Clinical trial NCT02849080
Conditions: Diabetes Diabetes Mellitus, Type 2
Sponsor: Novo Nordisk A/S
Start date: 2016-09-20; Completion date: 2019-03-27
Enrollment: 504 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This trial is globally conducted. The aim of this trial is to investigate Efficacy and Safety of Oral Semaglutide Using a Flexible Dose Adjustment Based on Clinical Evaluation versus Sitagliptin in Subjects with Type 2 Diabetes Mellitus.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: semaglutide intervention 2: sitagliptin
Intervention descriptions: intervention 1: Oral administration once-daily. intervention 2: Oral administration once-daily.

Protocol documents:
Prot_000.pdf: 
Cover Page for Protocol 
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT02849080 
Sponsor trial ID: 
NN9924-4257 
Official title of study: 
PIONEER 7 – Flexible dose adjustment. Efficacy and Safety 
of Oral Semaglutide Using a Flexible Dose Adjustment Based 
on Clinical Evaluation versus Sitagliptin in Subjects with Type 
2 Diabetes Mellitus 
Document date: 
25 October 2018 
 


Link
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List of contents
Protocol ...............................................................................................................................................
Attachment I and II............................................................................................................................
Appendix A - Calcitonin monitoring ................................................................................................
Appendix B - Adverse events requiring additional data collection................................................
Protocol amendment 1 - global..........................................................................................................
Protocol amendment 2 - global..........................................................................................................
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
Oral semaglutide
Trial ID: NN9924-4257
Clinical Trial Report
Appendix 16.1.1
25 October 2018
1.0
Final
16.1.1 Protocol and protocol amendments
CONFIDENTIAL
Redacted protocol 
Lncludes redaction of personal identifiable DQGFRPSDQ\
FRQILGHQWLDOinformation. 
. 


Protocol
CONFIDENTIAL
Date:
06 April 2016
Novo Nordisk
Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103 
Status:
Final
EudraCT no.: 2015-005593-38
Page:
1 of 118
Protocol
Trial ID: NN9924-4257
PIONEER 7 – Flexible dose adjustment
Efficacy and Safety of Oral Semaglutide Using a Flexible Dose
Adjustment Based on Clinical Evaluation versus Sitagliptin in
Subjects with Type 2 Diabetes Mellitus
A 52-week Randomised, Open-label, Active-controlled Trial
Trial phase: 3a
Protocol originator
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol
CONFIDENTIAL
Date:
06 April 2016
Novo Nordisk
Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103 
Status:
Final
EudraCT no.: 2015-005593-38
Page:
2 of 118
Table of Contents
Page
Table of Contents..............................................................................................................................................2
Table of Figures................................................................................................................................................6
Table of Tables..................................................................................................................................................6
List of abbreviations.........................................................................................................................................7
1
Summary..................................................................................................................................................10
2
Flow chart ................................................................................................................................................14
3
Background information and rationale for the trial............................................................................20
3.1
Background information..............................................................................................................20
3.1.1
Type 2 diabetes mellitus ............................................................................................20
3.1.2
Glucagon-like peptide-1 ............................................................................................20
3.1.3
Oral semaglutide........................................................................................................20
3.1.4
Nonclinical data.........................................................................................................21
3.1.4.1
Semaglutide.........................................................................................21
3.1.4.2
SNAC ..................................................................................................22
3.1.5
Clinical data for oral semaglutide..............................................................................23
3.1.5.1
Pharmacokinetics ................................................................................23
3.1.5.2
Efficacy ...............................................................................................24
3.1.5.3
Safety...................................................................................................24
3.1.6
Sitagliptin...................................................................................................................25
3.2
Rationale for the trial...................................................................................................................25
4
Objectives and endpoints........................................................................................................................26
4.1
Objectives ....................................................................................................................................26
4.1.1
Primary objective.......................................................................................................26
4.1.2
Secondary objectives .................................................................................................26
4.2
Endpoints .....................................................................................................................................26
4.2.1
Primary endpoint........................................................................................................26
4.2.2
Secondary endpoints..................................................................................................26
4.2.2.1
Confirmatory secondary endpoints .....................................................26
4.2.2.2
Supportive secondary endpoints..........................................................27
5
Trial design ..............................................................................................................................................29
5.1
Type of trial .................................................................................................................................29
5.2
Rationale for trial design..............................................................................................................29
5.3
Treatment of subjects...................................................................................................................30
5.3.1
Oral semaglutide treatment........................................................................................30
5.3.2
Sitagliptin treatment...................................................................................................31
5.3.3
Dosing instructions ....................................................................................................31
5.3.4
Background medication.............................................................................................31
5.4
Treatment after discontinuation of trial product ..........................................................................32
5.5
Rationale for treatment ................................................................................................................32
6
Trial population.......................................................................................................................................33
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
06 April 2016
Novo Nordisk
Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103 
Status:
Final
EudraCT no.: 2015-005593-38
Page:
3 of 118
6.1
Number of subjects......................................................................................................................33
6.2
Inclusion criteria ..........................................................................................................................33
6.3
Exclusion criteria.........................................................................................................................33
6.4
Rescue criteria..............................................................................................................................35
6.5
Criteria for premature discontinuation of trial product................................................................35
6.6
Withdrawal from trial ..................................................................................................................36
6.7
Subject replacement.....................................................................................................................36
6.8
Rationale for trial population.......................................................................................................36
7
Milestones.................................................................................................................................................37
8
Methods and assessments .......................................................................................................................38
8.1
Visit procedures...........................................................................................................................38
8.1.1
Screening, visit 1........................................................................................................38
8.1.2
Fasting visits ..............................................................................................................39
8.1.3
Randomisation and trial products administration ......................................................39
8.1.4
End-of-treatment (visit 10) and Follow-up (visit 11).................................................40
8.1.5
Premature discontinuation of trial product and follow-up (visits 10A and 11A) ......40
8.1.6
Withdrawal from trial ................................................................................................41
8.1.7
Investigator assessments............................................................................................41
8.2
Subject related information/assessments .....................................................................................42
8.2.1
Demography...............................................................................................................42
8.2.2
Diabetes history and diabetes complications .............................................................42
8.2.3
Hypoglycaemia unawareness.....................................................................................42
8.2.4
Concomitant illness and medical history...................................................................42
8.2.5
Concomitant medication............................................................................................43
8.2.6
Childbearing potential................................................................................................43
8.2.7
Tobacco use ...............................................................................................................44
8.3
Efficacy assessments....................................................................................................................44
8.3.1
Laboratory assessments for efficacy..........................................................................44
8.3.2
Self-measured plasma glucose...................................................................................45
8.3.3
Body weight and height .............................................................................................46
8.3.4
Waist circumference ..................................................................................................46
8.3.5
Point-of-care HbA1c measurement.............................................................................46
8.3.6
Patient reported outcomes questionnaires..................................................................46
8.4
Safety assessments.......................................................................................................................47
8.4.1
Adverse events...........................................................................................................47
8.4.1.1
Medication error..................................................................................47
8.4.1.2
Adverse events requiring additional data collection ...........................48
8.4.2
Physical examination.................................................................................................48
8.4.3
Vital signs ..................................................................................................................49
8.4.4
Eye examination ........................................................................................................49
8.4.5
Electrocardiogram (12–lead) .....................................................................................49
8.4.6
Laboratory assessments for safety .............................................................................50
8.4.7
Pregnancy testing.......................................................................................................51
8.4.8
Hypoglycaemic episodes ...........................................................................................52
8.5
Laboratory assessments ...............................................................................................................54
8.6
Other assessments........................................................................................................................55
8.6.1
Subject diary ..............................................................................................................55
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
06 April 2016
Novo Nordisk
Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103 
Status:
Final
EudraCT no.: 2015-005593-38
Page:
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8.7
Subject compliance......................................................................................................................55
9
Trial supplies ...........................................................................................................................................56
9.1
Trial products...............................................................................................................................56
9.2
Labelling......................................................................................................................................56
9.3
Storage .........................................................................................................................................56
9.4
Drug accountability and destruction............................................................................................57
9.5
Auxiliary supplies........................................................................................................................58
10 Interactive voice/web response system ..................................................................................................59
11 Randomisation procedure ......................................................................................................................60
12 Adverse events, technical complaints and pregnancies .......................................................................61
12.1
Definitions ...................................................................................................................................61
12.1.1
Adverse event ............................................................................................................61
12.1.2
Serious adverse event.................................................................................................62
12.1.3
Non-serious adverse event.........................................................................................63
12.1.4
Medication errors.......................................................................................................63
12.1.5
Adverse events requiring additional data collection..................................................64
12.1.6
Technical complaints.................................................................................................65
12.2
Reporting of adverse events.........................................................................................................66
12.3
Follow-up of adverse events........................................................................................................69
12.4
Technical complaints and technical complaint samples ..............................................................70
12.4.1
Reporting of technical complaints .............................................................................70
12.4.2
Collection, storage and shipment of technical complaint samples ............................70
12.5
Pregnancies in female subjects ....................................................................................................71
12.6
Precautions and/or overdose ........................................................................................................72
12.7
Committees related to safety........................................................................................................73
12.7.1
Novo Nordisk safety committee ................................................................................73
12.7.2
Event adjudication committee....................................................................................73
13 Case report forms....................................................................................................................................77
13.1
Corrections to case report forms..................................................................................................77
13.2
Case report form flow..................................................................................................................78
14 Monitoring procedures ...........................................................................................................................79
15 Data management....................................................................................................................................81
16 Computerised systems.............................................................................................................................82
17 Statistical considerations ........................................................................................................................83
17.1
Sample size calculation................................................................................................................85
17.2
Definition of analysis sets............................................................................................................86
17.3
Primary endpoint..........................................................................................................................88
17.3.1
Primary analysis for the primary estimand ................................................................88
17.3.2
Primary analysis for the secondary estimand.............................................................89
17.3.3
Sensitivity analyses....................................................................................................90
17.3.3.1
Pattern mixture models........................................................................91
17.3.3.2
Other sensitivity analysis ....................................................................91
17.4
Secondary endpoints....................................................................................................................92
17.4.1
Confirmatory secondary endpoints............................................................................92
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
06 April 2016
Novo Nordisk
Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103 
Status:
Final
EudraCT no.: 2015-005593-38
Page:
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17.4.2
Supportive secondary endpoints ................................................................................92
17.4.2.1
Efficacy endpoints...............................................................................92
17.4.2.2
Safety endpoints..................................................................................94
17.5
Interim analysis............................................................................................................................98
17.6
Patient reported outcomes............................................................................................................98
18 Ethics........................................................................................................................................................99
18.1
Benefit-risk assessment of the trial..............................................................................................99
18.1.1
Risks and precautions ................................................................................................99
18.1.1.1
Sitagliptin ..........................................................................................101
18.1.2
Benefits....................................................................................................................101
18.1.3
Risk and benefit conclusion.....................................................................................102
18.2
Informed consent .......................................................................................................................102
18.3
Data handling.............................................................................................................................103
18.4
Information to subjects during trial............................................................................................103
18.5
Premature termination of the trial and/or trial site.....................................................................103
19 Protocol compliance..............................................................................................................................104
19.1
Protocol deviations ....................................................................................................................104
19.2
Prevention of missing data.........................................................................................................104
20 Audits and inspections ..........................................................................................................................105
21 Critical documents ................................................................................................................................106
22 Responsibilities......................................................................................................................................108
23 Reports and publications......................................................................................................................109
23.1
Communication of results..........................................................................................................109
23.1.1
Authorship ...............................................................................................................110
23.1.2
Site-specific publication(s) by investigator(s) .........................................................110
23.2
Investigator access to data and review of results.......................................................................110
24 Retention of clinical trial documentation and human biosamples....................................................111
24.1
Retention of clinical trial documentation...................................................................................111
24.2
Retention of human biosamples.................................................................................................111
25 Institutional Review Boards/Independent Ethics Committees and regulatory authorities............112
26 Indemnity statement .............................................................................................................................113
27 References..............................................................................................................................................114
Attachment I – Global list of key staff and relevant departments and suppliers
Attachment II – Country list of key staff and relevant departments
Appendix A – Monitoring of Calcitonin
Appendix B – Adverse events requiring additional data collection 
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
06 April 2016
Novo Nordisk
Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103 
Status:
Final
EudraCT no.: 2015-005593-38
Page:
6 of 118
Table of Figures
Page
Figure 5–1
Trial design.............................................................................................................................29
Figure 12–1
Reporting of AEs...................................................................................................................68
Figure 17–1
Graphical illustration of the closed testing procedure ............................................................85
Figure 17–2
ADA classification of hypoglycaemia....................................................................................97
Table of Tables
Page
Table 5–1
Treatment of subjects..............................................................................................................30
Table 9–1
Investigational medicinal products.........................................................................................56
Table 9–2
Storage conditions ..................................................................................................................57
Table 12–1
Adverse events requiring completion of specific event forms and/or are subject to event 
adjudication ............................................................................................................................65
Table 12–2
Adverse events for adjudication .............................................................................................74
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
06 April 2016
Novo Nordisk
Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103 
Status:
Final
EudraCT no.: 2015-005593-38
Page:
7 of 118
List of abbreviations
AACE
American Association of Clinical Endocrinologists 
ADA
American Diabetes Association
AE
adverse event
ALP
alkaline phosphatase 
ALT
alanine aminotransferase
ANCOVA
analysis of covariance 
AST
aspartate aminotransferase
AUC
area under the curve
BG
blood glucose
BMI
body mass index
CFR
Code of Federal Regulations
CK
creatine kinase 
CKD-EPI
Chronic Kidney Disease Epidemiology 
Collaboration 
CLAE
clinical laboratory adverse event
CRF
case report form
DPP-4
dipeptidyl peptidase-4
DTSQ
Diabetes Treatment Satisfaction Questionnaire 
DUN
dispensing unit number
EAC
event adjudication committee 
ECG
electrocardiogram
eCRF
electronic case report form
eGFR
Estimated Glomerular Filtration rate 
FAS
full analysis set
FDA
U.S. Food and Drug Administration
FDAAA
Food and Drug Administration Amendment Act 
FPG
fasting plasma glucose
FSFV
first subject first visit
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
06 April 2016
Novo Nordisk
Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103 
Status:
Final
EudraCT no.: 2015-005593-38
Page:
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GCP
Good Clinical Practice
GLP-1
glucagon-like peptide-1
GLP-1 RA
glucagon-like peptide-1 receptor agonist
HbA1c
glycosylated haemoglobin
HDL
high density lipoprotein
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
ICMJE
International Committee of Medical Journal Editors
IEC
independent ethics committee
IMP
investigational medicinal product
IRB
institutional review board
IWRS
interactive web response system
LDL
low density lipoprotein
LLoQ
lower limit of quantification 
LOCF
last observation carried forward 
LSFV
last subject first visit
LSLV
last subject last visit
MAR
missing at random
MedDRA
Medical Dictionary for Regulatory Activities
MEN 2
Multiple Endocrine Neoplasia Type 2 
MI
myocardial infarction 
MMRM
mixed model for repeated measurements 
MTC
Medullary Thyroid Carcinoma 
NIMP
non-investigational medicinal product 
NSTEMI
Non-ST elevation acute myocardial infarction 
NYHA
New York Heart Association
OAD
oral anti-diabetic drug
PG
plasma glucose
PK
pharmacokinetics
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
06 April 2016
Novo Nordisk
Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103 
Status:
Final
EudraCT no.: 2015-005593-38
Page:
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PRO
patient reported outcome
REML
restricted maximum likelihood 
SAE
serious adverse event
SAP
statistical analysis plan
SAS
safety analysis set 
s.c.
subcutaneous
SF-36v2TM
Short Form-36 version 2
SGLT-2
sodium glucose co-transporter 2
SIF
safety information form
SmPC
summary of product characteristics
SMPG
self-measured plasma glucose
SNAC
absorption-enhancing excipient sodium N-[8-(2-
hydroxybenzoyl)amino]caprylate 
STEMI
ST-elevation acute myocardial infarction 
SU
sulfonylureas
SUSAR
suspected unexpected serious adverse reactions
T2DM
Type 2 diabetes mellitus 
TEAE
treatment-emergent adverse event
TIA
transient ischaemic attack
TMM
Trial Materials Manual
TZD
thiazolidinediones 
UNL
upper normal limit 
UTN
Universal Trial Number
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
06 April 2016
Novo Nordisk
Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103 
Status:
Final
EudraCT no.: 2015-005593-38
Page:
10 of 118
1
Summary
Objectives and endpoints:
Primary objective
To compare the effect of once-daily dosing of oral semaglutide using a flexible dose adjustment 
based on clinical evaluation versus sitagliptin once-daily, both in combination with 1-2 oral anti-
diabetic drugs (OADs) on glycaemic control in subjects with Type 2 diabetes mellitus (T2DM).
Secondary objectives
To compare the effect of once-daily dosing of oral semaglutide using a flexible dose adjustment 
based on clinical evaluation versus sitagliptin once-daily, both in combination with 1-2 OADs on 
body weight in subjects with T2DM.
To compare the safety and tolerability of once-daily dosing of oral semaglutide using a flexible 
dose adjustment based on clinical evaluation versus sitagliptin once-daily, both in combination with 
1-2 OADs in subjects with T2DM.
Primary endpoint
If a subject after week 52 achieves (yes/no) glycosylated haemoglobin (HbA1c) < 7% (53 
mmol/mol) American Diabetes Association target.
Key secondary endpoints
Change from baseline to week 52 in:
!
Body weight (kg)
!
HbA1c
!
Fasting plasma glucose 
Number of treatment-emergent adverse events during exposure to trial product, assessed up to 
approximately 57 weeks.
Number of treatment-emergent severe or blood glucose-confirmed symptomatic hypoglycaemic 
episodes during exposure to trial product, assessed up to approximately 57 weeks.
Trial design:
This is a 52-week randomised, open-label, active-controlled, parallel-group, multi-centre, multi-
national trial with two arms comparing the efficacy and safety of oral semaglutide using a flexible 
dose adjustment versus sitagliptin, in subjects with T2DM treated with 1-2 OADs. 
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
06 April 2016
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Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103 
Status:
Final
EudraCT no.: 2015-005593-38
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Subjects will be randomised 1:1 to receive one of the following treatments as add-on to their anti-
diabetic background medication:
!
flexible dosing (3, 7 or 14 mg) of oral semaglutide once-daily 
!
100 mg sitagliptin once-daily 
In this trial the dosing of oral semaglutide is flexible, following predefined dose adjustment criteria 
which are based on the subject’s individual HbA1c and tolerability (nausea/vomiting). Sitagliptin 
should be taken once-daily on a fixed dose of 100 mg throughout the trial.
The total trial duration for the individual subject will be approximately 59 weeks. The trial includes 
a 2-week screening period, a 52-week treatment period and a 5-week follow-up period. The trial is 
designed to have visits every 8 weeks, including a phone contact at week 4.
Trial population:
Number of subjects planned to be randomised: 500
Key inclusion criteria 
!
Informed consent obtained before any trial-related activities. Trial-related activities are any 
procedures that are carried out as part of the trial, including activities to determine suitability for 
the trial. 
!
Male or female, age above or equal to 18 years at the time of signing informed consent.
For Korea only: Male or female, age above or equal to 19 years at the time of signing informed 
consent.
!
Diagnosed with type 2 diabetes mellitus ≥ 90 days prior to day of screening.
!
HbA1c 7.5-9.5% (58-80 mmol/mol) (both inclusive).
!
Treatment target of HbA1c < 7.0% (53 mmol/mol), as judged by the investigator.
!
Stable daily dose(s) of 1-2 of the following anti-diabetic drugs within 90 days prior to the day of 
screening:
–
Metformin (≥1500 mg or maximum tolerated dose as documented in the subject medical 
record).
–
Sulfonylureas (≥ half of the maximum approved dose according to local label or maximum 
tolerated dose as documented in subject medical record). 
–
Sodium glucose co-transporter 2 inhibitors. 
–
Thiazolidinediones (≥ half of the maximum approved dose according to local label or 
maximum tolerated dose as documented in subject medical record).
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Protocol
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Date:
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Trial ID: NN9924-4257
Version:
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UTN: U1111-1177-5103 
Status:
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Key exclusion criteria
!
Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing 
potential and not using an adequate contraceptive method (adequate contraceptive measure as 
required by local regulation or practice).
For certain specific countries: Additional specific requirements apply.
!
Any disorder, which in the investigator’s opinion might jeopardise subject’s safety or 
compliance with the protocol.
!
Family or personal history of Multiple Endocrine Neoplasia Type 2 or Medullary Thyroid 
Carcinoma.
!
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).
!
Any of the following: myocardial infarction, stroke or hospitalisation for unstable angina or 
transient ischaemic attack within the past 180 days prior to the day of screening and 
randomisation. 
!
Subjects presently classified as being in New York Heart Association Class IV.
!
Planned coronary, carotid or peripheral artery revascularisation known on the day of screening.
!
Subjects with alanine aminotransferase > 2.5 x upper normal limit.
!
Renal impairment defined as Estimated Glomerular Filtration rate < 60 mL/min/1.73 m2 as per 
Chronic Kidney Disease Epidemiology Collaboration formula.
!
Treatment with any medication for the indication of diabetes or obesity other than stated in the 
inclusion criteria in a period of 90 days before the day of screening. An exception is short-term 
insulin treatment for acute illness for a total of ≤ 14 days.
!
Proliferative retinopathy or maculopathy requiring acute treatment. Verified by fundus 
photography or dilated fundoscopy performed within 90 days prior to randomisation.
!
History or presence of malignant neoplasms within the last 5 years (except basal and squamous 
cell skin cancer and carcinoma in situ).
!
History of diabetic ketoacidosis.
Key assessments:
Efficacy:
!
HbA1c
!
Fasting plasma glucose
!
Body weight
Safety:
!
Adverse events
!
Hypoglycaemic episodes 
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
06 April 2016
Novo Nordisk
Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103 
Status:
Final
EudraCT no.: 2015-005593-38
Page:
13 of 118
Trial products:
Investigational medicinal products:
!
Test product:
–
semaglutide, 3 mg tablet
–
semaglutide, 7 mg tablet
–
semaglutide, 14 mg tablet
!
Reference therapy:
–
sitagliptin (Januvia®), 100 mg tablet 
CONFIDENTIAL


