accordingly, the potential for adverse effects on 
the cardiovascular system is considered low. The collective nonclinical and clinical evidence on 
SNAC from 
 and Novo Nordisk has not identified safety signals related to cardiovascular
disease. However, information on potential long-term cardiovascular effects of SNAC is not yet 
available.
For an assessment of benefits and risks of the trial, see section 18.1.
3.2
Rationale for the trial
The purpose of this trial is to assess the cardiovascular safety of oral semaglutide in subjects with 
T2D at high risk of cardiovascular events. This trial has been designed to address the requirements 
contained in the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) 
guidance documents19,20 which specify how to demonstrate that a new antidiabetic therapy is not 
associated with an unacceptable increase in cardiovascular risk. 
4
Objectives and endpoints
4.1
Objectives
The primary objective is to confirm that treatment with oral semaglutide does not result in an 
unacceptable increase in cardiovascular risk compared to placebo (rule out 80% excess risk) in 
subjects with type 2 diabetes at high risk of cardiovascular events.
The secondary objectives are to compare the efficacy and safety of oral semaglutide versus 
placebo in subjects with type 2 diabetes at high risk of cardiovascular events.
4.2
Endpoints
The primary endpoint is time from randomisation to first occurrence of a MACE composite 
endpoint consisting of: cardiovascular death, non-fatal myocardial infarction or non-fatal stroke.
The confirmatory secondary endpoint is time from randomisation to first occurrence of an 
expanded composite cardiovascular endpoint consisting of: cardiovascular death, non-fatal 
myocardial infarction, non-fatal stroke, unstable angina requiring hospitalisation or hospitalisation 
for heart failure*


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The secondary endpoints are: 
!
Time from randomisation to first occurrence of each of the individual components in the 
expanded composite cardiovascular endpoint*
!
Time from randomisation to first occurrence of a composite endpoint consisting of: all-cause 
death, non-fatal myocardial infarction or non-fatal stroke*
!
Time from randomisation to all-cause death
!
Time to permanent discontinuation of trial product due to AE(s)
!
Number of serious adverse events (SAEs)
Change from baseline to last assessment of:
!
Biochemistry
!
Haematology
!
Calcitonin
!
Pulse
!
Systolic and diastolic blood pressure
!
Glycosylated haemoglobin (HbA1c)
!
Body weight
!
Lipids
* Key supportive secondary endpoint prospectively selected for disclosure (e.g. clinicaltrials.gov and EudraCT)
5
Trial design
5.1
Type of trial
This trial is a randomised, double-blind, placebo-controlled trial to assess the cardiovascular safety 
of oral semaglutide versus placebo when added to standard of care in subjects with T2D at high risk 
of cardiovascular events. Subjects will be randomised 1:1 to receive either oral semaglutide or 
placebo. Randomisation will be stratified according to evidence of cardiovascular disease at 
screening (presence of cardiovascular disease or risk factors only) to ensure even distribution of the 
two treatment arms within strata. The stratum ‘presence of cardiovascular disease’ consists of 
subjects at least 50 years of age and recognised as fulfilling at least one item of inclusion criterion 
no. 3a-h at screening, whereas the stratum ‘presence of cardiovascular risk factors only’ consists of 
subjects at least 60 years of age and recognised as fulfilling at least one item of inclusion criterion 
no. 3i-l and not fulfilling any of the items of inclusion criterion no. 3a-h at screening (see section
6.2).
All tablets containing oral semaglutide or placebo are identical with regards to visual appearance to 
maintain the blinding of the trial.


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The trial will be event-driven and will be continued until at least 122 first MACEs confirmed by 
adjudication have accrued. Throughout the remainder of this protocol, MACE will be defined as 
MACE confirmed by adjudication. 
The recruitment period is expected to last 7 months. The treatment period for each subject is 
estimated to be between 12 and 19 months, depending on the time-point of recruitment and the 
accrual of first MACEs. The follow-up period is 5 weeks to allow for wash-out of trial drug. A 
schematic diagram of the trial design is shown in Figure 5–1.
Figure 5–1
Trial design
The trial is designed to evaluate cardiovascular outcomes and will apply a targeted approach to 
collection of safety data focusing on SAEs, AEs leading to discontinuation of trial product and other 
selected AEs. An adequate characterisation of the less serious and more common AEs will be 
evaluated in the other phase 3a trials conducted with oral semaglutide comprising more than 4000 
subjects with T2D.
An external event adjudication committee (EAC) will perform ongoing adjudication of predefined 
cardiovascular events and other selected AEs in an independent and blinded manner. 
An independent external data monitoring committee (DMC) will have unblinded access to data 
from the trial and perform review of accumulating data on an ongoing basis. The DMC will provide 
recommendation on trial continuation, modification or termination. 
5.2
Rationale for trial design
A randomised, double-blind, placebo-controlled trial has been chosen in accordance with the trial 
objectives and to avoid bias of the results. The planned duration of the trial has been estimated 
based on the number of subjects randomised and the expected first MACE rate. The treatment 
period is expected to be between 12 and 19 months. This duration should be adequate to provide 
data to assess the cardiovascular safety of oral semaglutide. 


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5.3
Treatment of subjects
Subjects will be randomised in a 1:1 ratio to receive either oral semaglutide or placebo. Randomised 
subjects will initiate treatment with 3 mg oral semaglutide/placebo once daily and follow a fixed 4-
week dose escalation regimen until reaching the maximum dose of 14 mg oral semaglutide/placebo 
as illustrated in Table 5–1. The 4-week dose escalation intervals are applied in order to mitigate the 
risk of gastrointestinal adverse events (AEs). Subjects should remain on the 14 mg dose level 
throughout the maintenance period; however, if treatment with the trial product is associated with 
unacceptable AEs (as judged by the investigator), dose reductions and extensions of dose escalation
periods are allowed. In case the dose is reduced due to unacceptable AEs, the investigator should 
consider escalating the dose of oral semaglutide once the subject has recovered. Trial product dose 
and date of change or discontinuation should be recorded in the electronic case report form (eCRF)
throughout the trial. 
Table 5–1
Treatment of subjects
Trial periods
Screening
Trial period 1
Trial period 2
Trial period 3
Follow-up
Alias for trial period
Screening
Dose escalation
Dose escalation
Maintenance
Follow-up
First visit in each period
V1
V2
V4
V5
V17
Duration of each period
Up to 2 weeks
4 weeks
4 weeks
Up to 75 weeks
5 weeks
Treatment arm
N
Oral semaglutide
1588
Screening
3 mg
7 mg
14 mg
Follow-up
Placebo
1588
Screening
Placebo
Placebo
Placebo
Follow-up
5.3.1
Missed doses
The trial product should be administered once daily; however, if one or more doses of trial product 
are missed due to circumstances not related to the safety of the trial product (as judged by the 
investigator) and treatment with trial product is resumed, the below recommendations for dose 
adjustment apply: 
!
If ≤21 consecutive doses of 14 mg oral semaglutide/placebo are missed, the once-daily 
regimen can be resumed as prescribed without dose reduction. 
!
If 22-35 consecutive doses of 14 mg oral semaglutide/placebo are missed, it is 
recommended to resume treatment at 7 mg oral semaglutide/placebo and subsequently, 
escalate to the higher dose after 4 weeks of treatment. 
!
If ≥36 consecutive doses of 14 mg oral semaglutide/placebo are missed, it is recommended 
to resume treatment at 3 mg oral semaglutide/placebo and subsequently, escalate to the 
higher doses with 4-week dose escalation steps.


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Please refer to section 10 for instructions on how to use the interactive voice/web response system 
(IV/WRS) in relation to subjects discontinuing and resuming trial product treatment.
5.3.2
Dosing instructions
Absorption of oral semaglutide is significantly affected by food and fluid in the stomach, hence 
subjects should take the oral semaglutide/placebo tablets in the morning in a fasting state and at 
least 30 minutes before the first meal of the day. The tablets should be taken with up to half a glass 
of water (approximately 120 mL/4 fluid oz). The tablets must be swallowed whole and must not be 
broken or chewed. Other oral medication can be taken 30 minutes after the trial product. The tablets 
should be taken immediately after removal from the blister.
5.3.3
Background medication
The investigator will assume responsibility for the management of glycaemic control in each 
subject enrolled in the trial. The investigator is responsible for ensuring that glycaemic control is 
maintained and optimised in each subject while maintaining a low risk of hypoglycaemic episodes. 
If deemed necessary to achieve glycaemic target, antidiabetic medication (excluding GLP-1 RAs,
DPP-4 inhibitors and pramlintide from visit 1 to 17) may be adjusted or added, at the investigator’s 
discretion. The background medication should be used in accordance with standard of care and the 
current local label.
If episodes of hypoglycaemia require reduction of antidiabetic medication, investigators should 
reduce or modify the dosing of background medication. In particular, dose reduction of insulin 
should be done already at randomisation (e.g. 10-20% reduction of the insulin dose) to reduce the 
risk of hypoglycaemia when introducing an additional glucose lowering agent. Similar 
considerations should be made for subjects treated with sulphonylureas.
All subjects will be provided with a BG meter at randomisation and glycaemic management will be 
guided by review of fasting plasma glucose (FPG) and HbA1c results measured at the site as well as 
self-measured plasma glucose (SMPG) results measured at home by the subject. In addition, it is 
important that other information such as symptoms of hypo/hyperglycaemia, previous response to 
dose adjustments and other indicators of the subject’s level glycaemic control is taken into 
consideration when decisions on dose adjustments of the background antidiabetic medication are 
made. In subjects treated with insulins, close contact should be ensured in the initial 12 weeks after 
randomisation to allow for adequate adjustment of insulin dose, at the investigator’s discretion. 
Additional phone contacts in the weeks where no site visit is planned should be considered for 
subjects treated with insulins.
Please note that due to the long half-life of oral semaglutide and the gradual dose escalation, the full 
effect of the investigational product on glycaemic parameters may not be apparent until several 
weeks into the maintenance period.


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Cardiovascular diseases and risk factors will be treated according to local standard of care at the 
investigator’s discretion.
5.4
Treatment after discontinuation of trial product
When discontinuing trial product at the end of the treatment period, the subject should be switched 
to a suitable marketed product at the discretion of the investigator. Oral semaglutide will not be 
available for prescription until marketing authorisation is issued.
For Brazil only: At the end of the trial, subjects will be assured access to the best proved 
prophylactic, diagnostic and therapeutic methods identified during the trial.
5.5
Rationale for treatment
Blinded treatment with oral semaglutide or placebo offers a robust method for assessment of oral 
semaglutide’s effect on trial endpoints. Gradual dose escalation is applied in order to mitigate the 
risk of gastrointestinal AEs. Treatment intensification of the background medication is allowed 
throughout the course of the trial to ensure adequate glycaemic control in all participating subjects.
Use of other GLP-1 RAs and DPP-4 inhibitors and pramlintide is not allowed, because these drugs,
similarly to oral semaglutide, affect the incretin pathway.
6
Trial population
6.1
Number of subjects 
Number of subjects planned to be randomised: 3,176
For Mexico only: Approximately 150 subjects are planned to be randomised in Mexico
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 diagnosed with type 2 diabetes.


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3. Age ≥ 50 years at screening and at least one of the below conditions:
a.
prior myocardial infarction
b. prior stroke or transient ischaemic attack (TIA)
c.
prior coronary, carotid or peripheral arterial revascularisation
d. > 50% stenosis on angiography or imaging of coronary, carotid or lower 
extremity arteries
e.
history of symptomatic coronary heart disease documented by e.g. positive 
exercise stress test or any cardiac imaging or unstable angina pectoris with ECG 
changes
f.
asymptomatic cardiac ischaemia documented by positive nuclear imaging test or 
exercise test or stress echo or any cardiac imaging
g. chronic heart failure New York Heart Association (NYHA) class II-III
h. moderate renal impairment (corresponding to an estimated glomerular filtration 
rate (eGFR) between 30-59 mL/min/1.73 m2)
or
Age ≥ 60 years at screening and at least one of the below risk factors:
i.
microalbuminuria or proteinuria
j.
hypertension and left ventricular hypertrophy by ECG or imaging
k. left ventricular systolic or diastolic dysfunction by imaging
l.
ankle/brachial index < 0.9
6.3
Exclusion criteria
For an eligible subject, all exclusion criteria must be answered "no".
1. Known or suspected hypersensitivity to the trial product 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 childbearing 
potential and not using adequate contraceptive methods (adequate contraceptive measures as 
required by local regulation or practice. Local country regulations or practices are specified 
in section 8 of the protocol).
4. Receipt of any investigational medicinal product within 90 days before screening. 
For Brazil only: Participation in other clinical trials within one year prior to screening 
unless there is a direct benefit to the research subject at the investigator´s discretion.
5. Participation in another clinical trial of an investigational medicinal product. Participation in 
a clinical trial which evaluate stent(s) is allowed.
6. Current or previous (within 90 days prior to screening) treatment with any GLP-1 receptor 
agonist, DPP-4 inhibitor or pramlintide.
7. Any disorder, which in the investigator’s opinion might jeopardise subject’s safety or 
compliance with the protocol.


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8. Family or personal history of multiple endocrine neoplasia type 2 (MEN 2) or medullary 
thyroid carcinoma (MTC).
9. History of pancreatitis (acute or chronic).
10. History of major surgical procedures involving the stomach potentially affecting absorption 
of trial product (e.g. subtotal and total gastrectomy, sleeve gastrectomy, gastric bypass 
surgery).
11. Subjects presently classified as being in New York Heart Association (NYHA) Class IV
heart failure.
12. Planned coronary, carotid or peripheral artery revascularisation known on the day of 
screening.
13. Any of the following: myocardial infarction, stroke or hospitalisation for unstable angina or 
transient ischaemic attack within the past 60 days prior to screening.
14. Chronic or intermittent hemodialysis or peritoneal dialysis or severe renal impairment 
(corresponding to eGFR <30 mL/min/1.73 m2).
15. History or presence of malignant neoplasms within the last 5 years (except basal and 
squamous cell skin cancer and carcinoma in situ).
16. History of diabetic ketoacidosis.
6.4
Composition of overall trial population
In order to secure sufficient overall cardiovascular risk within the trial population, randomisation of 
subjects with risk factors only (inclusion criterion no. 3, i-l) will be stopped when 650 of these 
subjects have been randomised.
6.5
Premature discontinuation of trial product 
All efforts should be made to keep the subject on trial product throughout the trial. The subject may, 
however, decide to discontinue trial product for any reason, or they may be discontinued from trial 
product due to safety concerns at the discretion of the investigator. In case the trial product is 
interrupted due to suspicion of acute pancreatitis or a hypersensitivity reaction to the trial product, 
please see sections 8.2.1 and 8.2.2.
Furthermore, the subject must discontinue treatment with trial product if any of the following 
applies:
!
pregnancy
!
intention of becoming pregnant
!
participation in another clinical trial with an investigational medicinal product
!
calcitonin ≥ 100 ng/L
Discontinuation of treatment with trial product, whether temporary or permanent, must not prompt 
the investigator to withdraw the subject from the trial. Instead, the subject should maintain 
adherence to trial visits and procedures to the extent possible. In each separate case, the primary 


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reason for discontinuation of trial product must be specified in the eCRF. The subject should be 
encouraged to resume treatment with trial product once they are willing or when the safety concern 
has ceased, respectively.
A subject who does not fulfil the eligibility criteria (inclusion/exclusion criteria) must not be 
randomised. If a subject is randomised in error, this will be handled as an important protocol 
deviation, and the IEC/IRB and regulatory authorities must be notified according to local 
requirements. If there are no safety concerns, trial treatment may be continued or resumed at the 
discretion of the investigator following a discussion with the sponsor’s global medical expert.
See section 5.3.1 for instructions about resuming trial product treatment after a treatment pause. 
6.6
Withdrawal of consent
The subject may withdraw at will at any time. If a subject has withdrawn their consent, the
investigator must make every effort to establish the subject’s vital status at the end of the trial. See 
section 8.4 for further instructions about withdrawals.
For Mexico only: Should the subject, his/her family members, parents or legal representative 
decide to withdraw the consent for participation in the trial, the subject will be entitled to receive 
appropriate, free of charge medical care and/or trial drug during the follow up period of the 
protocol when it will be established with certainty that no untoward medical consequences of the 
subject´s participation in the research occurred.
6.7
Subject replacement
Subjects who have withdrawn their consent will not be replaced.
6.8
Rationale for trial population 
This trial will include subjects with T2D at high risk of cardiovascular events. This includes 
subjects with previous cardiovascular disease or well-established risk factors for cardiovascular
disease and advanced age, as based on their medical records. The inclusion of subjects with 
established risk for cardiovascular disease will ensure that the primary objective of the trial can be 
obtained within a reasonable timeframe.
Subjects with a recent event of myocardial infarction, stroke or hospitalisation for unstable angina 
or TIA prior to screening are excluded, aiming to avoid any effect of cardiovascular events that are 
likely to be secondary to another cardiovascular event or intervention.
6.8.1
Determining subject’s eligibility 
It is the responsibility of the investigator to ensure unequivocal evidence for a subject’s eligibility. 
When determining a subject’s eligibility based on medical history, it is at the investigator’s 


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discretion on a case by case basis to decide if further medical records are needed or if the available 
documentation is adequate. Any laboratory values used to assess eligibility must reflect the 
subject’s current health status.
6.8.2
Microalbuminuria and proteinuria
For the diagnosis of microalbuminuria and proteinuria, local guidelines, if such exist, can be used. 
Otherwise, commonly accepted guidelines should be used21. Table 6–1 shows examples of how 
albuminuria can be assessed22.
Table 6–1
Measurement of albuminuria
Normal
Microalbuminuria
Macroalbuminuria
Advantages
Disadvantages
Urine dipstick
for protein
-
-
+
Convenience
Dependent on 
level of hydration
Urine 24-hour
protein (mg)
< 150
< 500
≥ 500
Overcomes problem 
of diurnal variation 
in excretion
Subject to 
collection errors
Urine 24-hour
albumin (mg)
< 30
30-300
> 300
Overcomes problem 
of diurnal variation 
in excretion
Subject to 
collection errors
Timed urine
collection
(μg/min)
< 20
20-200
> 200
Overcomes problem 
of diurnal variation 
in excretion
Subject to 
collection errors
Spot urine
collection (μg
albumin/mg
creatinine)
< 30
30-300
> 300
Convenience
Not dependent on 
hydration level
Most reproducible
Ratios vary based 
on gender
6.8.3
Glomerular filtration rate, estimated (eGFR) 
To evaluate whether a subject meets inclusion criterion no. 3 and exclusion criterion no. 14, the 
creatinine level that best reflects the current status of the subject in the medical records should be 
used to calculate eGFR. The equation from the Chronic Kidney Disease Epidemiology 
Collaboration (CKD-Epi)21 including variables for age, sex, and race should be used to calculate 
eGFR.
7
Milestones
Planned duration of recruitment period (i.e. FSFV – LSFV): 7 months.


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End of trial is defined as Last Subject Last Visit (LSLV).
Novo Nordisk will follow the screening and randomisation rates closely via IV/WRS in order to 
estimate when to stop screening. Investigators will be notified immediately when the recruitment 
period ends, after which no further subjects may be screened, and IV/WRS will be closed for further 
screening.
The treatment period for the last randomised subject is expected to be 12 months. The trial duration 
is, however, decided by the first MACE rate (see section 5.1), and the trial duration will be adjusted 
as needed. When the trial comes to an end, investigators will be notified and instructed by Novo 
Nordisk regarding the visit schedules for their subjects.
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 Disclosure23, it will also be disclosed 
according to other applicable requirements such as those of the International Committee of Medical 
Journal Editors24, the Food and Drug Administration Amendment Act 25, European Commission 
Requirements26,27 and other relevant recommendations or regulations. If a subject requests to be 
included in the trial via the Novo Nordisk e-mail contact at these web sites, Novo Nordisk may 
disclose the investigator’s contact details to the subject. As a result of increasing requirements for 
transparency, some countries require public disclosure of investigator names and their affiliations.
8
Methods and assessments
8.1
Visit procedures
The duration of this trial is decided by the observed first MACE rate (see section 5.1). It is expected 
that each subject will be asked to attend maximum eighteen visits. Eleven of these are regular clinic 
visits, two visits can be performed over the telephone, and five visits are dispensing visits. 
Dispensing visits are a combination of dispensing trial product and collecting relevant information 
over the telephone (see section 2). If the subject provides the required information to site staff when 
collecting trial product, the telephone contact can be omitted.
Depending on when a subject entered the trial and the accrual of first MACEs, subject’s visit
schedule may be shortened. This will imply omission of visit(s) in the treatment period, as, when 
the trial comes to an end, all subjects should be asked to attend visit 17 and 18. For a subject who 
discontinued trial product prematurely (i.e. more than 5 weeks prior to the anticipated visit 17), visit 
17 can be postponed to the point when visit 18 is otherwise due.


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The timing and content of visits and the visit windows are outlined in section 2, while procedures
and assessments to be carried out at the visits are described in this section. 
8.1.1
Informed consent
In seeking and documenting informed consent, the investigator must comply with applicable 
regulatory requirement(s) and adhere to ICH GCP1 and the requirements in the Declaration of 
Helsinki2.
Before any trial-related activity, the investigator must give the subject verbal and written 
information about the trial and the procedures involved in a form that the subject can read and 
understand. This includes the use of an impartial witness, where required according to local 
regulations. The subject 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 product.
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.
8.1.2
In/exclusion criteria
Subjects should be assessed for eligibility according to sections 6.2 and 6.3 at visit 1. For further 
instructions about determining the eligibility of a subject, see sections 6.8.1, 6.8.2 and 6.8.3. 
For inclusion criterion no. 3 (section 6.2), the investigator must provide just one answer (yes or no)
on the inclusion criteria form in the eCRF for each subject.
For exclusion criterion no. 3 (section 6.3), each female of childbearing potential must have a 
negative pregnancy test in order to be randomised.
8.1.3
Screening 
At visit 1, the investigator must perform a screening session in IV/WRS (see section 10), and each 
subject will be assigned a unique 6-digit subject number which will remain the same throughout the 
trial. The investigator must keep a subject screening log, a subject identification code list and a 


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subject enrolment log. The subject screening log and subject enrolment log may be combined into
one list.
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.
Screening failures: If a subject is screened, but for some reason never randomised, the subject is a 
screening failure. For screening failures, the screening failure form in eCRF must be completed 
with the reason for not continuing in the trial. SAEs from screening failures must be transcribed by 
the investigator into the eCRF. Follow-up of SAEs must be carried out according to section 12. A 
screening failure session must be made in the IV/WRS. The case book must be signed
electronically. Re-screening is not allowed.
8.1.4
Demography
Demography (date of birth or age, sex, race and ethnicity) will be recorded at visit 1, unless 
prohibited according to local regulations.
8.1.5
Tobacco use
Details of tobacco use must be recorded at visit 1. Smoking is defined as smoking at least one 
cigarette, cigar or pipe daily. The collected information should include whether or not the subject 
smokes or has smoked. If the subject has smoked, record approximately when the subject stopped 
smoking.
8.1.6
Physical examination
Physical examinations should be performed according to local procedures, when indicated in 
section 2, and will as a minimum include examination of:
!
head, ears, eyes, nose, throat, neck
!
respiratory system
!
cardiovascular system
!
gastrointestinal system, incl. mouth
!
musculoskeletal system
!
central and peripheral nervous system
!
skin
!
lymph node palpation
!
general appearance
!
thyroid gland


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For each assessment, the investigator should indicate whether the outcome was normal or abnormal, 
and, if abnormal, indicate whether clinically significant. Relevant findings as a result of screening 
procedures conducted at visit 1 must be recorded as concomitant illness/medical history in 
accordance with section 8.1.8.
8.1.7
Pregnancy test
Female subjects of childbearing potential will have pregnancy tests (urine dipsticks) performed as 
per the flow chart in section 2. In addition, urine pregnancy test should be performed at any time 
during the trial if a menstrual period is missed, or if pregnancy is suspected, or as required by local 
law.
Pregnancy testing will not be required (unless required by local law) for women of non-childbearing 
potential defined as, but not limited to, women who have undergone hysterectomy, bilateral 
oophorectomy or bilateral tubal ligation, or who are postmenopausal (i.e. women above the age of 
50 with no menstrual periods for at least 1 year). This has to be documented in the medical records.
Contraceptive methods
Female subjects of childbearing potential must use adequate contraceptive methods until 5 weeks 
after the last date on trial product. Throughout the protocol, last date on trial product is defined as 
date of the subject’s last dosage of trial product.
For Argentina only: Adequate contraceptive measures are: Barrier methods (condom or 
diaphragm) with spermicide; contraceptive pills or intrauterine devices. Contraceptive methods 
will be reimbursed by Novo Nordisk Pharma Argentina S.A.
For Brazil only: For women who expressly declare free of the risk of pregnancy, either by not 
engaging in sexual activity or by having sexual activity with no birth potential risk, use of 
contraceptive method will not be mandatory.
For Germany only: Adequate contraceptive measures are implants, injectables, combined oral 
contraceptives, hormonal intrauterine devices, sexual abstinence or vasectomised partner.
For Thailand only: Adequate contraceptive measures are: Diaphragm, condom (by the partner), 
intrauterine device in place for last three months before trial starts, sponge, cap with spermicide, 
contraceptive patch, approved hormonal implant (i.e. Norplant), oral contraceptives taken without 
difficulty for the last three months before trial starts, post-menopausal state or sterilisation.
For United Kingdom only: Adequate contraceptive measures are defined as established use of oral, 
intravaginal, transdermal, combined estrogen and progestogen hormonal methods of 
contraception; oral, injected or implanted progestogen only hormonal methods of contraception; 
placement of an intrauterine device or intrauterine hormone releasing system, bilateral tubal 


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occlusion, barrier methods of contraception (condom or occlusive cap with spermicidal 
foam/gel/film/cream/suppository), female sterilisation, vasectomised partner (where partner is sole 
partner of subject), or true abstinence (when in line with preferred and usual lifestyle).
8.1.8
Concomitant illness and medical history
A concomitant illness is any illness that is present at the start of the trial (i.e. at visit 1) or found as 
a result of a screening procedure.
Medical history is a medical event that the subject has experienced in the past. Only relevant 
medical history as judged by the investigator should be transcribed to the eCRF.
The information collected for concomitant illness and medical history should include diagnosis,
date of onset and date of resolution or continuation, as applicable.
The following must be assessed at visit 1 and transcribed to disease-specific forms, i.e. not to the 
medical history/concomitant illness form:
!
Diabetes history/diabetes complications (e.g. date of diagnosis, diabetic retinopathy, diabetic 
neuropathy, diabetic nephropathy)
!
History of cardiovascular disease (e.g. ischaemic heart disease, myocardial infarction, heart 
failure incl. NYHA class28, hypertension, stroke, peripheral arterial disease) including 
answering yes or no/unknown for each cardiovascular condition/risk factor mentioned in 
inclusion criterion no. 3 a-l (see section 6.2)
!
History of gallbladder disease (e.g. gallstone, cholecystitis, cholecystectomy)
!
History of gastrointestinal disease (e.g. gastroesophageal reflux disease, ulcer disease, 
chronic gastritis)
Any change to a concomitant illness should be recorded during the trial. A clinically significant 
worsening of a concomitant illness must be assessed according to section 12.1 and reported if 
applicable as per section 12.2. 
8.1.9
Concomitant medication
A concomitant medication is any medication, other than the trial product, which is taken during 
the trial, i.e. as of visit 1 until the time point of visit 18.
Details of any concomitant medication must be recorded at visit 1. Changes in concomitant 
medication must be recorded at each subsequent visit as they occur. 
The information collected for each concomitant medication includes trade name or generic name, 
indication, total daily dose (only applicable for medication taken to treat diabetes and 
cardiovascular related disease), start date and stop date or continuation.


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For subjects treated with insulin(s), total daily dose administered on the day preceding each trial 
visit (if available) should be recorded in the eCRF. 
8.1.10
Body measurements (height and body weight)
Height is measured without shoes in centimetres or inches and recorded in the eCRF to the nearest 
½ cm or ¼ inch.
Body weight is measured wearing light clothes and no shoes and recorded in the eCRF in kilogram 
or pound (kg or lb) with one decimal. If possible, the same calibrated weighing scale equipment 
should be used throughout the trial.
8.1.11
Vital signs
Pulse and systolic and diastolic blood pressure should be assessed in a sitting position after the 
subject has been resting for at least 5 minutes and by using the standard clinical practice at the site. 
The measured values should be recorded without rounding. If possible, the same equipment should 
be used throughout the trial.
8.1.12
Electrocardiogram
12-lead ECGs will be performed at selected visits (see the flow chart in section 2). Investigator’s 
interpretation of each ECG must be documented on the document or in the subject’s medical 
records and abnormalities assessed according to section 12.1, and reported if applicable as per 
section 12.2. However, for abnormal clinically significant findings revealing baseline conditions at 
visit 2 the investigator must record these as concomitant illness/medical history, and, if applicable, 
update answer(s) related to inclusion criterion 3 (see section 8.1.8).
The ECGs will also undergo central assessment and the investigator must forward the ECGs to the 
central ECG readers as soon as possible. If the central evaluation of a baseline ECG is suggestive of 
a prior myocardial infarction, the investigator will be notified. Unless already done, the investigator 
should consider recording the condition as cardiovascular history and update the answer(s) related 
to inclusion criterion 3 (see section 8.1.8). If the central ECG evaluation of a post-baseline ECG is 
suggestive of new myocardial infarction, the investigator will be notified and a confirmatory ECG 
should be submitted to central ECG readers. Unless already done, and at the investigator’s 
discretion, the investigator should assess the finding according to section 12.1, and if applicable 
report it as per section 12.2.
If additional ECG recordings are performed at the investigator’s discretion at other visits than the 
planned ECG visits, such ECGs should also be submitted to the central ECG readers. The reason for 
recording an additional ECG should be documented.


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Findings suggestive of new myocardial infarction detected by the central ECG readers will be 
adjudicated by the EAC (see section 12.7.3).
8.1.13
Randomisation, dispensing of trial product and drug accountability
At visit 2, subjects are randomised into one of the two treatment arms. The randomisation session 
must be performed in IV/WRS and will include allocation of dispensing unit numbers (DUNs) to be 
dispensed to the subject.
All assessments pertaining to visit 2 must be performed before first dose of trial product is taken.
Date of first administration of trial product must be captured in the eCRF.
At each visit where dispensing of trial product is indicated (see section 2), IV/WRS must be used to 
allocate DUNs according to the subject’s assigned treatment group (assigned at randomisation). The 
allocated DUNs should be dispensed by the site, hospital pharmacy or equivalent. 
The investigator must ensure that the subject is reminded about dosing instructions (see section 
5.3.2) at every dispensing visit, as needed.
At each visit where the subject returns used, partially used or unused trial product, the investigator 
will account for the returned trial products in IV/WRS (see section 9.4).
8.1.14
Blood sampling
Laboratory kits and laboratory manual will be provided to each site. The manual will include 
instructions for handling, storage and shipment of blood samples, and contact information for the 
central laboratory, including a link to their website where current laboratory certificates can be 
obtained. Blood samples should be collected according to the flow chart in section 2 and the 
laboratory parameters listed below will be assessed at a central laboratory (see Attachment I).
Glucose metabolism:
!
HbA1c
!
FPG
Lipids:
!
Total cholesterol
!
LDL cholesterol
!
HDL cholesterol
!
Triglycerides


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Biochemistry:
!
Alanine aminotransferase (ALT)
!
Albumin
!
Alkaline phosphatase (ALP)
!
Amylase
!
Aspartate aminotransferase (AST)
!
Bilirubin, total
!
Calcium
!
Creatinine
–
eGFR will be calculated by the central laboratory
!
Lipase
!
Potassium
!
Sodium
!
Urea
!
Creatine kinase
Haematology:
!
Haematocrit
!
Haemoglobin
!
Leucocytes
!
Thrombocytes
!
Differential count (eosinophils, neutrophils, basophils, lymphocytes and monocytes)
Hormones: 
!
Calcitonin
The laboratory results will be made available for the investigator on an ongoing basis. The 
investigator must sign and date each laboratory report or ensure review is documented in the 
subject’s medical records. For laboratory results outside the reference range, the investigator must 
indicate as either clinically significant or not clinically significant. Concomitant illnesses and AEs 
must be assessed and reported according to this protocol, as applicable.
If a calcitonin assessment results in a value ≥10 ng/L, the investigator must follow the algorithm in 
Protocol Appendix A.
FPG levels are monitored to aid investigators in glycaemic management through adjustment of 
background medication, but will not be included as an endpoint.


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Subjects must attend visits fasting when FPG and lipids are assessed (see section 2). Fasting is 
defined as having consumed only water within the last 8 hours. Administration of trial product is 
allowed prior to the visit. If a subject attends the visit in a non-fasting state, the visit procedures 
should be performed, excluding blood sampling, and subjects must be asked to visit the site once 
more within the visit window to have blood sampling performed.
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 always 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. For Brazil only: All laboratory results will be 
communicated to the investigators. The investigator must review all laboratory results for 
concomitant illnesses and AEs and report these according to this protocol.
Blood samples will be destroyed at completion of the clinical trial report at the latest, except 
samples obtained for anti-semaglutide antibody analysis in relation to suspicion of hypersensitivity 
reaction (see section 8.2.2 and 24.2).
8.1.15
Hand out and instruct in BG meter use 
At visit 2, the subject should be provided with a BG meter including auxiliaries. The subject should
be instructed in how to use the device. The instructions should be repeated as necessary during the 
trial. 
The BG meters use test strips calibrated to plasma values. Therefore, all measurements performed 
with capillary blood are automatically calibrated to plasma equivalent glucose values, which will be 
shown on the display. 
The investigator should instruct and encourage the subject to measure and record fasting SMPG 
according to individual recommendation from the investigator. The SMPG measurements may be 
recorded anywhere as per the subject’s own choice or the investigator’s recommendation. The 
measurements will not be transcribed into the eCRF, i.e. these measurements are only encouraged 
in order to facilitate good diabetes management at the discretion of the investigator.
8.1.16
Adverse events and technical complaints
AEs and technical complaints must be reported in accordance with the procedures outlined in 
section 12.


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8.1.16.1
Hypoglycaemic episodes
All severe hypoglycaemic episodes defined according to the ADA classification29 must be reported 
as an AE with additional data collection, see section 12.1.4, 12.2 and Appendix B. The investigator 
is not required to report a hypoglycaemic episode if the episode is both non-serious and non-severe.
A severe hypoglycaemic episode is defined as 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.
If the hypoglycaemic episode fulfils the criteria for an SAE then a safety information form must 
also be filled in, see section 12.
8.1.16.2
Medication errors
If a medication error concerning trial product (see definition in section 12.1.4) is observed during 
the trial, the following information is required:
!
Trial product(s) involved
!
Classification of medication error
o
Wrong drug(s) administered
o
Wrong route of administration
o
Wrong dose administered
!
Whether the subject experienced any AE(s) as a result of the medication error
!
Suspected primary reason for the medication error
8.1.17
End of trial
When a subject completes visit 18, the investigator should fill in the end-of-trial forms in the eCRF.
If a subject proves difficult to reach for visit 18, and vital status is collected via sources other than 
the subject him/herself (see section 8.4), the investigator should fill in the end-of-trial forms after 
collecting the vital status. If, before the database lock, the investigator establishes contact with the 
subject, the investigator will update the end-of-trial forms.
8.2
Other assessments
8.2.1
Assessments in case of suspicion of acute pancreatitis
Most patients with acute pancreatitis experience 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, it is frequently unbearable, and characteristically persists for more than 24 


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hours without relief30.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 pancreatitis30. 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, trial product treatment should be promptly interrupted. 
Appropriate additional examinations must be performed, including measurement of amylase and 
lipase.
The diagnosis of acute pancreatitis requires two of the following three features31:
!
abdominal pain consistent with acute pancreatitis (acute onset of a persistent, severe, 
epigastric pain often radiating to the back)
!
serum lipase (and/or amylase) activity at least three times greater than upper limit of normal
!
characteristic findings of acute pancreatitis on imaging.
If acute pancreatitis is ruled out, the subject should resume trial product treatment, at the 
investigator’s discretion. 
If acute pancreatitis is confirmed, the investigator should initiate careful monitoring of the subject. 
The subject must be discontinued from trial product, but should remain in the trial (see section 6.5
and 8.4). 
The event must be assessed according to section 12.1 and reported if applicable as per section 12.2.
8.2.2
Assessments in case of suspicion of hypersensitivity reactions to the trial product
In case of suspicion of a severe immediate systemic hypersensitivity reaction32 to the trial product, 
the subject must be discontinued from trial product but should remain in the trial (see sections 6.5
and 8.4).
To assist in diagnosis it is recommended to draw a blood sample for measurement of tryptase (total 
and/or mature tryptase, to be assessed at a local laboratory) within 3 hours of the hypersensitivity 
reaction, and, if this is achieved, a tryptase sample should also be collected at next site visit. 
Furthermore, a blood sample for assessment of anti-semaglutide IgE antibodies and anti-
semaglutide antibodies should be drawn as soon as possible after the event and at next site visit and 
sent to central laboratory for analysis.
In case of suspicion of immune complex disease32, the subject must be discontinued from trial 
product but should remain in the trial (see sections 6.5 and 8.4). It is recommended to collect a 


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blood sample for assessment of complement levels (C3 and C4) to assist the diagnostic evaluation 
(to be assessed at a local laboratory).
The event must be assessed according to section 12.1 and reported if applicable as per section 12.2.
8.2.3
Assessments in case of increased levels of aminotransferases
In case of 
1. ALT or AST > 3x UNL and total bilirubin > 2x UNL,
2. ALT or AST > 5x UNL and total bilirubin ≤2x UNL, 
the event must be reported as an AE requiring additional data collection (see section 12 and 
Appendix B).
For both events, prompt repeat testing (at central laboratory) including ALT, AST, ALP and total 
bilirubin should be done and discontinuation of trial product considered. Thereafter, repeat testing 
(at 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 (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.
8.3
Treatment compliance
Treatment compliance will be assessed by monitoring of drug accountability. Subjects will be asked 
to bring along all used, partly used and unused trial products including empty packaging at each 
visit where drug accountability is performed (see sections 2 and 9.4). The investigator must assess 
the amounts of trial product used compared to expected usage since the last dispensing visit and, in 
case of discrepancies, question the subject. If a subject is found to be non-compliant, the 
investigator will remind them of the importance of following the instructions given including taking 
the trial products as prescribed.
8.4
Trial adherence 
Throughout the trial, the investigator will remind the subject to follow the trial procedures and 
requirements. It is the responsibility of the investigator to ensure that the subject’s visits occur 
according to schedule.
If a clinic visit is missed and it is not possible to reschedule, the investigator should ensure that 
relevant information is collected for example over the telephone. The subject should be asked to 
attend the next scheduled visit according to the visit schedule. 