Protocol
UTN: U1111-1177-5103 
Date:
06 April 2016
Status:
Final
Novo Nordisk
Trial ID: NN9924-4257
EudraCT no.: 2015-005593-38
Version:
1.0
Page:
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2
Flow chart
Trial Periods
Screening a
Randomisation
Treatment
End-of-treatment 
(EoT)
Follow-up b
EoT premature 
discontinuation c
Follow-up 
premature 
discontinuation c
Visit (V), Phone contact (P)
V1
V2
P3
V4
V5
V6
V7
V8
V9
V10
V11
V10A
V11A
Timing of visit
(weeks)
Up to 
-2
wks
0
4
8
16
24
32
40
48
52
57
Day of 
discontinuation 
of trial product 
5 weeks after 
discontinuation 
of trial product 
Visit window (days)
±3
±3
±3
±3
±3
±3
±3
±3
+3
+3
+3
SUBJECT RELATED
INFO/ASSESSMENTS
Informed consent
x
In/exclusion criteria
x
x
Concomitant medication
x
x
x
x
x
x
x
x
x
x
x
x
x
Concomitant illness and medical 
history
x
Demography
x
Diagnosis of diabetes/diabetes 
complications
x
Hypoglycaemia unawareness
x


Protocol
UTN: U1111-1177-5103 
Date:
06 April 2016
Status:
Final
Novo Nordisk
Trial ID: NN9924-4257
EudraCT no.: 2015-005593-38
Version:
1.0
Page:
15 of 118
Trial Periods
Screening a
Randomisation
Treatment
End-of-treatment 
(EoT)
Follow-up b
EoT premature 
discontinuation c
Follow-up 
premature 
discontinuation c
Visit (V), Phone contact (P)
V1
V2
P3
V4
V5
V6
V7
V8
V9
V10
V11
V10A
V11A
Timing of visit
(weeks)
Up to 
-2
wks
0
4
8
16
24
32
40
48
52
57
Day of 
discontinuation 
of trial product 
5 weeks after 
discontinuation 
of trial product 
Visit window (days)
±3
±3
±3
±3
±3
±3
±3
±3
+3
+3
+3
Tobacco use
x
History of cardiovascular 
disease 
x
History of gallbladder disease
x
History of gastrointestinal 
disease
x
Randomisation
x
Criteria for premature 
discontinuation of trial product
x
x
x
x
x
x
x
EFFICACY
Height
x
Body weight
x
x
x
x
x
x
x
x
x
Waist circumference
x
x
x
x
x


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UTN: U1111-1177-5103 
Date:
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Trial Periods
Screening a
Randomisation
Treatment
End-of-treatment 
(EoT)
Follow-up b
EoT premature 
discontinuation c
Follow-up 
premature 
discontinuation c
Visit (V), Phone contact (P)
V1
V2
P3
V4
V5
V6
V7
V8
V9
V10
V11
V10A
V11A
Timing of visit
(weeks)
Up to 
-2
wks
0
4
8
16
24
32
40
48
52
57
Day of 
discontinuation 
of trial product 
5 weeks after 
discontinuation 
of trial product 
Visit window (days)
±3
±3
±3
±3
±3
±3
±3
±3
+3
+3
+3
PRO questionnaires
x
x
x
x
x
x
Dose adjustment criteriad
x
x
x
x
x
x
Fasting plasma glucose
x
x
x
x
HbA1c
e
x
x
x
x
x
x
x
x
x
x
Lipids
x
x
x
x
SAFETY
Adverse eventsf
x
x
x
x
x
x
x
x
x
x
x
x
ECG
x
x
x
x
x
x
Eye examinationg
x
Physical examination
x
x
x
Vital signs
x
x
x
x
x
x
x
x
x
x
x


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UTN: U1111-1177-5103 
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Trial Periods
Screening a
Randomisation
Treatment
End-of-treatment 
(EoT)
Follow-up b
EoT premature 
discontinuation c
Follow-up 
premature 
discontinuation c
Visit (V), Phone contact (P)
V1
V2
P3
V4
V5
V6
V7
V8
V9
V10
V11
V10A
V11A
Timing of visit
(weeks)
Up to 
-2
wks
0
4
8
16
24
32
40
48
52
57
Day of 
discontinuation 
of trial product 
5 weeks after 
discontinuation 
of trial product 
Visit window (days)
±3
±3
±3
±3
±3
±3
±3
±3
+3
+3
+3
Biochemistryh
x
x
x
x
x
x
x
x
x
x
x
Haematology
x
x
x
x
x
x
x
x
x
x
Calcitonin
x
x
x
x
x
x
Pregnancy testi
x 
x
x
x
x
x
x
x
x
x
x
x
Technical complaints
x
x
x
x
x
x
x
x
x
Hypoglycaemic episodes
x
x
x
x
x
x
x
x
x
x
x
x
TRIAL MATERIAL
Dispensing visit
x
x
x
x
x
x
x
Drug accountability
x
x
x
x
x
x
x
x
x
IWRS call
x
x
x
x
x
x
x
x
x
x


Protocol
UTN: U1111-1177-5103 
Date:
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Status:
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Trial Periods
Screening a
Randomisation
Treatment
End-of-treatment 
(EoT)
Follow-up b
EoT premature 
discontinuation c
Follow-up 
premature 
discontinuation c
Visit (V), Phone contact (P)
V1
V2
P3
V4
V5
V6
V7
V8
V9
V10
V11
V10A
V11A
Timing of visit
(weeks)
Up to 
-2
wks
0
4
8
16
24
32
40
48
52
57
Day of 
discontinuation 
of trial product 
5 weeks after 
discontinuation 
of trial product 
Visit window (days)
±3
±3
±3
±3
±3
±3
±3
±3
+3
+3
+3
REMINDERS
Attend visit fastingj
x
x
x
x
Handout and instruct in BG 
meter use
x
Handout ID card
x
Training in dosing instructions
x
x
x
x
x
x
x
x
x
Dispense and/or collect diary
x
x
x
x
x
x
x
x
x
x
x
x


Protocol
UTN: U1111-1177-5103 
Date:
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Status:
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Footer
Description
xa
Subject can be randomised as soon as all inclusion and exclusion criteria are confirmed. The screening assessments must not exceed 2 weeks prior to randomisation (V2).
xb
Subjects who have discontinued trial product prematurely are not required to attend V11 (Follow-up).
xc
V10A and V11A are only applicable for subjects who have discontinued trial product prematurely.
xd
Dose adjustment criteria are subject's HbA1c (measured by point-of-care device) and tolerability (nausea/vomiting)
xe
Assessed at central laboratory
xf
Adverse events reporting includes adverse events from the first trial-related activity after the subject has signed the informed consent at V1. Pre-existing conditions identified as 
a result of the screening procedures should be reported as medical history.
xg
Fundus photography or dilated fundoscopy performed within 90 days before randomisation is acceptable if results are available for evaluation at visit 2 and no deterioration in 
visual function since last examination.
xh
At V1, only ALT, creatinine and eGFR will be assessed as part of Biochemistry.
xi
For women of child-bearing potential: Urine pregnancy test should also be performed at any time during the trial if menstrual period is missed, and/or according to local 
regulations/law. For details regarding local regulations/law see Section 6.3
xj
Fasting for blood sampling is defined as no food or liquid within the last 8 hours prior to blood sampling, however water is allowed up until 2 hours prior to blood sampling. 
Trial product must be taken after blood sampling. Other oral medication can be taken 30 minutes after trial product (for subjects randomised to oral semaglutide only). Injectable 
medications can be administered after blood sampling.


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3
Background information and rationale for the trial
The trial will be conducted in compliance with this protocol, International Conference on 
Harmonisation (ICH) Good Clinical Practice (GCP)1 and applicable regulatory requirements, and in 
accordance with the Declaration of Helsinki2.
In this document, the term investigator refers to the individual responsible for the overall conduct of 
the clinical trial at a trial site.
3.1
Background information
For an assessment of benefits and risks of the trial, see Section 18.1.
3.1.1
Type 2 diabetes mellitus 
Type 2 diabetes mellitus (T2DM) is a progressive metabolic disease primarily characterised by 
abnormal glucose metabolism. The pathogenesis is heterogeneous involving environmental, 
lifestyle and genetic factors leading to chronic hyperglycaemia caused by peripheral tissue insulin 
resistance, impaired insulin secretion due to abnormal beta-cell function and abnormal glucose 
metabolism in the liver3.
Optimal glycaemic control is the treatment goal in subjects with T2DM in order to prevent long-
term complications associated with chronic hyperglycaemia4. Despite the availability of several 
anti-diabetic drugs, a significant proportion of subjects with T2DM do not achieve the 
recommended targets for glycaemic control5, 6.
3.1.2
Glucagon-like peptide-1
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 islets7, 8. Subjects 
with T2DM have a decreased incretin effect9-12. 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 
supraphysiological levels13. In addition, supraphysiological levels of GLP-1 induce reduction in 
body weight14. GLP-1 is a physiological regulator of appetite and food intake and GLP-1 receptors 
are present in several areas of the brain involved in appetite regulation15, 16. Physiologically, GLP-1 
also has a pronounced inhibitory effect on gastric emptying; however this effect seems to diminish 
upon chronic exposure14-16. These mechanisms of action make GLP-1 receptor agonists (GLP-1 
RAs) an attractive pharmacological treatment for T2DM17-19.
3.1.3
Oral semaglutide
Semaglutide is a long-acting 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 T2DM. 
Compared to human native GLP-1, which has a short half-life, the semaglutide molecule has three 
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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 2620. 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 T2DM. As the bioavailability of 
GLP-1 RAs is low when administered orally, semaglutide has been co-formulated with the 
absorption-enhancing excipient sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC) to 
increase the bioavailability of semaglutide. The absorption-enhancing properties of SNAC co-
formulation is based on the 
concept developed by
SNAC facilitates the absorption of semaglutide in a strictly time- and size dependent manner, 
primarily via the transcellular route. The available data for semaglutide co-formulated with SNAC 
support that the absorption takes place in the stomach in a localised, buffered environment in close 
proximity of the tablet erosion. The absorption process is hampered if dosed with food, liquid or in 
the presence of significant stomach content. 
The absorption enhancement requires co-formulation between semaglutide and SNAC. Throughout 
this document “oral semaglutide” will refer to the drug product, that is, semaglutide co-formulated 
with 300 mg SNAC. 
3.1.4
Nonclinical data
3.1.4.1
Semaglutide
The nonclinical programme for semaglutide was designed according to the ICH M3 guideline21 to 
support the clinical development. The standard nonclinical data package required to support phase 3 
clinical trials has been completed. In addition, 2-year carcinogenicity studies and a pre- and 
postnatal development toxicity study have been completed. Semaglutide 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-
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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 low22.
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 maternal body weight loss associated with the 
pharmacological effect of semaglutide coincided with increased early foetal loss; however, there 
was no indication of a teratogenic potential of semaglutide in this species.
A review of the results from the nonclinical studies can be found in the investigator’s brochure (IB) 
for semaglutide (subcutaneous (s.c.) administration), edition 1023 and the IB for oral administration 
of semaglutide (NN9924), edition 624, or any updates of these documents.
3.1.4.2
SNAC
SNAC was developed as an absorption-enhancing excipient for the oral route of administration. The 
nonclinical 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.
 
 
 
 
 Measurements of lactate levels have 
been included at selected time points around peak concentrations of SNAC in two of the phase 3a 
trials in the PIONEER programme (PIONEER 1 and 2) with the intention to document that SNAC 
does not impair cellular respiration in humans. In addition, events of lactic acidosis must be 
reported as an adverse event (AE) requiring additional data collection, please refer to Section 
8.4.1.2, Section 12.1.5 and appendix B.
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The carcinogenicity studies demonstrated that SNAC was not carcinogenic to the transgenic rasH2 
mouse or the Sprague-Dawley rat. The doses tested covered total exposures of SNAC in plasma (in 
terms of area under the curve [AUC]) of 2-fold in the mouse and up to 44-fold in the rat when 
compared to the mean total exposure of SNAC in humans following a clinical dose of 300 mg 
SNAC/day.
A review of the SNAC results from the nonclinical studies can be found in the IB for oral 
administration of semaglutide (NN9924), edition 624, or any updates hereof.
3.1.5
Clinical data for 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 T2DM.
For details on the individual trials, please see the IB for oral administration of semaglutide 
(NN9924) edition 624, or any updates hereof.
3.1.5.1
Pharmacokinetics
In the multiple-dose trial (NN9924-3991), 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.
In multiple-dose pharmacokinetics (PK) 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 T2DM.
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 
PK properties of semaglutide, i.e. low clearance and long half-life, will limit the variation in 
exposure at steady state.
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.
 
 
 
 
 