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If extra trial product is needed, the investigator can perform an additional dispensing session in 
IV/WRS (see section 10).
The subject can remain in the trial regardless of lack of compliance with trial treatment, lack of 
adherence to the visit schedule, missed assessments, discontinuation of trial treatment for any 
reason or development of comorbidities or clinical outcomes. 
Premature discontinuation of trial product: Subjects who discontinue treatment with trial 
product should still be followed according to the visit schedule in section 2. For subjects who are 
off trial product, a reduced visit schedule and conversion of site visits to telephone visits may be 
considered if this becomes a prerequisite for their continued participation in the trial. Reasons for 
not adhering to the standard visit schedule must be documented in medical records. Premature trial 
product discontinuation should be registered in the eCRF (see section 5.3) and in IV/WRS (see 
section 10). 
Withdrawals: A subject who explicitly wants to withdraw their consent must be formally 
withdrawn from the trial. The end-of-trial form must be completed, and final drug accountability 
must be performed even if the subject is not able/willing to come to the trial site. Although a subject 
is not obliged to give his/her reason(s) for withdrawing from a trial, the investigator must make a 
reasonable effort to ascertain the reason(s), while fully respecting the subject’s rights. Where the 
reasons are obtained, the primary reason for not completing the trial must be specified on the end-
of-trial form in the eCRF.
A subject who agrees to provide information concerning relevant morbidities at the planned end of 
trial should not be considered withdrawn from the trial.
Regarding subjects who are withdrawn when the trial comes to an end, the investigator must 
scrutinise publicly available registries for relevant safety information, unless prohibited by local 
regulations. Vital status must be determined as a minimum, wherever possible.
Lost to follow-ups: If a subject proves difficult to reach for their visit 18, extensive attempts must 
be made to locate the subject and obtain relevant safety information, in particular related to MACE. 
This may include consulting contacts provided by the subject (e.g. relatives or emergency contacts), 
relevant health care professionals/clinics, medical records, local registries and locator agencies. A 
subject cannot be deemed lost to follow-up until at least the following contacts have been attempted 
and documented in medical records: 
!
to subjects: two phone calls and one written contact
!
to primary physician and/or other health care professionals: calls until contact is established
!
to relatives or other contacts provided by the subject: two phone calls and one written 
contact
!
to relevant publicly available registries


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A subject will only be considered lost to follow-up in case vital status cannot be determined at the 
time of visit 18, or at least before the trial database lock is initiated. 
9
Trial supplies
Trial supplies comprise trial products and auxiliary supplies. Additional details regarding trial 
supplies can be found in the Trial Materials Manual (TMM). 
Each trial site will be supplied with sufficient trial products for the trial on an ongoing basis 
controlled by IV/WRS. Trial products will be distributed to trial sites in accordance with subject 
enrolment rates at the individual site.
Trial product should only be dispensed to persons participating in the trial. If a subject is unable to 
attend the site for a dispensing visit (see flowchart in section 2), a non-participating person may,
however, collect the allocated trial product on behalf of the subject. If trial product is collected by a 
non-participant, this must be agreed with the subject on beforehand and thoroughly documented at 
the site e.g. by means of a letter of authorisation issued by the subject, and, on each occasion, the 
investigator must follow up by contacting the subject.
9.1
Trial products
The following trial products are considered investigational medicinal products and will be provided 
by Novo Nordisk A/S, Denmark:
Table 9–1
Investigational medicinal products
Trial product
Strength
Dosage form
Route of administration
Container
Semaglutide 3 mg tablet
3 mg
Tablet
Oral
Dose pack with 1 
blister card each 
containing 7 tablets
Semaglutide 7 mg tablet
7 mg
Semaglutide 14 mg tablet
14 mg
Placebo tablet 
N/A
Semaglutide and placebo tablets are white to light yellow oval-shaped tablets, embossed with “M8” 
on one side. All tablets are visually identical, irrespective of strength.
9.2
Labelling
The trial products will be labelled in accordance with Annex 1333, local regulations and trial 
requirements.


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9.3
Storage 
Storage conditions for the trial products are outlined in Table 9–2 and on the trial product labels.
Table 9–2
Storage conditions for trial products
Trial product
Storage conditions
In-use conditions
Semaglutide 3 mg tablet
Do not store above 30ºC (86ºF)
Do not freeze
Do not refrigerate
Store in the original package
Take the tablet immediately after 
dispensation from blister card
Take the tablets whole: Do not break or 
chew
Semaglutide 7 mg tablet
Semaglutide 14 mg tablet
Placebo tablet 
The investigator must ensure the availability of proper storage conditions, and also record and 
evaluate the temperature. The investigator must inform Novo Nordisk immediately if any trial 
product has been stored outside specified conditions (e.g. stored in a refrigerator).
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
Subjects must be instructed to bring along all used, partly used and unused trial products including 
empty packaging material on an ongoing basis. Returned trial product must be stored separately 
from non-allocated trial product.
Drug accountability is the responsibility of the investigator and should be done at tablet level by 
means of IV/WRS. All trial products received at site should be accounted for. Non-allocated trial 
product (expired, damaged and available) should be accounted as unused at closure of the trial site
at the latest.
Destruction of expired stock and damaged or returned trial product may be done on an ongoing 
basis throughout the trial, in accordance with local procedures, after accountability is finalised and 
reconciled by the monitor. Remaining stock can be destroyed after last end-of-treatment visit has 
been carried out at the site. On-site destruction may be arranged if local procedures allow. 
Destruction of trial products must be documented in IV/WRS.
9.5
Auxiliary supplies
The following will be provided by Novo Nordisk in accordance with the TMM:
!
BG meters and BG meter auxiliaries


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10
Interactive voice/web response system
A trial-specific IV/WRS will be set up which can be accessed at any time via the internet or 
telephone. Access to the IV/WRS must be restricted to and controlled by authorised persons. 
IV/WRS user manuals will be provided to each trial site. 
IV/WRS is used for: 
!
Screening
!
Screening failure
!
Randomisation
!
Data change
!
Medication arrival
!
Dispensing
o
Semaglutide 3 mg / placebo tablets
o
Semaglutide 7 mg / placebo tablets
o
Semaglutide 14 mg / placebo tablets
!
Subject treatment status change (treatment pause / treatment resume)
!
Code break
!
Drug accountability
At the screening session in IV/WRS, the investigator may need to indicate whether the subject 
fulfils one or more of the criteria a-h in inclusion criterion no. 3 (see section 6.2).
In case a subject discontinues trial treatment, or resumes trial treatment after a treatment pause, this 
should be registered in IV/WRS by means of the ‘subject treatment status change’ session.
When using the ‘subject treatment status change’ session to resume treatment, the investigator will 
need to decide which trial product dose to prescribe (cf. section 5.3.1). If trial product treatment is 
resumed at 3 or 7 mg oral semaglutide/placebo, IV/WRS will per default dispense trial product to 
support the dose escalation steps outlined in section 5.3.1, and extraordinary dispensing visits may 
be needed in order to get the subject back into the ordinary dispensing visit schedule outlined in the 
flow chart in section 2.
At all times during the trial, investigators must have robust procedures in place to ensure they only 
dispense the DUNs allocated to the particular subject by IV/WRS. This will ensure that: 
!
The subject receives the trial treatment they are randomised to
!
Adequate stock is available at site
!
Dispensed trial products can be accounted for 
If a subject needs trial product between dispensing visits, the investigator should make an additional 
dispensing session in IV/WRS. For subjects who withdraw from the trial or pass away during the 


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trial, final drug accountability will need to be performed. The system will then be updated by Novo 
Nordisk and the site will no longer be supplied with trial product for the particular subject.
11 Randomisation procedure and breaking of blinded codes
Only eligible subjects are allowed to be randomised. The investigator must use IV/WRS for 
randomisation of subjects. IV/WRS will ensure random assignment to the two treatment arms in a 
1:1 ratio and ensure even distribution of the two treatment arms within the strata described in 
section 5.1.
11.1
Breaking of blinded codes
The code for a particular subject may be broken in a medical emergency if knowing the actual 
treatment would influence the treatment of the subject. Whenever a code is broken the person 
breaking the code must print the Code Break Confirmation Notification generated by the IV/WRS, 
record the reason, and sign and date the document. The IV/WRS will notify Novo Nordisk (monitor 
and the Global Safety department) immediately after the code is broken.
When the code is broken, the treatment allocation will be accessible to the investigator and the 
Novo Nordisk Global Safety department. If IV/WRS is not accessible at the time of code break the 
IV/WRS helpdesk should be contacted. Contact details are listed in Attachment I.
The subject may resume or continue trial product treatment although their code was broken.
12 Adverse events, technical complaints and pregnancies
This trial is designed to evaluate cardiovascular outcomes and will apply a targeted approach for
collection of safety data focusing on SAEs, AEs leading to discontinuation of trial product and other 
selected events.
12.1
Definitions
12.1.1
Adverse event 
An adverse event (AE) is any untoward medical occurrence in a subject administered a product, and 
which does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom or disease temporally associated with the use of a product, whether or not 
considered related to the product. 


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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 considered as AEs:
!
Pre-existing conditions, including those found as a result of screening procedures (pre-
existing conditions should be reported as medical history or concomitant illness).
!
Pre-planned procedures unless the condition for which the procedure was planned has 
worsened from the first trial related activity after the subject has signed the informed 
consent.
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.
–
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.


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–
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 serious adverse event (SAE) is an experience that at any dose results in any of the following:
!
Death.
!
A life-threateninga experience.
!
In-patient hospitalisationb or prolongation of existing hospitalisation.
!
A persistent or significant disability or incapacityc.
!
A congenital anomaly or birth defect.
!
Important medical events that may not result in death, be life threateninga or require 
hospitalisationb may be considered an SAE when - based on appropriate medical judgement 
- they may jeopardise the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in the definition of SAEd. 
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, 
impairment, damage or disruption in his/her body function or structure, physical activity and/or 
quality of life).


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d. For example intensive treatment in an emergency room or at home of allergic bronchospasm, 
blood dyscrasiasis or convulsions that do not result in hospitalisation, or development of drug 
dependency or drug abuse.
The following events must always be reported as SAEs using the important medical event criterion 
if no other seriousness criterion is applicable:
!
Suspicion of transmission of infectious agents via the trial product
!
Risk of liver injury defined as ALT or AST > 3x UNL and total bilirubin > 2x 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
Adverse events requiring additional data collection
Adverse events requiring additional data collection are events which, in the evaluation of safety, 
have a special focus (e.g. required by the health authorities).
If any of the following AEs are applicable for reporting according to section 12.2, additional data 
collection is required:
!
Acute coronary syndrome (myocardial infarction or hospitalisation for unstable angina)
!
Cerebrovascular event (stroke or TIA)
!
Heart failure requiring hospitalisation
!
Pancreatitis 
!
Neoplasm (excluding thyroid neoplasm)
!
Thyroid disease (including thyroid neoplasm)
!
Renal event
!
Hypersensitivity reaction to the trial product
!
Lactic acidosis
!
Medication error concerning trial product:
o
Administration of wrong drug. 
-
Note: Use of wrong DUN is not considered a medication error per se.
o
Wrong route of administration
o
Administration of an overdose with the intention to cause harm (e.g. suicide 
attempt).
o
Accidental administration of a higher dose than intended. That is a dose of 1 tablet or 
more than the intended dose; however the administered dose must deviate from the 
intended dose to an extent where clinical consequences for the trial subject were 
likely to happen as judged by the investigator, although they did not necessarily 
occur.


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If a subject missed one or more doses of trial product, this should not be reported as a 
medication error.
!
Severe hypoglycaemic episode (see section 8.1.16.1)
!
Hepatic event:
o
ALT or AST > 5x UNL and total bilirubin ≤ 2x UNL
o
ALT or AST > 3x UNL and total bilirubin > 2x UNL
o
Hepatic events leading to trial product discontinuation 
Additional assessments should be made for hepatic events (see section 8.2.3).
12.1.5
Technical complaint
A technical complaint is any written, electronic, or oral communication that alleges product 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)
!
The packaging material (e.g. cracks or errors in labelling text)
12.2
Reporting of adverse events
In this trial the following events must be collected and reported:
!
SAEs
!
AEs leading to discontinuation of trial product
!
Medication errors
!
Severe hypoglycaemic episodes
!
Hepatic events
!
Pregnancies
Medication errors, severe hypoglycaemic episodes and hepatic events must be reported regardless 
of seriousness and whether trial product is discontinued.
Events occurring as of the first trial-related activity after the subject signed the informed consent 
until the end of the follow-up period are in scope for collection and reporting. The events must be 
recorded in the applicable CRFs 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, for example by 
asking: "Have you experienced any problems since the last contact?"
All SAEs, AEs leading to discontinuation of trial product, medication errors, severe hypoglycaemic 
episodes and hepatic events, either observed by the investigator or subject, must be reported by the 
investigator and evaluated. Novo Nordisk assessment of expectedness is performed according to the 


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following reference documents: IB for oral administration of semaglutide (NN9924), current 
edition18 or any updates thereto. 
All AEs applicable for reporting according to the above paragraphs must be recorded by the 
investigator on an AE form. The investigator should report the diagnosis, if available. If no 
diagnosis is available, the investigator should record each sign and symptom as individual AEs 
using separate AE forms.
For SAEs, a safety information form must be completed in addition to the AE form. A safety 
information form is tailored to collect supplementary clinical information. 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. 
AEs requiring additional data collection must be reported using both the AE form and the specific
event form. A specific event form is a form tailored to collect specific information related to the
individual event (see Appendix B for details about the specific event forms and the additional
information to report).
Certain events will undergo event adjudication by the Event Adjudication Committee (EAC), please 
refer to section 12.7.3. For such events, the Event Adjudication Form will also have to be completed 
in the eCRF. The Event Adjudication Form is a checklist of clinical data to be provided from the 
site.
Timelines for initial reporting of AEs:
The investigator must complete the following forms in the eCRF within the specified timelines:
!
SAEs: The AE form within 24 hours and the safety information form within 5 calendar
days of the investigator's first knowledge of the SAE.
Both forms must be signed within 7 calendar days from the date the information was entered 
in the eCRF.
!
SAEs fulfilling criteria for additional data collection: In addition to above, the 
corresponding specific event form within 14 calendar days of investigators knowledge of 
the event.
!
Events for adjudication: Event Adjudication Form within 14 calendar days of the 
investigator's first knowledge of the AE.
The investigator should preferably provide the medical documentation within 4 weeks of 
event identification.
CONFIDENTIAL


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If the eCRF is unavailable, the concerned AE information must be reported on paper forms and sent 
to Novo Nordisk by fax, e-mail or courier within the same timelines as stated above. When the 
eCRF becomes available again, the investigator must enter the information on the appropriate forms 
in the eCRF.
Contact details (fax, telephone, e-mail and address) are provided in the investigator trial master file. 
An AE is 
observed 
It is an SAE
complete:
!
AE form ≤ 24 hours
!
SIF ≤ 5 calendars days
Fulfilling 
seriousness 
criteria per 
protocol?
AE requiring 
additional data 
collection?
Complete ≤ 14 
calendar days:
!
Specific event form
No
Is the AE 
relevant for 
adjudication?
Complete ≤ 14 
calendar days:
!
Adjud cat on form 
No additional forms 
to be completed
AE Adverse Event
SIF  safety information form
AEs requiring addtional data collection
described n section 12.1.4
Events for adjudication 
described n section 12.7.3
All timelines are from the investigator’s 
first knowledge of the event
No
Any of the below apply?
!AE leading to discontinuation
     of trial product
!Medication error
!Severe hypoglycaemic 
     episode
!Hepatotoxicity event
No
The AE does not 
need to be reported
Complete: AE form 
Yes
No additional forms 
to be completed
No
Yes
Yes
Yes
Figure 12–1
Initial reporting of AEs
Reporting of trial product-related SUSARs by Novo Nordisk:
Novo Nordisk will notify the investigator of trial product-related suspected unexpected serious
adverse reactions (SUSARs) in accordance with local requirements and GCP1. In addition, the 
investigator will be informed of any trial-related SAEs that may warrant a change in any trial 
procedure.
In accordance with regulatory requirements, Novo Nordisk will inform the regulatory authorities, 
including EMA, of trial product-related SUSARs. In addition, Novo Nordisk will inform the 
IRBs/IECs of trial product-related SUSARs in accordance with local requirement and GCP1, unless 
locally this is an obligation of the investigator.
To avoid introducing bias and to maintain the integrity of the primary analysis, Novo Nordisk will 
exempt SAEs that are part of the primary endpoint evaluation from unblinding during regulatory 
reporting, even though the cases fulfil the definition of SUSARs. The DMC (see section 12.7.2) 
receives unblinded data and makes recommendations to the Novo Nordisk safety committee. This 
ensures adequate monitoring of safety while maintaining SAE reports related to the primary 
endpoint blinded for Novo Nordisk. 
CONFIDENTIAL


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At the end of the trial, when treatment is revealed, all exempted cases which meet the criteria for 
expedited reporting SUSARs will be submitted to the regulatory authorities. Because multiple cases 
will be identified simultaneously, Novo Nordisk will not be able to fulfil the 7-days requirement for 
fatal or life-threatening events but will within 60 days after code break have all SUSARs submitted 
to the regulatory authorities.
In case a regulatory authority requires the blinded report on an expedited basis, Novo Nordisk will 
submit individual blinded case reports related to investigational product to the relevant regulatory 
authorities on an expedited basis.
Novo Nordisk products used as concomitant medication:
If an SAE 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 
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.
CONFIDENTIAL


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The investigator must ensure that the worst case severity and seriousness of an event is kept 
throughout the trial. A worsening of an unresolved AE must be reported as follow up with re-
assessment of severity and/or seriousness of the event.
Queries or follow-up requests from Novo Nordisk must be responded to within 14 calendar days
from the date of receipt of the request, unless otherwise specified in the follow-up request.
12.4
Technical complaints and technical complaint samples
12.4.1
Reporting of technical complaints
All technical complaints on any of the following products:
!
Semaglutide 3 mg / placebo tablets
!
Semaglutide 7 mg / placebo tablets
!
Semaglutide 14 mg / placebo tablets
which occur from the time of first usage of the product until the time of the last usage of the 
product, must be collected and reported to Customer Complaint Center, Novo Nordisk.
Contact details (fax, e-mail and address) are provided in Attachment I to the protocol.
The investigator must assess whether the technical complaint is related to any AEs or SAEs.
Technical complaints must be reported on a separate technical complaint form. A technical 
complaint form for each code number or for each DUN must be completed.
The investigator must complete the technical complaint form in the eCRF within the following 
timelines of the trial site obtaining knowledge of the technical complaint:
!
Technical complaint assessed as related to an SAE within 24 hours
!
All other technical complaints within 5 calendar days
If the eCRF is unavailable or when reporting a technical complaint that is not subject related, the 
information must be provided on a paper form by fax, e-mail or courier to Customer Complaint 
Center, Novo Nordisk, within the same timelines as stated above. When the eCRF becomes 
available again, the investigator must enter the information on the technical complaint form in the 
eCRF.
12.4.2
Collection, storage and shipment of technical complaint samples
The investigator must collect the technical complaint sample and notify the monitor within 5 
calendar days of obtaining the sample at trial site. The monitor must coordinate the shipment to 
Customer Complaint Center, Novo Nordisk (the address is provided in Attachment I) and ensure 
CONFIDENTIAL