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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 regardless of the semaglutide dose. 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 T2DM. It is extensively metabolised and no accumulation of 
SNAC has been observed in clinical trials. 
3.1.5.2
Efficacy
The efficacy of oral semaglutide in adult subjects with T2DM was investigated in a 26-week phase 
2 dose-finding trial (NN9924-3790). 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 kg to -
6.98 kg). 
3.1.5.3
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, commonly 
reported AEs included nausea and vomiting, most of them were mild to moderate in 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 
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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 trials 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) was 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 IB for oral administration of semaglutide (NN9924) edition 624, or 
any updates hereof.
3.1.6
Sitagliptin
The selected active comparator in this trial is sitagliptin, an oral anti-diabetic drug (OAD) of the 
DPP-4 inhibitor class suitable for once-daily oral administration. Sitagliptin was developed by 
Merck & Co and has been marketed since 2006 under the trade name Januvia®. By inhibition of the 
enzyme DPP-4, which breaks down GLP-1 and gastric inhibitory polypeptide, secretion of insulin is 
increased and release of glucagon is suppressed. 
Further information can be obtained in the current locally approved label for Januvia®.
3.2
Rationale for the trial
Many patients with T2DM are not in glycaemic control with the currently marketed OADs. 
Nevertheless, treatment with more efficacious injectable therapies such as GLP-1 RAs and insulin 
are rarely added during the early stages of the disease. Oral semaglutide is the first GLP-1 RA in 
development in a tablet formulation and it has the potential of becoming a new attractive treatment
option early in the treatment cascade due to its effects on both hyperglycaemia and body weight.
The rationale for this trial is to compare the efficacy and safety of oral semaglutide employing a 
treatment regimen with a flexible dose adjustment of oral semaglutide according to pre-specified 
criteria. Oral semaglutide will be evaluated versus an established active comparator within the DPP-
4 inhibitor drug class (sitagliptin) in subjects with T2DM. The pre-specified criteria for dose 
adjustment of oral semaglutide are based on the subject’s individual HbA1c and tolerability 
(nausea/vomiting) evaluated every 8 weeks in the trial period. The individualised and flexible 
dosing strategy of oral semaglutide will ensure that each subject is treated with the optimal 
therapeutic dose. Hence, the trial is expected to provide data guiding the physicians on the use of 
oral semaglutide in subject with T2DM.
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4
Objectives and endpoints
4.1
Objectives
4.1.1
Primary objective
To compare the effect of once-daily dosing of oral semaglutide using a flexible dose adjustment 
based on clinical evaluation versus sitagliptin once-daily, both in combination with 1-2 OADs on 
glycaemic control in subjects with T2DM.
4.1.2
Secondary objectives
To compare the effect of once-daily dosing of oral semaglutide using a flexible dose adjustment 
based on clinical evaluation versus sitagliptin once-daily, both in combination with 1-2 OADs on 
body weight in subjects with T2DM.
To compare the safety and tolerability of once-daily dosing of oral semaglutide using a flexible 
dose adjustment based on clinical evaluation versus sitagliptin once-daily, both in combination with 
1-2 OADs in subjects with T2DM.
4.2
Endpoints
Baseline refers to randomisation, and week 52 refers to 52 weeks after randomisation.
4.2.1
Primary endpoint
If a subject after week 52 achieves (yes/no) HbA1c < 7% (53 mmol/mol) American Diabetes 
Association (ADA) target.
4.2.2
Secondary endpoints
4.2.2.1
Confirmatory secondary endpoints
Change from baseline to week 52 in body weight (kg)
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4.2.2.2
Supportive secondary endpoints
Key supportive secondary endpoints prospectively selected for disclosure (e.g. clinicaltrials.gov and 
EudraCT) are marked with an asterisk (*).
Supportive secondary efficacy endpoints
Change from baseline to week 52 in:
!
HbA1c*
!
Fasting plasma glucose (FPG)*
!
Body weight (%)
!
Body mass index (BMI)
!
Waist circumference
!
Fasting lipid profile (total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density 
lipoprotein (HDL) cholesterol, triglycerides)
!
Patient reported outcomes (PROs):
–
Short Form-36 version 2 (SF-36v2TM) (acute version) health survey
–
Diabetes Treatment Satisfaction Questionnaire (DTSQs) 
If a subject after week 52 achieves (yes/no):
!
HbA1c ≤6.5% (48 mmol/mol) American Association of Clinical Endocrinologists (AACE) 
target
!
HbA1c reduction ≥1%-point (10.9 mmol/mol)
!
Weight loss ≥3% 
!
Weight loss ≥5% 
!
Weight loss ≥10% 
!
HbA1c < 7.0% (53 mmol/mol) without hypoglycaemia (treatment-emergent severe or BG-
confirmed symptomatic hypoglycaemia) and no weight gain
!
HbA1c reduction ≥1%-point (10.9 mmol/mol) and weight loss ≥3%
Time to event:
!
Time to rescue medication
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Supportive secondary safety endpoints
!
Number of treatment-emergent adverse events (TEAEs) during exposure to trial product, 
assessed up to approximately 57 weeks*
!
Number of treatment-emergent severe or BG-confirmed symptomatic hypoglycaemic episodes 
during exposure to trial product, assessed up to approximately 57 weeks*
!
Treatment-emergent severe or BG-confirmed symptomatic hypoglycaemic episodes during 
exposure to trial product, assessed up to approximately 57 weeks (yes/no)
Change from baseline to week 52 in:
!
Haematology
!
Biochemistry
!
Calcitonin
!
Pulse
!
Systolic blood pressure
!
Diastolic blood pressure
!
Electrocardiogram (ECG) category
!
Physical examination
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5
Trial design
5.1
Type of trial
This is a 52-week randomised, open-label, active-controlled, parallel-group, multi-centre, multi-
national trial with two arms comparing the efficacy and safety of oral semaglutide using a flexible 
dose adjustment versus sitagliptin 100 mg once-daily, in subjects with T2DM treated with 1-2 
OADs (metformin, sulfonylureas [SU], thiazolidinediones [TZD], sodium glucose co-transporter 2 
[SGLT-2] inhibitors).
Subjects will be randomised 1:1 to receive one of the following treatments as add-on to their anti-
diabetic background medication:
!
flexible dosing (3, 7 or 14 mg) of oral semaglutide once-daily
!
100 mg sitagliptin once-daily 
The total trial duration for the individual subject will be approximately 59 weeks. The trial includes 
a 2-week screening period, a 52-week treatment period and a 5-week follow-up period. The trial is 
designed to have visits every 8 weeks, including a phone contact at week 4.
A schematic illustration of the trial design is shown in Figure 5–1.
Figure 5–1
Trial design
5.2
Rationale for trial design
The trial has been designed as an open-label, parallel-group, 2-arm superiority trial, where oral 
semaglutide will be compared with the DPP-4 inhibitor sitagliptin. Visits have been planned every 
8 weeks, including a phone contact at week 4. At the visits, the dose of oral semaglutide will be 
adjusted according to the subject’s HbA1c (measured by a point-of-care HbA1c device) and 
tolerability (nausea/vomiting). Accordingly, after the initial first 8 weeks on 3 mg, the dose of oral 
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semaglutide is flexible throughout the trial, depending on the subject’s individual needs (see Section
5.3.1). The trial is open-label as the dose of sitagliptin is fixed and cannot be changed during the 
trial. Treatment duration is 52 weeks to ensure adequate time to compare the full effect and 
sustainability of both treatments on glycaemic control and weight. Randomisation will be stratified 
(two strata) according to anti-diabetic background medication (with and without SU).
5.3
Treatment of subjects
Treatment of subjects is summarised in Table 5–1.
Table 5–1
Treatment of subjects 
Trial periods
Screening 
Treatment 
period 1 
Treatment 
period 2
Treatment 
period 3
Follow-up 
First visit in each period
V1
V2
V4
V5
V11
Duration of each period
2 weeks
8 weeks
8 weeks
36 weeks
5 weeks
Treatment arm
N
Oral semaglutide
250
Screening 
3 mg
flexible dosing   
(3 or 7 mg)
flexible dosing 
(3, 7 or 14 mg)
Follow-up
Sitagliptin
250
Screening 
100 mg
100 mg
100 mg
Follow-up 
5.3.1
Oral semaglutide treatment
Oral semaglutide is a long-acting GLP-1 RA to be administered orally once-daily. Dose-escalation 
of oral semaglutide is recommended to mitigate gastrointestinal AEs. 
Dose adjustment of oral semaglutide
The treatment target is HbA1c < 7.0% (53 mmol/mol). Subjects randomised to oral semaglutide will 
initiate treatment on the 3 mg dose level and maintain this dose for the first 8 weeks. Thereafter, the 
dose of oral semaglutide will be adjusted based on the subject’s HbA1c (measured by a point-of-care 
device) and tolerability of oral semaglutide according to the dose adjustment criteria detailed below 
(see Section 2). The basis for the assessment and the resulting dose of oral semaglutide must be 
documented in the medical records and entered into the electronic case report form (eCRF).
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The dose adjustment criteria are:
1. HbA1c
–
When HbA1c < 7.0% (53 mmol/mol), the current dose of oral semaglutide should be
continued
–
When HbA1c ≥7.0% (53 mmol/mol), the dose of oral semaglutide should be escalated to the 
next dose level
and
2. tolerability
–
In case the subject reports moderate to severe nausea or vomiting for 3 or more days in the 
week prior to the scheduled visit, the dose of oral semaglutide should be maintained or 
reduced, at the investigator’s discretion, irrespectively of the level of HbA1c.
Subjects on 3 mg of oral semaglutide cannot have their dose reduced. 
The point-of-care HbA1c device must be used to measure the subject’s HbA1c prior to evaluation of 
the dose adjustment criteria (see Section 2 and 8.3.5). 
5.3.2
Sitagliptin treatment
The selected active comparator in this trial is sitagliptin, an OAD of the DPP-4 inhibitor class 
suitable for once-daily oral administration. Subjects randomised to sitagliptin will receive 100 mg 
once-daily throughout the trial with no dose adjustment.
5.3.3
Dosing instructions
Oral semaglutide
Absorption of oral semaglutide is significantly affected by food and fluid in the stomach, hence 
dosing should be once-daily in the morning in a fasting state and at least 30 minutes before the first 
meal of the day. Oral semaglutide tablet can be taken with up to half a glass of water 
(approximately 120 mL/4 fluid oz). The tablets must be swallowed whole by the subject and must 
not be broken or chewed (see Table 9–2). Furthermore, other oral medication can be taken 30 
minutes after administration of trial product.
Sitagliptin
Sitagliptin tablet should be taken once-daily, with or without food.
5.3.4
Background medication
After signing the informed consent, subjects must continue their anti-diabetic background 
medication throughout the entire trial. The background medication must be maintained at the same 
dose level as given at trial entrance and with the same frequency during the entire treatment period 
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unless rescue medication is needed (see Section 6.4), any safety concerns related to the background 
medication arises or if the subject has unacceptable hypoglycaemia on a background of SU in which 
case the dose of SU can be reduced.
In addition, all background medication:
!
is considered to be non-investigational medicinal product (NIMP) 
!
will not be provided by Novo Nordisk A/S, except if required by local regulations
!
should be used in accordance with standard of care and current approved label in the individual 
country 
!
should not exceed the maximum approved dose in the individual country
5.4
Treatment after discontinuation of trial product
When discontinuing trial products, either at the scheduled end-of-treatment visit (see Section 8.1.4) 
or if trial product is discontinued prematurely (see Section 8.1.5), the subject should be switched to 
a suitable marketed product at the discretion of the investigator (for Brazil only: or it will be made 
available according to local regulations).
As this trial is a phase 3a trial, oral semaglutide will not be available for prescription until after 
marketing authorisation.
5.5
Rationale for treatment
The doses of oral semaglutide have been chosen based on the data from the phase 2 dose-finding 
trial. The selected doses are expected to have the optimal benefit risk profile for further 
development for treatment of T2DM. 
Sitagliptin has been chosen as comparator since it is an established OAD within DPP-4 inhibitor
drug class. 
The duration and doses of randomised treatments are considered adequate to collect sufficient data 
on efficacy and safety in accordance with the trial objectives.
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6
Trial population
6.1
Number of subjects 
Number of subjects planned to be screened:
830
Number of subjects planned to be randomised: 
500
Number of subjects expected to complete the trial on or off trial product:
425
6.2
Inclusion criteria
For an eligible subject, all inclusion criteria must be answered “yes”. 
1. Informed consent obtained before any trial-related activities. Trial-related activities are any 
procedures that are carried out as part of the trial, including activities to determine suitability for 
the trial. 
2. Male or female, age above or equal to 18 years at the time of signing informed consent
For Korea only: Male or female, age above or equal to 19 years at the time of signing informed 
consent.
3. Diagnosed with type 2 diabetes mellitus ≥ 90 days prior to day of screening.
4. HbA1c 7.5-9.5% (58-80 mmol/mol) (both inclusive).
5. Treatment target of HbA1c < 7.0% (53 mmol/mol), as judged by the investigator.
6. Stable daily dose(s) of 1-2 of the following anti-diabetic drugs within 90 days prior to the day of 
screening:
a.
Metformin (≥1500 mg or maximum tolerated dose documented in the subject 
medical record).
b. Sulfonylureas (≥ half of the maximum approved dose according to local label or 
maximum tolerated dose as documented in subject medical record). 
c.
Sodium glucose co-transporter 2 inhibitors. 
d. Thiazolidinediones (≥ half of the maximum approved dose according to local label 
or maximum tolerated dose as documented in subject medical record).
6.3
Exclusion criteria
For an eligible subject, all exclusion criteria must be answered ”no”.
1. Known or suspected hypersensitivity to trial product(s) or related products. 
2. Previous participation in this trial. Participation is defined as signed informed consent.
3. Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing 
potential and not using an adequate contraceptive method (adequate contraceptive measure as 
required by local regulation or practice).
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For Argentina only: Birth control methods will be reimbursed by Novo Nordisk Pharma 
Argentina S.A.
For Austria only: A monthly pregnancy test is mandatory for female subjects of childbearing 
potential
For Belgium only: Highly effective methods of birth control are defined as those, alone or in 
combination, that result in a low failure rate (i.e., less than 1% per year) when used consistently 
and correctly; such as implants, injectables, combined oral contraceptives, some IUDs, true 
sexual abstinence (i.e. refraining from heterosexual intercourse during the entire period of risk 
associated with the study treatments) or vasectomised partner.
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 Norway only: Highly effective methods are defined as established use of oral, injectable, 
transdermal, implantable or intravaginal hormonal methods of contraception associated with 
inhibition of ovulation, placement of an intrauterine device, female sterilisation, male 
sterilisation (where partner is sole partner of subject), or true abstinence (when in line with 
preferred and usual lifestyle).
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 visit
unless there is a direct benefit to the research subject at the investigator´s discretion 
5. Any disorder, which in the investigator’s opinion might jeopardise subject’s safety or 
compliance with the protocol.
6. Family or personal history of Multiple Endocrine Neoplasia Type 2 (MEN 2) or Medullary 
Thyroid Carcinoma (MTC).