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that the sample is sent as soon as possible. A copy of the technical complaint form must be sent 
with the sample.
The investigator must ensure that the technical complaint sample contains the code number and, if 
available, the DUN.
If the technical complaint sample is unobtainable, the investigator must specify on the technical 
complaint form why it is unobtainable. 
Storage of the technical complaint sample must be done in accordance with the conditions 
prescribed for the product. The shipment of the technical complaint sample should be done in 
accordance with the same conditions as for storage (see section 9).
12.5
Pregnancies
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. When needed, Novo Nordisk will provide paper forms for collection of the relevant 
information. The investigator must report the requested information to Novo Nordisk -
electronically (e.g. in PDF format), or by fax or courier.
12.6
Precautions and/or overdose
There are no specific antidotes to semaglutide. Treatment of an overdose should be symptomatic.
There is a potential risk of hypoglycaemia during dosing with semaglutide. The typical signs and 
symptoms of a non-severe hypoglycaemia (mild/moderate) include: hunger, slight headache, 
nausea, light-headedness, palpitations, and sweating. Severe hypoglycaemia may produce loss of 
consciousness. Symptoms of non-severe hypoglycaemia should be treated by ingestion of 
carbohydrates. Severe hypoglycaemia resulting in loss of consciousness should be treated at the 
investigator’s discretion according to best available medical practise.
One case of accidental overdose of oral semaglutide was reported in the 
 trial in a 
subject treated with 20 mg oral semaglutide once daily. The subject accidentally took the trial 
product twice on Day 52 of the trial. No AEs were reported at the same time. The medication error 
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was discovered at the next scheduled visit. The subject did not report any symptoms and treatment 
was continued without any change.
One case of accidental overdose has been reported in s.c. semaglutide once weekly treated subjects. 
The case was classified as moderate in severity and considered probably related to semaglutide and 
was reported by a subject enrolled in the trial 
. No hospitalisation was needed. The 
subject inadvertently injected 4 mg of semaglutide instead of 0.4 mg, which corresponds to a 
2.5-fold higher dose than the maximum dose included in that trial. After 4−5 hours the subject felt 
nauseated, vomited and had a headache. The subject was instructed to drink sufficient amounts of 
fluids. Symptoms had improved within one day of dosing, and the subject wished to continue in the 
trial. Plasma glucose levels, blood pressure and pulse were monitored during the following 5 days, 
and no symptoms of hypoglycaemia or any other symptoms or signs were noted. The subject was 
withdrawn from the trial after 19 days of treatment due to an AE (diarrhoea).
For further details please see the IB for oral administration of semaglutide (NN9924), current 
edition18, or any updates thereto.
12.7
Committees related to safety
12.7.1
Novo Nordisk safety committee
Novo Nordisk will constitute an internal oral semaglutide safety committee to perform ongoing 
safety surveillance.
12.7.2
Data monitoring committee
The independent data monitoring committee (DMC) is an independent, external committee 
composed of members whose expertise covers relevant specialities including statistics. The DMC is 
established to review and evaluate accumulated data from the trial at predefined time points as well 
as ad-hoc. This is in order to protect the safety of the subjects and to evaluate the risk-benefit 
balance. The DMC will have access to unblinded data, and will provide recommendations on the 
trial continuation, modification or termination.
Information regarding responsibilities, procedures and workflow to be used by the DMC are 
specified in the DMC charter.
12.7.3
Event adjudication committee
An independent external event adjudication committee (EAC) is established to perform qualitative 
or quantitative validation of selected AEs according to pre-defined diagnostic criteria. The 
validation is based on review of pre-defined clinical data related to the specific AE. Pre-defined 
clinical data consist of copies of source documents collected and delivered by the investigational 
sites.
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The EAC is composed of permanent members covering required medical specialities. EAC 
members must disclose any potential conflicts of interest and must be independent of Novo 
Nordisk.
The events are reviewed by the EAC in a blinded manner. The EAC will have no authorisation to 
impact trial conduct, trial protocol or amendments.
The EAC works in accordance with written guidelines included in the EAC Charter describing in 
details the composition, tasks, responsibilities, and work processes of the committee.
The events outlined in Table 12–1 have been selected for adjudication in order to obtain an external 
independent validation of the diagnosis. In addition, cardiovascular events are being adjudicated in 
accordance with FDA requirements34.
The EAC will review copies in English (translated if necessary) of medical documentation received 
in the adjudication packages (e.g. x-rays, ECGs, ultrasound images, discharge summaries, 
pathology reports and death certificates). The investigator must provide medical documentation as 
soon as possible, when they receive the request from Novo Nordisk or the event adjudication 
vendor.
AEs for adjudication can be identified in four different manners:
!
AEs reported by the investigator for adjudication
!
Screening of AEs reported by the investigator as not relevant for adjudication
!
Unreported AEs detected by the EAC while reviewing source data for other AEs reported by 
the investigator
!
ECGs suggestive of new myocardial infarction (see section 8.1.12)
The assessments made by the EAC will be included in the clinical trial report as well as assessments 
made by the investigator. However, the adjudication made by an EAC, given its independence and 
in-depth analysis of each event, will be attributed with greater importance of the two. The outcome 
of adjudication will be kept in the clinical trial database.
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Table 12–1
Adverse events for adjudication
Events
Description
Adjudication outcomes
Death
! All-cause death
! Cardiovascular death 
(including undetermined 
cause of death)
! Non-cardiovascular death
Acute Coronary 
Syndrome
! ST-elevation acute myocardial infarction (STEMI)
! Non-ST elevation acute myocardial infarction (NSTEMI)
! Silent myocardial infarction
! Unstable angina pectoris (UAP)
! Acute myocardial 
infarction (STEMI or 
NSTEMI), silent 
myocardial infarction
! Unstable angina pectoris 
requiring hospitalisation
Cerebrovascular 
events
! Episode of focal or global neurological dysfunction caused by 
brain, spinal cord, or retinal vascular injury as a result of 
haemorrhage or infarction
! Transient Ischaemic Attack (TIA) is defined as a transient episode 
(<24 hours) of focal neurological dysfunction caused by brain, 
spinal cord, or retinal ischaemia, without acute infarction
! Ischaemic stroke
! Haemorrhagic stroke
! Undetermined stroke
! TIA
Heart failure 
requiring 
hospitalisation
! Hospitalisation with a primary diagnosis of heart failure (new 
episode or worsening of existing heart failure)
! Heart failure requiring 
hospitalisation
Acute pancreatitis
The diagnosis of acute pancreatitis requires two of the following
three features:
! 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 limit of normal
! Characteristic findings of acute pancreatitis on imaging
! Acute pancreatitis
o
Mild
o
Moderate 
o
Severe
Malignant 
neoplasm
Malignant neoplasms are defined as:
! neoplasms in which abnormal cells divide without control and can 
invade nearby tissues and/or spread to other parts of the body 
through the blood and lymph systems
Thyroid neoplasms are excluded in this event category
! Malignant neoplasm
Thyroid disease, if 
malignant thyroid 
neoplasm or C-cell 
hyperplasia
Malignant thyroid neoplasms are defined as 
! thyroid neoplasms in which abnormal cells divide without control 
and can invade nearby tissues and/or spread to other parts of the 
body through the blood and lymph systems
! C-cell hyperplasia, defined as hyperplasia of the parafollicular 
C-cells of the thyroid gland
! Malignant thyroid 
neoplasm
! C-cell hyperplasia
Acute kidney 
injury
Acute kidney injury21 is defined as any of the following (not graded):
! Increase in serum creatinine by ≥0.3 mg/dL (≥26.5 μmol/L) within 
48 hours, or
! Increase in serum creatinine to ≥1.5 times baseline, which is 
known or presumed to have occurred within the prior 7 days, or
! Urine volume < .5 mL/kg/h for 6 hours
! Acute kidney injury
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Events
Description
Adjudication outcomes
Lactic acidosis
Lactic acidosis is characterized by increased blood lactate level in 
association with metabolic acidosis
! Lactic acidosis
The safety data accumulating during the trial will be screened for potential missed events for 
adjudication and, if needed, the investigator will be asked to provide additional information such as 
an alternative aetiology, underlying cause(s) and/or clinical details.
The event adjudication vendor or EAC can decide to have an AE adjudicated even if not initially 
reported as an event for adjudication by the investigator.
Event adjudication will be performed for AEs in randomised subjects including AEs with an onset 
date during the screening period. Event adjudication will not be performed for AEs in screening 
failures or subjects never randomised for whatever reason. 
AEs for adjudication must be reported according to section 12.2. In addition the specific event 
adjudication form should be completed within 14 calendar days of the investigator's first knowledge 
of the AE, and all relevant predefined documents provided according to instructions in the event 
adjudication site manual.
13 Case report forms 
Novo Nordisk will provide a system for the electronic case report forms (eCRFs). This system and 
support services to the system will be provided by an external supplier.
Ensure that all relevant questions are answered, and that no empty data field exists. If a test or an 
assessment has not been done and will not be available, or if the question is irrelevant (e.g. is not 
applicable), indicate this according to the data entry instructions.
The 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.
The following will be provided as paper CRFs:
!
Pregnancy forms (distributed to site if a pregnancy occurs)
In addition, paper AE forms, safety information forms and technical complaint forms will be 
provided. These must be used when access to the eCRF is revoked or if the eCRF is unavailable. 
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On the paper CRFs, print legibly, using a ballpoint pen. Ensure that all questions are answered, and 
that no empty data blocks exist. Ensure that no information is recorded outside the data blocks. If a 
test/assessment has not been done and will not be available, indicate this by writing "ND" (not 
done) in the appropriate answer field in the CRF. If the question is irrelevant (e.g. is not applicable) 
indicate this by writing "NA" (not applicable) in the appropriate answer field. Further guidance can 
be obtained from the instructions in the CRF. Corrections to the CRF data may be made by the 
investigator or the investigator's delegated staff. An audit trail will be maintained in the CRF 
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 data on paper CRFs may only be made by drawing a straight line through the 
incorrect data and then writing the correct data next to the original entry. Each correction must be 
initialled, dated and explained (if necessary).
The investigator must ensure that data is recorded in the eCRFs as soon as possible, preferably 
within 5 days after the visit/telephone contact. Once data has been entered, it will be available to 
Novo Nordisk for data verification and validation purposes.
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.
14 Monitoring procedures 
Monitoring will be conducted under a risk-based approach. 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 for trial sites with subjects in screening, treatment or follow-up.
The monitor must be given direct access to source documents (original documents, data and 
records). Direct access includes permission to examine, analyse, verify and reproduce any record(s) 
and report(s) that are important to the evaluation of the trial. If the electronic medical record does 
not have a visible audit trail, the investigator must provide the monitor with signed and dated 
printouts. In addition the relevant trial site staff should be available for discussions at monitoring 
visits and between monitoring visits (e.g. by telephone).
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The eCRF must not be used for capturing source data, i.e. all data recorded in the eCRF must be 
verifiable in source documentation. 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.
The monitor will ensure that the CRFs are completed and any paper CRFs are collected.
Monitor will review the subject's medical records and other source data to ensure consistency 
and/or identify omissions compared to the CRF. If discrepancies are found, the investigator will be 
questioned about these.
A follow-up letter (paper or electronic) will be sent to the investigator following each monitoring 
visit. This will address any action to be taken.
15 Data management
Data management is the responsibility of Novo Nordisk. Data management may be delegated under 
an agreement of transfer of responsibilities to a data management unit within Novo Nordisk or a 
CRO.
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 may use their own electronic systems to capture source data.
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17 Statistical considerations
The blinding of the randomised treatments will be maintained until the database has been released 
for statistical analysis. No interim analyses or other analyses of unblinded or between group data 
will be performed before the database is locked, with the exception of those highly confidential 
analyses performed by an external independent statistician to support the deliberations of the DMC 
(see section 12.7.2) or in direct response to a recommendation by the DMC.
If necessary, a statistical analysis plan (SAP) may be written in addition to the protocol, including a 
more technical and detailed elaboration of the statistical analyses. The SAP will be finalised before 
database lock.
Data from all sites will be analysed and reported together.
In statistical analyses where stratification is included, the evidence of cardiovascular disease at 
screening (presence of cardiovascular disease or risk factors only) will be included based on the 
actual information collected through the eCRF. In case of missing eCRF information the 
information collected in IV/WRS will be used.
The latest available measurement, at or prior to the randomisation visit, will be used as the baseline 
measurement. If no measurement(s) have been obtained, at or prior to randomisation, the baseline 
value will be left missing.
Laboratory values below the lower limit of quantification (LLoQ) will be set to ½LLoQ. Number of 
values below LLoQ by treatment and visit will be summarised if deemed relevant.
If no statistical analysis is specified, data will be presented using relevant summary statistics.
Primary estimand
The trial aims to confirm that treatment with oral semaglutide does not result in an unacceptable 
increase (80% excess risk) in cardiovascular risk compared to placebo in subjects with T2D at high 
risk of cardiovascular events. Time from randomisation to first MACE will be the primary endpoint 
and treatment arms will be compared using the hazard ratio. This is an event-driven trial and 
information is planned to be collected on all randomised subjects until at least 122 first MACEs 
have accumulated during the planned trial duration of 19 months.
Primary estimand:
!
de-facto estimand comparing oral semaglutide and placebo for all randomised subjects. 
Subjects who discontinue treatment with trial product should be followed according to the 
planned visit schedule. Estimation of the primary estimand will include all first MACEs 
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collected during the trial as defined by the in-trial observation period (see section 17.2) 
regardless of adherence to randomised treatment.
17.1
Sample size calculation
Firstly, the primary endpoint; time from randomisation to first occurrence of a MACE composite 
endpoint consisting of: cardiovascular death, non-fatal myocardial infarction or non-fatal stroke, 
will be tested for non-inferiority using a 1.8 non-inferiority margin. If the hypothesis is confirmed, 
the confirmatory secondary endpoint; time from randomisation to first occurrence of an expanded 
composite cardiovascular endpoint consisting of: cardiovascular death, non-fatal myocardial 
infarction, non-fatal stroke, unstable angina requiring hospitalisation or hospitalisation for heart 
failure, will be tested for non-inferiority using a 1.8 non-inferiority margin. The type-I-error will be 
preserved in the strong sense at 5% (two-sided) when using the hierarchical testing strategy.
The sample size is made to ensure a power of 90% for testing the confirmatory hypothesis for the 
primary endpoint. Based on a logrank test, a total of 122 first MACEs will provide 90% power to 
rule out hazard ratios exceeding 1.8, assuming a true hazard ratio of 1.0.
In order to have a total of 122 first MACEs with trial duration of 19 months and 1,588 subjects 
randomised to each treatment group (1:1 randomisation), in total 3,176 subjects, the following is 
assumed based on the ongoing trials EX2211-3748 (LEADER®) and NN9535-3744 
(SUSTAIN™6):
!
First MACEs occur at a rate of 3 per 100 patient years of observation time (PYO) in both 
treatment groups throughout the trial
!
Recruitment into the trial occurs uniformly during 7 months
!
The lost-to-follow-up rate is 1% per year throughout the trial
!
LSLV occurs 19 months after first subject was randomised
Table 17–1 shows expected trial duration for different event rates under the same assumptions as 
described above for the other parameters.
Table 17–1
Expected trial duration according to event rates
Event rate per 100 PYO in 
both treatment arms
2.5
2.75
3.0
3.25
3.5
Expected trial duration from 
randomisation of subject to 
LSLV (months)
22.2
20.4
19
17.8
16.7
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17.2
Definition of analysis sets
The following analysis set is defined:
!
Full analysis set (FAS): includes all randomised subjects. The statistical evaluation of the 
FAS will follow the intention-to-treat (ITT) principle and subjects will contribute to the 
evaluation “as randomised”.
In this trial, two observation periods will be defined. Definition of the observation periods:
!
In-trial observation period: This observation period will include information assessed 
from randomisation to the date of the last subject-site contact regardless of adherence to 
treatment, which is scheduled to take place 5 weeks (with a +3 days visit window) after last 
planned dose of the trial product. The 5 weeks follow-up period corresponds to 
approximately five half-lives of oral semaglutide. For subjects lost to follow-up the end-date 
will be the date of the last contact with the subject (site visit or by telephone). If a subject 
dies during the trial, the date of death will be the end-date of the in-trial observation period 
regardless of the above defined end-dates.
!
On-treatment observation period: This observation period is a subset of the in-trial 
observation period and will include information assessed on or after the first date of trial 
product up to and including the first date of (i) last date on trial product +38 days or (ii) 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 
oral semaglutide. In addition, the ascertainment window includes the follow-up visit 
window of +3 days after last date on trial product.
Subjects not having a MACE within the observation period will be censored at the end of the 
observation period in the primary analysis assuming independent censoring for subjects lost to 
follow-up. Hence, a subject censored at a given time should be representative of those still at risk at 
that time point. For EAC confirmed events the onset date will be the onset date assessed by the 
EAC. EAC confirmed events with adjudicated onset date prior to randomisation will be described in 
listings. EAC confirmed events with adjudicated onset date after in-trial observation period but 
prior to database lock will be evaluated and summarised descriptively. For events not subjected to 
adjudication or negatively adjudicated, the onset date for the adverse event reported by the 
investigator will be used.
17.3
Primary endpoint
!
Time from randomisation to first occurrence of a MACE composite endpoint consisting of: 
cardiovascular death, non-fatal myocardial infarction or non-fatal stroke
The primary estimand will be estimated based on the FAS and the in-trial observation period. The 
primary statistical analysis of the primary endpoint will be a stratified Cox proportional hazards 
model with treatment group (oral semaglutide, placebo) as fixed factor. The model will be stratified
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by evidence of cardiovascular disease at screening (presence of cardiovascular disease or risk 
factors only). From this model the estimated hazard ratio (HR) (oral semaglutide/placebo) together
with the 2-sided 95% confidence interval will be presented. Non-inferiority of oral semaglutide 
versus placebo will be considered confirmed if the upper limit of the two-sided 95% confidence 
interval for the HR is below 1.8 or equivalent if the p-value for the one-sided test of
H0: HR ≥ 1.8 against Ha: HR < 1.8
is less than 2.5% (or equivalent to 5% for a two-sided test).
A Kaplan-Meier plot with number of subjects at risk at specific time points will be presented and 
used graphically to assess the validity of the assumption of proportional hazards. This will be 
supported by the use of Schoenfeld residuals.
17.3.1
Sensitivity analysis
To explore the robustness of the primary analysis results the following sensitivity analyses will be 
performed. The sensitivity analyses will evaluate different de-jure estimands and, thus, will focus 
on events occurring while subjects to a greater extent compared to the primary estimand are 
treatment adherent. Different observation periods will be defined considering treatment adherence 
and different follow-up periods after last date on trial product. All sensitivity analyses will be based 
on FAS and analysed using the same model as the primary analysis including the censoring rules
and the assumption of independent censoring for subjects with shorter observation period than the 
trial duration.
Sensitivity analysis 1: Including additional covariates
This sensitivity analysis will explore the primary analysis by fitting a stratified Cox regression 
analysis and estimate of the treatment hazard ratio (oral semaglutide/placebo) with a 2-sided 95% 
confidence interval while including the additional covariates sex, region, baseline age, diabetes 
duration, smoking history, and eGFR at baseline. The model will be stratified by evidence of
cardiovascular disease at screening (presence of cardiovascular disease or risk factors only). The 
analysis will be based on the FAS and the in-trial observation period. 
Sensitivity analysis 2: Ascertainment window of 38 days after last date on trial product
This sensitivity analysis will include all first MACEs that are collected in the on-treatment 
observation period.
Sensitivity analysis 3: Ascertainment window of 7 days after last date on trial product
This sensitivity analysis will include all first MACEs that are collected on or after the first date on 
trial product up to and including the last date on trial product +7 days.
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17.4
Secondary endpoints
17.4.1
Confirmatory secondary endpoint
!
Time from randomisation to first occurrence of an expanded composite cardiovascular 
endpoint consisting of: cardiovascular death, non-fatal myocardial infarction,  non-fatal 
stroke, unstable angina requiring hospitalisation or hospitalisation for heart failure
The confirmatory secondary endpoint will be analysed using the same analysis including sensitivity 
analyses as for the primary endpoint.
17.4.2
Safety endpoints
Time to event endpoints
!
Time from randomisation to first occurrence of each of the individual components in the 
expanded composite cardiovascular endpoint
!
Time from randomisation to first occurrence of a composite endpoint consisting of: all-cause 
death, non-fatal myocardial infarction or non-fatal stroke
!
Time from randomisation to all-cause death
!
Time to permanent discontinuation of trial product due to AE(s)
The analyses of the above time-to-event composite endpoints (except for the last endpoint) will be 
the same as the primary analysis. The analysis of time to permanent discontinuation of trial product 
due to AE(s) will be adjusted for the competing risk of other predefined reasons for discontinuing 
trial product prematurely. The above analyses will be based on the FAS and performed for both the 
in-trial and on-treatment observation periods. Cumulative incidence functions will be plotted for all 
of the endpoints.
Adverse events
!
Number of SAEs
All AEs will be coded using the most recent version of Medical Dictionary for Regulatory 
Activities (MedDRA).
SAEs will be summarised 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 patient years of observation time (R). The summaries will be based on FAS and performed for 
both the in-trial and the on-treatment observation periods. Furthermore, events confirmed by 
adjudication and AEs leading to discontinuation of trial product will be summarised as above.
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Continuous safety endpoints
Change from baseline to last assessment of:
!
Pulse
!
Systolic and diastolic blood pressure
The last available measurement for the above endpoints will be analysed separately in an analysis of 
covariance (ANCOVA) with treatment group as fixed factors and the corresponding baseline value 
as a covariate. From the ANCOVAs the estimated treatment differences for oral semaglutide versus 
placebo together with the corresponding 2-sided 95% confidence intervals will be presented. The 
analyses will be based on FAS and performed for both the in-trial and the on-treatment observation 
periods.
Other safety endpoints
!
Biochemistry
!
Haematology
!
Calcitonin
The above assessments will be summarised using descriptive statistics by treatment group for all 
scheduled visits and for last available assessment based on FAS and performed for both the in-trial 
and the on-treatment observation periods. Categorical safety endpoints will be summarised as 
counts and relative frequencies. Calcitonin will also be presented by sex.
17.4.3
Efficacy endpoints
Change from baseline to last assessment of:
!
HbA1c
!
Body weight
!
Lipids
The last available measurement for the above endpoints will be analysed separately in an ANCOVA 
with treatment group as fixed factors and the corresponding baseline value as a covariate. From the 
ANCOVAs the estimated treatment differences for oral semaglutide versus placebo together with 
the corresponding 2-sided 95% confidence intervals will be presented. The analyses will be based 
on FAS and performed for both the in-trial and the on-treatment observation periods. 
18 Ethics
The trial will be conducted in compliance with ICH GCP1 and applicable regulatory requirements, 
and in accordance with the Declaration of Helsinki2. When treatment with trial product ends, the 
subject and investigator will decide on the best available treatment for each subject.
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18.1
Benefit–risk assessment of the trial
Risks and precautions
The nonclinical safety programme of oral semaglutide has not revealed any safety issues precluding 
use in humans. 
The sections below describe identified and potential risks and precautions associated with oral 
semaglutide treatment. These are based on findings in nonclinical and clinical trials with oral 
semaglutide as well as other GLP-1 RAs. For each of these risks and precautions, mitigating actions 
have been implemented to minimise the risks for subjects enrolled in this trial.
Identified risks
Gastrointestinal adverse events
Consistent with findings with other GLP-1 RAs, the most frequently reported AEs in clinical trials 
with oral semaglutide have been gastrointestinal disorders (nausea, vomiting, diarrhoea, dyspepsia 
and constipation). 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 
with 4 week dose-escalation steps have been implemented in the trial. In addition, in case a subject 
experiences unacceptable tolerability issues, dose reduction to a lower treatment dose is allowed. 
Potential risks
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 MEN 2 or MTC will not be enrolled in the trial. During the trial, calcitonin will be 
measured on a regular basis, and the guidance for investigators of further evaluation and action on 
elevated calcitonin concentrations is included in Appendix A. 
Acute pancreatitis
Acute pancreatitis has been reported in subjects treated with GLP-1 RAs including oral 
semaglutide. 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
Patients with T2D have an increased risk of certain types of cancer such as pancreatic cancer. There 
is currently no support from nonclinical- or clinical trials or postmarketing data that GLP-1-based 
therapies increase the risk of pancreatic cancer. However, pancreatic cancer has been included as a 
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separate potential risk due to the scientific debate surrounding a potential association to GLP-1-
based therapies and the unknown long-term effects of stimulation of β-cells and suppression of α-
cells. Pancreatic cancer has been classified as a potential class risk of GLP-1 RAs by EMA.
Allergic reactions
As in the case with all protein based pharmaceuticals treatment with oral semaglutide may evoke 
allergic reactions. These may include urticaria, rash, 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.
Severe hypoglycaemia
Based on current knowledge about the GLP-1 RA drug class, there is a risk of hypoglycaemic 
episodes. Hypoglycaemic episodes have mainly been observed when a GLP-1 RA is combined with 
sulphonylurea or insulin. The risk for development of hypoglycaemia with oral semaglutide in 
combination with sulphonylurea and insulin is currently unknown. In this trial, it is recommended to 
reduce the dose of insulin and sulphonylurea at randomisation to reduce the risk of hypoglycaemia 
when introducing an additional glucose lowering agent.
Acute renal impairment
In subjects treated with GLP-1 RAs including oral semaglutide, gastrointestinal AEs such as 
nausea, vomiting and diarrhoea may lead to significant dehydration and secondary acute renal 
impairment. 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.
Sodium-glucose cotransporter-2 (SGLT2) inhibitors, an allowed background treatment, have also 
been associated with volume depletion. It is recommended to monitor for signs and symptoms of 
fluid loss during therapy.
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.
Other
Teratogenicity (embryo-foetal development toxicity)
Semaglutide caused embryo-foetal malformations in the rat through a GLP-1 receptor mediated 
effect on the inverted yolk sac placenta leading to impaired nutrient supply to the developing 
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embryo. Primates do not have an inverted yolk sac placenta which makes this mechanism unlikely 
to be of relevance to humans. However, as a precaution, females who are pregnant, breast-feeding 
or intends 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 
at the site at screening, follow-up and at any time during the trial if a menstrual period is missed, or 
is required by local law.
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 treatment. It is the responsibility of the 
investigator to ensure the best possible care according to the principles outlined in Diabetes Care 
2014 Standards of Medical Care in Diabetes35.
Further details with regards to safety of trial product are described in the current edition of the IB 
for oral semaglutide (NN9924)18, or any updates thereto.
Benefits
For all participating subjects, the anticipated benefits include a close monitoring of their T2D and 
an optimised antidiabetic treatment. All subjects will be treated within an antidiabetic regimen 
anticipated to be better than or equal to the treatment that they receive at the time of entry into the 
trial. The investigator is responsible for adjusting or adding antidiabetic medication throughout the 
course of the trial to maintain an adequate level of glycaemic control in each subject. In addition, it 
is expected that all subjects will benefit from participation through close contact with the trial site 
including thorough medical examinations and close follow-up of their T2D.
Risk and benefit conclusion 
It is concluded that the potential benefits from participating in the trial outweigh the potential risks. 
The safety profile for the investigational medicinal product generated from the clinical and 
nonclinical development programme has not revealed any safety issues that would prohibit 
administration of oral semaglutide in accordance with the planned clinical trial.
18.2
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 data collected at follow-up will be retained by Novo Nordisk, 
entered into the database and used for the trial report. 
!
Safety events will be reported to Novo Nordisk and regulatory authorities according to 
local/national requirements.
If data is used, it will always be in accordance with local regulations and IRBs/IECs.
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18.3
Information to subject during trial
The site will be offered a communication package to the subject during the conduct of the trial. The 
package content is issued by Novo Nordisk. The communication package will contain letters 
intended for distribution to the subjects. The letters will be translated and adjusted to local 
requirements and distributed to the subject at the discretion of the investigator. The subject may e.g. 
receive a “patient newsletter” during trial participation and a “thank you for your participation 
letter” after the trial has ended.
All written information to subjects must be sent to IRB/IEC for approval/favourable opinion and to 
regulatory authorities for approval or notification according to local regulations.
18.4
Premature termination of the trial and/or trial site
The DMC may recommend premature termination of the trial (cf. section 12.7.2).
Novo Nordisk, the IRBs/IECs or a regulatory authority may decide to stop the trial, part of the trial 
or a trial site at any time, but agreement on procedures to be followed must be obtained.
If the trial is suspended or prematurely terminated, the investigator must inform the subjects 
promptly and ensure appropriate therapy and follow-up. The investigator and/or Novo Nordisk must 
also promptly inform the regulatory authorities and IRBs/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 IRBs/IECs in case it has an impact on the planned follow-up of subjects who have 
participated in the trial. If it has an impact, the actions needed to inform and protect the subjects 
should be described.
19 Protocol compliance
Deviations from the protocol should be avoided.
If deviations do occur, the investigator must inform the monitor and the implications of the 
deviation must be reviewed and discussed.
Deviations must be documented and explained in a protocol deviation by stating the reason, date, 
and the action(s) taken. Some deviations, for which corrections are not possible, can be 
acknowledged and confirmed via edit checks in the eCRF or via listings from the clinical database. 
Documentation on protocol deviations must be kept in the investigator's trial master file and 
sponsor trial master file.
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For Mexico only: The above will include the following responsibilities for the head of the 
Institution/Health Care Establishment, Ethics, Research and, when applicable, Biosafety 
Committees and sponsor within their scope of responsibility:
a) Investigation follow-up
b) Damages to health arising from the investigation development; as well as those arising from 
interruption or advanced suspension of treatment due to non-attributable reasons to the subject
c) Timely compliance of the terms in which the authorization of a research for health in human 
beings had been issued
d) To present in a timely manner the information required by the Health Authority
20 Audits and inspections
Any aspect of the clinical trial may be subject to audits conducted by Novo Nordisk or inspections 
from domestic or foreign regulatory authorities or from IRBs/IECs. Audits and inspections may 
take place during or after the trial. The investigator and the 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, the following documents must be available 
to Novo Nordisk:
!
Regulatory approval and/or acknowledgement of notification as required 
!
Approval/favourable opinion from IRBs/IECs clearly identifying the documents reviewed as 
follows: protocol, any protocol amendments, subject information/informed consent form, 
any other written information to be provided to the subject and subject recruitment materials
!
List of IRB/IEC members and/or constitution (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 Investigator's Brochure for oral semaglutide
!
Signed and dated Agreement on Protocol
!
Signed and dated agreement on protocol amendment, if applicable
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!
Contract, signed by the investigator and/or appropriate parties on behalf of the investigator’s 
site and Novo Nordisk
!
Source document agreement
!
Central laboratory certification and normal ranges
!
Insurance statement, if applicable
!
Financial disclosure form from investigator and sub-investigator(s)
For US only: 
!
For US trial sites: verification under disclosures per Code of Federal Regulations (CFR) of 
Financial Conflict of Interest
!
For US trial sites: FDA form 1572 must be completed and signed by the investigator at each 
site
FDA form 1572:
For US sites:
!
Intended for US sites
!
Conducted under the IND
!
All US investigators, as described above, will sign FDA Form 1572
For sites outside the US:
!
Intended for participating sites outside of the US
!
Not conducted under the IND
!
All investigators outside of the US will not sign FDA form 1572
By signing the protocol, each investigator agrees to comply fully with ICH GCP1, applicable 
regulatory requirements and the Declaration of Helsinki2. 
By signing the protocol, each investigator also agrees to allow Novo Nordisk to make investigator's 
name and information about site name and address publically available if this is required by 
national or international regulations.
22 Responsibilities
The investigator is accountable for the conduct of the trial at his/her site. If any tasks are delegated, 
the investigator must maintain a log of appropriately qualified persons to whom he/she has 
delegated specified trial-related duties. The investigator must ensure that there is adequate training 
for all staff participating in the conduct of the trial. It is the investigator's responsibility to supervise 
the conduct of the trial and to protect the rights, safety, and well-being of the subjects.
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A qualified physician, who is an investigator or a sub-investigator for the trial, must be responsible 
for all trial-related medical decisions.
The investigator must ensure adequate supervision of the conduct of the trial at the trial site. 
The investigator will follow instructions from Novo Nordisk when processing data.
The investigator is responsible for filing essential documents (i.e. those documents which 
individually and collectively permit evaluation of the conduct of a trial and the quality of the data
produced) in the investigator trial master file. The documents including the subject identification 
code list should be kept in a secure locked facility, so no unauthorised persons can get access to the 
data. 
The investigator will take all necessary technical and organisational safety measures to prevent 
accidental or wrongful destruction, loss or deterioration of data. The investigator will prevent any 
unauthorised access to data or any other processing of data against applicable law. The investigator 
must be able to provide the necessary information or otherwise demonstrate to Novo Nordisk that 
such technical and organisational safety measures have been taken.
During any period of unavailability, the investigator must delegate responsibility for medical care of 
subjects to a specific qualified physician who will be readily available to subjects during that time.
If the investigator is no longer able to fulfil the role as investigator (e.g. if he/she moves or retires), 
a new investigator will be appointed in consultation with Novo Nordisk. 
The investigator and other site personnel must have sufficient English skills according to their 
assigned task(s).
23 Reports and publications
The information obtained during the conduct of this trial is considered confidential, and may be 
used by or on behalf of Novo Nordisk for regulatory purposes as well as for the general 
development of the trial product. All information supplied by Novo Nordisk in connection with this 
trial shall remain the sole property of Novo Nordisk and is to be considered confidential 
information. 
No confidential information shall be disclosed to others without prior written consent from Novo 
Nordisk. Such information shall not be used except in the performance of this trial. The information 
obtained during this trial may be made available to other physicians who are conducting other 
clinical trials with the trial product, if deemed necessary by Novo Nordisk. Provided that certain 
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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 or more investigator(s) will be appointed by Novo Nordisk to review and sign the clinical trial 
report (signatory investigator(s)) on behalf of all participating investigators. The signatory 
investigator(s) will be appointed based upon the criteria defined by the International Committee of 
Medical Journal Editors for research publications36. 
23.1
Communication of results
Novo Nordisk commits to communicating, and otherwise making available for public disclosure, 
results of trials regardless of outcome. Public disclosure includes publication of a paper in a 
scientific journal, abstract submission with a poster or oral presentation at a scientific meeting, or 
disclosure by other means.
The results of this trial will be subject to public disclosure on external web sites according to 
international and national regulations, as reflected in the Novo Nordisk Code of Conduct for 
Clinical Trial Disclosure23.
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 
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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 Editors37 (sometimes referred to as the Vancouver 
Criteria).
At the end of the trial, one or more publications (abstracts, posters, manuscripts) will be prepared 
for submission to scientific congresses and peer-reviewed journals in collaboration between Novo 
Nordisk and investigator(s) appointed by Novo Nordisk. These investigator(s) must meet the 
International Committee of Medical Journal Editors authorship criteria to be named authors on 
publications.
23.1.2
Site-specific publication(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 trial subjects' data available, and will be 
provided with the randomisation codes after the end of the trial.
24 Retention of clinical trial documentation and human biospecimens
24.1
Retention of clinical trial documentation
Subject's medical records must be kept for the maximum period permitted by the hospital, 
institution or private practice.
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The investigator must agree to archive the documentation (this includes both electronic and paper-
based records) pertaining to the trial in an archive after completion or discontinuation of the trial if 
not otherwise notified. The investigator should not destroy any documents without prior permission 
from Novo Nordisk. If the investigator cannot archive the documents at the trial site, Novo Nordisk 
can refer the investigator to an independent archive provider that has a system in place to allow only 
the investigator to access the files.
The investigator must be able to access his/her trial documents without involving Novo Nordisk in 
any way. Site-specific CRFs and other subject data (in an electronic readable format or as paper 
copies or prints) will be provided to the investigator before access is revoked to the systems and/or 
electronic devices supplied by Novo Nordisk. These data must be retained by the trial site. If the 
provided data (e.g. the CD-ROM) is not readable during the entire storage period, the investigator 
can request a new copy. A copy of all data will be stored by Novo Nordisk.
Novo Nordisk will maintain Novo Nordisk documentation pertaining to the trial for as long as the 
product is on the market plus 20 years. 
The files from the trial site/institution must be retained for 15 years after the completion of the trial, 
or longer if required by local regulations or Novo Nordisk. In any case trial files cannot be 
destroyed until the trial site/institution is notified by Novo Nordisk. The deletion process must 
ensure confidentiality of data and must be done in accordance with local regulatory requirements.
24.2
Retention of human biospecimens
In order to comply with any future requests from health authorities to further characterise the 
antibody response, antibody samples collected in relation to suspicion of hypersensitivity reactions
during the trial may be stored at Novo Nordisk until no further marketing authorisations are pending
or maximum 15 years after the trial ended, whichever comes first. Stored antibody samples will be 
identified only by a subject number, a visit number and a trial identification number. The 
investigator is responsible for maintaining a list which links each subject number to a subject name. 
This list must be kept for at least 15 years after the trial ended. The list may be reviewed by Novo 
Nordisk staff including auditors or representatives from regulatory authorities.
For Brazil only: Biological samples from Brazil will be destroyed at the end of the trial.
25 Institutional Review Boards/Independent Ethics Committees and 
regulatory authorities
IRB/IEC:
Written approval or favourable opinion must be obtained from IRB/IEC prior to commencement of 
the trial.
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During the trial, the investigator or Novo Nordisk, as applicable, must promptly report the 
following to the IRB/IEC, in accordance with local requirements: updates to IB, SUSARs, protocol 
amendments according to local requirements, deviations to the protocol implemented to eliminate 
immediate hazards to the subjects, new information that may affect adversely the safety of the 
subjects or the conduct of the trial (including new benefit–risk analysis in case it will have an 
impact on the planned follow-up of the subjects), annually written summaries of the trial status, and 
other documents as required by the local IRB/IEC.
The investigator must ensure submission of the clinical trial report synopsis to the IRB/IEC.
Protocol amendments must not be implemented before approval or favourable opinion according to 
local regulations, unless necessary to eliminate immediate hazards to the subjects.
The investigator must maintain an accurate and complete record of all submissions made to the 
IRB/IEC. The records must be filed in the investigator trial master file and copies must be sent to 
Novo Nordisk.
Regulatory Authorities:
Regulatory authorities will receive the clinical trial application, protocol amendments, reports on 
SAEs, and the clinical trial report according to national requirements.
26 Indemnity statement
Novo Nordisk carries product liability for its products, and liability as assumed under the special 
laws, acts and/or guidelines for conducting clinical trials in any country, unless others have shown 
negligence.
Novo Nordisk assumes no liability in the event of negligence, or any other liability of the sites or 
investigators conducting the trial, or by persons for whom the said site or investigator are 
responsible.
Novo Nordisk accepts liability in accordance with:
For Argentina only: Novo Nordisk Pharma Argentina S.A. has contracted insurance as required by 
local law.
For Germany only: German Drug Law dated August 24, 1976, last amended by article 3 of the law 
dated December 17, 2014 (Federal Law Gazette I p. 2222).
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For Mexico only: Novo Nordisk carries product liability for its products and liability as assumed 
under the special laws, acts/and/or guidelines for conducting trials in any country, including those 
applicable provisions on the Mexican United States. If the subject feels that something goes wrong 
during the course of this trial, the subject should contact the trial staff in the first instance.
If during their participation in the trial the subject experiences a disease or injury that, according 
to the trial doctor and the sponsor, is directly caused by the study medication and/or a study 
procedure that otherwise would not have been part of his/her regular medical care, the subject will 
receive from the Institution or Medical Care Establishment and free of charge, the appropriate 
medical treatment as required. In this case, the costs resulting from such treatment as well as the 
costs of any indemnification established by law will be covered by the trial sponsor in accordance 
with the terms provided by all applicable regulations; even if the subject discontinues his/her 
participation in the study by his own will or by a decision from the investigator.
By signing the informed consent, the subject will not renounce to any compensation or 
indemnification he/she may be entitled to by law, nor will he/she will incur any additional expense 
as a result of his/her participation in the trial; any additional expense resulting from the subject’s 
participation in the trial will be covered by the trial sponsor.
For the Netherlands only: Wetgeving betreffende geneesmiddelen; geneesmiddelenwet 1 juli 2007 
(Medicines Law, 1 July 2007). De Wet Medisch-wetenschappelijk Onderzoek met mensen (WMO), 1 
maart 2006 (Medical Research Involving Human Subjects Act, 1 March 2006). Besluit verplichte 
verzekering bij medisch-wetenschappelijk onderzoek met mensen 2015, 24 november 2014 (Decree 
compulsory insurance in medical research involving human subjects 2015, 24 November 2014).
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 the investigators 
are covered by the insurance policy issued according to applicable Polish law.
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27 References
1 International Conference on Harmonisation. ICH Harmonised Tripartite Guideline: Guideline 
for Good Clinical Practice E6 (R1), Step 4. 1 May 1996.
2 Declaration of Helsinki. Ethical Principles for Medical Research Involving Human Subjects. 
Last amended by the 64th WMA General Assembly, Fortaleza, Brazil. world medical 
association. Oct 2013.
3 DeFronzo RA. Pathogenesis of type 2 diabetes mellitus. Med Clin North Am 2004; 88:787-
835.
4 Holst JJ, Vilsbøll T, Deacon CF. The incretin system and its role in type 2 diabetes mellitus. 
Mol Cell Endocrinol 2009; 297:127-136.
5 Kieffer TJ, Habener JL. The glucagon-like peptides. Endocr Rev 1999; 20(6):876-913.
6 Bagger JI, Knop FK, Lund A, Vestergaard H, Holst JJ, Vilsboll T. Impaired regulation of the 
incretin effect in patients with type 2 diabetes. J Clin Endocrinol Metab 2011; 96(3):737-745.
7 Nauck M, Stockmann F, Ebert R, Creutzfeldt W. Reduced incretin effect in type 2 (non-
insulin-dependent) diabetes. Diabetologia 1986; 29(1):46-52.
8 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.
9 Perley MJ, Kipnis DM. Plasma insulin responses to oral and intravenous glucose: studies in 
normal and diabetic subjects. J Clin Invest 1967; 46(12):1954-1962.
10 Højberg PV, Vilsbøll T, Rabøl 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; 52:199-207.
11 Meier JJ. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nat 
Rev Endocrinol 2012; 8(12):728-742.
12 Nauck MA, Weber I, Bach I, Richter S, Orskov C, Holst JJ et al. Normalization of fasting 
glycaemia by intravenous GLP-1 ([7-36 amide] or [7-37]) in type 2 diabetic patients. Diabet 
Med 1998; 15(11):937-945.
13 Nauck MA. Incretin based therapies for type 2 diabetes mellitus: properties, functions, and 
clinical implications. Am J Med 2011; 124 (1 Suppl):S3-S18.
CONFIDENTIAL


Protocol
Date:
12 February 2016
Novo Nordisk
Trial ID: NN9924-4221
Version:
3.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
78 of 79
14 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):3717-3723.
15 Nauck MA, Petrie JR, Sesti G, Mannucci E, Courreges JP, Atkin S et al. The once-weekly 
human GLP-1 analogue semaglutide provides significant reductions in HbA1c and body 
weight in patients with type 2 diabetes. Abstracts of the 48th European Association for the 
Study of Diabetes (EASD) Annual Meeting. October 1-5, 2012. Berlin, Germany. 
Diabetologia 2012; 55 Suppl 1:S7-537. doi: 10.1007/s00125-012-2688-9.:S7-537.
16 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 2014;1-12.
17 Investigators Brochure for s.c. Semaglutide (NN9535), Edition 10 or any updates hereof.  
2015. 
18 Investigators Brochure for oral Semaglutide (NN9924), Edition 6 or any updates hereof. 2015.
19 Food and Drug Administration. Guidance for Industry: Diabetes Mellitus — Evaluating 
Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. Dec 2008.
20 European Medecines Agency. Guideline on clinical investigation of medicinal products in the 
treatment of diabetes mellitus. 16 Sep 2011.
21 KDIGO. KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney international 
supplements 2012; 2(1):1-138.
22 Basi S, Fesler P, Mimran A, Lewis JB. Microalbuminuria in type 2 diabetes and hypertension: 
a marker, treatment target, or innocent bystander? Diabetes Care 2008; 31 Suppl 2:S194-S201.
23 Novo Nordisk. http://www.novonordisk-trials.com/website/content/how-we-disclose-trial-
information.aspx.  2015. 
24 De AC, Drazen JM, Frizelle FA, Haug C, Hoey J, Horton R et al. Clinical trial registration: a 
statement from the International Committee of Medical Journal Editors. Croat Med J 2004; 
45(5):531-532.
25 Food and Drug Administration Amendments Act of 2007. 11 Oct 2007.
26 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 May 2001.
CONFIDENTIAL


Protocol
Date:
12 February 2016
Novo Nordisk
Trial ID: NN9924-4221
Version:
3.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
79 of 79
27 The European Parliament and the Council of the European Council. Regulation (EC) No 
726/2004 of the European Parliament and of the Council of 31 March 2004 laying down 
Community procedures for the authorisation and supervision of medicinal products for human 
and veterinary use and establishing a European Medicines Agency, article 57. Official Journal 
of the European Communities April 2001.
28 Criteria Committee of the New York Heart Association. Nomenclature and criteria for 
diagnosis of diseases of the heart and great vessels. Boston, MA: Little, Brown & Co, 1994.
29 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; 36:1384-1395.
30 Banks PA, Freeman ML. Practice guidelines in acute pancreatitis. Am J Gastroenterol 2006; 
101(10):2379-2400.
31 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):102-111.
32 Food and Drug Administration. Guidance for Industry: Immunogenicity Assessment for 
Therapeutic Protein Products . Aug 2015.
33 European Union. The rules governing medicinal products in the European Union, Volume 4, 
Annex 13, manufacture of investigational products - Brussels. Feb 2010.
34 Hicks KA, Hung HMJ, Mahaffey KW, Mehran R, Nissen SE, Strockbridge NL et al. 
Standardized Definitions for Cardiovascular and Stroke End Point Events in Clinical Trials 
(DRAFT).  20 Aug 2014. 
35 Standards of medical care in diabetes. Diabetes Care 2014; 37(Supplement 1):S14-S80.
36 International Committee of Medical Journal Editors. Recommendations for the Conduct, 
Reporting, Editing and Publication of Scholarly Work in Medical Journals. Dec 2014.
37 International Committee of Medicinal Journal Editors. Uniform Requirements for Manuscripts 
submitted to Biomedical Journals. N Engl J Med 1997; 336:309-315.
CONFIDENTIAL


Protocol Appendix A
Date:
12 February 2016
Novo Nordisk
Trial ID: NN9924-4221
Version:
3.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
1 of 5
Appendix A
Monitoring of calcitonin
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol Appendix A
Date:
12 February 2016
Novo Nordisk
Trial ID: NN9924-4221
Version:
3.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
2 of 5
1
Background
Treatment with GLP-1 receptor agonists has shown to be associated with thyroid C-cell changes in 
rodents but not in non-human primates. The human relevance of this finding is unknown. However, 
based on the findings in rodents, monitoring of serum calcitonin (a sensitive biomarker for C-cell 
activation) is currently being performed in clinical trials 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
Date:
12 February 2016
Novo Nordisk
Trial ID: NN9924-4221
Version:
3.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
3 of 5
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 (see protocol Section 6.5 premature discontinuation of trial 
CONFIDENTIAL


Protocol Appendix A
Date:
12 February 2016
Novo Nordisk
Trial ID: NN9924-4221
Version:
3.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
4 of 5
product). The subject should remain in the trial, however, all 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 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 MEN2 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 disease1. Two of these subjects were diagnosed with MTC and two were diagnosed with 
C-cell hyperplasia, resulting in a positive predictive value of a C-cell anomaly of 50%.
Diagnostic evaluation should include: 
!
thyroid ultrasound examination 
!
if available and there are no contraindication, 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.
Background: Calcitonin values from 20-50 ng/L were found in up to 1% of subjects of the 
population of 5817 patients with thyroid nodular disease1. The predictive value of a C-cell anomaly 
CONFIDENTIAL


Protocol Appendix A
Date:
12 February 2016
Novo Nordisk
Trial ID: NN9924-4221
Version:
3.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
5 of 5
for this calcitonin level was 8.3%. However, the likelihood of having a medullary carcinoma >1 cm 
with calcitonin in this range is extremely low.
For calcitonin values between 10-20 ng/L Costante et al1 identified 216 (3.7%) patients. One patient 
out of the 216 had a subsequent basal (unstimulated) calcitonin of 33 ng/L, and had C-cell 
hyperplasia at surgery. Two other studies used a cut-off of CT > 10 ng/L to screen for C-cell 
disease, but they do not provide sufficient information on patients with basal CT > 10 and < 20 ng/L 
to allow conclusions. 2,3
3
References
1. Costante G, Meringolo D, Durante C, Bianchi D, Nocera M, Tumino S et al. Predictive value of 
serum calcitonin levels for preoperative diagnosis of medullary thyroid carcinoma in a cohort of 
5817 consecutive patients with thyroid nodules. J Clin Endocrinol Metab 2007; 92(2):450-455.
2. Scheuba C, Kaserer K, moritz A, drosten R. Sporadic hypercalcitoninemia: clinica and 
therapeutic consequences. Endocrine Related Cancer 2009; 16(1):243-253.
3. Verga U, Ferrero S, Vicentini L, Brambilla T, Cirello V, Muzza M et al. Histopathological and 
molecular studies in patients with goiter and hypercalcitoninemia: reactive or neoplastic C-cell 
hyperplasia? Endocr Relat Cancer 2007; 14(2):393-403.
CONFIDENTIAL


Protocol Appendix B
Date:
12 February 2016
Novo Nordisk
Trial ID: NN9924-4221
Version:
3.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
1 of 6
Appendix B
Adverse events requiring additional data collection
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol Appendix B
Date:
12 February 2016
Novo Nordisk
Trial ID: NN9924-4221
Version:
3.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
2 of 6
1
Adverse Events requiring additional data collection
AEs must be assessed according to section 12.1 and reported if applicable according to section 12.2.
If any of the following AEs are applicable for reporting, additional data collection is required and 
specific event forms must be completed in the eCRF in addition to the AE form:
!
Acute coronary syndrome (myocardial infarction or hospitalisation for unstable angina)
!
Cerebrovascular event (stroke or TIA)
!
Heart failure requiring hospitalisation
!
Pancreatitis
!
Neoplasm (excluding thyroid neoplasm)
!
Thyroid disease (including thyroid neoplasm)
!
Renal event
!
Hypersensitivity reaction to the trial product
!
Lactic acidosis
!
Medication error concerning trial product
!
Severe hypoglycaemic episode
!
Hepatic event:
o
ALT or AST > 5x UNL and total bilirubin ≤ 2x UNL
o
ALT or AST > 3x UNL and total bilirubin > 2x UNL
o
Hepatic event leading to trial product discontinuation
As specified in section 12.2, the majority of events listed above should only be reported if a
seriousness criterion is fulfilled or if the event leads to premature treatment discontinuation. 
Exempts are medication errors, severe hypoglycaemic episodes and hepatic events which must be 
reported regardless of the seriousness criteria.
Some of the events requiring additional data collection will also undergo event adjudication by the 
Event Adjudication Committee (EAC), please see section 12.7.3 and Table 12-1.
1.1
Acute coronary syndrome
If an event of acute coronary syndrome (myocardial infarction or hospitalisation for unstable 
angina) is applicable for reporting the following additional information must be reported, if 
available: 
!
Duration of symptoms
!
Changes in ECG
!
Collection of cardiac biomarkers
!
Cardiac imaging
!
Cardiac stress testing
!
Angiography
CONFIDENTIAL


Protocol Appendix B
Date:
12 February 2016
Novo Nordisk
Trial ID: NN9924-4221
Version:
3.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
3 of 6
!
Use of thrombolytic drugs
!
Revascularisation procedures 
1.2
Cerebrovascular event
If a cerebrovascular event (stroke or TIA) is applicable for reporting, the following additional 
information must be reported, if available: 
!
Type of event (stroke or TIA)
!
Contributing condition
!
Neurologic signs and symptoms
!
History of neurologic disease
!
Imaging supporting the condition
!
Treatment given for the condition
1.3
Heart failure requiring hospitalisation 
If an event of heart failure requiring hospitalisation (admission to an in-patient unit or a visit to an 
emergency department that results in at least a 24 hour stay) is applicable for reporting the 
following additional information must be reported, if available: 
!
Signs and symptoms of heart failure
!
NYHA Class
!
Supportive imaging
!
Supportive laboratory measurements
!
Initiation or intensification of treatment for this condition
1.4
Pancreatitis
If an event of pancreatitis is applicable for reporting the following additional information must 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 pancreatic disease
Please see section 8.2.1 for further details on assessments in case of suspicion of acute pancreatitis.
CONFIDENTIAL


Protocol Appendix B
Date:
12 February 2016
Novo Nordisk
Trial ID: NN9924-4221
Version:
3.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
4 of 6
1.5
Neoplasm
If an event of neoplasm (excluding thyroid neoplasm, which will be reported under thyroid disease) 
is applicable for reporting the following additional information must be reported, if available:
!
Type of neoplasm
!
Symptoms leading to identification of event
!
Diagnostic imaging
!
Pathological examination results
!
Treatment for the event
!
Participation in screening programs
!
Risk factors associated to the event
1.6
Thyroid disease
If an event of thyroid disease, including any thyroid neoplasms, is applicable for reporting the 
following additional information must be reported, if available:
!
History of thyroid disease
!
Signs and symptoms leading to investigations of thyroid disease
!
Specific laboratory tests describing thyroid function
!
Diagnostic imaging performed and any prior imaging supporting the disease history 
!
Pathologic examinations
!
Treatment given for the condition
!
Risk factors identified
!
Family history of thyroid disease
1.7
Renal event 
If a renal event is applicable for reporting the following additional information must be reported, if 
available:
!
Signs and symptoms of renal failure
!
Specific laboratory test supporting the diagnosis 
!
Imaging performed supporting the diagnosis
!
Kidney biopsy results
!
Risk or confounding factors identified including exposure to nephrotoxic agents
1.8
Hypersensitivity reaction to the trial product
If an event of hypersensitivity reaction to the trial product is applicable for reporting the following 
additional information must be reported, if available:
!
Signs and symptoms associated to the event
!
Time of appearance after administration of trial drug
!
Relevant immunological tests performed
CONFIDENTIAL


Protocol Appendix B
Date:
12 February 2016
Novo Nordisk
Trial ID: NN9924-4221
Version:
3.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
5 of 6
!
Treatment given for the reaction
!
Previous history of similar reactions
!
Risk or confounding factors identified
Please see section 8.2.2 for further details on assessments in case of suspicion of hypersensitivity
reaction to the trial product.
1.9
Lactic acidosis
If an event of lactic acidosis is applicable for reporting the following additional information must be 
reported, if available:
!
Signs and symptoms of lactic acidosis
!
Specific laboratory test results describing the event 
!
Possible cause(s) of the event
1.10
Medication error concerning trial product
If a medication error concerning trial product is observed during the trial, the following additional 
information must be reported, if available: 
!
Trial product(s) involved 
!
Classification of medication error
o
Wrong drug(s) administered
o
Wrong route of administration
o
Wrong dose administered
!
Whether the subject experienced any AE(s) as a result of the medication error 
!
Suspected primary reason for the medication error 
For definition of medication error concerning trial product, see section 12.1.4.
1.11
Severe hypoglycaemic episode
If a severe hypoglycaemic episode is observed during the trial, the following additional information 
must be reported, if available: 
!
Lowest glucose value recorded
!
Whether there were symptoms associated with the event
!
Contributing factors (e.g. diet change, physical activity)
!
Treatment given for the event
For definition of a severe hypoglycaemic episode, see section 8.1.16.1.
CONFIDENTIAL


Protocol Appendix B
Date:
12 February 2016
Novo Nordisk
Trial ID: NN9924-4221
Version:
3.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
6 of 6
1.12
Hepatic event
!
ALT or AST > 5x UNL and total bilirubin ≤ 2x UNL
!
ALT or AST > 3x UNL and total bilirubin > 2x UNL
!
Hepatic event leading to trial product discontinuation
If one of the above events is observed during the trial the following additional information must be 
reported, if available:
!
Signs and symptoms associated to the event 
!
Risk factors
!
Relevant laboratory test results 
!
Diagnostic imaging performed 
!
Possible cause(s) of the event 
Please see section 8.2.3 for further details on assessments in case of increased levels of 
aminotransferases.


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
Date:
Novo Nordisk
Version:
Status:
Oral semaglutide
Trial ID: NN9924 4221
Clinical Trial Report
Appendix 16.1.1
11 February 2019
1.0
Final


Protocol Amendment
Date:
18 February 2016
Novo Nordisk
Trial ID: NN9924-4221
Version:
1.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
1 of 2
Protocol Amendment
no 1
to Protocol, final version 3.0
dated 12 February 2016
Trial ID: NN9924-4221
PIONEER 6 – Cardiovascular outcomes
A trial investigating the cardiovascular safety of oral semaglutide 
in subjects with type 2 diabetes
Trial phase: 3a
Applicable to Germany
Amendment originator:
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
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
Date:
18 February 2016
Novo Nordisk
Trial ID: NN9924-4221
Version:
1.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
2 of 2
1
Introduction including rationale for the protocol amendment
This protocol amendment is generated to ensure the protocol requirements about contraception 
during participation in the clinical trial are in accordance with the current regulatory requirements in 
Germany.
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
2
Changes
Section 8.1.7   Pregnancy test
For Germany only: Adequate contraceptive measures are implants, injectables, combined oral 
contraceptives, hormonal intrauterine devices, sexual abstinence or vasectomised partner. 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.