7. History of pancreatitis (acute or chronic).
8. 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).
9. Any of the following: myocardial infarction, stroke or hospitalisation for unstable angina or 
transient ischaemic attack within the past 180 days prior to the day of screening and 
randomisation. 
10. Subjects presently classified as being in New York Heart Association (NYHA) Class IV.
11. Planned coronary, carotid or peripheral artery revascularisation known on the day of screening.
12. Subjects with alanine aminotransferase (ALT) > 2.5 x upper normal limit (UNL)
13. Renal impairment defined as Estimated Glomerular Filtration rate (eGFR) < 60 mL/min/1.73 m2 
as per Chronic Kidney Disease Epidemiology Collaboration formula (CKD-EPI).
14. Treatment with any medication for the indication of diabetes or obesity other than stated in the 
inclusion criteria in a period of 90 days before the day of screening. An exception is short-term 
insulin treatment for acute illness for a total of ≤14 days.
15. Proliferative retinopathy or maculopathy requiring acute treatment. Verified by fundus 
photography or dilated fundoscopy performed within 90 days prior to randomisation.
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16. History or presence of malignant neoplasms within the last 5 years (except basal and squamous 
cell skin cancer and carcinoma in situ).
17. History of diabetic ketoacidosis.
6.4
Rescue criteria
Subjects with persistent and unacceptable hyperglycaemia should be offered treatment 
intensification with rescue medication. It is important for trial integrity that only subjects actually 
needing treatment intensification (i.e. intensification of existing anti-diabetic medication and/or 
initiation of new anti-diabetic medication) are started on rescue medication. 
Subjects with persistent and unacceptable hyperglycaemia should be offered treatment 
intensification if:
HbA1c (central laboratory) > 8.5% (69.4 mmol/mol) from week 32 to end of treatment.
Rescue medication should be prescribed at the investigator’s discretion as add-on to randomised 
treatment and according to ADA/European Association for the Study of Diabetes guidelines25, 26
(excluding GLP-RAs, DPP-4 inhibitors and amylin analogues). Subjects that are started on rescue 
medication should continue to follow the protocol-specified visit schedule. 
Rescue medication and any changes hereto should be captured on the concomitant medication form 
in the eCRF, see Section 8.2.5. Rescue medication is considered to be NIMP and will not be 
provided by Novo Nordisk, unless required by local regulations.
6.5
Criteria for premature discontinuation of trial product
All efforts should be made to keep the subject on trial product. However, the subject may be 
prematurely discontinued from trial product at the discretion of the investigator due to a safety 
concern. 
The subject must be prematurely discontinued from trial product if the following applies:
!
Safety concern related to trial product or unacceptable intolerability
!
Included in the trial in violation of the inclusion and/or exclusion criteria
!
Pregnancy
!
Intention of becoming pregnant
!
Simultaneous participation in another clinical trial of an approved or non-approved  
investigational medicinal product (IMP)
!
Calcitonin ≥ 100 ng/L
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If a criterion for premature discontinuation of trial product is met, trial product should not be re-
initiated but subjects should continue with the scheduled site contacts.
See Section 8.1.5 for procedures to be performed for subjects discontinuing trial product 
prematurely.
6.6
Withdrawal from trial
The subject may withdraw consent at will at any time. The subject’s request to withdraw from the 
trial must always be respected. Only subjects who withdraw consent should be considered as 
withdrawn from trial. 
See Section 8.1.6 for procedures to be performed for subjects withdrawing consent. 
6.7
Subject replacement
Subjects who withdraw consent or discontinue trial product prematurely will not be replaced.
6.8
Rationale for trial population
Subjects with T2DM inadequately controlled on 1-2 OADs (metformin, SU, TZD, SGLT-2 
inhibitors) will be included in the trial. To ensure unbiased results, the background medication 
should be stable within 90 days prior to screening. The HbA1c limits of 7.5-9.5% (58-80 mmol/mol) 
have been chosen to include subjects needing intensification of their anti-diabetic medication. FPG 
and HbA1c will be monitored throughout the trial and rescue medication should be initiated in 
subjects with persistent, unacceptable hyperglycaemia. No BMI or blood pressure restrictions will 
be applied. Subjects with liver test abnormalities (ALT > 2.5 x UNL) will be excluded to avoid 
potential confounding of liver safety assessments. In addition, subjects with moderate, severe or 
end-stage-renal disease will be excluded due to restrictions in the labelling of background 
medications. As SGLT-2 inhibitors have been associated with euglycaemic diabetic ketoacidosis, 
subjects with a history of diabetic ketoacidosis will be excluded from this trial. The dose of oral 
semaglutide will be based on the subject’s individual needs and only subjects with a treatment 
target of HbA1c < 7% (53 mmol/mol) will be randomised. Overall, the eligibility criteria will allow 
for enrolment of a relatively broad trial population, resembling the target population in common 
practice.
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7
Milestones
Planned duration of recruitment period FSFV-LSFV:
18 weeks
Planned FSFV:
20-Sep-2016
Planned LSLV:
19-Mar-2018
End of trial is defined as:
LSLV
Recruitment:
The screening and randomisation rate will be followed closely via the interactive web response 
system (IWRS) in order to estimate when to stop screening. All investigators will be notified 
immediately when the recruitment period ends, after which no further subjects may be screened and 
the IWRS will be closed for further screening.
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 Disclosure27, it will also be disclosed 
according to other applicable requirements such as those of the International Committee of Medical 
Journal Editors (ICMJE)28, the Food and Drug Administration Amendment Act (FDAAA)29, 
European Commission Requirements30, 31 and other relevant recommendations or regulations. If a 
subject requests to be included in the trial via the Novo Nordisk e-mail contact at these web sites, 
Novo Nordisk may disclose the investigator’s contact details to the subject. As a result of increasing 
requirements for transparency, some countries require public disclosure of investigator names and 
their affiliations.
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8
Methods and assessments
8.1
Visit procedures
The following sections describe the assessments and procedures. These are also included in the flow 
chart (see Section 2). Informed consent must be obtained before any trial-related activity, see 
Section 18.2.
Refer to the flow chart (Section 2) for number and timing of visits and specific assessments to be 
performed. 
Each subject will have 10 site visits and 1 phone contact. It is the responsibility of the investigator 
to ensure that all visits/pone contact occur according to the flow chart (see Section 2).
Planned visits can be conducted and re-scheduled within the allowed visit window. If a visit is 
missed and it is not possible to re-schedule, every effort should be made to ensure information is 
collected at a telephone contact (within the visit window) and entered into the eCRF. Subjects will 
be invited for the next scheduled visit according to the visit schedule.
The investigator must keep a log of staff and a delegation of task(s) list at site. Investigator must 
sign the log of staff and the delegation of task(s) at site prior to the delegation of tasks.
The investigator must keep a subject screening log, a subject identification code list and a subject 
enrolment log. Only subjects who have signed the informed consent form should be included on the 
logs. The subject screening log and subject enrolment log may be combined in one log. 
8.1.1
Screening, visit 1
At screening, subjects will be provided with a card stating that they are participating in a trial and 
giving contact address(es) and telephone number(s) of relevant trial site staff. Subjects should be 
instructed to return the card to the investigator at the last trial visit or to destroy the card after the 
last visit.
A screening session must be made in the IWRS. Each subject will be assigned a unique 6-digit 
subject number which will remain the same throughout the trial.
Once all data relating to V1 have been obtained, these must be reviewed, dated and signed by the 
investigator and/or documented in medical records to assess that the subject is eligible to continue 
in the trial.
Screening failures: For screening failures the screening failure form in the eCRF must be 
completed with the reason for not continuing in the trial. Serious adverse events (SAEs) from 
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screening failures must be transcribed by the investigator into the eCRF. Follow-up on SAEs must 
be carried out according to Section 12.1.
A screening failure session must be made in the IWRS. The case book must be signed.
Re-screening is NOT allowed if the subject has failed one of the inclusion or exclusion criteria; this 
includes re-sampling if the subject has failed one of the inclusion or exclusion criteria related to 
laboratory parameters. However, in case laboratory samples are lost (e.g. haemolysed or displaced), 
re-sampling is allowed.
8.1.2
Fasting visits
The subjects must attend some visits in a fasting state (see Section 2). 
Fasting for blood sampling is defined as no food or liquid within the last 8 hours prior to blood 
sampling, however water is allowed up until 2 hours prior to blood sampling
Trial product must be taken after blood sampling (see Section 5.3.1 for dosing instructions). Other 
oral medication can be taken 30 minutes after trial product (for subjects randomised to oral 
semaglutide only). Injectable medications can be administered after blood sampling. 
In case a subject attends a fasting visit in a non-fasting state, all non-fasting measurements should 
be performed. The subject should return to the site in a fasting state to have fasting blood samples
done within the visit window for the relevant visit.
Fasting samples:
!
FPG
!
fasting lipid profile (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides)
8.1.3
Randomisation and trial products administration
Eligible subjects will be randomised into one of two treatment arms. The randomisation session 
must be made in the IWRS which will allocate the dispensing unit number (DUN) of trial product to 
be dispensed to the subject.
All V2 assessments must be performed before administration of first dose of trial product.
Trial products (see Section 9) will be dispensed to the subject by the site, hospital pharmacy or 
equivalent at each site visit during the trial from randomisation to last visit before the end-of-
treatment visit (see Section 2). The investigator must document that subjects are trained in the 
dosing instructions at every dispensing visit, see Section 5.3.1.
Date of first administration of trial product will be captured in the eCRF.
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8.1.4
End-of-treatment (visit 10) and Follow-up (visit 11)
Subjects, who stay on trial product throughout the trial, must attend the end-of-treatment visit (V10) 
52 weeks after randomisation and the follow-up visit (V11) 5 weeks after the last date on trial 
product (+3 days visit window). Throughout the protocol, last date on trial product is defined as 
date of the subject’s last dosage of trial product. A completion call must be performed in the IWRS 
after completion of V10 (see Section 10).
In case the subject cannot be reached (by clinic visit or phone contact) at the scheduled V11, the site 
should consult the contacts provided by the subject (e.g. close relatives), relevant physicians, 
medical records and locator agencies (if allowed according to local law) to collect health status. If 
no health status can be collected, the subject should be considered lost to follow up and this should 
be specified in the end-of-trial form.
8.1.5
Premature discontinuation of trial product and follow-up (visits 10A and 11A)
Subjects, who discontinue trial product prematurely, should attend V10A, scheduled to take place 
on the day of discontinuation of trial product (+ 3 days visit window). V11A should be scheduled 5 
weeks (+3 days visit window) after the last date on trial product. The primary reason for premature 
discontinuation of trial product must be specified in the end-of-trial form in the eCRF, and final 
drug accountability must be performed. A treatment discontinuation session must be made in the 
IWRS at V10A (see Section 10).
If premature discontinuation of trial product is decided during a scheduled visit, the visit will be 
converted into a V10A and trial procedures must be performed accordingly.
Subjects should continue with the originally scheduled site contacts after V11A and up to and 
including V10. If necessary, in order to retain the subject in the trial, site visits can be replaced by 
phone contacts after V11A. However, if a subject is unable or unwilling to attend all subsequent 
visit(s), the investigator should at least aim to have the subject attend V10 (end-of-treatment) at 
week 52 as this visit should be performed for all subjects, if at all possible (except subjects who 
withdraw informed consent, see Section 8.1.6).
Subjects, who only agree to attend or provide health status at the planned V10, should not be 
considered withdrawn from the trial. In case the subject cannot be reached (by clinic visit or phone 
contact) at the scheduled V10, the site should consult the contacts provided by the subject (e.g. 
close relatives), relevant physicians, medical records and locator agencies (if allowed according to 
local law) to collect health status. If no health status can be collected, the subject should be 
considered lost to follow-up and this should be specified in the end-of-trial form.
In summary, subjects should stay in the trial irrespective of lack of adherence to randomised 
treatment, lack of adherence to visit schedule, missing assessments or trial product discontinuation 
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for any reason. Only subjects who decline any further contact with the site in relation to the trial 
should be considered as withdrawn from the trial (see Section 8.1.6). 
8.1.6
Withdrawal from trial
If a subject considers withdrawing from the trial, the investigator must aim to undertake procedures 
for V10A as soon as possible and V11A should be scheduled 5 weeks (+3 days visit window) after 
the last date on trial product, if the subject agrees to it.
The end-of-trial form must be completed and final drug accountability must be performed even if 
the subject is not able to come to the trial site. A treatment discontinuation session must be made in 
the IWRS (see Section 10). The case book must be signed. 
Although a subject is not obliged to give his/her reason(s) for withdrawing consent, the investigator 
must make a reasonable effort to ascertain the reason(s), while fully respecting the subject’s rights. 
Where the reasons are obtained, the primary reason for withdrawing consent must be specified in 
the end-of-trial form in the eCRF.
8.1.7
Investigator assessments
Review of diaries, PROs, laboratory reports, ECGs, fundus photography or dilated fundoscopy, and 
point-of-care HbA1c measurements must be documented either on the documents or in the subject’s 
medical record.
If clarification of entries or discrepancies in the diary or PROs is needed, the subject must be 
questioned and a conclusion made in the subject’s medical record. Care must be taken not to bias 
the subject.
The documents must be retained at the site as source documentation.
For ECGs, physical examinations and eye examinations the evaluations must follow the categories:
!
Normal
!
Abnormal
–
Was the result clinically significant? (yes/no)
The evaluation should be based on investigator’s judgement.
For laboratory report values outside the reference range, the investigator must specify whether the 
value is clinically significant or not clinically significant. All laboratory printouts must be signed 
and dated by the investigator prior to the following visit. The signed laboratory report is retained at 
the site as source documentation.
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In case of abnormal clinically significant findings found as a result of screening procedures 
conducted at V1 or assessments revealing baseline conditions at V2, the investigator must state a 
comment in the subject’s medical record and record this in the medical history/concomitant illness 
form in the eCRF. 
The investigator or his/her delegate must collect and review the PROs and diaries for completeness 
and to ensure that AEs are reported.
8.2
Subject related information/assessments 
8.2.1
Demography
Demography will be recorded in the eCRF at screening and consists of:
!
Date of birth (according to local regulation)
!
Sex
!
Ethnicity (according to local regulation)
!
Race (according to local regulation)
8.2.2
Diabetes history and diabetes complications
Diabetes history and diabetes complications will be recorded on a disease specific form at screening
and consists of:
!
Date of diagnosis of type 2 diabetes
!
Information regarding diabetes complications including date of onset
–
Diabetic retinopathy
–
Diabetic neuropathy
–
Diabetic nephropathy
Please note that macroangiopathy (including peripheral arterial disease) should be reported on the 
disease specific form History of cardiovascular disease (see Section 8.2.4). 
8.2.3
Hypoglycaemia unawareness
Information on hypoglycaemia unawareness will be recorded at screening according to Clarke’s 
questionnaire, question 832. The investigator must ask the subject in the following way: “To what 
extent can you tell by your symptoms that your blood glucose is low?” The subject can answer 
never, rarely, sometimes, often or always. Subjects answering ‘never, rarely or sometimes’ are 
considered as having impaired awareness of hypoglycaemia.
8.2.4
Concomitant illness and medical history
A concomitant illness is any illness that is present at the start of the trial (V1) or found as a result 
of a screening procedure or other trial procedures performed before exposure to trial product.
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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 reported.
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 recorded in the eCRF on the disease specific forms only, i.e. not on the 
medical history/concomitant illness form:
!
History of cardiovascular disease (e.g. ischaemic heart disease, myocardial infarction (MI), 
heart failure including NYHA class, hypertension, stroke, peripheral arterial disease)
!
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 reported as an AE (see Section 12).
It must be possible to verify the subject’s medical history, treatment target of HbA1c < 7.0% (53 
mmol/mol) and a valid fundus photography or dilated fundoscopy measurement in source 
documents such as subject’s medical record. If a subject is not from the investigators own practice; 
the investigator must make reasonable effort to obtain a copy of subject’s medical record from 
relevant party e.g. primary physician. The investigator must document any attempt to obtain 
external medical information by noting the date(s) when information was requested and who has 
been contacted.
8.2.5
Concomitant medication 
A concomitant medication is any medication, other than the trial products, which is taken during 
the trial, including the screening and follow-up periods.
Details of any concomitant medication must be recorded at the first visit. Changes in concomitant 
medication must be recorded at each visit as they occur. 
The information collected for each concomitant medication includes: trade name or generic name;
indication; start date and stop date or continuation; and start date of current dose and total daily 
dose (only applicable for anti-diabetic medication).
If a change is due to an AE, then this must be reported according to Section 12. If the change 
influences the subject’s eligibility to continue in the trial, the monitor must be informed.
8.2.6
Childbearing potential
It must be recorded in the eCRF whether female subjects are of childbearing potential. 
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Pregnancy testing must be performed on female subjects of childbearing potential as described in 
Section 8.4.7 (pregnancy testing). Female subjects of childbearing potential must be instructed to 
use an adequate contraceptive method throughout the trial and until 5 weeks after end of treatment.
Female of non-childbearing potential is defined as:
!
Female who has undergone a hysterectomy, bilateral oophorectomy or bilateral tubal ligation 
!
Postmenopausal defined as no menses for 12 months without an alternative medical cause
!
Other medical reasons preventing childbearing potential
For Argentina only: Birth control methods will be reimbursed by Novo Nordisk Pharma Argentina
S.A.
For Austria only: A monthly pregnancy test is mandatory for female subjects of childbearing 
potential
For Belgium only: Highly effective methods of birth control are defined as those, alone or in 
combination, that result in a low failure rate (i.e., less than 1% per year) when used consistently 
and correctly; such as implants, injectables, combined oral contraceptives, some IUDs, true sexual 
abstinence (i.e. refraining from heterosexual intercourse during the entire period of risk associated 
with the study treatments) or vasectomised partner.
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 Norway only: Highly effective methods are defined as established use of oral, injectable, 
transdermal, implantable or intravaginal hormonal methods of contraception associated with 
inhibition of ovulation, placement of an intrauterine device, female sterilisation, male sterilisation 
(where partner is sole partner of subject), or true abstinence (when in line with preferred and usual 
lifestyle).
8.2.7
Tobacco use 
Details of tobacco use must be recorded at V1. Smoking is defined as smoking at least one cigarette 
or equivalent daily. 
Smoking status:
!
Never smoked
!
Previous smoker, smoking stop date
!
Current smoker
8.3
Efficacy assessments
8.3.1
Laboratory assessments for efficacy
For overall description of laboratory assessments see Section 8.5.
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Blood samples will be drawn according to the flow chart (see Section 2) and will be analysed at the 
central laboratory to determine levels of the following efficacy laboratory parameters:
Glucose metabolism:
!
HbA1c
!
FPG
FPG is measured at central laboratory in order to evaluate glycaemic control. The subject must 
attend these visits fasting (see Section 8.1.2).
A central FPG result ≤3.9 mmol/L (70 mg/dL) in relation to planned fasting visits should not be 
reported as a hypoglycaemic episode but as a clinical laboratory adverse event (CLAE) at the
discretion of the investigator (see Section 12.1.1).
Fasting lipid profile:
!
Total cholesterol
!
LDL cholesterol
!
HDL cholesterol
!
Triglycerides
8.3.2
Self-measured plasma glucose
At V2, subjects will be provided with a BG meter including auxiliaries as well as instructions for 
use. The subjects will be instructed in how to use the device, and the instruction will be repeated as 
necessary during the trial. In case a hypoglycaemic episode is suspected, the provided BG meter 
should be used for measurement of self-measured plasma glucose (SMPG) (see Section 8.4.8)
The BG meters use test strips calibrated to plasma values. Therefore, all measurements performed 
with capillary blood are automatically calibrated to plasma equivalent glucose values, which will be 
shown on the display. Only the BG meters provided by Novo Nordisk A/S should be used for the 
measurements required in the protocol.
Subjects should be instructed in how to record the results of the SMPG values in the diaries. The 
record of each SMPG value should include date, time and value. All data from the diary must be 
transcribed into the eCRF during or following the contact. If obtained via phone and a discrepancy 
is later detected between the diary and the SMPG data obtained at the phone contact, the values in 
the eCRF must be corrected.
Occasional review by the investigator of the values stored in the memory of the BG meter and 
correct reporting of these in the diary is advised in order to ensure adequacy of the data reported in 
the trial database. 
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8.3.3
Body weight and height
Body weight must be measured and recorded in the eCRF in kilogram or pound (kg or lb), with one 
decimal (with an empty bladder, without shoes and only wearing light clothing). The body weight 
should be assessed on the same calibrated weighing scale equipment throughout the trial, if 
possible.
Height is measured without shoes in centimetres or inches and recorded in the eCRF to nearest 
½ cm or ¼ inch.
8.3.4
Waist circumference
The waist circumference is defined as the minimal abdominal circumference located midway 
between the lower rib margin and the iliac crest.
The measurement of waist circumference must be performed and recorded in the eCRF. Waist 
circumference is measured in the horizontal plane and rounded up or down to the nearest ½ cm or 
¼ inch using a non-stretchable measuring tape. The same measuring tape should be used throughout 
the trial.
The circumference should be measured when the subject is in a standing position, with an empty 
bladder and wearing light clothing. The subject should be standing, feet together with arms down 
their side and waist accessible. The tape should touch the skin but not compress soft tissue and 
twists in the tape should be avoided. The subject should be asked to breathe normally and the 
measurement should be taken when the subject is breathing out gently.
8.3.5
Point-of-care HbA1c measurement
The investigator must measure the subject’s HbA1c by using a point-of-care device provided by 
Novo Nordisk A/S prior to adjustment of the oral semaglutide dose (see Section 2, Section 5.3.1
and Section 8.1.7). The HbA1c value must be used for evaluation of the dose adjustment criteria and 
reported into the eCRF. It is the investigator’s responsibility to set-up, calibrate and perform a 
quality control of the point-of-care HbA1c device.
8.3.6
Patient reported outcomes questionnaires
PRO will be assessed using the questionnaires:
!
SF-36v2™ (acute version) health survey33-35
!
DTSQs36
The questionnaires must be completed by the subject as specified in the flow chart, see Section 2,
preferably before any other trial-related activities for that visit. It takes approximately ten minutes 
to complete the two questionnaires. Subjects should be given the opportunity to complete the 
questionnaires by themselves without interruption. The completed questionnaires must be reviewed 
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for potential adverse events and missing data while the subject is still at the site. All results from the 
PRO questionnaires must be transferred into the eCRF.
All the questionnaires will be translated to local languages, and also be linguistically validated 
before being handed out to the subjects participating in the trial. 
SF-36v2TM
SF-36v2™ (acute version) health survey measures the individual overall health related quality of 
life on 8 domains; Physical functioning, Role physical, Bodily pain, General health, Vitality, Social 
functioning, Role emotional and Mental health. The acute version’s questions are based on a recall 
period of one week. SF-36v2™ (acute version) health survey contains 36 items.
DTSQs
The DTSQs questionnaire will be used to assess subject’s treatment satisfaction. This questionnaire 
contains 8 items and measures subject’s diabetes treatment in terms of convenience, flexibility and 
general feelings regarding treatment.
8.4
Safety assessments
8.4.1
Adverse events
Adverse events (AEs) must be reported at each visit in accordance with the procedures outlined in 
Section 12 and appendix B. 
8.4.1.1
Medication error 
If a medication error is observed during the trial, the following information is required and a 
specific event form must be completed in the eCRF in addition to the AE form (see Section 8.4.1.2, 
12.1.5 and appendix B): 
!
Trial product(s) involved 
!
Classification of medication error
!
Whether the subject experienced any hypoglycaemic episode and/or adverse event(s) as a result 
of the medication error 
!
Suspected primary reason for the medication error 
For definition of medication errors, see Section 12.1.4 and appendix B.
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8.4.1.2
Adverse events requiring additional data collection 
For the following AEs additional data collection is required and specific event forms must be 
completed in the eCRF in addition to the AE form:
!
Acute coronary syndrome (MI or hospitalisation for unstable angina)
!
Cerebrovascular event (stroke or transient ischaemic attack)
!
Heart failure
!
Pancreatitis
!
Neoplasm (excluding thyroid neoplasm)
!
Thyroid disease (including thyroid neoplasm)
!
Renal event
!
Hypersensitivity reaction
!
Acute gallstone disease
!
Medication error
!
Lactic acidosis
!
Creatine kinase (CK) > 10x UNL
!
Hepatic event defined as:
–
ALT or aspartate aminotransferase (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.
*Please note that in case of a hepatic event defined as ALT or AST > 3 x UNL and total 
bilirubin > 2 x UNL, where no alternative aetiology exists (Hy’s law), this must be reported as an 
SAE using the important medical event criterion if no other seriousness criteria are applicable.
See Section 12 and appendix B for details about the additional information to report. 
Note that additional assessments will be required according to appendix B in case of: 
!
suspicion of acute pancreatitis
!
suspicion of hypersensitivity reaction
!
increased levels of creatine kinase
!
increased levels of aminotransferases
In case any of these events fulfil the criteria for a serious adverse event, please report accordingly, 
see Section 12
8.4.2
Physical examination
A physical examination will be performed by the investigator according to local procedure (see 
Section 2 and Section 8.1.7). 
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A physical examination must include:
!
General appearance
!
Head, ears, eyes, nose, throat, neck
!
Thyroid gland
!
Respiratory system
!
Cardiovascular system
!
Gastrointestinal system including mouth
!
Musculoskeletal system
!
Central and peripheral nervous system
!
Skin
!
Lymph node palpation
8.4.3
Vital signs
Systolic and diastolic blood pressure
Systolic and diastolic blood pressure should be measured 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 data 
must be recorded in the eCRF. The actual value of the blood pressure measurement should be 
recorded in the eCRF (without rounding). The same equipment should be used throughout the trial.
Pulse
Pulse (beats per minute) must be recorded in the eCRF at site visits after resting for 5 minutes in a 
sitting position.
8.4.4
Eye examination 
Fundus photography or dilated fundoscopy will be performed as per the flow chart (see Section 2) 
by the investigator or according to local practice. Results of the fundus photography or dilated 
fundoscopy will be interpreted by the investigator (see Section 8.1.7).
If fundus photography or dilated fundoscopy has been performed within 90 days prior to 
randomisation, the procedure does not need to be repeated, unless worsening of visual function 
since the last examination. The results must be available prior to randomisation.
If the fundus photography or dilated fundoscopy is performed before the subject has signed the 
informed consent form, it must be documented in the medical records that the reason for performing 
the procedure was not related to this trial.
8.4.5
Electrocardiogram (12–lead)
12-lead ECG will be performed as per the flowchart (see Section 2) and the assessment must be 
reviewed as described in Section 8.1.7 by the investigator. The ECGs will also undergo central 
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assessment and the investigator must forward the ECGs to the central ECG reader as soon as 
possible.
If the central ECG evaluation of a baseline ECG is suggestive of a prior MI, the investigator will be 
notified. The investigator should consider if an update of the history of cardiovascular disease form 
is required.
If the central ECG evaluation of a post-baseline ECG is suggestive of new MI, the investigator will 
be notified and a confirmatory ECG should be performed. Unless already done, the investigator 
should report this as AE or SAE at investigator’s discretion and according to Section 12. 
Additional ECG recordings can be performed at the investigator’s site at investigator’s discretion at 
other visits than the planned ECG visits. All these ECGs will undergo central assessment. The 
reason for additional ECG assessments should be documented and an AE should be reported if 
applicable.
All findings suggestive of new MI detected by the central ECG reading will be adjudicated by the 