Protocol Amendment no 2
Date:
21 July 2016
Novo Nordisk
Trial ID: NN9924-4221
Version:
1.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
1 of 8
Protocol Amendment
no 2
to Protocol, final version 3.0
dated 12 February 2016
Trial ID:
NN9924-4221
PIONEER 6 – Cardiovascular outcomes
A trial investigating the cardiovascular safety of oral 
semaglutide in subjects with type 2 diabetes
Trial phase: 3a
Applicable to all countries
Amendment originator:
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
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 no 2
Date:
21 July 2016
Novo Nordisk
Trial ID: NN9924-4221
Version:
1.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
2 of 8
Table of Contents   
Page
Table of Contents..............................................................................................................................................2
1
Introduction including rationale for the protocol amendment.............................................................3
1.1
A new screening procedure and an additional exclusion criterion related to diabetic 
retinopathy .....................................................................................................................................3
1.2
Minor updates and clarifications....................................................................................................3
2
Changes......................................................................................................................................................4
2.1
Section 2 Flow chart ......................................................................................................................4
2.2
Section 3.1.5 Oral semaglutide and cardiovascular risk................................................................4
2.3
Section 5.1 Type of trial ................................................................................................................5
2.4
Section 5.3 Treatment of subjects..................................................................................................5
2.5
Section 5.3.3 Background medication ...........................................................................................5
2.6
Section 5.5 Rationale for treatment ...............................................................................................5
2.7
Section 6.3 Exclusion criteria ........................................................................................................6
2.8
Section 8.1.2 In/exclusion criteria .................................................................................................6
2.9
Section 8.1.7 Eye examination.......................................................................................................6
2.10
Section numbers for sections 8.1.7 to 8.1.17 .................................................................................7
2.11
Section 17.1 Sample size calculation.............................................................................................7
2.12
Section 18.1 Benefit–risk assessment of the trial ..........................................................................7
2.13
Section 27 References....................................................................................................................8
2.14
Reference numbers ........................................................................................................................8


Protocol Amendment no 2
Date:
21 July 2016
Novo Nordisk
Trial ID: NN9924-4221
Version:
1.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
3 of 8
1
Introduction including rationale for the protocol amendment
This protocol amendment introduces: 1) A new screening procedure to ensure that a recent 
fundoscopic examination has been performed for each subject before they are randomised into the 
trial, 2) an additional exclusion criterion to disallow enrolment of patients with proliferative 
retinopathy or maculopathy requiring acute treatment, and 3) minor updates and clarifications. The 
changes are introduced and described in details below.
1.1
A new screening procedure and an additional exclusion criterion related to diabetic 
retinopathy
Transient worsening of diabetic retinopathy is a recognised complication in selected patients with 
diabetes after initiation of intensive antidiabetic treatment. Risk factors for these events include 
long-standing poor glycaemic control and presence of proliferative retinopathy, and initial large 
improvements in blood glucose may be an additional aggravating factor. In a recently completed 
cardiovascular outcomes trial with s.c. semaglutide, results indicate an increased risk of events 
related to diabetic retinopathy in subjects treated with semaglutide compared to placebo. The 
majority of the related adverse events were moderate in severity and did not lead to premature 
discontinuation of trial product. However, as a precaution in this trial, an additional exclusion 
criterion is added requiring all subjects to have a fundus photography or dilated fundoscopy 
performed within 90 days prior to screening or within the period from screening to randomisation; 
moreover, subjects with proliferative retinopathy or maculopathy requiring acute treatment will not 
be included in the trial. To accommodate the additional screening procedure, the screening period is 
extended from up to 2 weeks to up to 3 weeks.
1.2
Minor updates and clarifications
The following minor revisions and clarifications are implemented:
!
The protocol is updated to reflect results from the recent completion of the cardiovascular 
outcomes trials for once-weekly s.c. administration of semaglutide (SUSTAIN™ 6 –
NN9535-3744) and once-daily subcutaneous administration of liraglutide (LEADER® –
EX2211-3748).
!
The protocol is updated to clarify the rationale for the selected trial product dose levels.
!
Text is added to highlight the investigator’s responsibility in ensuring evaluation and 
management of not only cardiovascular disease but also microvascular complications such 
as diabetic kidney disease and diabetic retinopathy.
!
Text is added to highlight that severe dehydration may be a risk factor for diabetic 
ketoacidosis in subjects using sodium-glucose cotransporter-2 (SGLT2) inhibitors.


Protocol Amendment no 2
Date:
21 July 2016
Novo Nordisk
Trial ID: NN9924-4221
Version:
1.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
4 of 8
2
Changes
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
2.1
Section 2 Flow chart
Trial Periods
Scree-
ning
Ran-
domi-
sation
Treatment
Visit (V) Phone (P)
V1
V2
P3
V4
V5
V6
Timing of visit (weeks after V2)
Up to -32
0
2
4
8
14
Visit window (days)
±3
±3
±3
±3
Informed consent
X
In/exclusion criteria
X
Demography, tobacco use
X
Physical examination
X
Eye examination3
X
Pregnancy test, urine dipsticks34
X
3Fundus photography or dilated fundoscopy must be performed within 90 days prior to screening or 
within the period between screening and randomisation.
34 For women of childbearing potential only. In addition to the planned assessment at screening and 
end-of-treatment, urine dipstick pregnancy test should be performed at site at any time during the 
trial if a menstrual period is missed, or if pregnancy is suspected, or as required by local law.
2.2
Section 3.1.5 Oral semaglutide and cardiovascular risk
In support, findings results from the recently completed ELIXA™LEADER® trial (EX2211-3748)
confirmed showed that treatment with the once-daily injectable GLP 1 RA lixisenatide s.c. 
liraglutide does not increase the risk of MACE as compared to placebo. In fact, treatment with 
liraglutide reduced the risk of the primary composite endpoint consisting of death from 
cardiovascular causes, non-fatal myocardial infarction and non-fatal stroke by 13% versus 
placebo38. Also, the SUSTAIN™6 trial (NN9535-3744) achieved its primary objective by showing 
non-inferiority of once-weekly s.c. semaglutide versus placebo on cardiovascular outcomes; 
moreover, s.c. semaglutide statistically significantly reduced cardiovascular risk versus placebo39.
This trial is the first cardiovascular outcomes trial within the GLP 1 RA drug class to report and 
several others (including SUSTAIN™ 6 investigating the cardiovascular safety of s.c. semaglutide) 
are ongoing. 


Protocol Amendment no 2
Date:
21 July 2016
Novo Nordisk
Trial ID: NN9924-4221
Version:
1.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
5 of 8
2.3
Section 5.1 Type of trial
Figure 5–1
Trial design
2.4
Section 5.3 Treatment of subjects
Table 5–1
Treatment of subjects
Trial periods
Screening
Trial period 1
Trial period 2
Trial period 3
Follow-up
Alias for trial period
Screening
Dose escalation
Dose escalation
Maintenance
Follow-up
First visit in each period
V1
V2
V4
V5
V17
Duration of each period
Up to 23 weeks 4 weeks
4 weeks
Up to 75 weeks
5 weeks
Treatment arm
N
Oral semaglutide
1588
Screening
3 mg
7 mg
14 mg
Follow-up
Placebo
1588
Screening
Placebo
Placebo
Placebo
Follow-up
2.5
Section 5.3.3 Background medication
The investigator is responsible for ensuring ongoing management of Ccardiovascular diseases and 
risk factors as well as potential microvascular complications such as diabetic kidney disease and 
diabetic retinopathy will be treated according to local standard of care at the investigator’s 
discretion.
2.6
Section 5.5 Rationale for treatment
Three treatment doses of oral semaglutide will be investigated in the phase 3a development 
programme: 3 mg, 7 mg and 14 mg. The selected doses are based on the data derived from the 
NN9924-3790 dose-finding trial. This dose range is expected to have the optimal benefit-risk profile 
for further development of oral semaglutide. In addition, the increments between the three doses are 
expected to provide clinically meaningful differentiation between the effects on glycaemic control 
while ensuring mitigation of gastrointestinal AEs through gradual dose escalation. For further 
details regarding the results obtained in the phase 2 dose-finding trial (NN9924-3790), please refer 


Protocol Amendment no 2
Date:
21 July 2016
Novo Nordisk
Trial ID: NN9924-4221
Version:
1.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
6 of 8
to the current edition of the IB for oral administration of semaglutide (NN9924)18, or any updates 
thereto.
Similar to other cardiovascular outcomes trials, the maximum treatment dose (14 mg oral 
semaglutide) will be investigated and compared to placebo in the present trial. Blinded treatment 
with oral semaglutide or placebo offers a robust method for assessment of oral semaglutide’s effect 
on trial endpoints. Gradual dose escalation is applied in order to mitigate the risk of gastrointestinal 
AEs. 
2.7
Section 6.3 Exclusion criteria
17. Proliferative retinopathy or maculopathy requiring acute treatment. Verified by fundus 
photography or dilated fundoscopy performed within 90 days prior to screening or within the 
period between screening and randomisation.
2.8
Section 8.1.2 In/exclusion criteria
For exclusion criterion no. 17 (section 6.3), each subject must have a fundus photography or 
dilated fundoscopy performed and evaluated before randomisation, in accordance with the 
instructions in section 8.1.7.
2.9
Section 8.1.7 Eye examination
Results of a fundus photography or dilated fundoscopy must be available and evaluated by the 
investigator before randomisation. If the subject had a fundus photography or dilated fundoscopy 
performed within 90 days prior to screening, the investigator may base their evaluation upon the 
results of that examination. However, the examination must be repeated before randomisation if the 
subject experienced worsening of visual function since the last examination. 
If the subject did not have a fundus photography or dilated fundoscopy performed within 90 days 
prior to screening, such examination must be performed by the investigator or other qualified 
health care professional prior to randomisation.
The investigator should indicate whether the outcome of the eye examination was normal or 
abnormal, and, if abnormal, indicate whether clinically significant. Relevant findings as a result of 
this screening procedure must be recorded as concomitant illness/medical history in accordance 
with section 8.1.9.
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.


Protocol Amendment no 2
Date:
21 July 2016
Novo Nordisk
Trial ID: NN9924-4221
Version:
1.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
7 of 8
2.10
Section numbers for sections 8.1.7 to 8.1.17
Will change to 8.1.8 to 8.1.18.
2.11
Section 17.1 Sample size calculation
In order to have a total of 122 first MACEs with trial duration of 19 months and 1,588 subjects 
randomised to each treatment group (1:1 randomisation), in total 3,176 subjects, the following is 
assumed based on the ongoing trials EX2211-3748 (LEADER®) and NN9535-3744 
(SUSTAIN™6):
2.12
Section 18.1 Benefit–risk assessment of the trial
Potential risks
Acute renal impairment
Sodium-glucose cotransporter-2 (SGLT2) inhibitors, an allowed background treatment, have also 
been associated with volume depletion. It is recommended to monitor for signs and symptoms of 
fluid loss during therapy. Severe dehydration may be a risk factor for diabetic ketoacidosis.
Other
Diabetic retinopathy
A transient worsening of diabetic retinopathy is a recognised complication in selected patients with 
diabetes after initiation of intensive antidiabetic treatment40-42. Risk factors for these events include 
long-standing poor glycaemic control and presence of proliferative retinopathy, and initial large 
improvements in blood glucose may be an additional aggravating factor. Several studies have, 
however, documented long-term beneficial effects of intensive glycaemic treatment in reducing 
retinopathy progression43,44 even in intensively treated patients who experienced early worsening41. 
In a cardiovascular outcomes trial with s.c. semaglutide, results indicate an increased risk of events 
related to diabetic retinopathy in subjects treated with semaglutide compared to placebo. 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.
Benefits 
In addition, it is expected that all subjects will benefit from participation through close contact with 
the trial site including thorough medical examinations and close follow-up of their T2D. Finally, 
data from two cardiovascular outcomes trials investigating treatment with GLP-1 RAs compared to 
placebo have indicated that there might be a potential beneficial effect of these drugs on 
cardiovascular outcomes when added to standard of care in subjects with T2D at high risk of 
cardiovascular events (see section 3.1.5).


Protocol Amendment no 2
Date:
21 July 2016
Novo Nordisk
Trial ID: NN9924-4221
Version:
1.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
8 of 8
2.13
Section 27 References
17) Investigators Brochure for s.c. Semaglutide (NN9535), Edition 1011 or any updates hereof.  
20152016.
18) Investigators Brochure for oral Semaglutide (NN9924), Edition 67 or any updates hereof. 
20152016.
38) Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, et al. 
Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016.
39) Novo Nordisk A/S. Company Announcement: SUSTAIN 6. 2016.
40) K Dahl-Jørgensen, O Brinchmann-Hansen, K F Hanssen, L Sandvik, O Aagenaes. Rapid 
tightening of blood glucose control leads to transient deterioration of retinopathy in insulin 
dependent diabetes mellitus: the Oslo study. Br Med J (Clin Res Ed) 1985; 290
41) The Diabetes Control and Complications Trial Research Group. Early Worsening of 
Diabetic Retinopathy in the Diabetes Control and Complications Trial. Arch Ophthalmol. 
1998 Jul;116(7):874-86.
42) Varadhan L1, Humphreys T2, Walker AB3, Varughese GI4. The impact of improved 
glycaemic control with GLP-1 receptor agonist therapy on diabetic retinopathy. Diabetes 
Res Clin Pract. 2014 Mar;103(3):e37-9. doi: 10.1016/j.diabres.2013.12.041. Epub 2014 
Jan 6
43) UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with 
sulphonylureas or insulin compared with conventional treatment and risk of complications 
in patients with type 2 diabetes (UKPDS 33). Lancet 1999 Aug 14;354(9178):602.
44) 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 Jun; dc160024. 
http://dx.doi.org/10.2337/dc16-0024 
2.14
Reference numbers 
Will change throughout the updated protocol when new references numbered 38-44 above are 
introduced.


Protocol Amendment no. 3
Date:
03 November 2016
Novo Nordisk
Trial ID: NN9924-4221
Version:
1.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
1 of 10
Protocol Amendment
No. 3
to Protocol, final version 4.0
dated 21 July 2016
Trial ID:
NN9924-4221
PIONEER 6 – Cardiovascular outcomes
A trial investigating the cardiovascular safety of oral
semaglutide in subjects with type 2 diabetes
Trial phase: 3a
Applicable to all countries
Amendment originator:
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
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 no. 3
Date:
03 November 2016
Novo Nordisk
Trial ID: NN9924-4221
Version:
1.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
2 of 10
Table of Contents   
Page
Table of Contents..............................................................................................................................................2
1
Introduction including rationale for the protocol amendment.............................................................3
1.1
Additional eye examinations and additional data collection for events of diabetic 
retinopathy or related complications..............................................................................................3
1.2
Addition of bicarbonate as a part of the biochemistry laboratory assessments .............................3
1.3
Clarification in relation to physical examination...........................................................................3
1.4
Minor corrections or clarifications.................................................................................................3
2
Changes......................................................................................................................................................4
2.1
Section 2 Flow chart ......................................................................................................................4
2.2
Section 4.2 Endpoints ....................................................................................................................5
2.3
Section 8.1.6 Physical examination ...............................................................................................5
2.4
Section 8.1.7 Eye examination.......................................................................................................5
2.5
Section 8.1.15 Blood sampling......................................................................................................6
2.6
Section 12.1.4 Adverse events requiring additional data collection..............................................6
2.7
Section 12.2 Reporting of adverse events......................................................................................7
2.8
Section 12.7.3 Event adjudication committee................................................................................8
2.9
Section 17.4.2 Safety endpoints.....................................................................................................9
2.10
Section 18.1 Benefit-risk assessment of the trial, new subtitle......................................................9
2.11
Section 27 References....................................................................................................................9
2.12
Reference numbers ........................................................................................................................9
2.13
Appendix B, Section 1 Adverse events requiring additional data collection.................................9
2.14
Appendix B, new section.............................................................................................................10


Protocol Amendment no. 3
Date:
03 November 2016
Novo Nordisk
Trial ID: NN9924-4221
Version:
1.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
3 of 10
1
Introduction including rationale for the protocol amendment
This protocol amendment introduces:
1. Additional eye examinations and additional data collection for events of diabetic retinopathy or 
related complications
2. Addition of bicarbonate as a part of the biochemistry laboratory assessments
3. Clarification in relation to physical examination
4. Minor corrections or clarifications
1.1
Additional eye examinations and additional data collection for events of diabetic 
retinopathy or related complications
In a recently completed cardiovascular outcomes trial with s.c. semaglutide, results indicate an 
increased risk of events related to diabetic retinopathy in subjects treated with semaglutide 
compared to placebo. Based on feedback from the US Food and Drug Administration (FDA) in 
relation to these findings, additional eye examinations will be implemented in the present trial 
(NN9924-4221) after approximately one year of treatment and at the end of the treatment period. 
Also, to further understand this safety signal, the targeted safety reporting in this trial will be 
broadened to include diabetic retinopathy and related complications. Furthermore, additional 
information will be collected for events of diabetic retinopathy and related complications reported 
during the trial. 
1.2
Addition of bicarbonate as a part of the biochemistry laboratory assessments
The FDA has requested that bicarbonate is added as a routine laboratory test in trials where sodium-
glucose cotransporter-2 (SGLT2) inhibitors are used as background medication, because SGLT2 
inhibitors have been associated with a risk for metabolic acidosis.
1.3
Clarification in relation to physical examination
As per agreement with the FDA, text is added to highlight the investigator’s responsibility in 
relation to further evaluation of potential incidental thyroid nodules discovered at the physical 
examinations.
1.4
Minor corrections or clarifications
Clarification in relation to event adjudication and initial AE reporting.


Protocol Amendment no. 3
UTN: U1111-1173-0750
Date:
03 November 2016
Status:
Final
Novo Nordisk
Trial ID: NN9924-4221
EudraCT No.: 2015-003563-10
Version:
1.0
Page:
4 of 10
2
Changes
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
2.1
Section 2 Flow chart
Trial Periods
Scree-
ning
Ran-
domi-
sation
Treatment
End of 
treat-
ment
Follow-
up
Visit (V) Phone (P)
V1
V2
P3
V4
V5
V6
P72
V8
P92
V10
P112
V12
P132
V14
P152
V16
V171
P181
Timing of visit (weeks after V2)
Up to -3
0
2
4
8
14
20
26
32
38
44
50
56
62
69
76
83
88
Visit window (days)
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+3
Informed consent
X
In/exclusion criteria
X
Demography, tobacco use
X
Physical examination
X
X
Eye examination3
X3
X4
X4
Pregnancy test, urine dipsticks45
X
X
3 Fundus photography or dilated fundoscopy must be performed within 90 days prior to screening or within the period between screening and randomisation.
4 Fundus photography or dilated fundoscopy should be performed at Visit 12 and 17 or within 5 weeks prior to those visits.
5 For women of childbearing potential only. In addition to the planned assessment at screening and end-of-treatment, urine dipstick pregnancy test should be performed 
at site at any time during the trial if a menstrual period is missed, or if pregnancy is suspected, or as required by local law


Protocol Amendment no. 3
Date:
03 November 2016
Novo Nordisk
Trial ID: NN9924-4221
Version:
1.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
5 of 10
2.2
Section 4.2 Endpoints
Change from baseline to last assessment of:
!
Biochemistry
!
Haematology
!
Calcitonin
!
Eye examination category
!
Pulse
!
Systolic and diastolic blood pressure
!
Glycosylated haemoglobin (HbA1c)
!
Body weight
!
Lipids
2.3
Section 8.1.6 Physical examination
Please note that the diagnostic evaluation of thyroid nodules should be in accordance with the 
American Thyroid Association Management Guidelines or any updates hereof 30, adapted to local 
treatment guidelines.
2.4
Section 8.1.7 Eye examination 
Results of a fundus photography or dilated fundoscopy must be available and evaluated by the 
investigator before randomisation. If the subject had a fundus photography or dilated fundoscopy 
performed within 90 days prior to screening, the investigator may base their evaluation upon the 
results of that examination. However, the examination must be repeated before randomisation if the 
subject experienced worsening of visual function since the last examination. 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.
If the subject did not have a fundus photography or dilated fundoscopy performed within 90 days 
prior to screening, such examination must be performed by the investigator or other qualified health 
care professional prior to randomisation.
In addition to the eye examination performed at screening, fundus photography or dilated 
fundoscopy should be performed at visit 12 and visit 17 as per the flow chart in section 2.
Fundoscopy requires pharmacological dilation of both pupils. The investigator should indicate 
whether the outcome of the each eye examination was normal or abnormal, and, if abnormal, 
indicate whether clinically significant. Relevant findings as a result of the this screening procedure 
must be recorded as concomitant illness/medical history in accordance with section 8.1.9, and


Protocol Amendment no. 3
Date:
03 November 2016
Novo Nordisk
Trial ID: NN9924-4221
Version:
1.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
6 of 10
relevant findings occurring after randomisation should be reported as an AE if applicable 
according to section 12.2.
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.
2.5
Section 8.1.15 Blood sampling
Biochemistry:
!
Alanine aminotransferase (ALT)
!
Albumin
!
Alkaline phosphatase (ALP)
!
Amylase
!
Aspartate aminotransferase (AST)
!
Bicarbonate
!
Bilirubin, total
!
Calcium
!
Creatinine
-
eGFR will be calculated by the central laboratory
!
Lipase
!
Potassium
!
Sodium
!
Urea
!
Creatine kinase
2.6
Section 12.1.4 Adverse events requiring additional data collection
Adverse events requiring additional data collection are events which, in the evaluation of safety, 
have a special focus (e.g. required by the health authorities).
If any of the following AEs are applicable for reporting according to section 12.2, additional data 
collection is required:
!
Acute coronary syndrome (myocardial infarction or hospitalisation for unstable angina)
!
Cerebrovascular event (stroke or TIA)
!
Heart failure requiring hospitalisation
!
Pancreatitis 
!
Neoplasm (excluding thyroid neoplasm)
!
Thyroid disease (including thyroid neoplasm)
!
Renal event
!
Hypersensitivity reaction to the trial product


Protocol Amendment no. 3
Date:
03 November 2016
Novo Nordisk
Trial ID: NN9924-4221
Version:
1.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
7 of 10
!
Lactic acidosis
!
Medication error concerning trial product:
o
Administration of wrong drug. 

Note: Use of wrong DUN is not considered a medication error per se.
o
Wrong route of administration
o
Administration of an overdose with the intention to cause harm (e.g. suicide 
attempt).
o
Accidental administration of a higher dose than intended. That is a dose of 1 tablet or 
more than the intended dose; however the administered dose must deviate from the 
intended dose to an extent where clinical consequences for the trial subject were 
likely to happen as judged by the investigator, although they did not necessarily 
occur.
If a subject missed one or more doses of trial product, this should not be reported as 
a medication error.
!
Severe hypoglycaemic episode (see section 8.1.17.1)
!
Hepatic event:
o
ALT or AST > 5x UNL and total bilirubin ≤ 2x UNL
o
ALT or AST > 3x UNL and total bilirubin > 2x UNL
o
Hepatic events leading to trial product discontinuation 
Additional assessments should be made for hepatic events (see section 8.2.3).
!
Diabetic retinopathy and related complications
2.7
Section 12.2 Reporting of adverse events
In this trial the following events must be collected and reported:
!
SAEs
!
AEs leading to discontinuation of trial product
!
Medication errors
!
Severe hypoglycaemic episodes
!
Hepatic events
!
Diabetic retinopathy and related complications
!
Pregnancies
Medication errors, severe hypoglycaemic episodes, and hepatic events and diabetic retinopathy and 
related complications must be reported regardless of seriousness and whether trial product is 
discontinued.
Events occurring as of the first trial-related activity after the subject signed the informed consent 
until the end of the follow-up period are in scope for collection and reporting. The events must be 
recorded in the applicable CRFs in a timely manner, see timelines below and Figure 12-1.


Protocol Amendment no. 3
Date:
03 November 2016
Novo Nordisk
Trial ID: NN9924-4221
Version:
1.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
8 of 10
During each contact with the trial site staff, the subject must be asked about AEs, for example by 
asking: "Have you experienced any problems since the last contact?"
All SAEs, AEs leading to discontinuation of trial product, medication errors, severe hypoglycaemic 
episodes, and hepatic events, and diabetic retinopathy and related complications, either observed 
by the investigator or subject, must be reported by the investigator and evaluated. Novo Nordisk 
assessment of expectedness is performed according to the following reference documents: IB for 
oral administration of semaglutide (NN9924), current edition18 or any updates thereto.  
An AE is 
observed 
It is an SAE
complete:
!
AE form ≤< 24 hours
!
SIF ≤< 5 calendars days
Fulfilling 
seriousness 
criteria per 
protocol?
AE requiring 
additional data 
collection?
Complete ≤< 14 
calendar days:
!
Specific event form
No
Is the AE 
relevant for 
adjudication?
Complete ≤< 14 
calendar days:
!
Adjudication form 
No additional forms 
to be completed
AE: Adverse Event
SIF: safety information form
AEs requiring addtional data collection
described in section 12.1.4
Events for adjudication 
described in section 12.7.3
All timelines are from the investigator’s 
first knowledge of the event
No
Any of the below apply?
! AE leading to discontinuation
     of trial product
! Medication error
! Severe hypoglycaemic 
     episode
! Hepatotoxicity Hepatic event
! Diabetic retinopathy and 
  related complication
No
The AE does not 
need to be reported
Complete: AE form 
Yes
No additional forms 
to be completed
No
Yes
Yes
Yes
Figure 12–1
Initial reporting of AEs
2.8
Section 12.7.3 Event adjudication committee
Table 12-1 Adverse events for adjudication
Events
Description
Adjudication outcomes
Death
!
All-cause death
!
Cardiovascular death 
(including undetermined 
cause of death)
!
Non-cardiovascular death
Acute Coronary 
Syndrome
!
ST-elevation acute myocardial infarction 
(STEMI)
!
Non-ST elevation acute myocardial infarction 
(NSTEMI)
!
Silent myocardial infarction
!
Unstable angina pectoris (UAP) requiring 
hospitalisation
!
Acute myocardial 
infarction (STEMI or 
NSTEMI), silent 
myocardial infarction
!
Unstable angina pectoris 
requiring hospitalisation


Protocol Amendment no. 3
Date:
03 November 2016
Novo Nordisk
Trial ID: NN9924-4221
Version:
1.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
9 of 10
2.9
Section 17.4.2 Safety endpoints
Other safety endpoints
!
Biochemistry
!
Haematology
!
Calcitonin
!
Eye examination category
2.10
Section 18.1 Benefit-risk assessment of the trial, new subtitle 
Diabetic retinopathy complications
2.11
Section 27 References 
30.
Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, et al. 
2015 American Thyroid Association Management Guidelines for Adult Patients with 
Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association 
Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. 
2016;26(1):1-133.
2.12
Reference numbers
Reference numbers will change throughout the updated protocol when new reference numbered 30
above is introduced.
2.13
Appendix B, Section 1 Adverse events requiring additional data collection
AEs must be assessed according to section 12.1 and reported if applicable according to section 12.2.
If any of the following AEs are applicable for reporting, additional data collection is required and 
specific event forms must be completed in the eCRF in addition to the AE form:
!
Acute coronary syndrome (myocardial infarction or hospitalisation for unstable angina)
!
Cerebrovascular event (stroke or TIA)
!
Heart failure requiring hospitalisation
!
Pancreatitis
!
Neoplasm (excluding thyroid neoplasm)
!
Thyroid disease (including thyroid neoplasm)
!
Renal event
!
Hypersensitivity reaction to the trial product
!
Lactic acidosis
!
Medication error concerning trial product
!
Severe hypoglycaemic episode
!
Hepatic event:
o
ALT or AST > 5x UNL and total bilirubin ≤ 2x UNL


Protocol Amendment no. 3
Date:
03 November 2016
Novo Nordisk
Trial ID: NN9924-4221
Version:
1.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
10 of 10
o
ALT or AST > 3x UNL and total bilirubin > 2x UNL
o
Hepatic event leading to trial product discontinuation
!
Diabetic retinopathy and related complications
2.14
Appendix B, new section 
1.13 Diabetic retinopathy and related complications
If an event of diabetic retinopathy or related complications is observed during the trial the 
following additional information must be reported, if available:
!
Signs and symptoms associated with the event
!
Results of the eye examination 
!
Treatment for and complications of the event
!
Contributing conditions 


Protocol
Date:
03 November 2016
Novo Nordisk
Trial ID: NN9924-4221
Version:
5.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
1 of 82
Protocol
Updated Protocol including:
Protocol, Final version 3.0, dated 12-Feb-2016
Protocol Amendment no. 1, Germany, Final version 1.0, dated 18-Feb-2016
Protocol Amendment no. 2, Global, Final version 1.0, dated 21-Jul-2016
Protocol Amendment no. 3, Global, Final version 1.0, dated 03-Nov-2016
Trial ID: NN9924-4221
PIONEER 6 – Cardiovascular outcomes
A trial investigating the cardiovascular safety of oral semaglutide in 
subjects with type 2 diabetes
Trial phase: 3a
Protocol originator
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
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
Date:
03 November 2016
Novo Nordisk
Trial ID: NN9924-4221
Version:
5.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
2 of 82
Table of Contents
Page
Table of Contents..............................................................................................................................................2
Table of Figures................................................................................................................................................5
Table of Tables..................................................................................................................................................5
List of abbreviations.........................................................................................................................................6
1
Summary....................................................................................................................................................8
2
Flow chart ................................................................................................................................................10
3
Background information and rationale for the trial............................................................................12
3.1
Background information..............................................................................................................12
3.1.1
Type 2 diabetes and GLP-1........................................................................................12
3.1.2
Oral semaglutide........................................................................................................12
3.1.3
Non-clinical data........................................................................................................13
3.1.3.1
Semaglutide.........................................................................................13
3.1.3.2
SNAC ..................................................................................................14
3.1.4
Clinical data oral semaglutide....................................................................................14
3.1.4.1
Pharmacokinetics ................................................................................14
3.1.4.2
Efficacy ...............................................................................................16
3.1.4.3
Safety...................................................................................................16
3.1.5
Oral semaglutide and cardiovascular risk..................................................................16
3.2
Rationale for the trial...................................................................................................................17
4
Objectives and endpoints........................................................................................................................17
4.1
Objectives ....................................................................................................................................17
4.2
Endpoints .....................................................................................................................................17
5
Trial design ..............................................................................................................................................18
5.1
Type of trial .................................................................................................................................18
5.2
Rationale for trial design..............................................................................................................20
5.3
Treatment of subjects...................................................................................................................20
5.3.1
Missed doses..............................................................................................................20
5.3.2
Dosing instructions ....................................................................................................21
5.3.3
Background medication.............................................................................................21
5.4
Treatment after discontinuation of trial product ..........................................................................22
5.5
Rationale for treatment ................................................................................................................22
6
Trial population.......................................................................................................................................23
6.1
Number of subjects......................................................................................................................23
6.2
Inclusion criteria ..........................................................................................................................23
6.3
Exclusion criteria.........................................................................................................................23
6.4
Composition of overall trial population.......................................................................................24
6.5
Premature discontinuation of trial product ..................................................................................25
6.6
Withdrawal of consent.................................................................................................................25
6.7
Subject replacement.....................................................................................................................26
6.8
Rationale for trial population.......................................................................................................26
CONFIDENTIAL


Protocol
Date:
03 November 2016
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Trial ID: NN9924-4221
Version:
5.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
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3 of 82
6.8.1
Determining subject’s eligibility................................................................................26
6.8.2
Microalbuminuria and proteinuria.............................................................................26
6.8.3
Glomerular filtration rate, estimated (eGFR).............................................................27
7
Milestones.................................................................................................................................................27
8
Methods and assessments .......................................................................................................................28
8.1
Visit procedures...........................................................................................................................28
8.1.1
Informed consent .......................................................................................................28
8.1.2
In/exclusion criteria ...................................................................................................29
8.1.3
Screening ...................................................................................................................29
8.1.4
Demography...............................................................................................................30
8.1.5
Tobacco use ...............................................................................................................30
8.1.6
Physical examination.................................................................................................30
8.1.7
Eye examination ........................................................................................................31
8.1.8
Pregnancy test............................................................................................................31
8.1.9
Concomitant illness and medical history...................................................................32
8.1.10
Concomitant medication............................................................................................33
8.1.11
Body measurements (height and body weight)..........................................................33
8.1.12
Vital signs ..................................................................................................................34
8.1.13
Electrocardiogram......................................................................................................34
8.1.14
Randomisation, dispensing of trial product and drug accountability.........................34
8.1.15
Blood sampling..........................................................................................................35
8.1.16
Hand out and instruct in BG meter use......................................................................37
8.1.17
Adverse events and technical complaints ..................................................................37
8.1.17.1
Hypoglycaemic episodes.....................................................................38
8.1.17.2
Medication errors ................................................................................38
8.1.18
End of trial .................................................................................................................38
8.2
Other assessments........................................................................................................................38
8.2.1
Assessments in case of suspicion of acute pancreatitis..............................................38
8.2.2
Assessments in case of suspicion of hypersensitivity reactions to the trial 
product .......................................................................................................................39
8.2.3
Assessments in case of increased levels of aminotransferases ..................................40
8.3
Treatment compliance..................................................................................................................40
8.4
Trial adherence ............................................................................................................................40
9
Trial supplies ...........................................................................................................................................42
9.1
Trial products...............................................................................................................................42
9.2
Labelling......................................................................................................................................42
9.3
Storage .........................................................................................................................................43
9.4
Drug accountability and destruction............................................................................................43
9.5
Auxiliary supplies........................................................................................................................43
10 Interactive voice/web response system ..................................................................................................44
11 Randomisation procedure and breaking of blinded codes..................................................................45
11.1
Breaking of blinded codes ...........................................................................................................45
12 Adverse events, technical complaints and pregnancies .......................................................................45
12.1
Definitions ...................................................................................................................................45
12.1.1
Adverse event ............................................................................................................45
CONFIDENTIAL


Protocol
Date:
03 November 2016
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Trial ID: NN9924-4221
Version:
5.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
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12.1.2
Serious adverse event.................................................................................................47
12.1.3
Non-serious adverse event.........................................................................................48
12.1.4
Adverse events requiring additional data collection..................................................48
12.1.5
Technical complaint...................................................................................................49
12.2
Reporting of adverse events.........................................................................................................49
12.3
Follow-up of adverse events........................................................................................................52
12.4
Technical complaints and technical complaint samples ..............................................................53
12.4.1
Reporting of technical complaints .............................................................................53
12.4.2
Collection, storage and shipment of technical complaint samples ............................54
12.5
Pregnancies..................................................................................................................................54
12.6
Precautions and/or overdose ........................................................................................................54
12.7
Committees related to safety........................................................................................................55
12.7.1
Novo Nordisk safety committee ................................................................................55
12.7.2
Data monitoring committee .......................................................................................55
12.7.3
Event adjudication committee....................................................................................56
13 Case report forms....................................................................................................................................58
14 Monitoring procedures ...........................................................................................................................59
15 Data management....................................................................................................................................60
16 Computerised systems.............................................................................................................................60
17 Statistical considerations ........................................................................................................................61
17.1
Sample size calculation................................................................................................................62
17.2
Definition of analysis sets............................................................................................................63
17.3
Primary endpoint..........................................................................................................................63
17.3.1
Sensitivity analysis ....................................................................................................64
17.4
Secondary endpoints....................................................................................................................65
17.4.1
Confirmatory secondary endpoint..............................................................................65
17.4.2
Safety endpoints.........................................................................................................65
17.4.3
Efficacy endpoints .....................................................................................................66
18 Ethics........................................................................................................................................................67
18.1
Benefit–risk assessment of the trial .............................................................................................67
18.2
Data handling...............................................................................................................................70
18.3
Information to subject during trial...............................................................................................70
18.4
Premature termination of the trial and/or trial site.......................................................................70
19 Protocol compliance................................................................................................................................71
20 Audits and inspections ............................................................................................................................71
21 Critical documents ..................................................................................................................................72
22 Responsibilities........................................................................................................................................73
23 Reports and publications........................................................................................................................74
23.1
Communication of results............................................................................................................75
23.1.1
Authorship .................................................................................................................75
23.1.2
Site-specific publication(s) by investigator(s) ...........................................................76
23.2
Investigator access to data and review of results.........................................................................76


Protocol
Date:
03 November 2016
Novo Nordisk
Trial ID: NN9924-4221
Version:
5.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
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24 Retention of clinical trial documentation and human biospecimens..................................................76
24.1
Retention of clinical trial documentation.....................................................................................76
24.2
Retention of human biospecimens...............................................................................................77
25 Institutional Review Boards/Independent Ethics Committees and regulatory authorities..............77
26 Indemnity statement ...............................................................................................................................78
27 References................................................................................................................................................80
Appendix A – Calcitonin monitoring
Appendix B – Adverse events requiring additional data collection
Attachment I – Global list of key staff and relevant departments and suppliers
Attachment II – Country list of key staff and relevant departments, if applicable for the individual 
country
Table of Figures
Page
Figure 5–1
Trial design.............................................................................................................................19
Figure 12–1
Initial reporting of AEs...........................................................................................................51
Table of Tables
Page
Table 5–1
Treatment of subjects..............................................................................................................20
Table 6–1
Measurement of albuminuria..................................................................................................27
Table 9–1
Investigational medicinal products.........................................................................................42
Table 9–2
Storage conditions for trial products.......................................................................................43
Table 12–1
Adverse events for adjudication .............................................................................................57
Table 17–1
Expected trial duration according to event rates.....................................................................62


Protocol
Date:
03 November 2016
Novo Nordisk
Trial ID: NN9924-4221
Version:
5.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
6 of 82
List of abbreviations
ADA
American Diabetes Association
AE
adverse event
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
AUC
area under the curve
BG
blood glucose
CRF
case report form
CRO
contract research organisation
DMC
data monitoring committee
DPP-4
dipeptidyl peptidase-4
DUN
dispensing unit number
EAC
event adjudication committee
ECG
electrocardiogram
eCRF
electronic case report form
eGFR
glomerular filtration rate, estimated 
EMA
European Medicines Agency
FAS
full analysis set
FDA
U.S. Food and Drug Administration
FPG
fasting plasma glucose
FSFV
first subject first visit
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
HR
hazard ratio
IB
Investigator’s Brochure


Protocol
Date:
03 November 2016
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Trial ID: NN9924-4221
Version:
5.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
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IEC
independent ethics committee
IRB
institutional review board
ITT
intention-to-treat
IV/WRS
interactive voice/web response system
LDL
low density lipoprotein
LLoQ
lower limit of quantification 
LSFV
last subject first visit
LSLV
last subject last visit
MACE
major adverse cardiovascular event
MedDRA
Medical Dictionary for Regulatory Activities
MEN 2
multiple endocrine neoplasia type 2
MTC
medullary thyroid carcinoma
NYHA
New York Heart Association
PYO
patient years of observation time
SAE
serious adverse event
SAP
statistical analysis plan
s.c.
subcutaneous(ly)
SDV
source data verification
SGLT2
sodium-glucose cotransporter-2
SMPG
self-measured plasma glucose
SNAC
sodium N-(8-(2-hydroxybenzoyl) amino) caprylate
SUSAR
suspected unexpected serious adverse reaction
T2D
type 2 diabetes
TIA
transient ischaemic attack 
TMM
Trial Materials Manual
UTN
Universal Trial Number


Protocol
Date:
03 November 2016
Novo Nordisk
Trial ID: NN9924-4221
Version:
5.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
8 of 82
1
Summary
Objectives and endpoints:
The primary objective is to confirm that treatment with oral semaglutide does not result in an 
unacceptable increase in cardiovascular risk compared to placebo (rule out 80% excess risk) in 
subjects with type 2 diabetes at high risk of cardiovascular events. 
The primary endpoint is time from randomisation to first occurrence of a major adverse 
cardiovascular event (MACE) composite endpoint consisting of: cardiovascular death, non-fatal 
myocardial infarction or non-fatal stroke.
The secondary objectives are to compare the efficacy and safety of oral semaglutide versus 
placebo in subjects with type 2 diabetes at high risk of cardiovascular events.
Key secondary endpoints:
!
Time from randomisation to first occurrence of an expanded composite cardiovascular 
endpoint consisting of: cardiovascular death, non-fatal myocardial infarction, non-fatal 
stroke, unstable angina requiring hospitalisation or hospitalisation for heart failure
!
Time from randomisation to first occurrence of each of the individual components in the 
expanded composite cardiovascular endpoint
!
Time from randomisation to first occurrence of a composite endpoint consisting of: all-cause 
death, non-fatal myocardial infarction or non-fatal stroke
For the primary and the key secondary endpoints, maximum treatment duration is dependent on 
event rates and is estimated to be no longer than 19 months.
Trial design:
This trial is a randomised, double-blind, placebo-controlled trial to assess the cardiovascular safety 
of oral semaglutide versus placebo when added to standard of care in subjects with type 2 diabetes 
at high risk of cardiovascular events. Subjects will be randomised 1:1 to receive either oral 
semaglutide or placebo. The trial will be event-driven and will be continued until at least 122 first 
MACEs confirmed by adjudication have accrued. The treatment period for each subject is estimated 
to be between 12 and 19 months, depending on the time-point of recruitment and the accrual of first 
MACEs confirmed by adjudication. 
Trial population:
Number of subjects planned to be randomised is 3,176


Protocol
Date:
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Trial ID: NN9924-4221
Version:
5.0
UTN: U1111-1173-0750
Status:
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EudraCT No.: 2015-003563-10
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Key inclusion criteria: 
!
Male or female diagnosed with type 2 diabetes
!
Age ≥50 years at screening and presence of cardiovascular disease, or age ≥60 years at 
screening and presence of at least one cardiovascular risk factor
Key exclusion criteria:
!
Current or previous (within 90 days prior to screening) treatment with any GLP-1 receptor 
agonist, DPP-4 inhibitor or pramlintide
!
Family or personal history of multiple endocrine neoplasia type 2 (MEN 2) or medullary 
thyroid carcinoma (MTC)
!
History of pancreatitis (acute or chronic)
!
History of major surgical procedures involving the stomach potentially affecting absorption 
of trial product (e.g. subtotal and total gastrectomy, sleeve gastrectomy, gastric bypass 
surgery)
!
Subjects presently classified as being in New York Heart Association (NYHA) Class IV
heart failure
!
Planned coronary, carotid or peripheral artery revascularisation known on the day of 
screening
!
Any of the following: myocardial infarction, stroke or hospitalisation for unstable angina or 
transient ischaemic attack within the past 60 days prior to screening
!
Chronic or intermittent hemodialysis or peritoneal dialysis or severe renal impairment 
(corresponding to eGFR <30 mL/min/1.73 m2)
!
History or presence of malignant neoplasms within the last 5 years (except basal and 
squamous cell skin cancer and carcinoma in situ)
Key assessments:
!
Adverse events
Trial products:
!
Semaglutide 3 mg tablet
!
Semaglutide 7 mg tablet
!
Semaglutide 14 mg tablet
!
Placebo tablet


Protocol
UTN: U1111-1173-0750
Date:
03 November 2016
Status:
Final
Novo Nordisk
Trial ID: NN9924-4221
EudraCT No.: 2015-003563-10
Version:
5.0
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2
Flow chart
Trial Periods
Scree-
ning
Ran-
domi-
sation
Treatment
End of 
treat-
ment
Follow-
up
Visit (V) Phone (P)
V1
V2
P3
V4
V5
V6
P72
V8
P92
V10
P112
V12
P132
V14
P152
V16
V171
P181
Timing of visit (weeks after V2)
Up to -3
0
2
4
8
14
20
26
32
38
44
50
56
62
69
76
83
88
Visit window (days)
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+3
Informed consent
X
In/exclusion criteria
X
Demography, tobacco use
X
Physical examination
X
X
Eye examination
X3
X4
X4
Pregnancy test, urine dipsticks5
X
X
Concomitant illness, medical 
history
X
Concomitant medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
Body weight
X
X
X
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
Electrocardiogram
X
X
X
X
Blood sampling
X
X
X
X
X
X
X
X
X
X
HbA1c
X
X
X
X
X
X
X
X
X
Fasting plasma glucose
X
X
X
X
X
X
Lipids
X
X
X
X
Biochemistry
X
X
X
X
X
X
X
X
X
X
Haematology
X
X
X
X
X
X
X
X
X
X
Hormones
X
X
X
X
X
X
X
X


Protocol
UTN: U1111-1173-0750
Date:
03 November 2016
Status:
Final
Novo Nordisk
Trial ID: NN9924-4221
EudraCT No.: 2015-003563-10
Version:
5.0
Page:
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Trial Periods
Scree-
ning
Ran-
domi-
sation
Treatment
End of 
treat-
ment
Follow-
up
Visit (V) Phone (P)
V1
V2
P3
V4
V5
V6
P72
V8
P92
V10
P112
V12
P132
V14
P152
V16
V171
P181
Timing of visit (weeks after V2)
Up to -3
0
2
4
8
14
20
26
32
38
44
50
56
62
69
76
83
88
Visit window (days)
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+3
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Technical complaints
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
IV/WRS call
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Randomisation
X
Dispensing of trial product
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Drug accountability
X
X
X
X
X
X
X
X
X
X
X
X
X
X
REMINDERS
Handout ID card
X
Handout and instruct in BG 
meter use
X
Attend visit fasting
X
X
X
X
X
X
End of trial 
X
1 V17 (End of treatment) and P18 (Follow-up) are applicable for all randomised subjects. P18 can be conducted over the telephone. For a subject who discontinued trial 
product prematurely (i.e. more than 5 weeks prior to the anticipated V17), V17 can be postponed to the point when P18 is otherwise due.
2 Dispensing visit (i.e. a combination of dispensing trial product and collecting relevant information over the telephone. If the subject provides the required information to 
site staff when collecting trial product, the telephone contact can be omitted).
3 Fundus photography or dilated fundoscopy must be performed within 90 days prior to screening or within the period between screening and randomisation.
4 Fundus photography or dilated fundoscopy should be performed at Visit 12 and 17 or within 5 weeks prior to those visits.
5 For women of childbearing potential only. In addition to the planned assessment at screening and end-of-treatment, urine dipstick pregnancy test should be performed at 
site at any time during the trial if a menstrual period is missed, or if pregnancy is suspected, or as required by local law.


Protocol
Date:
03 November 2016
Novo Nordisk
Trial ID: NN9924-4221
Version:
5.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
12 of 82
3
Background information and rationale for the trial
The trial will be conducted in compliance with this protocol, ICH GCP1 and applicable regulatory 
requirements, and in accordance with the Declaration of Helsinki2.
In this document, the term investigator refers to the individual responsible for the overall conduct of 
the clinical trial at a trial site.
3.1
Background information
3.1.1
Type 2 diabetes and GLP-1
Type 2 diabetes (T2D) is a progressive metabolic disease primarily characterised by abnormal 
glucose metabolism. The pathogenesis is heterogeneous, and characterised by chronic 
hyperglycaemia caused by peripheral tissue insulin resistance, impaired insulin secretion due to 
abnormal beta-cell function and abnormal glucose metabolism in the liver3.
Glucagon-like peptide-1 (GLP-1) is an incretin hormone with a glucose-dependent stimulatory 
effect on insulin- and inhibitory effect on glucagon secretion from the pancreatic islets4, 5. Subjects 
with T2D have a decreased incretin effect6-9. However, the insulinotropic action of GLP-1 and thus, 
the ability to lower blood glucose (BG) levels, is preserved when GLP-1 is administered at supra 
physiological levels10. In addition, supra physiological levels of GLP-1 lower body weight due to 
decreased energy intake induced by reduced appetite11. These mechanisms of action make GLP-1 
an attractive pharmacological treatment for T2D12-14.
3.1.2
Oral semaglutide
Semaglutide is a long-acting GLP-1 receptor agonist (GLP-1 RA) structurally similar to liraglutide 
(Victoza®), a once-daily GLP-1 RA developed by Novo Nordisk and approved worldwide for the 
treatment of T2D. Compared to human native GLP-1, which has a very short half-life, the 
semaglutide molecule has three minor but important modifications ensuring protraction of its 
action: amino acid substitutions at position 8 (alanine to alfa-aminoisobutyric acid, a synthetic 
amino acid) and position 34 (lysine to arginine), and acylation of the peptide backbone with a 
spacer and C-18 fatty di-acid chain to lysine in position 2615. The fatty di-acid side chain and the 
spacer mediate strong binding to albumin, thereby reducing renal clearance. The amino acid 
substitution at position 8 makes semaglutide less susceptible to degradation by dipeptidyl peptidase-
4 (DPP-4). The change in position 34 from a lysine to an arginine is included to have only one 
lysine in the sequence where to a spacer can be attached.
Semaglutide is in development for oral once-daily treatment of T2D. As the bioavailability of 
GLP-1 RAs is very low when administered orally, semaglutide has been co-formulated with the 
absorption enhancing excipient sodium N-(8-(2-hydroxybenzoyl) amino) caprylate (SNAC) based 
on the 
 concept developed by 
 in order to increase 


Protocol
Date:
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Trial ID: NN9924-4221
Version:
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UTN: U1111-1173-0750
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bioavailability. When semaglutide is co-formulated with SNAC, SNAC has the capacity to augment 
the absorption of semaglutide across the gastrointestinal epithelium. The absorption enhancement 
by SNAC is dose, size and time-dependent and is believed to take place in close proximity of the 
tablet in the stomach. The absorption process is hampered if dosed with food, liquid or in the 
presence of significant stomach content. Throughout this document oral semaglutide will refer to 
the drug product, that is, semaglutide co-formulated with 300 mg SNAC. 
Novo Nordisk is currently also developing semaglutide for once-weekly subcutaneous (s.c.) 
administration in subjects with T2D.
3.1.3
Non-clinical data
3.1.3.1
Semaglutide
The non-clinical programme for semaglutide was designed according to the ICH M3 guideline to 
support the clinical development. The standard non-clinical 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 was generally well 
tolerated in animals (mice, rats and cynomolgus monkeys). Two potential safety issues have been 
identified and these are detailed below.
Thyroid C-cell tumours in rodents
Treatment-related non-genotoxic proliferative changes in the thyroid C-cells of mice and rats were 
observed in 2-year carcinogenicity studies with semaglutide; thyroid hyperplasia was preceded by 
an increase in serum calcitonin. C-cell changes have not been observed in long-term studies in non-
human primate. The observed pattern of effects in mice and rats and lack of these effects in the non-
human primate and in man suggest that the mechanism by which semaglutide acts on the thyroid C-
cells in rodents is the same as has been demonstrated for other GLP-1 RAs, including liraglutide. 
According to this mechanism, C-cell hyperplasia is mediated by the GLP-1 receptor and is not 
associated with RET (re-arranged during transfection) gene activation and rodents appear to be 
particularly sensitive, whereas humans are not. The relevance for human subjects is currently 
unknown, but considered to be low16.
Embryo−foetal development toxicity
Semaglutide caused embryo-foetal development toxicity in the rat through a GLP-1 receptor 
mediated effect on the inverted yolk sac placenta leading to impaired nutrient supply to the 
developing embryo. Primates do not have an inverted yolk sac placenta which makes this 
mechanism unlikely to be of relevance to humans and cynomolgus monkeys. In the developmental 
toxicity studies in cynomolgus monkey, a marked pharmacology mediated maternal body weight 
loss coincided with increased early foetal loss; however, there was no indication of a teratogenic 


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potential of semaglutide in this species. These data suggest an important species-dependent 
mechanism, whereby semaglutide is teratogenic in rats but not in primates.
A review of results from the non-clinical studies can be found in the current edition of the 
investigator’s brochure (IB) for s.c. semaglutide (NN9535)17, and the current edition of the IB for 
oral administration of semaglutide (NN9924)18or any updates to these documents.
3.1.3.2
SNAC
SNAC was developed as an absorption enhancing excipient for the oral route of administration. The 
non-clinical programme to support clinical phase 3 development and marketing authorisation 
application submission has been conducted including a 26-week carcinogenicity study in transgenic 
rasH2 mice and a 2-year carcinogenicity study in Sprague-Dawley rats.
The most common observations related to oral dosing of SNAC were, depending on species, 
salivation, emesis and other clinical signs such as hypoactivity, lethargy, somnolence and ataxia. 
When SNAC is administered at high doses (200 mg/kg/day or more, depending on species) 
mortality has been observed in all toxicology species. The mortality is considered to be due to 
inhibition of cellular respiration, mainly via an inhibition of complex 1 in the electron transport 
chain. The mortality was found to be related to high doses and very high initial plasma 
concentration levels in animals. Similar plasma concentrations have not been observed in humans 
and are not achievable following administration of oral semaglutide.
The carcinogenicity studies demonstrated that SNAC was not carcinogenic to the transgenic rasH2 
mouse or the Sprague-Dawley rat. The doses tested covered plasma exposures (area under the curve 
(AUC)) of 2-fold in the mouse and up to 44-fold in the rat when compared to the mean human 
exposure following a clinical dose of 300 mg SNAC/day.
A review of results from the non-clinical studies can be found in the current edition of the IB for 
oral administration of semaglutide (NN9924)18, or any updates thereto.
3.1.4
Clinical data oral semaglutide
A comprehensive clinical pharmacology programme including 12 trials has been completed, as well 
as a 26-week phase 2 dose-finding trial involving more than 600 subjects with T2D.
For details on the individual trials, please see the current edition of the IB for oral administration of 
semaglutide (NN9924)18, or any updates thereto.
3.1.4.1
Pharmacokinetics
In single dose trials, oral semaglutide has demonstrated a long mean terminal half-life (t½) ranging 
from 153 to 161 hours (~1 week) and a median time to reach maximum observed concentration 
(tmax) ranging from 1 to 2 hours in healthy subjects. 


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In multiple-dose pharmacokinetics trials, the exposure to oral semaglutide increased with increasing 
dose. Overall, the pharmacokinetic properties of semaglutide appeared similar in healthy subjects 
and in subjects with T2D.
Exposure of semaglutide exhibits a substantially greater dose-to-dose variation following oral 
administration compared to s.c. administration. However, when administered orally once-daily the 
pharmacokinetic properties of semaglutide, i.e. low clearance and long half-life, will limit the 
variation in steady state plasma exposure.
Data obtained following investigation of different dosing conditions for oral semaglutide have 
demonstrated that subjects should take the oral semaglutide tablet in the morning in a fasting state 
and at least 30 minutes before the first meal of the day. The tablet should be taken with up to half a 
glass of water (i.e. 120mL/4 fluid oz).
Drug-drug interaction investigations have explored the effect of oral semaglutide on the exposure to 
lisinopril, warfarin, metformin and digoxin as well as the effect of omeprazole on oral semaglutide 
and SNAC. It was demonstrated that oral semaglutide did not change the exposure to lisinopril, 
warfarin or digoxin, but increased the exposure to metformin when taken simultaneously. The 
increase in exposure to metformin may be related to delayed gastric emptying caused by 
semaglutide as observed for other GLP-1 RAs. Based on the wide therapeutic index of metformin, 
the increased exposure to metformin was however not considered clinically relevant. Further, it was 
demonstrated that the exposure to semaglutide appeared to be slightly higher when administered 
with omeprazole in comparison to semaglutide alone, but the effect was not statistically significant 
or considered clinically relevant. In subjects with mild to end-stage renal impairment, the exposure 
to semaglutide appeared similar in subjects with normal and impaired renal function, whereas the 
AUC for SNAC was greater in subjects with impaired renal function than in subjects with normal 
renal function. The Cmax of SNAC appeared similar in subjects with normal and impaired renal 
function. The renal clearance of all SNAC metabolites was decreased in subjects with renal 
impairment. 
In subjects with mild to severe hepatic impairment, the exposure to semaglutide appeared to be 
unaffected by the degree of hepatic impairment, whereas the exposure to SNAC (in terms of both 
AUC and Cmax) was increased for subjects with hepatic impairment as compared to subjects with 
normal hepatic function.
All tablets of oral semaglutide contain 300 mg of SNAC. SNAC is rapidly absorbed with a median 
tmax ranging from 0.35−0.5 hours in healthy subjects and from 0.52−1.43 hours in subjects with 
T2D. It is extensively metabolized and no accumulation of SNAC has been observed in clinical 
trials. 


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3.1.4.2
Efficacy
The efficacy of oral semaglutide in adult subjects with T2D was investigated in a 26-week phase 2 
dose-finding trial. In this trial, placebo or one of the following doses of oral semaglutide were 
administered once daily: 2.5, 5, 10, 20 and 40 mg.
Results from the trial showed that oral semaglutide effectively lowered glycosylated haemoglobin 
(HbA1c) and body weight. Placebo-adjusted reductions in HbA1c were dose-dependent and 
statistically significant for all oral semaglutide treatment arms at week 26 (range: -0.40% to -
1.59%). Placebo-adjusted reductions in body weight were dose-dependent and statistically 
significant for oral semaglutide treatment doses of 10 mg and above at week 26 (range: -3.61 to -
6.98 kg). 
3.1.4.3
Safety
In the clinical trials completed so far, no unexpected safety findings have been identified for oral 
semaglutide administered up to 40 mg once daily. Consistent with other GLP-1 RAs, common 
adverse events (AEs) included nausea and vomiting, most of them of mild to moderate severity. In 
line with findings for other GLP-1 RAs, an increase in heart rate and serum levels of lipase and 
amylase has also been observed in subjects exposed to oral semaglutide.
In addition to the 13 completed clinical trials with oral semaglutide, SNAC has been investigated in 
the programme of orally administrated heparin in combination with SNAC (heparin/SNAC). The 
heparin/SNAC programme 
 included 29 phase 1 trials (SNAC doses 
ranged from 0.172-10.5 g). In three of these trials SNAC alone was investigated (to a maximum 
dose of 10.5 g). The studies covered formulation development, food effect, hepatic and renal 
impairment, age-effect and drug-drug interaction. The programme also included a total of three 
phase 2 and 3 trials in which the effects of orally delivered heparin solution (with >1.5 g SNAC 
three times a day) were investigated. The overall safety profile of oral semaglutide and 
heparin/SNAC indicates that SNAC is safe and well-tolerated.
For further details please see the current edition of the IB for oral administration of semaglutide 
(NN9924)18, or any updates thereto.
3.1.5
Oral semaglutide and cardiovascular risk
Based on the nonclinical and clinical data obtained with semaglutide dosed either orally or 
subcutaneously to date, no adverse safety signals have been identified that indicate an increased risk 
of cardiovascular events. In addition, although an increase in heart rate has been observed as a class 
effect for GLP-1 RAs, the extensive amount of clinical data from marketed products have not 
indicated that this drug class increases risk of cardiovascular events. In support, results from the 
LEADER® (EX2211-3748) trial showed that treatment with once-daily s.c. liraglutide does not 
increase the risk of MACE as compared to placebo. In fact, treatment with liraglutide reduced the 


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risk of the primary composite endpoint consisting of death from cardiovascular causes, non-fatal 
myocardial infarction and non-fatal stroke by 13% versus placebo19. Also, the SUSTAIN™ 6 trial 
(NN9535-3744) achieved its primary objective by showing non-inferiority of once-weekly s.c. 
semaglutide versus placebo on cardiovascular outcomes; moreover, s.c. semaglutide statistically 
significantly reduced cardiovascular risk versus placebo20.
The absorption enhancer SNAC used in the formulation of oral semaglutide is an excipient with no 
discernable systemic or pharmacodynamic effects. Accordingly, the potential for adverse effects on 
the cardiovascular system is considered low. The collective nonclinical and clinical evidence on 
SNAC from 
 and Novo Nordisk has not identified safety signals related to cardiovascular
disease. However, information on potential long-term cardiovascular effects of SNAC is not yet 
available.
For an assessment of benefits and risks of the trial, see section 18.1.
3.2
Rationale for the trial
The purpose of this trial is to assess the cardiovascular safety of oral semaglutide in subjects with 
T2D at high risk of cardiovascular events. This trial has been designed to address the requirements 
contained in the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) 
guidance documents21, 22 which specify how to demonstrate that a new antidiabetic therapy is not 
associated with an unacceptable increase in cardiovascular risk. 
4
Objectives and endpoints
4.1
Objectives
The primary objective is to confirm that treatment with oral semaglutide does not result in an 
unacceptable increase in cardiovascular risk compared to placebo (rule out 80% excess risk) in 
subjects with type 2 diabetes at high risk of cardiovascular events.
The secondary objectives are to compare the efficacy and safety of oral semaglutide versus 
placebo in subjects with type 2 diabetes at high risk of cardiovascular events.
4.2
Endpoints
The primary endpoint is time from randomisation to first occurrence of a MACE composite 
endpoint consisting of: cardiovascular death, non-fatal myocardial infarction or non-fatal stroke.
The confirmatory secondary endpoint is time from randomisation to first occurrence of an 
expanded composite cardiovascular endpoint consisting of: cardiovascular death, non-fatal 


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myocardial infarction, non-fatal stroke, unstable angina requiring hospitalisation or hospitalisation 
for heart failure*
The secondary endpoints are: 
!
Time from randomisation to first occurrence of each of the individual components in the 
expanded composite cardiovascular endpoint*
!
Time from randomisation to first occurrence of a composite endpoint consisting of: all-cause 
death, non-fatal myocardial infarction or non-fatal stroke*
!
Time from randomisation to all-cause death
!
Time to permanent discontinuation of trial product due to AE(s)
!
Number of serious adverse events (SAEs)
Change from baseline to last assessment of:
!
Biochemistry
!
Haematology
!
Calcitonin
!
Eye examination category
!
Pulse
!
Systolic and diastolic blood pressure
!
Glycosylated haemoglobin (HbA1c)
!
Body weight
!
Lipids
* Key supportive secondary endpoint prospectively selected for disclosure (e.g. clinicaltrials.gov and EudraCT)
5
Trial design
5.1
Type of trial
This trial is a randomised, double-blind, placebo-controlled trial to assess the cardiovascular safety 
of oral semaglutide versus placebo when added to standard of care in subjects with T2D at high risk 
of cardiovascular events. Subjects will be randomised 1:1 to receive either oral semaglutide or 
placebo. Randomisation will be stratified according to evidence of cardiovascular disease at 
screening (presence of cardiovascular disease or risk factors only) to ensure even distribution of the 
two treatment arms within strata. The stratum ‘presence of cardiovascular disease’ consists of 
subjects at least 50 years of age and recognised as fulfilling at least one item of inclusion criterion 
no. 3a-h at screening, whereas the stratum ‘presence of cardiovascular risk factors only’ consists of 
subjects at least 60 years of age and recognised as fulfilling at least one item of inclusion criterion 
no. 3i-l and not fulfilling any of the items of inclusion criterion no. 3a-h at screening (see section
6.2).


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All tablets containing oral semaglutide or placebo are identical with regards to visual appearance to 
maintain the blinding of the trial.
The trial will be event-driven and will be continued until at least 122 first MACEs confirmed by 
adjudication have accrued. Throughout the remainder of this protocol, MACE will be defined as 
MACE confirmed by adjudication. 
The recruitment period is expected to last 7 months. The treatment period for each subject is 
estimated to be between 12 and 19 months, depending on the time-point of recruitment and the 
accrual of first MACEs. The follow-up period is 5 weeks to allow for wash-out of trial drug. A 
schematic diagram of the trial design is shown in Figure 5–1.
Figure 5–1
Trial design
The trial is designed to evaluate cardiovascular outcomes and will apply a targeted approach to 
collection of safety data focusing on SAEs, AEs leading to discontinuation of trial product and other 
selected AEs. An adequate characterisation of the less serious and more common AEs will be 
evaluated in the other phase 3a trials conducted with oral semaglutide comprising more than 4000 
subjects with T2D.
An external event adjudication committee (EAC) will perform ongoing adjudication of predefined 
cardiovascular events and other selected AEs in an independent and blinded manner. 
An independent external data monitoring committee (DMC) will have unblinded access to data 
from the trial and perform review of accumulating data on an ongoing basis. The DMC will provide 
recommendation on trial continuation, modification or termination. 


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5.2
Rationale for trial design
A randomised, double-blind, placebo-controlled trial has been chosen in accordance with the trial 
objectives and to avoid bias of the results. The planned duration of the trial has been estimated 
based on the number of subjects randomised and the expected first MACE rate. The treatment 
period is expected to be between 12 and 19 months. This duration should be adequate to provide 
data to assess the cardiovascular safety of oral semaglutide. 
5.3
Treatment of subjects
Subjects will be randomised in a 1:1 ratio to receive either oral semaglutide or placebo. Randomised 
subjects will initiate treatment with 3 mg oral semaglutide/placebo once daily and follow a fixed 4-
week dose escalation regimen until reaching the maximum dose of 14 mg oral semaglutide/placebo 
as illustrated in Table 5–1. The 4-week dose escalation intervals are applied in order to mitigate the 
risk of gastrointestinal adverse events (AEs). Subjects should remain on the 14 mg dose level 
throughout the maintenance period; however, if treatment with the trial product is associated with 
unacceptable AEs (as judged by the investigator), dose reductions and extensions of dose escalation
periods are allowed. In case the dose is reduced due to unacceptable AEs, the investigator should 
consider escalating the dose of oral semaglutide once the subject has recovered. Trial product dose 
and date of change or discontinuation should be recorded in the electronic case report form (eCRF)
throughout the trial. 
Table 5–1
Treatment of subjects
Trial periods
Screening
Trial period 1
Trial period 2
Trial period 3
Follow-up
Alias for trial period
Screening
Dose escalation
Dose escalation
Maintenance
Follow-up
First visit in each period
V1
V2
V4
V5
V17
Duration of each period
Up to 3 weeks
4 weeks
4 weeks
Up to 75 weeks
5 weeks
Treatment arm
N
Oral semaglutide
1588
Screening
3 mg
7 mg
14 mg
Follow-up
Placebo
1588
Screening
Placebo
Placebo
Placebo
Follow-up
5.3.1
Missed doses
The trial product should be administered once daily; however, if one or more doses of trial product 
are missed due to circumstances not related to the safety of the trial product (as judged by the 
investigator) and treatment with trial product is resumed, the below recommendations for dose 
adjustment apply: 
!
If ≤21 consecutive doses of 14 mg oral semaglutide/placebo are missed, the once-daily 
regimen can be resumed as prescribed without dose reduction. 


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!
If 22-35 consecutive doses of 14 mg oral semaglutide/placebo are missed, it is 
recommended to resume treatment at 7 mg oral semaglutide/placebo and subsequently, 
escalate to the higher dose after 4 weeks of treatment. 
!
If ≥36 consecutive doses of 14 mg oral semaglutide/placebo are missed, it is recommended 
to resume treatment at 3 mg oral semaglutide/placebo and subsequently, escalate to the 
higher doses with 4-week dose escalation steps.
Please refer to section 10 for instructions on how to use the interactive voice/web response system 
(IV/WRS) in relation to subjects discontinuing and resuming trial product treatment.
5.3.2
Dosing instructions
Absorption of oral semaglutide is significantly affected by food and fluid in the stomach, hence 
subjects should take the oral semaglutide/placebo tablets in the morning in a fasting state and at 
least 30 minutes before the first meal of the day. The tablets should be taken with up to half a glass 
of water (approximately 120 mL/4 fluid oz). The tablets must be swallowed whole and must not be 
broken or chewed. Other oral medication can be taken 30 minutes after the trial product. The tablets 
should be taken immediately after removal from the blister.
5.3.3
Background medication
The investigator will assume responsibility for the management of glycaemic control in each 
subject enrolled in the trial. The investigator is responsible for ensuring that glycaemic control is 
maintained and optimised in each subject while maintaining a low risk of hypoglycaemic episodes. 
If deemed necessary to achieve glycaemic target, antidiabetic medication (excluding GLP-1 RAs,
DPP-4 inhibitors and pramlintide from visit 1 to 17) may be adjusted or added, at the investigator’s 
discretion. The background medication should be used in accordance with standard of care and the 
current local label.
If episodes of hypoglycaemia require reduction of antidiabetic medication, investigators should 
reduce or modify the dosing of background medication. In particular, dose reduction of insulin 
should be done already at randomisation (e.g. 10-20% reduction of the insulin dose) to reduce the 
risk of hypoglycaemia when introducing an additional glucose lowering agent. Similar 
considerations should be made for subjects treated with sulphonylureas.
All subjects will be provided with a BG meter at randomisation and glycaemic management will be 
guided by review of fasting plasma glucose (FPG) and HbA1c results measured at the site as well as 
self-measured plasma glucose (SMPG) results measured at home by the subject. In addition, it is 
important that other information such as symptoms of hypo/hyperglycaemia, previous response to 
dose adjustments and other indicators of the subject’s level glycaemic control is taken into 
consideration when decisions on dose adjustments of the background antidiabetic medication are 
made. In subjects treated with insulins, close contact should be ensured in the initial 12 weeks after 


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randomisation to allow for adequate adjustment of insulin dose, at the investigator’s discretion. 
Additional phone contacts in the weeks where no site visit is planned should be considered for 
subjects treated with insulins.
Please note that due to the long half-life of oral semaglutide and the gradual dose escalation, the full 
effect of the investigational product on glycaemic parameters may not be apparent until several 
weeks into the maintenance period.
The investigator is responsible for ensuring ongoing management of cardiovascular diseases and 
risk factors as well as potential microvascular complications such as diabetic kidney disease and 
diabetic retinopathy according to local standard of care at the investigator’s discretion.
5.4
Treatment after discontinuation of trial product
When discontinuing trial product at the end of the treatment period, the subject should be switched 
to a suitable marketed product at the discretion of the investigator. Oral semaglutide will not be 
available for prescription until marketing authorisation is issued.
For Brazil only: At the end of the trial, subjects will be assured access to the best proved 
prophylactic, diagnostic and therapeutic methods identified during the trial.
5.5
Rationale for treatment
Three treatment doses of oral semaglutide will be investigated in the phase 3a development 
programme: 3 mg, 7 mg and 14 mg. The selected doses are based on the data derived from the 
NN9924-3790 dose-finding trial. This dose range is expected to have the optimal benefit-risk 
profile for further development of oral semaglutide. In addition, the increments between the three 
doses are expected to provide clinically meaningful differentiation between the effects on glycaemic 
control while ensuring mitigation of gastrointestinal AEs through gradual dose escalation. For 
further details regarding the results obtained in the phase 2 dose-finding trial (NN9924-3790), 
please refer to the current edition of the IB for oral administration of semaglutide (NN9924)18, or 
any updates thereto.
Similar to other cardiovascular outcomes trials, the maximum treatment dose (14 mg oral 
semaglutide) will be investigated and compared to placebo in the present trial. Blinded treatment 
with oral semaglutide or placebo offers a robust method for assessment of oral semaglutide’s effect 
on trial endpoints. Treatment intensification of the background medication is allowed throughout 
the course of the trial to ensure adequate glycaemic control in all participating subjects. Use of other 
GLP-1 RAs and DPP-4 inhibitors and pramlintide is not allowed, because these drugs, similarly to 
oral semaglutide, affect the incretin pathway.


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6
Trial population
6.1
Number of subjects 
Number of subjects planned to be randomised: 3,176
For Mexico only: Approximately 150 subjects are planned to be randomised in Mexico
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 diagnosed with type 2 diabetes.
3. Age ≥ 50 years at screening and at least one of the below conditions:
a.
prior myocardial infarction
b. prior stroke or transient ischaemic attack (TIA)
c.
prior coronary, carotid or peripheral arterial revascularisation
d. > 50% stenosis on angiography or imaging of coronary, carotid or lower 
extremity arteries
e.
history of symptomatic coronary heart disease documented by e.g. positive 
exercise stress test or any cardiac imaging or unstable angina pectoris with ECG 
changes
f.
asymptomatic cardiac ischaemia documented by positive nuclear imaging test or 
exercise test or stress echo or any cardiac imaging
g. chronic heart failure New York Heart Association (NYHA) class II-III
h. moderate renal impairment (corresponding to an estimated glomerular filtration 
rate (eGFR) between 30-59 mL/min/1.73 m2)
or
Age ≥ 60 years at screening and at least one of the below risk factors:
i.
microalbuminuria or proteinuria
j.
hypertension and left ventricular hypertrophy by ECG or imaging
k. left ventricular systolic or diastolic dysfunction by imaging
l.
ankle/brachial index < 0.9
6.3
Exclusion criteria
For an eligible subject, all exclusion criteria must be answered "no".
1. Known or suspected hypersensitivity to the trial product or related products. 
2. Previous participation in this trial. Participation is defined as signed informed consent. 


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3. Female who is pregnant, breast-feeding or intends to become pregnant or is of childbearing 
potential and not using adequate contraceptive methods (adequate contraceptive measures as 
required by local regulation or practice. Local country regulations or practices are specified 
in section 8 of the protocol).
4. Receipt of any investigational medicinal product within 90 days before screening. 
For Brazil only: Participation in other clinical trials within one year prior to screening 
unless there is a direct benefit to the research subject at the investigator´s discretion.
5. Participation in another clinical trial of an investigational medicinal product. Participation in 
a clinical trial which evaluate stent(s) is allowed.
6. Current or previous (within 90 days prior to screening) treatment with any GLP-1 receptor 
agonist, DPP-4 inhibitor or pramlintide.
7. Any disorder, which in the investigator’s opinion might jeopardise subject’s safety or 
compliance with the protocol.
8. Family or personal history of multiple endocrine neoplasia type 2 (MEN 2) or medullary 
thyroid carcinoma (MTC).
9. History of pancreatitis (acute or chronic).
10. History of major surgical procedures involving the stomach potentially affecting absorption 
of trial product (e.g. subtotal and total gastrectomy, sleeve gastrectomy, gastric bypass 
surgery).
11. Subjects presently classified as being in New York Heart Association (NYHA) Class IV
heart failure.
12. Planned coronary, carotid or peripheral artery revascularisation known on the day of 
screening.
13. Any of the following: myocardial infarction, stroke or hospitalisation for unstable angina or 
transient ischaemic attack within the past 60 days prior to screening.
14. Chronic or intermittent hemodialysis or peritoneal dialysis or severe renal impairment 
(corresponding to eGFR <30 mL/min/1.73 m2).
15. History or presence of malignant neoplasms within the last 5 years (except basal and 
squamous cell skin cancer and carcinoma in situ).
16. History of diabetic ketoacidosis.
17. Proliferative retinopathy or maculopathy requiring acute treatment. Verified by fundus 
photography or dilated fundoscopy performed within 90 days prior to screening or within 
the period between screening and randomisation.
6.4
Composition of overall trial population
In order to secure sufficient overall cardiovascular risk within the trial population, randomisation of 
subjects with risk factors only (inclusion criterion no. 3, i-l) will be stopped when 650 of these 
subjects have been randomised.


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6.5
Premature discontinuation of trial product 
All efforts should be made to keep the subject on trial product throughout the trial. The subject may, 
however, decide to discontinue trial product for any reason, or they may be discontinued from trial 
product due to safety concerns at the discretion of the investigator. In case the trial product is 
interrupted due to suspicion of acute pancreatitis or a hypersensitivity reaction to the trial product, 
please see sections 8.2.1 and 8.2.2.
Furthermore, the subject must discontinue treatment with trial product if any of the following
applies:
!
pregnancy
!
intention of becoming pregnant
!
participation in another clinical trial with an investigational medicinal product
!
calcitonin ≥ 100 ng/L
Discontinuation of treatment with trial product, whether temporary or permanent, must not prompt 
the investigator to withdraw the subject from the trial. Instead, the subject should maintain 
adherence to trial visits and procedures to the extent possible. In each separate case, the primary 
reason for discontinuation of trial product must be specified in the eCRF. The subject should be 
encouraged to resume treatment with trial product once they are willing or when the safety concern 
has ceased, respectively.
A subject who does not fulfil the eligibility criteria (inclusion/exclusion criteria) must not be 
randomised. If a subject is randomised in error, this will be handled as an important protocol 
deviation, and the IEC/IRB and regulatory authorities must be notified according to local 
requirements. If there are no safety concerns, trial treatment may be continued or resumed at the 
discretion of the investigator following a discussion with the sponsor’s global medical expert.
See section 5.3.1 for instructions about resuming trial product treatment after a treatment pause. 
6.6
Withdrawal of consent
The subject may withdraw at will at any time. If a subject has withdrawn their consent, the 
investigator must make every effort to establish the subject’s vital status at the end of the trial. See 
section 8.4 for further instructions about withdrawals.
For Mexico only: Should the subject, his/her family members, parents or legal representative 
decide to withdraw the consent for participation in the trial, the subject will be entitled to receive 
appropriate, free of charge medical care and/or trial drug during the follow up period of the 
protocol when it will be established with certainty that no untoward medical consequences of the 
subject´s participation in the research occurred.