event adjudication committee (EAC) (see Section 12.7.2).
8.4.6
Laboratory assessments for safety
For overall description of laboratory assessments see Section 8.5.
Blood samples will be drawn according to the flow chart (see Section 2) and will be analysed at the 
central laboratory to determine levels of the following safety laboratory parameters:
Haematology:
!
Haemoglobin
!
Haematocrit
!
Leucocytes
!
Thrombocytes
!
Differential count (eosinophils, neutrophils, basophils, lymphocytes and monocytes)
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Biochemistry:
!
Alanine aminotransferase (ALT)
!
Albumin
!
Alkaline phosphatase (ALP)
!
Amylase
!
Aspartate aminotransferase (AST)
!
Bilirubin, total
!
Calcium, total
!
Creatinine 
!
eGFR per CKD-EPI37
!
Creatine kinase (CK)
!
Lipase
!
Potassium
!
Sodium
!
Urea
Hormones:
!
Calcitonin
In case any calcitonin value at any time during the trial is ≥ 10 ng/L, the algorithm in appendix A
must be followed.
8.4.7
Pregnancy testing
Females of childbearing potential will have a urine dip-stick pregnancy test performed at site as 
specified in Section 2 or as required by local law. For definition of female of non-childbearing 
potential and contraceptive methods, see Section 8.2.6.
In case a menstrual period is missed or if pregnancy is suspected between the scheduled visits, a 
urine pregnancy test should be performed. Investigator should instruct the subject to contact the site 
in case the pregnancy test is positive. At V2, females of childbearing potential will be provided with 
a urine dip-stick pregnancy test.
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8.4.8
Hypoglycaemic episodes
Plasma glucose (PG) should always be measured and recorded when a hypoglycaemic episode is 
suspected.
All PG values:
!
≤ 3.9 mmol/L (70 mg/dL) or 
!
> 3.9 mmol/L (70 mg/dL) occurring in conjunction with hypoglycaemic symptoms 
should be reported in the diary according to the instructions below throughout the trial from V1 to 
end of trial.
Upon onset of a hypoglycaemic episode the subject is recommended to measure PG every 15 
minutes until the SMPG value is > 3.9 mmol/L (70 mg/dL) and/or symptoms have been resolved in 
accordance to current guidelines38.
A SMPG value ≤ 3.9 mmol/L (70 mg/dL) or hypoglycaemic symptoms must trigger a 
hypoglycaemic episode form to be completed by the subject. Repeated SMPG measurements and/or 
symptoms will per default be considered as one hypoglycaemic episode until a succeeding SMPG 
value is > 3.9 mmol/L (70 mg/dL) and/or symptoms have been resolved. One hypoglycaemic 
episode form is to cover these measurements and/or symptoms.
In case of several low SMPG values within the hypoglycaemic episode, the lowest value is the one 
that will be reported as the SMPG value for the hypoglycaemic episode but the start time of the 
episode will remain as the time for the first SMPG value and/or symptom.
The record should include the following information: 
!
Start date and time of the hypoglycaemic episode.
!
Stop date and time of the hypoglycaemic episode (stop time is the first time the PG value is 
> 3.9 mmol/L (70 mg/dL and/or symptoms have been resolved).
If a stop date and time is not reported, a hypoglycaemic episode will cover a period of 60 
minutes.
!
The PG level before treating the episode (if available) and any follow up measurements.
The lowest value measured during the hypoglycaemic episode will be reported as the PG value 
for the episode, the remaining values will be kept as source data in the diary.
!
Whether the episode was symptomatic (Yes/No).
A hypoglycaemic episode starting without symptoms should be updated to symptomatic if the 
subject experiences symptoms later during the episode. 
!
Whether the subject was able to treat him/herself.
If the severity of a hypoglycaemic episode aggravates, only one hypoglycaemic episode should 
be reported, reflecting the most severe degree of hypoglycaemia.
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!
Date and time of last trial product administration, and for selected anti-diabetic medications 
administered prior to the episode, date and time as well as dose must be collected.
!
Date and time of last main meal (not including snacks) prior to the episode.
!
Whether the episode occurred in relation to physical activity.
!
Change in any concomitant illness.
!
Any sign of fever and/or other acute disease.
!
Whether the subject was asleep when the episode occurred.
–
If yes, whether the symptoms of the episode woke up the subject.
The answer to the question: “Was the subject able to treat him/herself?” must be answered “No” for 
an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or 
take other corrective actions. PG concentrations may not be available during an event, but 
neurological recovery following the return of PG to normal is considered sufficient evidence that 
the event was induced by a low PG concentration38.
Oral carbohydrates must not be given if the subject is unconscious.
If the question “Was the subject able to treat him/herself?” is answered “No”, the following 
information should be recorded by the subject:
!
Who assisted in the treatment of the hypoglycaemic episode (i.e. medical person or non-medical 
person)?
!
Where the treatment was administered (in clinic/emergency room/hospital or other. If the 
subject was treated in clinic/emergency room/hospital, whether they were transported in an 
ambulance or not)
!
Type of treatment provided by another person (i.e. oral carbohydrates, glucagon, IV glucose or 
other)
!
Were symptoms alleviated after administration of treatment?
!
Factors contributing to the episode (i.e. physical activity, missed meal, diet change, medication 
error (i.e. overdose, mix-up between products, incorrect use of device), other factors not listed 
or unknown)
!
Did the subject experience seizure?
!
Was the subject unconscious/comatose?
!
Did the subject experience any of the following symptoms39 (layman term used in the diary is 
specified in brackets if different from the protocol term)?
–
Autonomic: sweating, trembling, hunger or palpitations (rapid or irregular heart beat)
–
Neuroglycopenic: confusion, drowsiness, speech difficulty, visual disturbances, odd 
behaviour, impaired balance or incoordination (reduced ability to coordinate movement)
–
General malaise: headache or malaise (feeling discomfort/unease)
!
Other symptoms
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8.5
Laboratory assessments
The laboratory analyses will mainly be performed by a central laboratory. In case of suspicion of 
hypersensitivity reaction, anti-semaglutide antibodies and IgE anti-semaglutide antibodies samples 
will be analysed by Novo Nordisk A/S (see appendix B). For some of the analyses related to 
suspicion of pancreatitis and hypersensitivity reaction, a local laboratory must be used (see 
appendix B).
The handling, transportation and storage of biological samples are described in the laboratory 
manual (for central laboratory details see Attachment I).
Samples will be coded in order to keep subject identity anonymous.
Laboratory samples not drawn on the day of the actual visit should preferably be drawn on another 
day within the visit window stated in the flow chart (see Section 2). Please note that a laboratory 
sample pertaining to a specific visit must always be reported to that visit.
For some of the samples drawn during the trial, subjects will be asked to attend the site visits fasting 
(fasting for blood sampling is defined in Section 8.1.2).
The central laboratory will provide laboratory results to the investigator on an on-going basis.
However, results obtained in case of suspicion of hypersensitivity reaction will be provided to the 
investigator upon request.
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. The investigator must review all laboratory results for 
concomitant illnesses and AEs and report these according to Section 8.2.5 and Section 12.
For Brazil only: All laboratory results will be communicated to the investigators.
Laboratory samples will be destroyed at the latest at the completion of the clinical trial report, or 
according to local regulations, except antibody samples collected in relation to suspicion of 
hypersensitivity reaction that will be stored as described in Section 24.2.
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8.6
Other assessments
8.6.1
Subject diary
The diaries should be handed out at the visits described in the flow chart Section 2. The recordings 
must be reviewed as described in Section 8.1.7 and transcribed to the eCRF at the following visit.
Entries in the diaries are only to be made by the subject, unless otherwise specified.
The investigator should instruct the subject in recording the following data in the diary:
!
date of first trial product administration
!
hypoglycaemic episodes
!
changes in concomitant medication
!
AEs
8.7
Subject compliance
Throughout the trial, the investigator will remind the subjects to follow the trial procedures and 
requirements to ensure subject compliance.
Treatment compliance: Will be assessed by monitoring of drug accountability. Prior to visits 
where drug accountability is performed, the subject will be asked to return all used, partly used and 
unused trial products. The investigator must assess the amount of trial products returned compared 
to what was dispensed at the last dispensing visit and, in case of discrepancies, question the subject.
If a subject is found to be non-compliant, the investigator will remind the subject of the importance 
of following the instructions given including taking the trial products as prescribed and should 
document this discussion in the subject’s medical records.
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9
Trial supplies
Trial supplies comprise trial products and auxiliary supplies. Additional details regarding trial 
supplies can be found in the Trial Materials Manual (TMM). 
Trial products must not be dispensed to any person not included in the trial. 
9.1
Trial products
The following trial products are considered as investigational medicinal products and will be 
provided by Novo Nordisk A/S, Denmark Table 9–1:
Table 9–1
Investigational medicinal products
Trial product
Strength
Dosage form
Route of 
administration
Container/
delivery device 
Semaglutide 3 mg tablet 
3 mg
Tablet
Oral
Dosepacka
Semaglutide 7 mg tablet
7 mg
Semaglutide 14 mg tablet 
14 mg
Sitagliptin film-coated tablet
100 mg
Tablet
Oral
Dosepackb
a One dosepack contains one blister card with 7 tablets.
b One dosepack contains one blister card with 14 tablets.
Metformin, SU, TZD, SGLT-2 inhibitors and rescue medication are considered NIMPs and will not 
be supplied by Novo Nordisk. However, metformin, SU, TZD, SGLT-2 inhibitors will be 
reimbursed if required by the country’s regulatory authority or institutional review board 
(IRB)/independent ethics committee (IEC). 
9.2
Labelling 
The trial products will be labelled in accordance with Annex 1340, local regulations and trial 
requirements.
Each trial site will be supplied with sufficient trial products for the trial on an on-going basis 
controlled by the IWRS. Trial products will be distributed to the trial sites according to enrolment 
and randomisation.
9.3
Storage 
Storage conditions of the trial products are outlined in Table 9–2.
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Table 9–2
Storage conditions
Trial product
Storage conditions
(not-in-use)
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
Sitagliptin 100 mg tablet
No special storage conditions
N/A
The investigator must ensure that trial product is kept under proper storage conditions and record 
and evaluate the temperature. The investigator must inform Novo Nordisk immediately if any trial 
product has been stored outside specified conditions (e.g. outside temperature range). Additional 
details regarding handling of temperature deviations can be found in the TMM.
Trial product that has been stored improperly must not be dispensed to any subject before it has 
been evaluated and approved for further use by Novo Nordisk. The investigator must take 
appropriate action to ensure correct storage.
9.4
Drug accountability and destruction
Drug accountability of all trial products received at site is the responsibility of the investigator.
Subjects must be instructed to return all used, partly used and unused trial products including empty 
packaging material at each dispensing visit.
Returned trial product (used/partly used and/or unused), expired or damaged trial product can be 
stored at room temperature and must be stored separately from non-allocated trial product. Non-
allocated trial products including expired or damaged products must be accounted as unused at the 
latest at closure of the trial site.
Drug accountability is performed by using the IWRS. Drug accountability must be done on tablet 
level.
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Destruction of trial products can be performed on an on-going basis and will be done according to 
local procedures after accountability is finalised and reconciled by the monitor. Destruction of 
products must be documented in the IWRS
9.5
Auxiliary supplies
The following will be provided by Novo Nordisk in accordance with the TMM:
•
BG meter and BG meter auxiliaries 
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10
Interactive voice/web response system
A trial-specific IWRS will be set up which can be accessed at any time via the internet or telephone. 
Access to the IWRS must be restricted to and controlled by authorised persons. 
IWRS is used for: 
!
Screening
!
Screening failure
!
Randomisation
!
Medication arrival
!
Dispensing
!
Treatment discontinuation
!
Completion
!
Drug accountability
!
Data change
IWRS user manuals will be provided to each trial site. DUNs will be allocated using the IWRS. It is 
important to dispense the exact allocated DUNs to a subject.
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11 Randomisation procedure 
The trial is an open-label trial. A randomisation session will be made for all eligible subjects using 
IWRS.
At V2, eligible subjects will be randomised to one of the two parallel treatment arms as described in 
Section 5.1 and Section 5.2.
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12 Adverse events, technical complaints and pregnancies
12.1
Definitions
12.1.1
Adverse event 
An adverse event (AE) is any untoward medical occurrence in a subject administered a medicinal 
product and which does not necessarily have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom or disease temporally associated with the use of a product, whether or not 
considered related to the product.
An AE includes:
!
A clinically significant worsening of a concomitant illness.
!
A CLAE: a clinical laboratory abnormality which is clinically significant, i.e. an abnormality 
that suggests a disease and/or organ toxicity and is of a severity that requires active 
management. Active management includes active treatment or further investigations, for 
example change of medicine dose or more frequent follow-up due to the abnormality.
The following should not be reported as AEs:
!
Pre-existing conditions, including those found as a result of screening or other trial procedures 
performed before exposure to trial product (pre-existing conditions should be reported as 
medical history or concomitant illness).
!
Pre-planned procedures unless the condition for which the procedure was planned has worsened 
from the first trial-related activity after the subject has signed the informed consent.
!
Non-serious hypoglycaemia is an AE, but is reported on a hypoglycaemic episode form instead 
of on an AE form, see Section 8.4.8.
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.
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!
Final outcome
–
Recovered/resolved - The subject has fully recovered, or by medical or surgical treatment 
the condition has returned to the level observed at the first trial-related activity after the 
subject signed the informed consent.
–
Recovering/resolving - The condition is improving and the subject is expected to recover 
from the event. This term is only applicable if the subject has completed the trial or has died 
from another AE.
–
Recovered/resolved with sequelae - The subject has recovered from the condition, but 
with lasting effect due to a disease, injury, treatment or procedure. If a sequela meets an 
SAE criterion, the AE must be reported as an SAE.
–
Not recovered/not resolved - The condition of the subject has not improved and the 
symptoms are unchanged, or the outcome is not known.
–
Fatal - This term is only applicable if the subject died from a condition related to the 
reported AE. Outcomes of other reported AEs in a subject before he/she died should be 