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6.7
Subject replacement
Subjects who have withdrawn their consent will not be replaced.
6.8
Rationale for trial population 
This trial will include subjects with T2D at high risk of cardiovascular events. This includes 
subjects with previous cardiovascular disease or well-established risk factors for cardiovascular
disease and advanced age, as based on their medical records. The inclusion of subjects with 
established risk for cardiovascular disease will ensure that the primary objective of the trial can be 
obtained within a reasonable timeframe.
Subjects with a recent event of myocardial infarction, stroke or hospitalisation for unstable angina 
or TIA prior to screening are excluded, aiming to avoid any effect of cardiovascular events that are 
likely to be secondary to another cardiovascular event or intervention.
6.8.1
Determining subject’s eligibility 
It is the responsibility of the investigator to ensure unequivocal evidence for a subject’s eligibility. 
When determining a subject’s eligibility based on medical history, it is at the investigator’s 
discretion on a case by case basis to decide if further medical records are needed or if the available 
documentation is adequate. Any laboratory values used to assess eligibility must reflect the 
subject’s current health status.
6.8.2
Microalbuminuria and proteinuria
For the diagnosis of microalbuminuria and proteinuria, local guidelines, if such exist, can be used. 
Otherwise, commonly accepted guidelines should be used23. Table 6–1 shows examples of how 
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Table 6–1
Measurement of albuminuria
Normal
Microalbuminuria
Macroalbuminuria
Advantages
Disadvantages
Urine dipstick
for protein
-
-
+
Convenience
Dependent on 
level of hydration
Urine 24-hour
protein (mg)
< 150
< 500
≥ 500
Overcomes problem 
of diurnal variation 
in excretion
Subject to 
collection errors
Urine 24-hour
albumin (mg)
< 30
30-300
> 300
Overcomes problem 
of diurnal variation 
in excretion
Subject to 
collection errors
Timed urine
collection
(μg/min)
< 20
20-200
> 200
Overcomes problem 
of diurnal variation 
in excretion
Subject to 
collection errors
Spot urine
collection (μg
albumin/mg
creatinine)
< 30
30-300
> 300
Convenience
Not dependent on 
hydration level
Most reproducible
Ratios vary based 
on gender
6.8.3
Glomerular filtration rate, estimated (eGFR) 
To evaluate whether a subject meets inclusion criterion no. 3 and exclusion criterion no. 14, the 
creatinine level that best reflects the current status of the subject in the medical records should be 
used to calculate eGFR. The equation from the Chronic Kidney Disease Epidemiology 
Collaboration (CKD-Epi)23 including variables for age, sex, and race should be used to calculate 
eGFR.
7
Milestones
Planned duration of recruitment period (i.e. FSFV – LSFV): 7 months.
End of trial is defined as Last Subject Last Visit (LSLV).
Novo Nordisk will follow the screening and randomisation rates closely via IV/WRS in order to 
estimate when to stop screening. Investigators will be notified immediately when the recruitment 
period ends, after which no further subjects may be screened, and IV/WRS will be closed for further 
screening.
The treatment period for the last randomised subject is expected to be 12 months. The trial duration 
is, however, decided by the first MACE rate (see section 5.1), and the trial duration will be adjusted 
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as needed. When the trial comes to an end, investigators will be notified and instructed by Novo 
Nordisk regarding the visit schedules for their subjects.
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 Disclosure25, it will also be disclosed 
according to other applicable requirements such as those of the International Committee of Medical 
Journal Editors26, the Food and Drug Administration Amendment Act27, European Commission 
Requirements28, 29 and other relevant recommendations or regulations. If a subject requests to be 
included in the trial via the Novo Nordisk e-mail contact at these web sites, Novo Nordisk may 
disclose the investigator’s contact details to the subject. As a result of increasing requirements for 
transparency, some countries require public disclosure of investigator names and their affiliations.
8
Methods and assessments
8.1
Visit procedures
The duration of this trial is decided by the observed first MACE rate (see section 5.1). It is expected 
that each subject will be asked to attend maximum eighteen visits. Eleven of these are regular clinic 
visits, two visits can be performed over the telephone, and five visits are dispensing visits. 
Dispensing visits are a combination of dispensing trial product and collecting relevant information 
over the telephone (see section 2). If the subject provides the required information to site staff when 
collecting trial product, the telephone contact can be omitted.
Depending on when a subject entered the trial and the accrual of first MACEs, subject’s visit
schedule may be shortened. This will imply omission of visit(s) in the treatment period, as, when 
the trial comes to an end, all subjects should be asked to attend visit 17 and 18. For a subject who 
discontinued trial product prematurely (i.e. more than 5 weeks prior to the anticipated visit 17), visit 
17 can be postponed to the point when visit 18 is otherwise due.
The timing and content of visits and the visit windows are outlined in section 2, while procedures
and assessments to be carried out at the visits are described in this section. 
8.1.1
Informed consent
In seeking and documenting informed consent, the investigator must comply with applicable 
regulatory requirement(s) and adhere to ICH GCP1 and the requirements in the Declaration of 
Helsinki2.
Before any trial-related activity, the investigator must give the subject verbal and written 
information about the trial and the procedures involved in a form that the subject can read and 
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understand. This includes the use of an impartial witness, where required according to local 
regulations. The subject 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 product.
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.
8.1.2
In/exclusion criteria
Subjects should be assessed for eligibility according to sections 6.2 and 6.3 at visit 1. For further 
instructions about determining the eligibility of a subject, see sections 6.8.1, 6.8.2 and 6.8.3. 
For inclusion criterion no. 3 (section 6.2), the investigator must provide just one answer (yes or no)
on the inclusion criteria form in the eCRF for each subject.
For exclusion criterion no. 3 (section 6.3), each female of childbearing potential must have a 
negative pregnancy test in order to be randomised.
For exclusion criterion no. 17 (section 6.3), each subject must have a fundus photography or dilated 
fundoscopy performed and evaluated before randomisation, in accordance with the instructions in 
section 8.1.7.
8.1.3
Screening 
At visit 1, the investigator must perform a screening session in IV/WRS (see section 10), and each 
subject will be assigned a unique 6-digit subject number which will remain the same throughout the 
trial. The investigator must keep a subject screening log, a subject identification code list and a 
subject enrolment log. The subject screening log and subject enrolment log may be combined into
one list.
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 
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instructed to return the card to the investigator at the last trial visit or to destroy the card after the 
last visit.
Screening failures: If a subject is screened, but for some reason never randomised, the subject is a 
screening failure. For screening failures, the screening failure form in eCRF must be completed 
with the reason for not continuing in the trial. SAEs from screening failures must be transcribed by 
the investigator into the eCRF. Follow-up of SAEs must be carried out according to section 12. A 
screening failure session must be made in the IV/WRS. The case book must be signed
electronically. Re-screening is not allowed.
8.1.4
Demography
Demography (date of birth or age, sex, race and ethnicity) will be recorded at visit 1, unless 
prohibited according to local regulations.
8.1.5
Tobacco use
Details of tobacco use must be recorded at visit 1. Smoking is defined as smoking at least one 
cigarette, cigar or pipe daily. The collected information should include whether or not the subject 
smokes or has smoked. If the subject has smoked, record approximately when the subject stopped 
smoking.
8.1.6
Physical examination
Physical examinations should be performed according to local procedures, when indicated in 
section 2, and will as a minimum include examination of:
!
head, ears, eyes, nose, throat, neck
!
respiratory system
!
cardiovascular system
!
gastrointestinal system, incl. mouth
!
musculoskeletal system
!
central and peripheral nervous system
!
skin
!
lymph node palpation
!
general appearance
!
thyroid gland
For each assessment, the investigator should indicate whether the outcome was normal or abnormal, 
and, if abnormal, indicate whether clinically significant. Relevant findings as a result of screening 
procedures conducted at visit 1 must be recorded as concomitant illness/medical history in 
accordance with section 8.1.9.
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Please note that the diagnostic evaluation of thyroid nodules should be in accordance with the 
American Thyroid Association Management Guidelines or any updates hereof30, adapted to local 
treatment guidelines.
8.1.7
Eye examination
Results of a fundus photography or dilated fundoscopy must be available and evaluated by the 
investigator before randomisation. If the subject had a fundus photography or dilated fundoscopy 
performed within 90 days prior to screening, the investigator may base their evaluation upon the 
results of that examination. However, the examination must be repeated before randomisation if the 
subject experienced worsening of visual function since the last examination. 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.
If the subject did not have a fundus photography or dilated fundoscopy performed within 90 days 
prior to screening, such examination must be performed by the investigator or other qualified health 
care professional prior to randomisation.
In addition to the eye examination performed at screening, fundus photography or dilated
fundoscopy should be performed at visit 12 and visit 17 as per the flow chart in section 2.
Fundoscopy requires pharmacological dilation of both pupils. The investigator should indicate 
whether the outcome of each eye examination was normal or abnormal, and, if abnormal, indicate 
whether clinically significant. Relevant findings as a result of the screening procedure must be 
recorded as concomitant illness/medical history in accordance with section 8.1.9, and relevant 
findings occurring after randomisation should be reported as an AE if applicable according to 
section 12.2.
8.1.8
Pregnancy test
Female subjects of childbearing potential will have pregnancy tests (urine dipsticks) performed as 
per the flow chart in section 2. In addition, urine pregnancy test should be performed at any time 
during the trial if a menstrual period is missed, or if pregnancy is suspected, or as required by local 
law.
Pregnancy testing will not be required (unless required by local law) for women of non-childbearing 
potential defined as, but not limited to, women who have undergone hysterectomy, bilateral 
oophorectomy or bilateral tubal ligation, or who are postmenopausal (i.e. women above the age of 
50 with no menstrual periods for at least 1 year). This has to be documented in the medical records.
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Contraceptive methods
Female subjects of childbearing potential must use adequate contraceptive methods until 5 weeks 
after the last date on trial product. Throughout the protocol, last date on trial product is defined as 
date of the subject’s last dosage of trial product.
For Argentina only: Adequate contraceptive measures are: Barrier methods (condom or 
diaphragm) with spermicide; contraceptive pills or intrauterine devices. Contraceptive methods 
will be reimbursed by Novo Nordisk Pharma Argentina S.A.
For Brazil only: For women who expressly declare free of the risk of pregnancy, either by not 
engaging in sexual activity or by having sexual activity with no birth potential risk, use of 
contraceptive method will not be mandatory.
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..
For Thailand only: Adequate contraceptive measures are: Diaphragm, condom (by the partner), 
intrauterine device in place for last three months before trial starts, sponge, cap with spermicide, 
contraceptive patch, approved hormonal implant (i.e. Norplant), oral contraceptives taken without 
difficulty for the last three months before trial starts, post-menopausal state or sterilisation.
For United Kingdom only: Adequate contraceptive measures are defined as established use of oral, 
intravaginal, transdermal, combined estrogen and progestogen hormonal methods of 
contraception; oral, injected or implanted progestogen only hormonal methods of contraception; 
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), female sterilisation, vasectomised partner (where partner is sole 
partner of subject), or true abstinence (when in line with preferred and usual lifestyle).
8.1.9
Concomitant illness and medical history
A concomitant illness is any illness that is present at the start of the trial (i.e. at visit 1) or found as 
a result of a screening procedure.
Medical history is a medical event that the subject has experienced in the past. Only relevant 
medical history as judged by the investigator should be transcribed to the eCRF.
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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The following must be assessed at visit 1 and transcribed to disease-specific forms, i.e. not to the 
medical history/concomitant illness form:
!
Diabetes history/diabetes complications (e.g. date of diagnosis, diabetic retinopathy, diabetic 
neuropathy, diabetic nephropathy)
!
History of cardiovascular disease (e.g. ischaemic heart disease, myocardial infarction, heart 
failure incl. NYHA class31, hypertension, stroke, peripheral arterial disease) including 
answering yes or no/unknown for each cardiovascular condition/risk factor mentioned in 
inclusion criterion no. 3 a-l (see section 6.2)
!
History of gallbladder disease (e.g. gallstone, cholecystitis, cholecystectomy)
!
History of gastrointestinal disease (e.g. gastroesophageal reflux disease, ulcer disease, 
chronic gastritis)
Any change to a concomitant illness should be recorded during the trial. A clinically significant 
worsening of a concomitant illness must be assessed according to section 12.1 and reported if 
applicable as per section 12.2. 
8.1.10
Concomitant medication
A concomitant medication is any medication, other than the trial product, which is taken during 
the trial, i.e. as of visit 1 until the time point of visit 18.
Details of any concomitant medication must be recorded at visit 1. Changes in concomitant 
medication must be recorded at each subsequent visit as they occur. 
The information collected for each concomitant medication includes trade name or generic name, 
indication, total daily dose (only applicable for medication taken to treat diabetes and 
cardiovascular related disease), start date and stop date or continuation.
For subjects treated with insulin(s), total daily dose administered on the day preceding each trial 
visit (if available) should be recorded in the eCRF. 
8.1.11
Body measurements (height and body weight)
Height is measured without shoes in centimetres or inches and recorded in the eCRF to the nearest 
½ cm or ¼ inch.
Body weight is measured wearing light clothes and no shoes and recorded in the eCRF in kilogram 
or pound (kg or lb) with one decimal. If possible, the same calibrated weighing scale equipment 
should be used throughout the trial.
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8.1.12
Vital signs
Pulse and systolic and diastolic blood pressure should be assessed in a sitting position after the 
subject has been resting for at least 5 minutes and by using the standard clinical practice at the site. 
The measured values should be recorded without rounding. If possible, the same equipment should 
be used throughout the trial.
8.1.13
Electrocardiogram
12-lead ECGs will be performed at selected visits (see the flow chart in section 2). Investigator’s 
interpretation of each ECG must be documented on the document or in the subject’s medical 
records and abnormalities assessed according to section 12.1, and reported if applicable as per 
section 12.2. However, for abnormal clinically significant findings revealing baseline conditions at 
visit 2 the investigator must record these as concomitant illness/medical history, and, if applicable, 
update answer(s) related to inclusion criterion 3 (see section 8.1.9).
The ECGs will also undergo central assessment and the investigator must forward the ECGs to the 
central ECG readers as soon as possible. If the central evaluation of a baseline ECG is suggestive of 
a prior myocardial infarction, the investigator will be notified. Unless already done, the investigator 
should consider recording the condition as cardiovascular history and update the answer(s) related 
to inclusion criterion 3 (see section 8.1.9). If the central ECG evaluation of a post-baseline ECG is 
suggestive of new myocardial infarction, the investigator will be notified and a confirmatory ECG 
should be submitted to central ECG readers. Unless already done, and at the investigator’s 
discretion, the investigator should assess the finding according to section 12.1, and if applicable 
report it as per section 12.2.
If additional ECG recordings are performed at the investigator’s discretion at other visits than the 
planned ECG visits, such ECGs should also be submitted to the central ECG readers. The reason for 
recording an additional ECG should be documented.
Findings suggestive of new myocardial infarction detected by the central ECG readers will be 
adjudicated by the EAC (see section 12.7.3).
8.1.14
Randomisation, dispensing of trial product and drug accountability
At visit 2, subjects are randomised into one of the two treatment arms. The randomisation session 
must be performed in IV/WRS and will include allocation of dispensing unit numbers (DUNs) to be 
dispensed to the subject.
All assessments pertaining to visit 2 must be performed before first dose of trial product is taken.
Date of first administration of trial product must be captured in the eCRF.
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At each visit where dispensing of trial product is indicated (see section 2), IV/WRS must be used to 
allocate DUNs according to the subject’s assigned treatment group (assigned at randomisation). The 
allocated DUNs should be dispensed by the site, hospital pharmacy or equivalent. 
The investigator must ensure that the subject is reminded about dosing instructions (see section 
5.3.2) at every dispensing visit, as needed.
At each visit where the subject returns used, partially used or unused trial product, the investigator 
will account for the returned trial products in IV/WRS (see section 9.4).
8.1.15
Blood sampling
Laboratory kits and laboratory manual will be provided to each site. The manual will include 
instructions for handling, storage and shipment of blood samples, and contact information for the 
central laboratory, including a link to their website where current laboratory certificates can be 
obtained. Blood samples should be collected according to the flow chart in section 2 and the 
laboratory parameters listed below will be assessed at a central laboratory (see Attachment I).
Glucose metabolism:
!
HbA1c
!
FPG
Lipids:
!
Total cholesterol
!
LDL cholesterol
!
HDL cholesterol
!
Triglycerides
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Biochemistry:
!
Alanine aminotransferase (ALT)
!
Albumin
!
Alkaline phosphatase (ALP)
!
Amylase
!
Aspartate aminotransferase (AST)
!
Bicarbonate
!
Bilirubin, total
!
Calcium
!
Creatinine
–
eGFR will be calculated by the central laboratory
!
Lipase
!
Potassium
!
Sodium
!
Urea
!
Creatine kinase
Haematology:
!
Haematocrit
!
Haemoglobin
!
Leucocytes
!
Thrombocytes
!
Differential count (eosinophils, neutrophils, basophils, lymphocytes and monocytes)
Hormones: 
!
Calcitonin
The laboratory results will be made available for the investigator on an ongoing basis. The 
investigator must sign and date each laboratory report or ensure review is documented in the 
subject’s medical records. For laboratory results outside the reference range, the investigator must 
indicate as either clinically significant or not clinically significant. Concomitant illnesses and AEs 
must be assessed and reported according to this protocol, as applicable.
If a calcitonin assessment results in a value ≥10 ng/L, the investigator must follow the algorithm in 
Protocol Appendix A.
FPG levels are monitored to aid investigators in glycaemic management through adjustment of 
background medication, but will not be included as an endpoint.
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Subjects must attend visits fasting when FPG and lipids are assessed (see section 2). Fasting is 
defined as having consumed only water within the last 8 hours. Administration of trial product is 
allowed prior to the visit. If a subject attends the visit in a non-fasting state, the visit procedures 
should be performed, excluding blood sampling, and subjects must be asked to visit the site once 
more within the visit window to have blood sampling performed.
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 always 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. For Brazil only: All laboratory results will be 
communicated to the investigators. The investigator must review all laboratory results for 
concomitant illnesses and AEs and report these according to this protocol.
Blood samples will be destroyed at completion of the clinical trial report at the latest, except 
samples obtained for anti-semaglutide antibody analysis in relation to suspicion of hypersensitivity 
reaction (see section 8.2.2 and 24.2).
8.1.16
Hand out and instruct in BG meter use 
At visit 2, the subject should be provided with a BG meter including auxiliaries. The subject should
be instructed in how to use the device. The instructions should be repeated as necessary during the 
trial. 
The BG meters use test strips calibrated to plasma values. Therefore, all measurements performed 
with capillary blood are automatically calibrated to plasma equivalent glucose values, which will be 
shown on the display. 
The investigator should instruct and encourage the subject to measure and record fasting SMPG 
according to individual recommendation from the investigator. The SMPG measurements may be 
recorded anywhere as per the subject’s own choice or the investigator’s recommendation. The 
measurements will not be transcribed into the eCRF, i.e. these measurements are only encouraged 
in order to facilitate good diabetes management at the discretion of the investigator.
8.1.17
Adverse events and technical complaints
AEs and technical complaints must be reported in accordance with the procedures outlined in 
section 12.
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8.1.17.1
Hypoglycaemic episodes
All severe hypoglycaemic episodes defined according to the ADA classification32 must be reported 
as an AE with additional data collection, see section 12.1.4, 12.2 and Appendix B. The investigator 
is not required to report a hypoglycaemic episode if the episode is both non-serious and non-severe.
A severe hypoglycaemic episode is defined as 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.
If the hypoglycaemic episode fulfils the criteria for an SAE then a safety information form must 
also be filled in, see section 12.
8.1.17.2
Medication errors
If a medication error concerning trial product (see definition in section 12.1.4) is observed during 
the trial, the following information is required:
!
Trial product(s) involved
!
Classification of medication error
o
Wrong drug(s) administered
o
Wrong route of administration
o
Wrong dose administered
!
Whether the subject experienced any AE(s) as a result of the medication error
!
Suspected primary reason for the medication error
8.1.18
End of trial
When a subject completes visit 18, the investigator should fill in the end-of-trial forms in the eCRF.
If a subject proves difficult to reach for visit 18, and vital status is collected via sources other than 
the subject him/herself (see section 8.4), the investigator should fill in the end-of-trial forms after 
collecting the vital status. If, before the database lock, the investigator establishes contact with the 
subject, the investigator will update the end-of-trial forms.
8.2
Other assessments
8.2.1
Assessments in case of suspicion of acute pancreatitis
Most patients with acute pancreatitis experience 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, it is frequently unbearable, and characteristically persists for more than 24 
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hours without relief33.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 pancreatitis33. 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, trial product treatment should be promptly interrupted. 
Appropriate additional examinations must be performed, including measurement of amylase and 
lipase.
The diagnosis of acute pancreatitis requires two of the following three features34:
!
abdominal pain consistent with acute pancreatitis (acute onset of a persistent, severe, 
epigastric pain often radiating to the back)
!
serum lipase (and/or amylase) activity at least three times greater than upper limit of normal
!
characteristic findings of acute pancreatitis on imaging.
If acute pancreatitis is ruled out, the subject should resume trial product treatment, at the 
investigator’s discretion. 
If acute pancreatitis is confirmed, the investigator should initiate careful monitoring of the subject. 
The subject must be discontinued from trial product, but should remain in the trial (see section 6.5
and 8.4). 
The event must be assessed according to section 12.1 and reported if applicable as per section 12.2.
8.2.2
Assessments in case of suspicion of hypersensitivity reactions to the trial product
In case of suspicion of a severe immediate systemic hypersensitivity reaction35 to the trial product, 
the subject must be discontinued from trial product but should remain in the trial (see sections 6.5
and 8.4).
To assist in diagnosis it is recommended to draw a blood sample for measurement of tryptase (total 
and/or mature tryptase, to be assessed at a local laboratory) within 3 hours of the hypersensitivity 
reaction, and, if this is achieved, a tryptase sample should also be collected at next site visit. 
Furthermore, a blood sample for assessment of anti-semaglutide IgE antibodies and anti-
semaglutide antibodies should be drawn as soon as possible after the event and at next site visit and 
sent to central laboratory for analysis.
In case of suspicion of immune complex disease35, the subject must be discontinued from trial 
product but should remain in the trial (see sections 6.5 and 8.4). It is recommended to collect a 
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blood sample for assessment of complement levels (C3 and C4) to assist the diagnostic evaluation 
(to be assessed at a local laboratory).
The event must be assessed according to section 12.1 and reported if applicable as per section 12.2.
8.2.3
Assessments in case of increased levels of aminotransferases
In case of 
1. ALT or AST > 3x UNL and total bilirubin > 2x UNL,
2. ALT or AST > 5x UNL and total bilirubin ≤2x UNL, 
the event must be reported as an AE requiring additional data collection (see section 12 and 
Appendix B).
For both events, prompt repeat testing (at central laboratory) including ALT, AST, ALP and total 
bilirubin should be done and discontinuation of trial product considered. Thereafter, repeat testing 
(at 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 (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.
8.3
Treatment compliance
Treatment compliance will be assessed by monitoring of drug accountability. Subjects will be asked 
to bring along all used, partly used and unused trial products including empty packaging at each 
visit where drug accountability is performed (see sections 2 and 9.4). The investigator must assess 
the amounts of trial product used compared to expected usage since the last dispensing visit and, in 
case of discrepancies, question the subject. If a subject is found to be non-compliant, the 
investigator will remind them of the importance of following the instructions given including taking 
the trial products as prescribed.
8.4
Trial adherence 
Throughout the trial, the investigator will remind the subject to follow the trial procedures and 
requirements. It is the responsibility of the investigator to ensure that the subject’s visits occur 
according to schedule.
If a clinic visit is missed and it is not possible to reschedule, the investigator should ensure that 
relevant information is collected for example over the telephone. The subject should be asked to 
attend the next scheduled visit according to the visit schedule. 
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If extra trial product is needed, the investigator can perform an additional dispensing session in 
IV/WRS (see section 10).
The subject can remain in the trial regardless of lack of compliance with trial treatment, lack of 
adherence to the visit schedule, missed assessments, discontinuation of trial treatment for any 
reason or development of comorbidities or clinical outcomes. 
Premature discontinuation of trial product: Subjects who discontinue treatment with trial 
product should still be followed according to the visit schedule in section 2. For subjects who are 
off trial product, a reduced visit schedule and conversion of site visits to telephone visits may be 
considered if this becomes a prerequisite for their continued participation in the trial. Reasons for 
not adhering to the standard visit schedule must be documented in medical records. Premature trial 
product discontinuation should be registered in the eCRF (see section 5.3) and in IV/WRS (see 
section 10). 
Withdrawals: A subject who explicitly wants to withdraw their consent must be formally 
withdrawn from the trial. The end-of-trial form must be completed, and final drug accountability 
must be performed even if the subject is not able/willing to come to the trial site. Although a subject 
is not obliged to give his/her reason(s) for withdrawing from a trial, the investigator must make a 
reasonable effort to ascertain the reason(s), while fully respecting the subject’s rights. Where the 
reasons are obtained, the primary reason for not completing the trial must be specified on the end-
of-trial form in the eCRF.
A subject who agrees to provide information concerning relevant morbidities at the planned end of 
trial should not be considered withdrawn from the trial.
Regarding subjects who are withdrawn when the trial comes to an end, the investigator must 
scrutinise publicly available registries for relevant safety information, unless prohibited by local 
regulations. Vital status must be determined as a minimum, wherever possible.
Lost to follow-ups: If a subject proves difficult to reach for their visit 18, extensive attempts must 
be made to locate the subject and obtain relevant safety information, in particular related to MACE. 
This may include consulting contacts provided by the subject (e.g. relatives or emergency contacts), 
relevant health care professionals/clinics, medical records, local registries and locator agencies. A 
subject cannot be deemed lost to follow-up until at least the following contacts have been attempted 
and documented in medical records: 
!
to subjects: two phone calls and one written contact
!
to primary physician and/or other health care professionals: calls until contact is established
!
to relatives or other contacts provided by the subject: two phone calls and one written 
contact
!
to relevant publicly available registries
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A subject will only be considered lost to follow-up in case vital status cannot be determined at the 
time of visit 18, or at least before the trial database lock is initiated. 
9
Trial supplies
Trial supplies comprise trial products and auxiliary supplies. Additional details regarding trial 
supplies can be found in the Trial Materials Manual (TMM). 
Each trial site will be supplied with sufficient trial products for the trial on an ongoing basis 
controlled by IV/WRS. Trial products will be distributed to trial sites in accordance with subject 
enrolment rates at the individual site.
Trial product should only be dispensed to persons participating in the trial. If a subject is unable to 
attend the site for a dispensing visit (see flowchart in section 2), a non-participating person may,
however, collect the allocated trial product on behalf of the subject. If trial product is collected by a 
non-participant, this must be agreed with the subject on beforehand and thoroughly documented at 
the site e.g. by means of a letter of authorisation issued by the subject, and, on each occasion, the 
investigator must follow up by contacting the subject.
9.1
Trial products
The following trial products are considered investigational medicinal products and will be provided 
by Novo Nordisk A/S, Denmark:
Table 9–1
Investigational medicinal products
Trial product
Strength
Dosage form
Route of administration
Container
Semaglutide 3 mg tablet
3 mg
Tablet
Oral
Dose pack with 1 
blister card each 
containing 7 tablets
Semaglutide 7 mg tablet
7 mg
Semaglutide 14 mg tablet
14 mg
Placebo tablet 
N/A
Semaglutide and placebo tablets are white to light yellow oval-shaped tablets, embossed with “M8” 
on one side. All tablets are visually identical, irrespective of strength.
9.2
Labelling
The trial products will be labelled in accordance with Annex 1336, local regulations and trial 
requirements.
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9.3
Storage 
Storage conditions for the trial products are outlined in Table 9–2 and on the trial product labels.
Table 9–2
Storage conditions for trial products
Trial product
Storage conditions
In-use conditions
Semaglutide 3 mg tablet
Do not store above 30ºC (86ºF)
Do not freeze
Do not refrigerate
Store in the original package
Take the tablet immediately after 
dispensation from blister card
Take the tablets whole: Do not break or 
chew
Semaglutide 7 mg tablet
Semaglutide 14 mg tablet
Placebo tablet 
The investigator must ensure the availability of proper storage conditions, and also record and 
evaluate the temperature. The investigator must inform Novo Nordisk immediately if any trial 
product has been stored outside specified conditions (e.g. stored in a refrigerator).
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
Subjects must be instructed to bring along all used, partly used and unused trial products including 
empty packaging material on an ongoing basis. Returned trial product must be stored separately 
from non-allocated trial product.
Drug accountability is the responsibility of the investigator and should be done at tablet level by 
means of IV/WRS. All trial products received at site should be accounted for. Non-allocated trial 
product (expired, damaged and available) should be accounted as unused at closure of the trial site
at the latest.
Destruction of expired stock and damaged or returned trial product may be done on an ongoing 
basis throughout the trial, in accordance with local procedures, after accountability is finalised and 
reconciled by the monitor. Remaining stock can be destroyed after last end-of-treatment visit has 
been carried out at the site. On-site destruction may be arranged if local procedures allow. 
Destruction of trial products must be documented in IV/WRS.
9.5
Auxiliary supplies
The following will be provided by Novo Nordisk in accordance with the TMM:
!
BG meters and BG meter auxiliaries
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10
Interactive voice/web response system
A trial-specific IV/WRS will be set up which can be accessed at any time via the internet or 
telephone. Access to the IV/WRS must be restricted to and controlled by authorised persons. 
IV/WRS user manuals will be provided to each trial site. 
IV/WRS is used for: 
!
Screening
!
Screening failure
!
Randomisation
!
Data change
!
Medication arrival
!
Dispensing
o
Semaglutide 3 mg / placebo tablets
o
Semaglutide 7 mg / placebo tablets
o
Semaglutide 14 mg / placebo tablets
!
Subject treatment status change (treatment pause / treatment resume)
!
Code break
!
Drug accountability
At the screening session in IV/WRS, the investigator may need to indicate whether the subject 
fulfils one or more of the criteria a-h in inclusion criterion no. 3 (see section 6.2).
In case a subject discontinues trial treatment, or resumes trial treatment after a treatment pause, this 
should be registered in IV/WRS by means of the ‘subject treatment status change’ session.
When using the ‘subject treatment status change’ session to resume treatment, the investigator will 
need to decide which trial product dose to prescribe (cf. section 5.3.1). If trial product treatment is 
resumed at 3 or 7 mg oral semaglutide/placebo, IV/WRS will per default dispense trial product to 
support the dose escalation steps outlined in section 5.3.1, and extraordinary dispensing visits may 
be needed in order to get the subject back into the ordinary dispensing visit schedule outlined in the 
flow chart in section 2.
At all times during the trial, investigators must have robust procedures in place to ensure they only 
dispense the DUNs allocated to the particular subject by IV/WRS. This will ensure that: 
!
The subject receives the trial treatment they are randomised to
!
Adequate stock is available at site
!
Dispensed trial products can be accounted for 
If a subject needs trial product between dispensing visits, the investigator should make an additional 
dispensing session in IV/WRS. For subjects who withdraw from the trial or pass away during the 
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trial, final drug accountability will need to be performed. The system will then be updated by Novo 
Nordisk and the site will no longer be supplied with trial product for the particular subject.
11 Randomisation procedure and breaking of blinded codes
Only eligible subjects are allowed to be randomised. The investigator must use IV/WRS for 
randomisation of subjects. IV/WRS will ensure random assignment to the two treatment arms in a 
1:1 ratio and ensure even distribution of the two treatment arms within the strata described in 
section 5.1.
11.1
Breaking of blinded codes
The code for a particular subject may be broken in a medical emergency if knowing the actual 
treatment would influence the treatment of the subject. Whenever a code is broken the person 
breaking the code must print the Code Break Confirmation Notification generated by the IV/WRS, 
record the reason, and sign and date the document. The IV/WRS will notify Novo Nordisk (monitor 
and the Global Safety department) immediately after the code is broken.
When the code is broken, the treatment allocation will be accessible to the investigator and the 
Novo Nordisk Global Safety department. If IV/WRS is not accessible at the time of code break the 
IV/WRS helpdesk should be contacted. Contact details are listed in Attachment I.
The subject may resume or continue trial product treatment although their code was broken.
12 Adverse events, technical complaints and pregnancies
This trial is designed to evaluate cardiovascular outcomes and will apply a targeted approach for
collection of safety data focusing on SAEs, AEs leading to discontinuation of trial product and other 
selected events.
12.1
Definitions
12.1.1
Adverse event 
An adverse event (AE) is any untoward medical occurrence in a subject administered a product, and 
which does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom or disease temporally associated with the use of a product, whether or not 
considered related to the product. 
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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 considered as AEs:
!
Pre-existing conditions, including those found as a result of screening procedures (pre-
existing conditions should be reported as medical history or concomitant illness).
!
Pre-planned procedures unless the condition for which the procedure was planned has 
worsened from the first trial related activity after the subject has signed the informed 
consent.
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.
–
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.
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–
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 serious adverse event (SAE) is an experience that at any dose results in any of the following:
!
Death.
!
A life-threateninga experience.
!
In-patient hospitalisationb or prolongation of existing hospitalisation.
!
A persistent or significant disability or incapacityc.
!
A congenital anomaly or birth defect.
!
Important medical events that may not result in death, be life threateninga or require 
hospitalisationb may be considered an SAE when - based on appropriate medical judgement 
- they may jeopardise the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in the definition of SAEd. 
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, 
impairment, damage or disruption in his/her body function or structure, physical activity and/or 
quality of life).
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d. For example intensive treatment in an emergency room or at home of allergic bronchospasm, 
blood dyscrasiasis or convulsions that do not result in hospitalisation, or development of drug 
dependency or drug abuse.
The following events must always be reported as SAEs using the important medical event criterion 
if no other seriousness criterion is applicable:
!
Suspicion of transmission of infectious agents via the trial product
!
Risk of liver injury defined as ALT or AST > 3x UNL and total bilirubin > 2x 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
Adverse events requiring additional data collection
Adverse events requiring additional data collection are events which, in the evaluation of safety, 
have a special focus (e.g. required by the health authorities).
If any of the following AEs are applicable for reporting according to section 12.2, additional data 
collection is required:
!
Acute coronary syndrome (myocardial infarction or hospitalisation for unstable angina)
!
Cerebrovascular event (stroke or TIA)
!
Heart failure requiring hospitalisation
!
Pancreatitis 
!
Neoplasm (excluding thyroid neoplasm)
!
Thyroid disease (including thyroid neoplasm)
!
Renal event
!
Hypersensitivity reaction to the trial product
!
Lactic acidosis
!
Medication error concerning trial product:
o
Administration of wrong drug. 
-
Note: Use of wrong DUN is not considered a medication error per se.
o
Wrong route of administration
o
Administration of an overdose with the intention to cause harm (e.g. suicide 
attempt).
o
Accidental administration of a higher dose than intended. That is a dose of 1 tablet or 
more than the intended dose; however the administered dose must deviate from the 
intended dose to an extent where clinical consequences for the trial subject were 
likely to happen as judged by the investigator, although they did not necessarily 
occur.
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If a subject missed one or more doses of trial product, this should not be reported as a 
medication error.
!
Severe hypoglycaemic episode (see section 8.1.17.1)
!
Hepatic event:
o
ALT or AST > 5x UNL and total bilirubin ≤ 2x UNL
o
ALT or AST > 3x UNL and total bilirubin > 2x UNL
o
Hepatic events leading to trial product discontinuation 
Additional assessments should be made for hepatic events (see section 8.2.3).
!
Diabetic retinopathy and related complications
12.1.5
Technical complaint
A technical complaint is any written, electronic, or oral communication that alleges product 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)
!
The packaging material (e.g. cracks or errors in labelling text)
12.2
Reporting of adverse events
In this trial the following events must be collected and reported:
!
SAEs
!
AEs leading to discontinuation of trial product
!
Medication errors
!
Severe hypoglycaemic episodes
!
Hepatic events
!
Diabetic retinopathy and related complications
!
Pregnancies
Medication errors, severe hypoglycaemic episodes, hepatic events and diabetic retinopathy and 
related complications must be reported regardless of seriousness and whether trial product is 
discontinued.
Events occurring as of the first trial-related activity after the subject signed the informed consent 
until the end of the follow-up period are in scope for collection and reporting. The events must be 
recorded in the applicable CRFs 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, for example by 
asking: "Have you experienced any problems since the last contact?"
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All SAEs, AEs leading to discontinuation of trial product, medication errors, severe hypoglycaemic 
episodes, hepatic events and diabetic retinopathy and related complications, either observed by the 
investigator or subject, must be reported by the investigator and evaluated. Novo Nordisk 
assessment of expectedness is performed according to the following reference documents: IB for 
oral administration of semaglutide (NN9924), current edition18 or any updates thereto. 
All AEs applicable for reporting according to the above paragraphs must be recorded by the 
investigator on an AE form. The investigator should report the diagnosis, if available. If no
diagnosis is available, the investigator should record each sign and symptom as individual AEs 
using separate AE forms.
For SAEs, a safety information form must be completed in addition to the AE form. A safety 
information form is tailored to collect supplementary clinical information. 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. 
AEs requiring additional data collection must be reported using both the AE form and the specific
event form. A specific event form is a form tailored to collect specific information related to the
individual event (see Appendix B for details about the specific event forms and the additional
information to report).
Certain events will undergo event adjudication by the Event Adjudication Committee (EAC), please 
refer to section 12.7.3. For such events, the Event Adjudication Form will also have to be completed 
in the eCRF. The Event Adjudication Form is a checklist of clinical data to be provided from the 
site.
Timelines for initial reporting of AEs:
The investigator must complete the following forms in the eCRF within the specified timelines:
!
SAEs: The AE form within 24 hours and the safety information form within 5 calendar
days of the investigator's first knowledge of the SAE.
Both forms must be signed within 7 calendar days from the date the information was entered 
in the eCRF.
!
SAEs fulfilling criteria for additional data collection: In addition to above, the 
corresponding specific event form within 14 calendar days of investigators knowledge of 
the event.
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!
Events for adjudication: Event Adjudication Form within 14 calendar days of the 
investigator's first knowledge of the AE.
The investigator should preferably provide the medical documentation within 4 weeks of 
event identification.
If the eCRF is unavailable, the concerned AE information must be reported on paper forms and sent 
to Novo Nordisk by fax, e-mail or courier within the same timelines as stated above. When the 
eCRF becomes available again, the investigator must enter the information on the appropriate forms 
in the eCRF.
Contact details (fax, telephone, e-mail and address) are provided in the investigator trial master file. 
An AE is 
observed 
It is an SAE
complete:
!
AE form < 24 hours
!
SIF < 5 calendars days
Fulfilling 
seriousness 
criteria per 
protocol?
AE requiring 
additional data 
collection?
Complete < 14 
calendar days:
!
Specif c event form
No
Is the AE 
relevant for 
adjudication?
Complete < 14 
calendar days:
!
Adjud cat on form 
No add t onal forms 
to be completed
AE Adverse Event
SIF  safety information form
AEs requiring addtional data collection
described in section 12.1.4
Events for adjudication 
described in section 12.7.3
All timelines are from the investigator’s 
first knowledge of the event
No
Any of the below apply?
! AE leading to discontinuation
     of trial product
! Medication error
! Severe hypoglycaemic 
     episode
! Hepat c event
! Diabet c retinopathy and related 
complicat ons
No
The AE does not 
need to be reported
Complete: AE form 
Yes
No additional forms 
to be completed
No
Yes
Yes
Yes
Figure 12–1
Initial reporting of AEs
Reporting of trial product-related SUSARs by Novo Nordisk:
Novo Nordisk will notify the investigator of trial product-related suspected unexpected serious
adverse reactions (SUSARs) in accordance with local requirements and GCP1. In addition, the 
investigator will be informed of any trial-related SAEs that may warrant a change in any trial 
procedure.
In accordance with regulatory requirements, Novo Nordisk will inform the regulatory authorities, 
including EMA, of trial product-related SUSARs. In addition, Novo Nordisk will inform the 
IRBs/IECs of trial product-related SUSARs in accordance with local requirement and GCP1, unless 
locally this is an obligation of the investigator.
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To avoid introducing bias and to maintain the integrity of the primary analysis, Novo Nordisk will 
exempt SAEs that are part of the primary endpoint evaluation from unblinding during regulatory 
reporting, even though the cases fulfil the definition of SUSARs. The DMC (see section 12.7.2) 
receives unblinded data and makes recommendations to the Novo Nordisk safety committee. This 
ensures adequate monitoring of safety while maintaining SAE reports related to the primary 
endpoint blinded for Novo Nordisk. 
At the end of the trial, when treatment is revealed, all exempted cases which meet the criteria for 
expedited reporting SUSARs will be submitted to the regulatory authorities. Because multiple cases 
will be identified simultaneously, Novo Nordisk will not be able to fulfil the 7-days requirement for 
fatal or life-threatening events but will within 60 days after code break have all SUSARs submitted 
to the regulatory authorities.
In case a regulatory authority requires the blinded report on an expedited basis, Novo Nordisk will 
submit individual blinded case reports related to investigational product to the relevant regulatory 
authorities on an expedited basis.
Novo Nordisk products used as concomitant medication:
If an SAE 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. 
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!
Non-serious AEs: Non-serious AEs must be followed until the outcome of the event is 
“recovering/resolving”, “recovered/resolved” or “recovered/resolved with sequelae” or until 
the end of the follow-up period stated in the protocol, whichever comes first, and until all 
queries related to these AEs have been resolved. Cases of chronic conditions, cancer or AEs 
ongoing at time of death (where death is due to another AE) may be closed with the 
outcome “recovering/resolving” or “not recovered/not resolved”. Cases can be closed with 
the outcome of “recovering/resolving” when the subject has completed the follow-up period 
and is expected by the investigator to recover.
The investigator must ensure that the worst case severity and seriousness of an event is kept 
throughout the trial. A worsening of an unresolved AE must be reported as follow up with re-
assessment of severity and/or seriousness of the event.
Queries or follow-up requests from Novo Nordisk must be responded to within 14 calendar days
from the date of receipt of the request, unless otherwise specified in the follow-up request.
12.4
Technical complaints and technical complaint samples
12.4.1
Reporting of technical complaints
All technical complaints on any of the following products:
!
Semaglutide 3 mg / placebo tablets
!
Semaglutide 7 mg / placebo tablets
!
Semaglutide 14 mg / placebo tablets
which occur from the time of first usage of the product until the time of the last usage of the 
product, must be collected and reported to Customer Complaint Center, Novo Nordisk.
Contact details (fax, e-mail and address) are provided in Attachment I to the protocol.
The investigator must assess whether the technical complaint is related to any AEs or SAEs.
Technical complaints must be reported on a separate technical complaint form. A technical 
complaint form for each code number or for each DUN must be completed.
The investigator must complete the technical complaint form in the eCRF within the following 
timelines of the trial site obtaining knowledge of the technical complaint:
!
Technical complaint assessed as related to an SAE within 24 hours
!
All other technical complaints within 5 calendar days
If the eCRF is unavailable or when reporting a technical complaint that is not subject related, the 
information must be provided on a paper form by fax, e-mail or courier to Customer Complaint 
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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 sent 
with the sample.
The investigator must ensure that the technical complaint sample contains the code number and, if 
available, the DUN.
If the technical complaint sample is unobtainable, the investigator must specify on the technical 
complaint form why it is unobtainable. 
Storage of the technical complaint sample must be done in accordance with the conditions 
prescribed for the product. The shipment of the technical complaint sample should be done in 
accordance with the same conditions as for storage (see section 9).
12.5
Pregnancies
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. When needed, Novo Nordisk will provide paper forms for collection of the relevant 
information. The investigator must report the requested information to Novo Nordisk -
electronically (e.g. in PDF format), or by fax or courier.
12.6
Precautions and/or overdose
There are no specific antidotes to semaglutide. Treatment of an overdose should be symptomatic.
There is a potential risk of hypoglycaemia during dosing with semaglutide. The typical signs and 
symptoms of a non-severe hypoglycaemia (mild/moderate) include: hunger, slight headache, 
nausea, light-headedness, palpitations, and sweating. Severe hypoglycaemia may produce loss of 
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consciousness. Symptoms of non-severe hypoglycaemia should be treated by ingestion of 
carbohydrates. Severe hypoglycaemia resulting in loss of consciousness should be treated at the 
investigator’s discretion according to best available medical practise.
One case of accidental overdose of oral semaglutide was reported in the NN9924-3692 trial in a 
subject treated with 20 mg oral semaglutide once daily. The subject accidentally took the trial 
product 
of the trial. No AEs were reported at the same time. The medication error 
was discovered 
 The subject did not report any symptoms and treatment 
was continued without any change.
One case of accidental overdose has been reported in s.c. semaglutide once weekly treated subjects. 
The case was classified as moderate in severity and considered probably related to semaglutide and 
was reported by a subject enrolled in the trial NN9535-1821. No hospitalisation was needed. The 
subject inadvertently injected mg of semaglutide instead of 0.4 mg, which corresponds to a 
-fold higher dose than the maximum dose included in that trial. After 
 hours the subject felt 
nauseated, vomited and had a headache. The subject was instructed to drink sufficient amounts of 
fluids. 
 and the subject wished to continue in the 
trial. Plasma glucose levels, blood pressure and pulse were monitored during the following 5 days, 
and no symptoms of hypoglycaemia or any other symptoms or signs were noted. The subject was 
withdrawn from the trial after 19 days of treatment due to an AE (diarrhoea).
For further details please see the IB for oral administration of semaglutide (NN9924), current 
edition18, or any updates thereto.
12.7
Committees related to safety
12.7.1
Novo Nordisk safety committee
Novo Nordisk will constitute an internal oral semaglutide safety committee to perform ongoing 
safety surveillance.
12.7.2
Data monitoring committee
The independent data monitoring committee (DMC) is an independent, external committee 
composed of members whose expertise covers relevant specialities including statistics. The DMC is 
established to review and evaluate accumulated data from the trial at predefined time points as well 
as ad-hoc. This is in order to protect the safety of the subjects and to evaluate the risk-benefit 
balance. The DMC will have access to unblinded data, and will provide recommendations on the 
trial continuation, modification or termination.
Information regarding responsibilities, procedures and workflow to be used by the DMC are 
specified in the DMC charter.
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12.7.3
Event adjudication committee
An independent external event adjudication committee (EAC) is established to perform qualitative 
or quantitative validation of selected AEs according to pre-defined diagnostic criteria. The 
validation is based on review of pre-defined clinical data related to the specific AE. Pre-defined 
clinical data consist of copies of source documents collected and delivered by the investigational 
sites.
The EAC is composed of permanent members covering required medical specialities. EAC 
members must disclose any potential conflicts of interest and must be independent of Novo 
Nordisk.
The events are reviewed by the EAC in a blinded manner. The EAC will have no authorisation to 
impact trial conduct, trial protocol or amendments.
The EAC works in accordance with written guidelines included in the EAC Charter describing in 
details the composition, tasks, responsibilities, and work processes of the committee.
The events outlined in Table 12–1 have been selected for adjudication in order to obtain an external 
independent validation of the diagnosis. In addition, cardiovascular events are being adjudicated in 
accordance with FDA requirements37.
The EAC will review copies in English (translated if necessary) of medical documentation received 
in the adjudication packages (e.g. x-rays, ECGs, ultrasound images, discharge summaries, 
pathology reports and death certificates). The investigator must provide medical documentation as 
soon as possible, when they receive the request from Novo Nordisk or the event adjudication 
vendor.
AEs for adjudication can be identified in four different manners:
!
AEs reported by the investigator for adjudication
!
Screening of AEs reported by the investigator as not relevant for adjudication
!
Unreported AEs detected by the EAC while reviewing source data for other AEs reported by 
the investigator
!
ECGs suggestive of new myocardial infarction (see section 8.1.13)
The assessments made by the EAC will be included in the clinical trial report as well as assessments 
made by the investigator. However, the adjudication made by an EAC, given its independence and 
in-depth analysis of each event, will be attributed with greater importance of the two. The outcome 
of adjudication will be kept in the clinical trial database.
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Table 12–1
Adverse events for adjudication
Events
Description
Adjudication outcomes
Death
! All-cause death
! Cardiovascular death 
(including undetermined 
cause of death)
! Non-cardiovascular death
Acute Coronary 
Syndrome
! ST-elevation acute myocardial infarction (STEMI)
! Non-ST elevation acute myocardial infarction (NSTEMI)
! Silent myocardial infarction
! Unstable angina pectoris (UAP) requiring hospitalisation
! Acute myocardial 
infarction (STEMI or 
NSTEMI), silent 
myocardial infarction
! Unstable angina pectoris 
requiring hospitalisation
Cerebrovascular 
events
! Episode of focal or global neurological dysfunction caused by 
brain, spinal cord, or retinal vascular injury as a result of 
haemorrhage or infarction
! Transient Ischaemic Attack (TIA) is defined as a transient episode 
(<24 hours) of focal neurological dysfunction caused by brain, 
spinal cord, or retinal ischaemia, without acute infarction
! Ischaemic stroke
! Haemorrhagic stroke
! Undetermined stroke
! TIA
Heart failure 
requiring 
hospitalisation
! Hospitalisation with a primary diagnosis of heart failure (new 
episode or worsening of existing heart failure)
! Heart failure requiring 
hospitalisation
Acute pancreatitis
The diagnosis of acute pancreatitis requires two of the following
three features:
! 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 limit of normal
! Characteristic findings of acute pancreatitis on imaging
! Acute pancreatitis
o
Mild
o
Moderate 
o
Severe
Malignant 
neoplasm
Malignant neoplasms are defined as:
! neoplasms in which abnormal cells divide without control and can 
invade nearby tissues and/or spread to other parts of the body 
through the blood and lymph systems
Thyroid neoplasms are excluded in this event category
! Malignant neoplasm
Thyroid disease, if 
malignant thyroid 
neoplasm or C-cell 
hyperplasia
Malignant thyroid neoplasms are defined as 
! thyroid neoplasms in which abnormal cells divide without control 
and can invade nearby tissues and/or spread to other parts of the 
body through the blood and lymph systems
! C-cell hyperplasia, defined as hyperplasia of the parafollicular 
C-cells of the thyroid gland
! Malignant thyroid 
neoplasm
! C-cell hyperplasia
Acute kidney 
injury
Acute kidney injury23 is defined as any of the following (not graded):
! Increase in serum creatinine by ≥0.3 mg/dL (≥26.5 μmol/L) within 
48 hours, or
! Increase in serum creatinine to ≥1.5 times baseline, which is 
known or presumed to have occurred within the prior 7 days, or
! Urine volume < .5 mL/kg/h for 6 hours
! Acute kidney injury
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Events
Description
Adjudication outcomes
Lactic acidosis
Lactic acidosis is characterized by increased blood lactate level in 
association with metabolic acidosis
! Lactic acidosis
The safety data accumulating during the trial will be screened for potential missed events for 
adjudication and, if needed, the investigator will be asked to provide additional information such as 
an alternative aetiology, underlying cause(s) and/or clinical details.
The event adjudication vendor or EAC can decide to have an AE adjudicated even if not initially 
reported as an event for adjudication by the investigator.
Event adjudication will be performed for AEs in randomised subjects including AEs with an onset 
date during the screening period. Event adjudication will not be performed for AEs in screening 
failures or subjects never randomised for whatever reason. 
AEs for adjudication must be reported according to section 12.2. In addition the specific event 
adjudication form should be completed within 14 calendar days of the investigator's first knowledge 
of the AE, and all relevant predefined documents provided according to instructions in the event 
adjudication site manual.
13 Case report forms 
Novo Nordisk will provide a system for the electronic case report forms (eCRFs). This system and 
support services to the system will be provided by an external supplier.
Ensure that all relevant questions are answered, and that no empty data field exists. If a test or an 
assessment has not been done and will not be available, or if the question is irrelevant (e.g. is not 
applicable), indicate this according to the data entry instructions.
The 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.
The following will be provided as paper CRFs:
!
Pregnancy forms (distributed to site if a pregnancy occurs)
In addition, paper AE forms, safety information forms and technical complaint forms will be 
provided. These must be used when access to the eCRF is revoked or if the eCRF is unavailable. 
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On the paper CRFs, print legibly, using a ballpoint pen. Ensure that all questions are answered, and 
that no empty data blocks exist. Ensure that no information is recorded outside the data blocks. If a 
test/assessment has not been done and will not be available, indicate this by writing "ND" (not 
done) in the appropriate answer field in the CRF. If the question is irrelevant (e.g. is not applicable) 
indicate this by writing "NA" (not applicable) in the appropriate answer field. Further guidance can 
be obtained from the instructions in the CRF. Corrections to the CRF data may be made by the 
investigator or the investigator's delegated staff. An audit trail will be maintained in the CRF 
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 data on paper CRFs may only be made by drawing a straight line through the 
incorrect data and then writing the correct data next to the original entry. Each correction must be 
initialled, dated and explained (if necessary).
The investigator must ensure that data is recorded in the eCRFs as soon as possible, preferably 
within 5 days after the visit/telephone contact. Once data has been entered, it will be available to 
Novo Nordisk for data verification and validation purposes.
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.
14 Monitoring procedures 
Monitoring will be conducted under a risk-based approach. 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 for trial sites with subjects in screening, treatment or follow-up.
The monitor must be given direct access to source documents (original documents, data and 
records). Direct access includes permission to examine, analyse, verify and reproduce any record(s) 
and report(s) that are important to the evaluation of the trial. If the electronic medical record does 
not have a visible audit trail, the investigator must provide the monitor with signed and dated 
printouts. In addition the relevant trial site staff should be available for discussions at monitoring 
visits and between monitoring visits (e.g. by telephone).
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The eCRF must not be used for capturing source data, i.e. all data recorded in the eCRF must be 
verifiable in source documentation. 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.
The monitor will ensure that the CRFs are completed and any paper CRFs are collected.
Monitor will review the subject's medical records and other source data to ensure consistency 
and/or identify omissions compared to the CRF. If discrepancies are found, the investigator will be 
questioned about these.
A follow-up letter (paper or electronic) will be sent to the investigator following each monitoring 
visit. This will address any action to be taken.
15 Data management
Data management is the responsibility of Novo Nordisk. Data management may be delegated under 
an agreement of transfer of responsibilities to a data management unit within Novo Nordisk or a 
CRO.
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 may use their own electronic systems to capture source data.
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17 Statistical considerations
The blinding of the randomised treatments will be maintained until the database has been released 
for statistical analysis. No interim analyses or other analyses of unblinded or between group data 
will be performed before the database is locked, with the exception of those highly confidential 
analyses performed by an external independent statistician to support the deliberations of the DMC 
(see section 12.7.2) or in direct response to a recommendation by the DMC.
If necessary, a statistical analysis plan (SAP) may be written in addition to the protocol, including a 
more technical and detailed elaboration of the statistical analyses. The SAP will be finalised before 
database lock.
Data from all sites will be analysed and reported together.
In statistical analyses where stratification is included, the evidence of cardiovascular disease at 
screening (presence of cardiovascular disease or risk factors only) will be included based on the 
actual information collected through the eCRF. In case of missing eCRF information the 
information collected in IV/WRS will be used.
The latest available measurement, at or prior to the randomisation visit, will be used as the baseline 
measurement. If no measurement(s) have been obtained, at or prior to randomisation, the baseline 
value will be left missing.
Laboratory values below the lower limit of quantification (LLoQ) will be set to ½LLoQ. Number of 
values below LLoQ by treatment and visit will be summarised if deemed relevant.
If no statistical analysis is specified, data will be presented using relevant summary statistics.
Primary estimand
The trial aims to confirm that treatment with oral semaglutide does not result in an unacceptable 
increase (80% excess risk) in cardiovascular risk compared to placebo in subjects with T2D at high 
risk of cardiovascular events. Time from randomisation to first MACE will be the primary endpoint 
and treatment arms will be compared using the hazard ratio. This is an event-driven trial and 
information is planned to be collected on all randomised subjects until at least 122 first MACEs 
have accumulated during the planned trial duration of 19 months.
Primary estimand:
!
de-facto estimand comparing oral semaglutide and placebo for all randomised subjects. 
Subjects who discontinue treatment with trial product should be followed according to the 
planned visit schedule. Estimation of the primary estimand will include all first MACEs 
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collected during the trial as defined by the in-trial observation period (see section 17.2) 
regardless of adherence to randomised treatment.
17.1
Sample size calculation
Firstly, the primary endpoint; time from randomisation to first occurrence of a MACE composite 
endpoint consisting of: cardiovascular death, non-fatal myocardial infarction or non-fatal stroke, 
will be tested for non-inferiority using a 1.8 non-inferiority margin. If the hypothesis is confirmed, 
the confirmatory secondary endpoint; time from randomisation to first occurrence of an expanded 
composite cardiovascular endpoint consisting of: cardiovascular death, non-fatal myocardial 
infarction, non-fatal stroke, unstable angina requiring hospitalisation or hospitalisation for heart 
failure, will be tested for non-inferiority using a 1.8 non-inferiority margin. The type-I-error will be 
preserved in the strong sense at 5% (two-sided) when using the hierarchical testing strategy.
The sample size is made to ensure a power of 90% for testing the confirmatory hypothesis for the 
primary endpoint. Based on a logrank test, a total of 122 first MACEs will provide 90% power to 
rule out hazard ratios exceeding 1.8, assuming a true hazard ratio of 1.0.
In order to have a total of 122 first MACEs with trial duration of 19 months and 1,588 subjects 
randomised to each treatment group (1:1 randomisation), in total 3,176 subjects, the following is 
assumed based on the trials EX2211-3748 (LEADER®) and NN9535-3744 (SUSTAIN™6):
!
First MACEs occur at a rate of 3 per 100 patient years of observation time (PYO) in both 
treatment groups throughout the trial
!
Recruitment into the trial occurs uniformly during 7 months
!
The lost-to-follow-up rate is 1% per year throughout the trial
!
LSLV occurs 19 months after first subject was randomised
Table 17–1 shows expected trial duration for different event rates under the same assumptions as 
described above for the other parameters.
Table 17–1
Expected trial duration according to event rates
Event rate per 100 PYO in 
both treatment arms
2.5
2.75
3.0
3.25
3.5
Expected trial duration from 
randomisation of subject to 
LSLV (months)
22.2
20.4
19
17.8
16.7
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17.2
Definition of analysis sets
The following analysis set is defined:
!
Full analysis set (FAS): includes all randomised subjects. The statistical evaluation of the 
FAS will follow the intention-to-treat (ITT) principle and subjects will contribute to the
evaluation “as randomised”.
In this trial, two observation periods will be defined. Definition of the observation periods:
!
In-trial observation period: This observation period will include information assessed 
from randomisation to the date of the last subject-site contact regardless of adherence to 
treatment, which is scheduled to take place 5 weeks (with a +3 days visit window) after last 
planned dose of the trial product. The 5 weeks follow-up period corresponds to 
approximately five half-lives of oral semaglutide. For subjects lost to follow-up the end-date 
will be the date of the last contact with the subject (site visit or by telephone). If a subject 
dies during the trial, the date of death will be the end-date of the in-trial observation period 
regardless of the above defined end-dates.
!
On-treatment observation period: This observation period is a subset of the in-trial 
observation period and will include information assessed on or after the first date of trial 
product up to and including the first date of (i) last date on trial product +38 days or (ii) 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 
oral semaglutide. In addition, the ascertainment window includes the follow-up visit 
window of +3 days after last date on trial product.
Subjects not having a MACE within the observation period will be censored at the end of the 
observation period in the primary analysis assuming independent censoring for subjects lost to 
follow-up. Hence, a subject censored at a given time should be representative of those still at risk at 
that time point. For EAC confirmed events the onset date will be the onset date assessed by the 
EAC. EAC confirmed events with adjudicated onset date prior to randomisation will be described in 
listings. EAC confirmed events with adjudicated onset date after in-trial observation period but 
prior to database lock will be evaluated and summarised descriptively. For events not subjected to 
adjudication or negatively adjudicated, the onset date for the adverse event reported by the 
investigator will be used.
17.3
Primary endpoint
!
Time from randomisation to first occurrence of a MACE composite endpoint consisting of: 
cardiovascular death, non-fatal myocardial infarction or non-fatal stroke
The primary estimand will be estimated based on the FAS and the in-trial observation period. The 
primary statistical analysis of the primary endpoint will be a stratified Cox proportional hazards 
model with treatment group (oral semaglutide, placebo) as fixed factor. The model will be stratified
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by evidence of cardiovascular disease at screening (presence of cardiovascular disease or risk 
factors only). From this model the estimated hazard ratio (HR) (oral semaglutide/placebo) together 
with the 2-sided 95% confidence interval will be presented. Non-inferiority of oral semaglutide 
versus placebo will be considered confirmed if the upper limit of the two-sided 95% confidence 
interval for the HR is below 1.8 or equivalent if the p-value for the one-sided test of
H0: HR ≥ 1.8 against Ha: HR < 1.8
is less than 2.5% (or equivalent to 5% for a two-sided test).
A Kaplan-Meier plot with number of subjects at risk at specific time points will be presented and 
used graphically to assess the validity of the assumption of proportional hazards. This will be 
supported by the use of Schoenfeld residuals.
17.3.1
Sensitivity analysis
To explore the robustness of the primary analysis results the following sensitivity analyses will be 
performed. The sensitivity analyses will evaluate different de-jure estimands and, thus, will focus 
on events occurring while subjects to a greater extent compared to the primary estimand are 
treatment adherent. Different observation periods will be defined considering treatment adherence 
and different follow-up periods after last date on trial product. All sensitivity analyses will be based 
on FAS and analysed using the same model as the primary analysis including the censoring rules
and the assumption of independent censoring for subjects with shorter observation period than the 
trial duration.
Sensitivity analysis 1: Including additional covariates
This sensitivity analysis will explore the primary analysis by fitting a stratified Cox regression 
analysis and estimate of the treatment hazard ratio (oral semaglutide/placebo) with a 2-sided 95% 
confidence interval while including the additional covariates sex, region, baseline age, diabetes 
duration, smoking history, and eGFR at baseline. The model will be stratified by evidence of 
cardiovascular disease at screening (presence of cardiovascular disease or risk factors only). The 
analysis will be based on the FAS and the in-trial observation period. 
Sensitivity analysis 2: Ascertainment window of 38 days after last date on trial product
This sensitivity analysis will include all first MACEs that are collected in the on-treatment 
observation period.
Sensitivity analysis 3: Ascertainment window of 7 days after last date on trial product
This sensitivity analysis will include all first MACEs that are collected on or after the first date on 
trial product up to and including the last date on trial product +7 days.
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Protocol
Date:
03 November 2016
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Trial ID: NN9924-4221
Version:
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UTN: U1111-1173-0750
Status:
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17.4
Secondary endpoints
17.4.1
Confirmatory secondary endpoint
!
Time from randomisation to first occurrence of an expanded composite cardiovascular 
endpoint consisting of: cardiovascular death, non-fatal myocardial infarction,  non-fatal 
stroke, unstable angina requiring hospitalisation or hospitalisation for heart failure
The confirmatory secondary endpoint will be analysed using the same analysis including sensitivity 
analyses as for the primary endpoint.
17.4.2
Safety endpoints
Time to event endpoints
!
Time from randomisation to first occurrence of each of the individual components in the 
expanded composite cardiovascular endpoint
!
Time from randomisation to first occurrence of a composite endpoint consisting of: all-cause 
death, non-fatal myocardial infarction or non-fatal stroke
!
Time from randomisation to all-cause death
!
Time to permanent discontinuation of trial product due to AE(s)
The analyses of the above time-to-event composite endpoints (except for the last endpoint) will be 
the same as the primary analysis. The analysis of time to permanent discontinuation of trial product 
due to AE(s) will be adjusted for the competing risk of other predefined reasons for discontinuing 
trial product prematurely. The above analyses will be based on the FAS and performed for both the 
in-trial and on-treatment observation periods. Cumulative incidence functions will be plotted for all 
of the endpoints.
Adverse events
!
Number of SAEs
All AEs will be coded using the most recent version of Medical Dictionary for Regulatory 
Activities (MedDRA).
SAEs will be summarised 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 patient years of observation time (R). The summaries will be based on FAS and performed for 
both the in-trial and the on-treatment observation periods. Furthermore, events confirmed by 
adjudication and AEs leading to discontinuation of trial product will be summarised as above.
CONFIDENTIAL


Protocol
Date:
03 November 2016
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Trial ID: NN9924-4221
Version:
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UTN: U1111-1173-0750
Status:
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EudraCT No.: 2015-003563-10
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Continuous safety endpoints
Change from baseline to last assessment of:
!
Pulse
!
Systolic and diastolic blood pressure
The last available measurement for the above endpoints will be analysed separately in an analysis of 
covariance (ANCOVA) with treatment group as fixed factors and the corresponding baseline value 
as a covariate. From the ANCOVAs the estimated treatment differences for oral semaglutide versus 
placebo together with the corresponding 2-sided 95% confidence intervals will be presented. The 
analyses will be based on FAS and performed for both the in-trial and the on-treatment observation 
periods.
Other safety endpoints
!
Biochemistry
!
Haematology
!
Calcitonin
!
Eye examination category
The above assessments will be summarised using descriptive statistics by treatment group for all 
scheduled visits and for last available assessment based on FAS and performed for both the in-trial 
and the on-treatment observation periods. Categorical safety endpoints will be summarised as 
counts and relative frequencies. Calcitonin will also be presented by sex.
17.4.3
Efficacy endpoints
Change from baseline to last assessment of:
!
HbA1c
!
Body weight
!
Lipids
The last available measurement for the above endpoints will be analysed separately in an ANCOVA 
with treatment group as fixed factors and the corresponding baseline value as a covariate. From the 
ANCOVAs the estimated treatment differences for oral semaglutide versus placebo together with 
the corresponding 2-sided 95% confidence intervals will be presented. The analyses will be based 
on FAS and performed for both the in-trial and the on-treatment observation periods. 
CONFIDENTIAL


Protocol
Date:
03 November 2016
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Trial ID: NN9924-4221
Version:
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UTN: U1111-1173-0750
Status:
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18 Ethics
The trial will be conducted in compliance with ICH GCP1 and applicable regulatory requirements, 
and in accordance with the Declaration of Helsinki2. When treatment with trial product ends, the 
subject and investigator will decide on the best available treatment for each subject.
18.1
Benefit–risk assessment of the trial
Risks and precautions
The nonclinical safety programme of oral semaglutide has not revealed any safety issues precluding 
use in humans. 
The sections below describe identified and potential risks and precautions associated with oral 
semaglutide treatment. These are based on findings in nonclinical and clinical trials with oral 
semaglutide as well as other GLP-1 RAs. For each of these risks and precautions, mitigating actions 
have been implemented to minimise the risks for subjects enrolled in this trial.
Identified risks
Gastrointestinal adverse events
Consistent with findings with other GLP-1 RAs, the most frequently reported AEs in clinical trials 
with oral semaglutide have been gastrointestinal disorders (nausea, vomiting, diarrhoea, dyspepsia 
and constipation). 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 
with 4 week dose-escalation steps have been implemented in the trial. In addition, in case a subject 
experiences unacceptable tolerability issues, dose reduction to a lower treatment dose is allowed. 
Potential risks
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 MEN 2 or MTC will not be enrolled in the trial. During the trial, calcitonin will be 
measured on a regular basis, and the guidance for investigators of further evaluation and action on 
elevated calcitonin concentrations is included in Appendix A. 
Acute pancreatitis
Acute pancreatitis has been reported in subjects treated with GLP-1 RAs including oral 
semaglutide. 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.
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Protocol
Date:
03 November 2016
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Trial ID: NN9924-4221
Version:
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Pancreatic cancer
Patients with T2D have an increased risk of certain types of cancer such as pancreatic cancer. There 
is currently no support from nonclinical- or clinical trials or postmarketing data that GLP-1-based 
therapies increase the risk of pancreatic cancer. However, pancreatic cancer has been included as a 
separate potential risk due to the scientific debate surrounding a potential association to GLP-1-
based therapies and the unknown long-term effects of stimulation of β-cells and suppression of α-
cells. Pancreatic cancer has been classified as a potential class risk of GLP-1 RAs by EMA.
Allergic reactions
As in the case with all protein based pharmaceuticals treatment with oral semaglutide may evoke 
allergic reactions. These may include urticaria, rash, 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.
Severe hypoglycaemia
Based on current knowledge about the GLP-1 RA drug class, there is a risk of hypoglycaemic 
episodes. Hypoglycaemic episodes have mainly been observed when a GLP-1 RA is combined with 
sulphonylurea or insulin. The risk for development of hypoglycaemia with oral semaglutide in 
combination with sulphonylurea and insulin is currently unknown. In this trial, it is recommended to 
reduce the dose of insulin and sulphonylurea at randomisation to reduce the risk of hypoglycaemia 
when introducing an additional glucose lowering agent.
Acute renal impairment
In subjects treated with GLP-1 RAs including oral semaglutide, gastrointestinal AEs such as 
nausea, vomiting and diarrhoea may lead to significant dehydration and secondary acute renal 
impairment. 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.
Sodium-glucose cotransporter-2 (SGLT2) inhibitors, an allowed background treatment, have also 
been associated with volume depletion. It is recommended to monitor for signs and symptoms of 
fluid loss during therapy. Severe dehydration may be a risk factor for diabetic 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.
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Date:
03 November 2016
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Trial ID: NN9924-4221
Version:
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Status:
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Other
Teratogenicity (embryo-foetal development toxicity)
Semaglutide caused embryo-foetal malformations in the rat through a GLP-1 receptor mediated 
effect on the inverted yolk sac placenta leading to impaired nutrient supply to the developing 
embryo. Primates do not have an inverted yolk sac placenta which makes this mechanism unlikely 
to be of relevance to humans. However, as a precaution, females who are pregnant, breast-feeding 
or intends 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 
at the site at screening, follow-up and at any time during the trial if a menstrual period is missed, or 
is required by local law.
Diabetic retinopathy complications
A transient worsening of diabetic retinopathy is a recognised complication in selected patients with 
diabetes after initiation of intensive antidiabetic treatment38-40. Risk factors for these events include 
long-standing poor glycaemic control and presence of proliferative retinopathy, and initial large 
improvements in blood glucose may be an additional aggravating factor. Several studies have, 
however, documented long-term beneficial effects of intensive glycaemic treatment in reducing 
retinopathy progression41, 42 even in intensively treated patients who experienced early worsening39. 
In a cardiovascular outcomes trial with s.c. semaglutide, results indicate an increased risk of events 
related to diabetic retinopathy in subjects treated with semaglutide compared to placebo. 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.
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 treatment. It is the responsibility of the 
investigator to ensure the best possible care according to the principles outlined in Diabetes Care 
2014 Standards of Medical Care in Diabetes43.
Further details with regards to safety of trial product are described in the current edition of the IB 
for oral semaglutide (NN9924)18, or any updates thereto.
Benefits
For all participating subjects, the anticipated benefits include a close monitoring of their T2D and 
an optimised antidiabetic treatment. All subjects will be treated within an antidiabetic regimen 
anticipated to be better than or equal to the treatment that they receive at the time of entry into the 
trial. The investigator is responsible for adjusting or adding antidiabetic medication throughout the 
course of the trial to maintain an adequate level of glycaemic control in each subject. In addition, it 
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Date:
03 November 2016
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Trial ID: NN9924-4221
Version:
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is expected that all subjects will benefit from participation through close contact with the trial site 
including thorough medical examinations and close follow-up of their T2D. Finally, data from two 
cardiovascular outcomes trials investigating treatment with GLP-1 RAs compared to placebo have 
indicated that there might be a potential beneficial effect of these drugs on cardiovascular outcomes 
when added to standard of care in subjects with T2D at high risk of cardiovascular events (see 
section 3.1.5).
Risk and benefit conclusion 
It is concluded that the potential benefits from participating in the trial outweigh the potential risks. 
The safety profile for the investigational medicinal product generated from the clinical and 
nonclinical development programme has not revealed any safety issues that would prohibit 
administration of oral semaglutide in accordance with the planned clinical trial.
18.2
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 data collected at follow-up will be retained by Novo Nordisk, 
entered into the database and used for the trial report. 
!
Safety events will be reported to Novo Nordisk and regulatory authorities according to 
local/national requirements.
If data is used, it will always be in accordance with local regulations and IRBs/IECs.
18.3
Information to subject during trial
The site will be offered a communication package to the subject during the conduct of the trial. The 
package content is issued by Novo Nordisk. The communication package will contain letters 
intended for distribution to the subjects. The letters will be translated and adjusted to local 
requirements and distributed to the subject at the discretion of the investigator. The subject may e.g. 
receive a “patient newsletter” during trial participation and a “thank you for your participation 
letter” after the trial has ended.
All written information to subjects must be sent to IRB/IEC for approval/favourable opinion and to 
regulatory authorities for approval or notification according to local regulations.
18.4
Premature termination of the trial and/or trial site
The DMC may recommend premature termination of the trial (cf. section 12.7.2).
Novo Nordisk, the IRBs/IECs or a regulatory authority may decide to stop the trial, part of the trial 
or a trial site at any time, but agreement on procedures to be followed must be obtained.
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Date:
03 November 2016
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Trial ID: NN9924-4221
Version:
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UTN: U1111-1173-0750
Status:
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If the trial is suspended or prematurely terminated, the investigator must inform the subjects 
promptly and ensure appropriate therapy and follow-up. The investigator and/or Novo Nordisk must 
also promptly inform the regulatory authorities and IRBs/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 IRBs/IECs in case it has an impact on the planned follow-up of subjects who have 
participated in the trial. If it has an impact, the actions needed to inform and protect the subjects 
should be described.
19 Protocol compliance
Deviations from the protocol should be avoided.
If deviations do occur, the investigator must inform the monitor and the implications of the 
deviation must be reviewed and discussed.
Deviations must be documented and explained in a protocol deviation by stating the reason, date, 
and the action(s) taken. Some deviations, for which corrections are not possible, can be 
acknowledged and confirmed via edit checks in the eCRF or via listings from the clinical database. 
Documentation on protocol deviations must be kept in the investigator's trial master file and 
sponsor trial master file.
For Mexico only: The above will include the following responsibilities for the head of the 
Institution/Health Care Establishment, Ethics, Research and, when applicable, Biosafety 
Committees and sponsor within their scope of responsibility:
a) Investigation follow-up
b) Damages to health arising from the investigation development; as well as those arising from 
interruption or advanced suspension of treatment due to non-attributable reasons to the subject
c) Timely compliance of the terms in which the authorization of a research for health in human 
beings had been issued
d) To present in a timely manner the information required by the Health Authority
20 Audits and inspections
Any aspect of the clinical trial may be subject to audits conducted by Novo Nordisk or inspections 
from domestic or foreign regulatory authorities or from IRBs/IECs. Audits and inspections may 
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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, the following documents must be available 
to Novo Nordisk:
!
Regulatory approval and/or acknowledgement of notification as required 
!
Approval/favourable opinion from IRBs/IECs clearly identifying the documents reviewed as 
follows: protocol, any protocol amendments, subject information/informed consent form, 
any other written information to be provided to the subject and subject recruitment materials
!
List of IRB/IEC members and/or constitution (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 Investigator's Brochure for oral semaglutide
!
Signed and dated Agreement on Protocol
!
Signed and dated agreement on protocol amendment, if applicable
!
Contract, signed by the investigator and/or appropriate parties on behalf of the investigator’s 
site and Novo Nordisk
!
Source document agreement
!
Central laboratory certification and normal ranges
!
Insurance statement, if applicable
!
Financial disclosure form from investigator and sub-investigator(s)
For US only: 
!
For US trial sites: verification under disclosures per Code of Federal Regulations (CFR) of 
Financial Conflict of Interest
!
For US trial sites: FDA form 1572 must be completed and signed by the investigator at each 
site
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FDA form 1572:
For US sites:
!
Intended for US sites
!
Conducted under the IND
!
All US investigators, as described above, will sign FDA Form 1572
For sites outside the US:
!
Intended for participating sites outside of the US
!
Not conducted under the IND
!
All investigators outside of the US will not sign FDA form 1572
By signing the protocol, each investigator agrees to comply fully with ICH GCP1, applicable 
regulatory requirements and the Declaration of Helsinki2. 
By signing the protocol, each investigator also agrees to allow Novo Nordisk to make investigator's 
name and information about site name and address publically available if this is required by 
national or international regulations.
22 Responsibilities
The investigator is accountable for the conduct of the trial at his/her site. If any tasks are delegated, 
the investigator must maintain a log of appropriately qualified persons to whom he/she has 
delegated specified trial-related duties. The investigator must ensure that there is adequate training 
for all staff participating in the conduct of the trial. It is the investigator's responsibility to supervise 
the conduct of the trial and to protect the rights, safety, and well-being of the subjects.
A qualified physician, who is an investigator or a sub-investigator for the trial, must be responsible 
for all trial-related medical decisions.
The investigator must ensure adequate supervision of the conduct of the trial at the trial site. 
The investigator will follow instructions from Novo Nordisk when processing data.
The investigator is responsible for filing essential documents (i.e. those documents which 
individually and collectively permit evaluation of the conduct of a trial and the quality of the data
produced) in the investigator trial master file. The documents including the subject identification 
code list should be kept in a secure locked facility, so no unauthorised persons can get access to the 
data. 
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The investigator will take all necessary technical and organisational safety measures to prevent 
accidental or wrongful destruction, loss or deterioration of data. The investigator will prevent any 
unauthorised access to data or any other processing of data against applicable law. The investigator 
must be able to provide the necessary information or otherwise demonstrate to Novo Nordisk that 
such technical and organisational safety measures have been taken.
During any period of unavailability, the investigator must delegate responsibility for medical care of 
subjects to a specific qualified physician who will be readily available to subjects during that time.
If the investigator is no longer able to fulfil the role as investigator (e.g. if he/she moves or retires), 
a new investigator will be appointed in consultation with Novo Nordisk. 
The investigator and other site personnel must have sufficient English skills according to their 
assigned task(s).
23 Reports and publications
The information obtained during the conduct of this trial is considered confidential, and may be 
used by or on behalf of Novo Nordisk for regulatory purposes as well as for the general 
development of the trial product. All information supplied by Novo Nordisk in connection with this 
trial shall remain the sole property of Novo Nordisk and is to be considered confidential 
information. 
No confidential information shall be disclosed to others without prior written consent from Novo 
Nordisk. Such information shall not be used except in the performance of this trial. The information 
obtained during this trial may be made available to other physicians who are conducting other 
clinical trials with the trial product, if deemed necessary by Novo Nordisk. Provided that certain 
conditions are fulfilled, Novo Nordisk may grant access to information obtained during this trial to 
researchers who require access for research projects studying the same disease and/or trial product 
studied in this trial.
Novo Nordisk may publish on its clinical trials website a redacted clinical trial report for this trial.
One or more investigator(s) will be appointed by Novo Nordisk to review and sign the clinical trial 
report (signatory investigator(s)) on behalf of all participating investigators. The signatory 
investigator(s) will be appointed based upon the criteria defined by the International Committee of 
Medical Journal Editors for research publications44. 
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23.1
Communication of results
Novo Nordisk commits to communicating, and otherwise making available for public disclosure, 
results of trials regardless of outcome. Public disclosure includes publication of a paper in a 
scientific journal, abstract submission with a poster or oral presentation at a scientific meeting, or 
disclosure by other means.
The results of this trial will be subject to public disclosure on external web sites according to 
international and national regulations, as reflected in the Novo Nordisk Code of Conduct for 
Clinical Trial Disclosure25.
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 Editors45 (sometimes referred to as the Vancouver 
Criteria).
At the end of the trial, one or more publications (abstracts, posters, manuscripts) will be prepared 
for submission to scientific congresses and peer-reviewed journals in collaboration between Novo 
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Nordisk and investigator(s) appointed by Novo Nordisk. These investigator(s) must meet the 
International Committee of Medical Journal Editors authorship criteria to be named authors on 
publications.
23.1.2
Site-specific publication(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 trial subjects' data available, and will be 
provided with the randomisation codes after the end of the trial.
24 Retention of clinical trial documentation and human biospecimens
24.1
Retention of clinical trial documentation
Subject's medical records must be kept for the maximum period permitted by the hospital, 
institution or private practice.
The investigator must agree to archive the documentation (this includes both electronic and paper-
based records) pertaining to the trial in an archive after completion or discontinuation of the trial if 
not otherwise notified. The investigator should not destroy any documents without prior permission 
from Novo Nordisk. If the investigator cannot archive the documents at the trial site, Novo Nordisk 
can refer the investigator to an independent archive provider that has a system in place to allow only 
the investigator to access the files.
The investigator must be able to access his/her trial documents without involving Novo Nordisk in 
any way. Site-specific CRFs and other subject data (in an electronic readable format or as paper 
copies or prints) will be provided to the investigator before access is revoked to the systems and/or 
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electronic devices supplied by Novo Nordisk. These data must be retained by the trial site. If the 
provided data (e.g. the CD-ROM) is not readable during the entire storage period, the investigator 
can request a new copy. A copy of all data will be stored by Novo Nordisk.
Novo Nordisk will maintain Novo Nordisk documentation pertaining to the trial for as long as the 
product is on the market plus 20 years. 
The files from the trial site/institution must be retained for 15 years after the completion of the trial, 
or longer if required by local regulations or Novo Nordisk. In any case trial files cannot be 
destroyed until the trial site/institution is notified by Novo Nordisk. The deletion process must 
ensure confidentiality of data and must be done in accordance with local regulatory requirements.
24.2
Retention of human biospecimens
In order to comply with any future requests from health authorities to further characterise the 
antibody response, antibody samples collected in relation to suspicion of hypersensitivity reactions
during the trial may be stored at Novo Nordisk until no further marketing authorisations are pending
or maximum 15 years after the trial ended, whichever comes first. Stored antibody samples will be 
identified only by a subject number, a visit number and a trial identification number. The 
investigator is responsible for maintaining a list which links each subject number to a subject name. 
This list must be kept for at least 15 years after the trial ended. The list may be reviewed by Novo 
Nordisk staff including auditors or representatives from regulatory authorities.
For Brazil only: Biological samples from Brazil will be destroyed at the end of the trial.
25 Institutional Review Boards/Independent Ethics Committees and 
regulatory authorities
IRB/IEC:
Written approval or favourable opinion must be obtained from IRB/IEC prior to commencement of 
the trial.
During the trial, the investigator or Novo Nordisk, as applicable, must promptly report the 
following to the IRB/IEC, in accordance with local requirements: updates to IB, SUSARs, protocol 
amendments according to local requirements, deviations to the protocol implemented to eliminate 
immediate hazards to the subjects, new information that may affect adversely the safety of the 
subjects or the conduct of the trial (including new benefit–risk analysis in case it will have an 
impact on the planned follow-up of the subjects), annually written summaries of the trial status, and 
other documents as required by the local IRB/IEC.
CONFIDENTIAL


Protocol
Date:
03 November 2016
Novo Nordisk
Trial ID: NN9924-4221
Version:
5.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
78 of 82
The investigator must ensure submission of the clinical trial report synopsis to the IRB/IEC.
Protocol amendments must not be implemented before approval or favourable opinion according to 
local regulations, unless necessary to eliminate immediate hazards to the subjects.
The investigator must maintain an accurate and complete record of all submissions made to the 
IRB/IEC. The records must be filed in the investigator trial master file and copies must be sent to 
Novo Nordisk.
Regulatory Authorities:
Regulatory authorities will receive the clinical trial application, protocol amendments, reports on 
SAEs, and the clinical trial report according to national requirements.
26 Indemnity statement
Novo Nordisk carries product liability for its products, and liability as assumed under the special 
laws, acts and/or guidelines for conducting clinical trials in any country, unless others have shown 
negligence.
Novo Nordisk assumes no liability in the event of negligence, or any other liability of the sites or 
investigators conducting the trial, or by persons for whom the said site or investigator are 
responsible.
Novo Nordisk accepts liability in accordance with:
For Argentina only: Novo Nordisk Pharma Argentina S.A. has contracted insurance as required by 
local law.
For Germany only: German Drug Law dated August 24, 1976, last amended by article 3 of the law 
dated December 17, 2014 (Federal Law Gazette I p. 2222).
For Mexico only: Novo Nordisk carries product liability for its products and liability as assumed
under the special laws, acts/and/or guidelines for conducting trials in any country, including those 
applicable provisions on the Mexican United States. If the subject feels that something goes wrong 
during the course of this trial, the subject should contact the trial staff in the first instance.
If during their participation in the trial the subject experiences a disease or injury that, according 
to the trial doctor and the sponsor, is directly caused by the study medication and/or a study 
procedure that otherwise would not have been part of his/her regular medical care, the subject will 
receive from the Institution or Medical Care Establishment and free of charge, the appropriate 
CONFIDENTIAL


Protocol
Date:
03 November 2016
Novo Nordisk
Trial ID: NN9924-4221
Version:
5.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
79 of 82
medical treatment as required. In this case, the costs resulting from such treatment as well as the 
costs of any indemnification established by law will be covered by the trial sponsor in accordance 
with the terms provided by all applicable regulations; even if the subject discontinues his/her 
participation in the study by his own will or by a decision from the investigator.
By signing the informed consent, the subject will not renounce to any compensation or 
indemnification he/she may be entitled to by law, nor will he/she will incur any additional expense 
as a result of his/her participation in the trial; any additional expense resulting from the subject’s 
participation in the trial will be covered by the trial sponsor.
For the Netherlands only: Wetgeving betreffende geneesmiddelen; geneesmiddelenwet 1 juli 2007 
(Medicines Law, 1 July 2007). De Wet Medisch-wetenschappelijk Onderzoek met mensen (WMO), 1 
maart 2006 (Medical Research Involving Human Subjects Act, 1 March 2006). Besluit verplichte 
verzekering bij medisch-wetenschappelijk onderzoek met mensen 2015, 24 november 2014 (Decree 
compulsory insurance in medical research involving human subjects 2015, 24 November 2014).
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 the investigators 
are covered by the insurance policy issued according to applicable Polish law.
CONFIDENTIAL


Protocol
Date:
03 November 2016
Novo Nordisk
Trial ID: NN9924-4221
Version:
5.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
80 of 82
27 References
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DeFronzo RA. Pathogenesis of type 2 diabetes mellitus. Med Clin North Am.
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Bagger JI, Knop FK, Lund A, Vestergaard H, Holst JJ, Vilsboll T. Impaired regulation of 
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normalisation of blood glucose improves the insulin response to glucagon-like peptide-1 and 
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Toft-Nielsen MB, Damholt MB, Madsbad S, Hilsted LM, Hughes TE, Michelsen BK, et al. 
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Investigator's Brochure for s.c. Semaglutide (NN9535), Edition 11 or any updates hereof. 
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CONFIDENTIAL


Protocol
Date:
03 November 2016
Novo Nordisk
Trial ID: NN9924-4221
Version:
5.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
81 of 82
18.
Investigator's Brochure for oral semaglutide (NN9924), edition 7 or any updates hereof. 
2016.
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Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, et al. 
Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016.
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Novo Nordisk A/S. Company Announcement: SUSTAIN 6. 2016.
21.
European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP). 
Guideline on clinical investigation of medicinal products in the treatment or prevention of 
diabetes mellitus (CPMP/EWP/1080/00 Rev. 1). Adoption by CHMP. 14 May 2012.
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U.S. Food and Drug Administration. Guidance for Industry. Diabetes Mellitus - Evaluating 
Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. 2008.
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KDIGO. KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney international 
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Basi S, Fesler P, Mimran A, Lewis JB. Microalbuminuria in type 2 diabetes and 
hypertension: a marker, treatment target, or innocent bystander? Diabetes Care. 2008;31 
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Novo Nordisk A/S. How we disclose trial information. 2015.
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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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Drug Administration Amendments Act of 2007. 27 September 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 Councill of 4 April 2001 on the approximation of the 
laws, regulations and administrative provisions of the Member States relating to the 
implementation of good clinical practice in the conduct of clinical trials on medicinal 
products for human use, article 11. Official Journal of the European Communities. 1 May 
2001.
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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. 
Official Journal of the European Communities. 2004.
30.
Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, et al. 2015 
American Thyroid Association Management Guidelines for Adult Patients with Thyroid 
Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines 
Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. 2016;26(1):1-
133.
31.
Criteria Committee of the New York Heart Association. Nomenclature and criteria for 
diagnosis of diseases of the heart and great vessels. 9th ed. Boston, MA: Little, Brown & 
Co. 1994.
32.
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.
CONFIDENTIAL


Protocol
Date:
03 November 2016
Novo Nordisk
Trial ID: NN9924-4221
Version:
5.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
82 of 82
33.
Banks PA, Freeman ML, Practice Parameters Committee of the American College of G. 
Practice guidelines in acute pancreatitis. Am J Gastroenterol. 2006;101(10):2379-400.
34.
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.
35.
Food and Drug Administration. Guidance for Industry:Immunogenicity Assessment for 
Therapeutic Protein Products. 8/2015 2015.
36.
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). 3 February 2010.
37.
Hicks KA, Hung HMJ, Mahaffey KW, Mehran R, Nissen SE, Strockbridge NL, et al. 
Standardized Definitions for Cardiovascular and Stroke End Point Events in Clinical Trials 
(Draft). 20 Aug 2014.
38.
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 
dependent diabetes mellitus: the Oslo study. Br Med J (Clin Res Ed). 1985;290(6471):811-
5.
39.
Early worsening of diabetic retinopathy in the Diabetes Control and Complications Trial. 
Arch Ophthalmol. 1998;116(7):874-86.
40.
Varadhan L, Humphreys T, Walker AB, Varughese GI. The impact of improved glycaemic 
control with GLP-1 receptor agonist therapy on diabetic retinopathy. Diabetes Res Clin 
Pract. 2014;103(3):e37-9.
41.
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.
42.
UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with 
sulphonylureas or insulin compared with conventional treatment and risk of complications 
in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352(9131):837-53.
43.
American Diabetes Association. Standards of medical care in diabetes (2014). Diabetes care. 
2014;37 Suppl 1:S14-S80.
44.
International Committee of Medical Journal Editors. Recommendations for the Conduct, 
Reporting, Editing, and Publication of Scholarly Work in Medical Journals. 12/16/2014 
2014.
45.
International Committee of Medicinal Journal Editors. Uniform Requirements for 
Manuscripts submitted to Biomedical Journals. N Engl J Med. 1997;336:309-15.
CONFIDENTIAL

SAP_001.pdf: 
Cover Page for Statistical analysis plan 
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT02692716 
Sponsor trial ID: 
NN9924-4221 
Official title of study: 
PIONEER 6 – Cardiovascular outcomes trial. 
A trial investigating the cardiovascular safety of oral 
semaglutide in subjects with type 2 diabetes 
Document date: 
11 February 2019 
 


Link
List of contents
Statistical analysis plan......................................................................................................................
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
Oral semaglutide
Trial ID: NN9924-4221
Clinical Trial Report
Appendix 16.1.9
11 February 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:
01 November 2018
Novo Nordisk
Trial ID: NN9924-4221
Version:
2.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
1 of 16
Statistical Analysis Plan
Trial ID: NN9924-4221
PIONEER 6 – Cardiovascular outcomes
A trial investigating the cardiovascular safety of oral 
semaglutide in subjects with type 2 diabetes
Author:
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.


Statistical Analysis Plan
CONFIDENTIAL
Date:
01 November 2018
Novo Nordisk
Trial ID: NN9924-4221
Version:
2.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
2 of 16
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 .....................................................................................................................6
2.1
Sample size calculation .............................................................................................................7
2.2
Definition of analysis sets..........................................................................................................8
2.3
Trial completers, treatment completers, and lost to follow-up ....................................................9
2.4
Primary endpoint.......................................................................................................................9
2.4.1
Sensitivity analyses................................................................................................10
2.4.2
Exploratory subgroup analyses of the primary endpoint..........................................11
2.5
Secondary endpoints ...............................................................................................................12
2.5.1
Safety endpoints ....................................................................................................12
2.5.2
Efficacy endpoints .................................................................................................14
2.6
Adverse events and adjudication..............................................................................................14
3
Changes to the statistical analyses planned in the protocol..............................................................15
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
01 November 2018
Novo Nordisk
Trial ID: NN9924-4221
Version:
2.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
3 of 16
List of abbreviations
AE
adverse event
BMI
body mass index
CI
confidence interval
CKD-Epi
Chronic Kidney Disease Epidemiology Collaboration
CTR
clinical trial report
eCRF
electronic case report form
DMC
data monitoring committee
EAC 
event adjudication committee
eGFR
glomerular filtration rate, estimated
FAS 
full analysis set
HbA1c
glycosylated haemoglobin
HR
hazard ratio
ITT
intention-to-treat
IV/WRS
interactive voice/web response system
LLoQ 
lower limit of quantification
LSLV
last subject last visit
MACE
major adverse cardiovascular event
MedDRA
Medical Dictionary for Regulatory Activities
PYO
patient years of observation time
SAP
statistical analysis plan
s.c.
subcutaneous(ly)
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
01 November 2018
Novo Nordisk
Trial ID: NN9924-4221
Version:
2.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
4 of 16
1
Introduction
1.1
Trial information
This trial is a randomised, double-blind, placebo-controlled trial to assess the cardiovascular safety 
of oral semaglutide versus placebo when added to standard of care in subjects with type 2 diabetes 
at high risk of cardiovascular events.
Primary objective
The primary objective is to confirm that treatment with oral semaglutide does not result in an 
unacceptable increase in cardiovascular risk compared to placebo (rule out 80% excess risk) in 
subjects with type 2 diabetes at high risk of cardiovascular events.
Secondary objectives
The secondary objectives are to compare the efficacy and safety of oral semaglutide versus placebo 
in subjects with type 2 diabetes at high risk of cardiovascular events.
Trial design
Subjects will be randomised 1:1 to receive either oral semaglutide or placebo. The randomisation 
will be stratified according to evidence of cardiovascular disease at screening (presence of 
cardiovascular disease or presence of cardiovascular risk factors only). The stratum ‘presence of 
cardiovascular disease’ consists of subjects at least 50 years of age and recognised as fulfilling at 
least one item of inclusion criterion no. 3a-h at screening, whereas the stratum ‘presence of 
cardiovascular risk factors only’ consists of subjects at least 60 years of age and recognised as 
fulfilling at least one item of inclusion criterion no. 3i-l and not fulfilling any of the items of 
inclusion criterion no. 3a-h at screening (see protocol, section 6.2).
The trial will be event-driven and will be continued until at least 122 first major adverse 
cardiovascular events (MACE) confirmed by the external event adjudication committee (EAC) have 
accrued. Throughout the remainder of this statistical analysis plan (SAP), MACEs will be defined 
as MACEs confirmed by adjudication. Adverse events with fatal outcome where the EAC have 
adjudicated the cause of death as undetermined cause of death will also be counted as a 
cardiovascular death. 
The recruitment period is expected to last 7 months. The treatment period for each subject is 
expected to be between 12 and 19 months, depending on the time-point of recruitment and the 
accrual of first MACEs. The follow-up period is 5 weeks to allow for wash-out of trial product.
1.2
Scope of the statistical analysis plan
This SAP is based on the protocol for trial NN9924-4221, version 5.0 (03 November 2016), and 
includes more detailed procedures for executing the statistical analyses of the primary and 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
01 November 2018
Novo Nordisk
Trial ID: NN9924-4221
Version:
2.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
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secondary endpoints. Statistical analyses (additional to those specified in the trial protocol) and a 
number of changes and clarifications are pre-specified within this SAP. All changes to the statistical 
analyses planned in the trial protocol are documented in section 3.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
01 November 2018
Novo Nordisk
Trial ID: NN9924-4221
Version:
2.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
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2
Statistical considerations
General considerations
Novo Nordisk will be responsible for the statistical analyses and reporting. 
The blinding of the randomised treatments will be maintained until the database has been released 
for statistical analysis. No interim analyses or other analyses of unblinded or between group data 
will be performed before the database is locked, with the exception of those highly confidential 
analyses performed by an external independent statistician to support the deliberations of the data 
monitoring committee (DMC) or in direct response to a recommendation by the DMC.
Data from all sites will be analysed and reported together.
In statistical analyses where stratification is included, the evidence of cardiovascular disease at 
screening (presence of cardiovascular disease or presence of cardiovascular risk factors only) will 
be included based on the actual information collected through the electronic case report form 
(eCRF). In case of missing eCRF information the information collected in the interactive voice/web 
response system (IV/WRS) will be used.
The latest available measurement, at or prior to the randomisation visit, will be used as the baseline 
measurement. If no measurement(s) have been obtained, at or prior to randomisation, the baseline 
value will be left missing.
Laboratory values below the lower limit of quantification (LLoQ) will be set to ½LLoQ. The 
number of values below the LLoQ will be summarised by treatment group and visit if deemed 
relevant.
If no statistical analysis is specified, data will be presented using relevant summary statistics.
Estimand
The trial aims to confirm that treatment with oral semaglutide does not result in an unacceptable 
increase (80% excess risk) in cardiovascular risk compared to placebo in subjects with type 2 
diabetes at high risk of cardiovascular events. Time from randomisation to first MACE will be the 
primary endpoint and treatment arms will be compared using the hazard ratio. This is an event-
driven trial and information is planned to be collected on all randomised subjects until at least 122 
first MACEs have accumulated during the planned trial duration of 19 months.
Estimand – ‘Treatment policy’: 
!
Treatment policy estimand comparing oral semaglutide and placebo for all randomised subjects. 
Subjects who discontinue treatment with trial product should be followed according to the 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
01 November 2018
Novo Nordisk
Trial ID: NN9924-4221
Version:
2.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
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planned visit schedule. Evaluation of the primary estimand will include all first MACEs 
collected during the trial as defined by the in-trial observation period (see section 2.2) regardless 
of adherence to randomised treatment.
2.1
Sample size calculation
Firstly, the primary endpoint, time from randomisation to first occurrence of a MACE composite 
endpoint consisting of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke will 
be tested for non-inferiority using a 1.8 non-inferiority margin. 
Secondly, if non-inferiority is confirmed, the endpoint will be tested for superiority. The type-I-
error will be preserved in the strong sense at 5% (two-sided) when using the hierarchical testing 
strategy.
The sample size is made to ensure a power of 90% for testing the confirmatory hypothesis for the 
primary endpoint with respect to non-inferiority. Based on a logrank test, a total of 122 first 
MACEs will provide 90% power to rule out a hazard ratio exceeding 1.8, assuming a true hazard 
ratio of 1.0.
In order to have a total of 122 first MACEs with trial duration of 19 months and 1,588 subjects 
randomised to each treatment group (1:1 randomisation), in total 3,176 subjects, the following is 
assumed based on the trials EX2211-3748 (LEADER®) and NN9535-3744 (SUSTAIN 6):
!
First MACEs occur at a rate of 3 per 100 patient years of observation time (PYO) in both 
treatment groups throughout the trial
!
Recruitment into the trial occurs uniformly during 7 months
!
The lost to follow-up rate is 1% per year throughout the trial
!
Last subject last visit (LSLV) occurs 19 months after first subject was randomised
Table 2–1 shows expected trial duration for different event rates under the same assumptions as 
described above for the other parameters.
Table 2–2 shows the power of the superiority test for different true hazard ratios of oral semaglutide 
vs. placebo, and for different expected number of accrued first MACEs. Furthermore, the power 
calculations are based on the actual recruitment time of 225 days, anticipated total trial duration of 
619 days and a lost-to-follow-up rate of 1% per year throughout the trial. The first MACE rate is set 
to 3.3 per 100 PYO.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
01 November 2018
Novo Nordisk
Trial ID: NN9924-4221
Version:
2.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
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Table 2–1
Expected trial duration according to event rates
Event rate per 100 PYO in 
both treatment arms
2.5
2.75
3.0
3.25
3.5
Expected trial duration from 
randomisation of subject to 
LSLV (months)
22.2
20.4
19
17.8
16.7
Table 2–2
Calculated powers for the superiority test
True hazard ratio of oral 
semaglutide vs. placebo
0.75
0.8
0.85
0.90
Power (%), 122 events
36
24
15
9
Power (%), 130 events
38
25
15
9
Power (%), 140 events
40
27
16
9
2.2
Definition of analysis sets
The following analysis set is defined:
!
Full analysis set (FAS): includes all randomised subjects. The statistical evaluation of the FAS 
will follow the intention-to-treat (ITT) principle and subjects will contribute to the evaluation 
“as randomised”.
In this trial, two observation periods will be defined:
!
In-trial observation period: This observation period will include information assessed from 
randomisation to the date of the follow-up visit regardless of adherence to randomised 
treatment. For subjects withdrawn or lost to follow-up the end date will be the date of last 
contact with the subject (site visit or by telephone). If a subject dies during trial, the end date 
will be the date of death. If a subject dies after the follow-up visit and the death is linked by 
adjudication to a MACE occurring during the trial, the end date will be the date of death.
!
On-treatment observation period: This observation period is a subset of the in-trial 
observation period and will include information assessed on or after the first date of trial 
product up to and including the first date of (i) last date on trial product +38 days or (ii) 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 oral 
semaglutide. In addition, the ascertainment window includes the follow-up visit window of +3 
days after last date on trial product.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
01 November 2018
Novo Nordisk
Trial ID: NN9924-4221
Version:
2.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
9 of 16
Subjects not having a MACE within the observation period will be censored at the end of the 
observation period in the analysis of the primary endpoint assuming independent censoring for 
subjects withdrawn or lost to follow-up. Hence, a subject censored at a given time should be 
representative of those still at risk at that time point. For events confirmed by the EAC, the onset 
date used will be the onset date given by the EAC. EAC confirmed events with EAC given onset 
date either before randomisation or after the in-trial observation period will be presented in listings 
in the clinical trial report (CTR). For events not subjected to adjudication or not confirmed by the 
EAC, the onset date for the adverse event (AE) reported by the investigator will be used.
2.3
Trial completers, treatment completers, and lost to follow-up
Trial completers are defined as subjects who either attend the follow-up visit (visit P18) or who die 
while considered an active trial participant. 
Treatment completers are defined as exposed subjects who are still on trial product at the end of 
treatment visit and hence, have not discontinued treatment permanently earlier in the trial. Subjects 
who die while on trial product are also considered treatment completers.
A subject is considered lost to follow-up for visit P18 if the subject does not complete the trial and 
does not withdraw consent. 
Subjects who do not complete the trial and for whom a vital status cannot be determined before 
database lock are considered lost to follow-up for vital status.
2.4
Primary endpoint
The primary endpoint of the trial is:
!
Time from randomisation to first occurrence of a MACE composite endpoint consisting of: 
cardiovascular death, non-fatal myocardial infarction or non-fatal stroke
The analysis of the primary endpoint will be carried out for the treatment policy estimand using data 
from subjects in the FAS and in-trial observation period. The statistical analysis of the primary 
endpoint will be a stratified Cox proportional hazards model with treatment group (oral 
semaglutide, placebo) as fixed factor. The model will be stratified by evidence of cardiovascular 
disease at screening (presence of cardiovascular disease or presence of cardiovascular risk factors 
only). From this model the estimated hazard ratio (HR) (oral semaglutide/placebo) together with the 
2-sided 95% confidence interval (CI) will be presented. Non-inferiority of oral semaglutide versus 
placebo will be considered confirmed if the upper limit of the two-sided 95% confidence interval 
for the HR is strictly below 1.8 or equivalently if the p-value for the one-sided Wald test of
H0: HR ≥ 1.8 against HA: HR < 1.8
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
01 November 2018
Novo Nordisk
Trial ID: NN9924-4221
Version:
2.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
10 of 16
is strictly less than 2.5% (or equivalent to 5% for a two-sided Wald test).
A cumulative incidence function plot that accounts for the competing risk of non-cardiovascular 
death will be presented with number of subjects at risk at specific time points. The validity of the 
assumption of proportional hazards will be assessed graphically by the use of Schoenfeld residuals.
If the analysis of the primary endpoint confirms non-inferiority of oral semaglutide vs. placebo, it 
will be tested if oral semaglutide is also superior to placebo. Operationally the above analysis of the 
primary endpoint will be repeated and superiority of oral semaglutide vs. placebo is confirmed if the 
upper limit of the two-sided 95% confidence interval for the HR is strictly below 1.0.
2.4.1
Sensitivity analyses
To explore the robustness of the analysis of the primary endpoint the following sensitivity analyses 
will be performed. One sensitivity analysis will include additional covariates, whereas two other 
sensitivity analyses will be based on a different estimand evaluating the effect while subjects are on 
trial product, that is, prior to any permanent discontinuation of trial product. The two latter, will 
focus on events occurring during the on-treatment observation period and the on-treatment 
observation period using a more narrow period (+ 7 days) after the last of trial product, respectively. 
All three sensitivity analyses will be based on FAS and analysed using the same model as the 
analysis of the primary endpoint including the censoring rules and the assumption of independent 
censoring for subjects with shorter observation period than the trial duration.
Sensitivity analysis 1: Including additional covariates
This sensitivity analysis will explore the analysis of the primary endpoint by fitting a stratified Cox 
regression analysis and estimating the treatment hazard ratio (oral semaglutide/placebo) with a two-
sided 95% CI while including the additional covariates sex, region, baseline age, diabetes duration, 
smoking history, and eGFR at baseline. The model will be stratified by evidence of cardiovascular 
disease at screening (presence of cardiovascular disease or presence of cardiovascular risk factors 
only). The analysis will be based on the FAS and the in-trial observation period.
Age, duration of diabetes, and renal function (eGFR as per CKD-Epi) at baseline will be included as 
continuous variables. The other covariates will contain the following levels:
!
Sex: Female; male
!
Region: Africa (Algeria and South Africa); Asia (India, Malaysia, Taiwan, and Thailand); 
Europe (Denmark, Germany, Israel, Italy, The Netherlands, Poland, Romania, Spain, Turkey, 
and the United Kingdom); North America (Canada and the United States); and South America 
(Argentina, Brazil, and Mexico)
!
Smoking history: Current smoker; Never smoked; Previous smoker
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
01 November 2018
Novo Nordisk
Trial ID: NN9924-4221
Version:
2.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
11 of 16
Sensitivity analysis 2: Ascertainment window of 38 days after last date on trial product
This sensitivity analysis will include all first MACEs that are collected in the on-treatment 
observation period.
Sensitivity analysis 3: Ascertainment window of 7 days after last date on trial product
This sensitivity analysis will include all first MACEs that are collected on or after the first date on 
trial product up to and including the last date on trial product +7 days.
Sensitivity analysis 4: Tipping point analysis
If superiority is established for the primary endpoint, the following sensitivity analysis is 
performed. The primary analysis assumes independent censoring for patients who are lost to follow-
up or who withdrew consent. To investigate the impact of this assumption on the superiority results 
of the primary analysis, a tipping point analysis will be made. In this analysis, subjects in the oral 
semaglutide treatment group will have their event times imputed with an increasing penalty in the 
sense that their risk of MACE is increased (the penalty) following censoring compared to while 
under observation. The placebo subjects will be imputed with no penalty, i.e. assuming same event 
before and after censoring. One thousand (1000) imputed data sets will be analysed for each penalty 
using the above Cox model and results will be combined using Rubin’s rule. The tipping point is 
then defined as the penalty needed to turn around the superiority conclusion.
Sensitivity analysis 5: Including out-of-trial events
If superiority is established for the primary endpoint, two sensitivity analyses including out-of-trial 
observations will be performed. The analyses will include MACEs collected in the in-trial 
observation period and
1) reported EAC-confirmed deaths with EAC date of death after the in-trial period and before 
date of planned follow-up visit for subjects who withdrew consent or were lost to follow-up
2) reported MACEs with onset after the in-trial period and before global last patient last visit.
2.4.2
Exploratory subgroup analyses of the primary endpoint
The consistency in the treatment effect for the primary endpoint will be explored separately by the 
below defined subgroups based on baseline information: 
!
Sex: Female; male
!
Age: < 65 years; ≥ 65 years
!
Region: North America (Unites States and Canada); rest of the world
!
Race: White; Black or African American; Asian; Other
!
Body mass index (BMI): ≤ 30 kg/m2; > 30 kg/m2
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
01 November 2018
Novo Nordisk
Trial ID: NN9924-4221
Version:
2.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
12 of 16
!
HbA1c: ≤ 8.5%; > 8.5%
!
Myocardial infarction or stroke prior to randomisation: Yes; no
!
Renal function (eGFR) as per CKD-Epi: < 60 mL/min/1.73 m2; ≥60 mL/min/1.73 m2
!
Evidence of cardiovascular disease at screening: Presence of cardiovascular disease; presence of 
cardiovascular risk factors only
The subgroup analyses will be based on the FAS using the in-trial observation period. For each 
subgroup analysis, the primary endpoint will be analysed using a stratified Cox proportional hazards 
model with an interaction between treatment group (oral semaglutide, placebo) and the relevant 
subgroup as fixed factor. The model will be stratified by evidence of cardiovascular disease at 
screening (presence of cardiovascular disease or presence of cardiovascular risk factors only). From 
this model, the estimated hazard ratio for (oral semaglutide/placebo) together with corresponding 2-
sided 95% CI for each subgroup level will be presented. A forest plot showing the estimated hazard 
ratio and 95% CI by each subgroup level will be presented to explore the consistency of the primary 
analysis results across subgroup levels together with a p-value for an interaction effect. Merging of 
subgroup levels may be necessary if the amount of data is otherwise too small to perform the
subgroup analysis. In this case, the subgroup levels will be merged by combining the two levels 
with the smallest number of subjects until each level has a sufficient number of events.
2.5
Secondary endpoints
2.5.1
Safety endpoints
Time to event endpoints
!
Time from randomisation to first occurrence of an expanded composite cardiovascular endpoint 
consisting of: cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, unstable 
angina requiring hospitalisation or hospitalisation for heart failure
!
Time from randomisation to first occurrence of each of the individual components in the 
expanded composite cardiovascular endpoint
!
Time from randomisation to first occurrence of a composite endpoint consisting of: all-cause 
death, non-fatal myocardial infarction or non-fatal stroke
!
Time from randomisation to all-cause death
!
Time to first AE leading to permanent trial product discontinuation
The analyses of the above time-to-event endpoints will be the same as the primary analysis. The 
analyses will be based on the FAS and performed for both the in-trial and on-treatment observation 
periods, except for time to first AE leading to permanent trial product discontinuation which will 
only be based on the period from date of first dose on trial product to end of treatment visit. For 
subjects who are withdrawn or lost to follow up, the period will end at date of withdrawal. The 
cumulative incidence over time will be presented graphically based on the cumulative incidence 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
01 November 2018
Novo Nordisk
Trial ID: NN9924-4221
Version:
2.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
13 of 16
function accounting for competing risks. When competing risks are not present the cumulative 
incidence function reduces to a Kaplan-Meier based estimate.
Analysis of time from randomisation to first occurrence of fatal or non-fatal myocardial infarction, 
and to first occurrence of fatal or non-fatal stroke will also be performed in a similar manner as 
defined above.
Adverse events
!
Number of serious AEs
All AEs will be coded using version 20.1 of the Medical Dictionary for Regulatory Activities 
(MedDRA).
Serious AEs will be summarised 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 patient years of observation time (R). The summaries will be based on FAS and performed for 
both the in-trial and the on-treatment observation periods. Furthermore, events confirmed by 
adjudication and AEs leading to discontinuation of trial product will be summarised as above.
Continuous safety endpoints
Change from baseline to last assessment of:
!
Pulse
!
Systolic and diastolic blood pressure
Change from baseline will be summarised using descriptive statistics by treatment group for all 
scheduled visits and for last available assessment based on FAS and performed for both the in-trial 
and the on-treatment observation periods.
Other safety endpoints
!
Eye examination category
This endpoint will be summarised using counts and relative frequencies.
Other continuous safety assessments
!
Biochemistry
!
Haematology
!
Calcitonin
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
01 November 2018
Novo Nordisk
Trial ID: NN9924-4221
Version:
2.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
14 of 16
The above assessments will be summarised using descriptive statistics by treatment group for all 
scheduled visits and for last available assessment based on FAS and performed for both the in-trial
and the on-treatment observation periods. Calcitonin will also be presented by sex.
2.5.2
Efficacy endpoints
Change from baseline to last assessment of:
!
HbA1c
!
Body weight
!
Lipids
Change from baseline will be summarised using descriptive statistics by treatment group for all 
scheduled visits and for last available assessment based on FAS and performed for both the in-trial 
and the on-treatment observation periods.
2.6
Adverse events and adjudication
The PIONEER 6 trial employs selective safety data reporting (see protocol, section 12.2). Adverse 
events reported that can not be considered systematically collected as per protocol will not be 
included in the CTR. However, all events sent for adjudication, whether systematically collected or 
not, will be presented in listings in the CTR.
Fatal myocardial infarction and stroke are defined as EAC confirmed events of myocardial 
infarction or stroke where the EAC has related a death to the event. Other EAC confirmed events of 
myocardial infarction and stroke are defined as non-fatal.
The adjudication process will continue until database lock. Events occurring after the in-trial 
observation period will be presented in listings in the CTR.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
01 November 2018
Novo Nordisk
Trial ID: NN9924-4221
Version:
2.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
15 of 16
3
Changes to the statistical analyses planned in the protocol
The main analyses were described in the protocol for trial NN9924-4221. However, clarifications as 
well as more detailed descriptions of endpoints and analyses are provided in this SAP. The changes 
from protocol NN9924-4221 are summarised below:
!
Based on the findings in SUSTAIN 6, where subcutaneous (s.c.) administration of semaglutide 
showed a significant hazard ratio of s.c. semaglutide vs. placebo in the analysis of the same 
primary endpoint as in this trial, it has been decided to add a superiority test in the testing 
hierarchy in PIONEER 6. Hence, if non-inferiority of oral semaglutide vs. placebo is confirmed, 
a test for superiority will also be conducted. Consequently, the secondary confirmatory endpoint 
time from randomisation to first occurrence of an expanded composite cardiovascular endpoint
is now a secondary endpoint, and no sensitivity analyses will be carried out for this endpoint.
!
The consistency in the treatment effect for the primary endpoint will also be explored separately 
in a number of subgroups. 
!
Definitions of trial completers and treatment completers have been added. In addition, two types 
of lost to follow-up are specified: Lost to follow-up (subjects who do not complete the trial and 
do not withdraw consent), and lost to follow-up for vital status (subjects who do not complete 
the trial and where vital status is not determined at database lock).
!
The levels of the covariates in sensitivity analysis 1 have been specified.
!
The primary estimand has changed name from de-facto to treatment policy.
!
Where relevant, Kaplan-Meier plots have been replaced with cumulative incidence plots,
because Kaplan-Meier estimates do not take into account the possible confounding of
competing risks.
!
Sensitivity analyses have been added in the case that the outcome of the primary analysis shows 
superiority of oral semaglutide vs. placebo.
!
The analysis of time to permanent discontinuation of trial product due to AE(s) has been 
replaced by an analysis of time to first AE leading to permanent trial product discontinuation.
!
Analysis of time from randomisation to first occurrence of fatal or non-fatal myocardial 
infarction, and to first occurrence of fatal or non-fatal stroke has been added.
!
It has been specified that efficacy endpoints will be presented using summary statistics instead 
of performing statistical analyses. Since the trial is event driven the actual treatment period will 
vary from approximately 11 to 19 months between subjects completing the trial, so there will 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
01 November 2018
Novo Nordisk
Trial ID: NN9924-4221
Version:
2.0
UTN: U1111-1173-0750
Status:
Final
EudraCT No.: 2015-003563-10
Page:
16 of 16
not be a common landmark visit at the end of trial. For this reason the analyses of change from 
baseline to last assessment for the efficacy endpoints have been removed.
!
It has been specified that continuous safety endpoints will be presented using summary statistics 
instead of performing statistical analyses. The reason for this is that the endpoints were included 
to ensure that the investigators can monitor the individual subjects and to allow for detection of 
potential safety signals on a trial-level that is not reflected in adverse event reporting. In 
addition, biochemistry, haematology and calcitonin endpoints have been downgraded to 
assessments.
!
It has been clarified how to handle special situations with respect to event adjudication of 
adverse events.
CONFIDENTIAL