assessed as “recovered/resolved”, “recovering/resolving”, “recovered/resolved with 
sequelae” or “not recovered/not resolved”. An AE with fatal outcome must be reported as 
an SAE.
–
Unknown - This term is only applicable if the subject is lost to follow-up.
12.1.2
Serious adverse event
An 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
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Medical judgement must always be exercised and, when in doubt, the hospital contact should be 
regarded as a hospitalisation. Hospitalisations for administrative, trial-related and social 
purposes do not constitute AEs and should therefore not be reported as AEs or SAEs. Hospital 
admissions for surgical procedures, planned before trial inclusion, are not considered AEs or 
SAEs.
c
A substantial disruption of a subject’s ability to conduct normal life functions (e.g. following the 
event or clinical investigation the subject has significant, persistent or permanent change, 
impairment, damage or disruption in his/her body function or structure, physical activity and/or 
quality of life).
d
For example intensive treatment in an emergency room or at home of allergic bronchospasm, 
blood dyscrasia or convulsions that do not result in hospitalisation, or development of drug 
dependency or drug abuse.
The following AEs must always be reported as an SAE using the important medical event criterion
if no other seriousness criteria are applicable:
!
suspicion of transmission of infectious agents via the trial product
!
risk of liver injury defined as ALT or AST > 3 x UNL and total bilirubin >2 x UNL, where no 
alternative aetiology exists (Hy’s law).
Additional assessments should be made for events meeting the criterion of Hy’s law as stated above 
(see appendix B). 
12.1.3
Non-serious adverse event
A non-serious AE is any AE which does not fulfil the definition of an SAE.
12.1.4
Medication errors
A medication error concerning trial products is defined as:
!
Administration of wrong drug. 
Note: Use of wrong DUN is not considered a medication error unless it results in administration 
of wrong drug
!
Wrong route of administration
!
Administration of an overdose with the intention to cause harm (e.g. suicide attempt), misuse or 
abuse of trial product
!
Accidental administration of a higher dose than intended. A higher dose is a dose of at least one 
tablet 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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Medication errors must be reported on an AE form and a specific event form, see Section 8.4.1.1,
12.1.5 and appendix B.
12.1.5
Adverse events requiring additional data collection
AEs requiring additional data collection are AEs where the additional data will benefit the 
evaluation of the product safety. A number of adverse events that always require additional data 
collection have been pre-specified. See appendix B for details about these events and the additional 
information to report.
Some events in this trial will be adjudicated by an independent external committee as described in 
Section 12.7.2.
Table 12–1 lists AEs that require completion of specific event forms in the eCRFs and/or are 
subject to event adjudication.
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Table 12–1
Adverse events requiring completion of specific event forms and/or are subject 
to event adjudication
Event
Specific event 
form
Event adjudication
Death
No
Yes
Acute coronary syndrome (MI or hospitalisation for 
unstable angina)
Yes
Yes
Cerebrovascular event (stroke or transient ischaemic 
attack [TIA])
Yes
Yes
Heart failure 
Yes
Yes (only if requiring 
hospitalisation)
Pancreatitis
Yes
Yes (only if acute pancreatitis)
Neoplasm (excluding thyroid neoplasm)
Yes
Yes (only if malignant)
Thyroid disease (including thyroid neoplasm)
Yes
Yes (only if malignant thyroid 
neoplasm or C-cell hyperplasia)
Renal event
Yes
Yes (only if acute kidney injury)
Hypersensitivity reaction
Yes
No
Acute gallstone disease
Yes
No
Medication error
Yes
No
Lactic acidosis
Yes
Yes
CK > 10 x UNL
Yes
No
Hepatic event defined as:
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.
Yes
No
* Please note that in case of a hepatic event defined as ALT or AST > 3 x UNL and total bilirubin > 2 x UNL, where no 
alternative aetiology exists (Hy’s law), this must be reported as an SAE using the important medical event criterion if 
no other seriousness criteria are applicable.
For details about specific event forms, see appendix B.
12.1.6
Technical complaints
A technical complaint is any written, electronic, or oral communication that alleges product 
(medicine or device) defects. The technical complaint may be associated with an AE, but does not 
concern the AE itself.
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Examples of technical complaints:
!
The physical or chemical appearance of trial products (e.g. discoloration, particles or 
contamination)
!
All packaging material including labelling
Only technical complaints related to adverse events will be reported in the clinical trial report.
12.2
Reporting of adverse events
All events meeting the definition of an AE must be collected and reported. This includes events 
occurring from the first trial-related activity after the subject has signed the informed consent until 
the end of the post-treatment follow-up period (V11) for subjects on trial product or until the end of 
trial (V10 or V11A, whichever comes last) for the subjects who have discontinued trial product 
prematurely. Events for withdrawn subjects will be collected and reported until last trial-related 
contact with the subject. The events must be recorded in the applicable eCRF forms in a timely 
manner, see timelines below and Figure 12–1. 
During each contact with the trial site staff, the subject must be asked about AEs and technical 
complaints, for example by asking: “Have you experienced any problems since the last contact?”
All AEs, either observed by the investigator or subject, must be reported by the investigator and 
evaluated.
All AEs must be recorded by the investigator on an AE form. The investigator should report the 
diagnosis, if available. If no diagnosis is available, the investigator should record each sign and 
symptom as individual AEs using separate AE forms.
For SAEs, a safety information form must be completed in addition to the AE form. A safety 
information form is a form 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 events and the additional information to 
report.
In case any of the above events fulfil the criteria for seriousness in Section 12.1, then the event 
should be reported as serious.
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Some events will undergo event adjudication by the EAC, please refer to Section 12.7.2. For AEs 
qualifying for event adjudication, the adjudication form will also have to be completed in the eCRF. 
The adjudication form is a checklist of clinical data to be provided from the site.
For all non-serious AEs, the applicable forms should be signed when the event is resolved or at the 
end of the trial at the latest. 
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. 
For SAEs requiring reporting on a specific event form: In addition to the above, the specific 
event form within 14 calendar days from the investigator’s first knowledge of the AE.
!
Events for adjudication: The adjudication form should be completed within 14 calendar days
of investigator’s first knowledge of the AE, see Section 12.7.2. The investigator should 
preferably provide the medical documentation within 4 weeks of event identification according 
to instructions in the event adjudication site manual. 
If the eCRF is unavailable, the concerned AE information must be reported on a paper AE form and 
sent to Novo Nordisk by fax, e-mail or courier within the same timelines as stated above. When the 
eCRF becomes available again, the investigator must enter the information on the form into the 
eCRF.
Contact details (fax, telephone, e-mail and address) are provided in the investigator trial master file.
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AE identified
Does the AE require 
a specific event 
form?
Is the AE subject to 
adjudication and/or 
is the outcome 
fatal?
AE form < 24 hours
SIF < 5 calendar days
Specific event form 
For SAEs:
< 14 calendar days
Is the AE serious or 
non-serious?
AE form
Adjudication form
< 14 calendar days
Source data < 4 weeks
Non-serious
Serious
No
Yes
Yes
Queries and follow-up 
requests to be resolved 
< 14 calendar days
Timelines are for the completion of forms from the time of investigator’s awareness.
AEs requiring specific event forms are described in Section 12.1.4, 12.1.5 and appendix B.
AEs for adjudication are described in Section 12.7.2
AE: Adverse event  SAE: Serious adverse event  SIF: Safety Information form 
No additional action
No additional action
No
Figure 12–1
Reporting of AEs
Novo Nordisk assessment of AE expectedness:
Novo Nordisk assessment of expectedness is performed according to the following reference 
documents: IB for oral semaglutide (NN9924), edition 624 and Summary of Product Characteristics
(SmPC) for Januvia® (sitagliptin)41; current version and any updates thereto. 
Reporting of trial product-related SUSARs by Novo Nordisk:
Novo Nordisk will notify the investigator of trial product-related suspected unexpected serious 
adverse reactions (SUSARs) in accordance with local requirements and ICH GCP1. In addition, the 
investigator will be informed of any trial-related SAEs that may warrant a change in any trial 
procedure.
In accordance with regulatory requirements, Novo Nordisk will inform the regulatory authorities, 
including European Medicines Agency, 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 ICH GCP1, unless locally this is an obligation of the investigator.
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Novo Nordisk products used as concomitant medication or non-investigational medicinal 
product:
If an AE is considered to have a causal relationship with a Novo Nordisk marketed product used as 
NIMP or 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 AE to relevant regulatory authorities.
12.3
Follow-up of adverse events
The investigator must record follow-up information by updating the medical records and 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.
The investigator must ensure that the recording of the worst case severity and seriousness of an 
event is kept throughout the trial. A worsening of an unresolved AE must be reported as follow up 
with re-assessment of severity and/or seriousness of the event.
Queries or follow-up requests from Novo Nordisk must be responded to within 14 calendar days
from the date of receipt of the request, unless otherwise specified in the follow-up request.
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SAEs after end of trial: If the investigator becomes aware of an SAE with a suspected causal 
relationship to the investigational medicinal product occurring to a subject after the subject has 
ended the trial, the investigator should report this SAE within the same timelines as for SAEs 
during the trial. 
12.4
Technical complaints and technical complaint samples
12.4.1
Reporting of technical complaints
All technical complaints on any of the following products: 
!
semaglutide 3 mg tablets
!
semaglutide 7 mg tablets
!
semaglutide 14 mg tablets
!
sitagliptin 100 mg 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 and/or SAEs.
Technical complaints must be reported on a separate technical complaint form:
!
One technical complaint form must be completed for each affected DUN
!
If DUN is not available, a technical complaint form for each batch number must be completed
The investigator must complete the technical complaint form in the eCRF within the following 
timelines of the trial site obtaining knowledge of the technical complaint:
!
Technical complaint assessed as related to an SAE within 24 hours
!
All other technical complaints within 5 calendar days
If the eCRF is unavailable or when reporting a technical complaint that is not subject related, the 
information must be provided on a paper form by fax, e-mail or courier to Customer Complaint 
Center, Novo Nordisk, within the same timelines as stated above. When the eCRF becomes 
available again, the investigator must enter the information on the technical complaint form in the 
eCRF.
12.4.2
Collection, storage and shipment of technical complaint samples
The investigator must collect the technical complaint sample and notify the monitor within 5 
calendar days of obtaining the sample at trial site. The monitor must coordinate the shipment to 
Customer Complaint Center, Novo Nordisk (the address is provided in Attachment I) and ensure 
that the sample is sent as soon as possible. A copy of the technical complaint form must be included 
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in the shipment of the sample. If several samples are returned in one shipment, the individual 
sample and the corresponding technical complaint form must be clearly separated.
The investigator must ensure that the technical complaint sample contains the batch number and, if 
available, the DUN. All parts of the DUN should be returned.
If the technical complaint sample is unobtainable, the investigator must specify on the technical 
complaint form why it is unobtainable.
Storage of the technical complaint sample must be done in accordance with the conditions 
prescribed for the product. 
12.5
Pregnancies in female subjects
Female subjects must be instructed to notify the investigator immediately if they become pregnant 
during the trial. The investigator must report any pregnancy in subjects who have received trial 
product(s).
The investigator must follow the pregnancy until the pregnancy outcome and the newborn infant is 
one month of age.
The investigator must report information about the pregnancy, pregnancy outcome and health of the 
newborn infant(s), as well as AEs in connection with the pregnancy and AEs in the foetus and 
newborn infant.
The following must be collected and reported by the investigator to Novo Nordisk - electronically 
(e.g. in PDF format), or by fax or courier:
1. Reporting of pregnancy information
Information about the pregnancy and pregnancy outcome/health of the newborn infant(s) has to 
be reported on Maternal Form 1A and 1B, respectively. 
When the pregnancy outcome is abnormal (i.e. congenital anomalies, foetal death including 
spontaneous abortion and/or any anomalies of the foetus observed at gross examination or 
during autopsy) and/or when a congenital anomaly is diagnosed within the first month, further 
information has to be reported for the female subject on Maternal Form 2. In addition, 
information from the male partner has to be reported on the Paternal Form, after an informed 
consent has been obtained from the male partner. 
Initial reporting and follow-up information must be reported within 14 calendar days of the 
investigator’s first knowledge of initial or follow-up information. 
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2. Reporting of AE information
The investigator has to report AEs in connection with the pregnancy as well as in the foetus and 
newborn infant(s). The SAEs that must be reported include abnormal outcome, such as foetal death 
(including spontaneous abortion), congenital anomalies (including those observed at gross 
examination or during autopsy of the foetus), as well as other pregnancy complications fulfilling the 
criteria of an SAE.
Forms and timelines for reporting AEs:
Non-serious AEs: 
–
AE forma within 14 calendar days of the investigator’s first knowledge of the initial or 
follow-up information to the non-serious AE.
SAEs: 
–
AE forma within 24 hours of the investigator’s first knowledge of the SAE.
–
Safety information form within 5 calendar days of the investigator’s first knowledge of the 
SAE.
–
SAE follow-up information to the AE form and/or safety information form within 24 
hours of the investigator’s first knowledge of the follow-up information.
a
It must be clearly stated in the AE diagnosis field on the AE form if the event occurred in 
the subject, foetus or newborn infant. If the AE occurred in the foetus or newborn infant, the 
AE can only be reported on paper AE and safety information form.
Any queries or follow-up requests from Novo Nordisk to non-serious AEs, SAEs and pregnancy 
forms must be responded to by the investigator within 14 calendar days from the date of receipt of 
the request, unless otherwise specified in the follow-up request.
12.6
Precautions and/or overdose
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 include: hunger, slight headache, nausea, light-
headedness, palpitations and sweating. Symptoms of non-severe hypoglycaemia should be treated 
by ingestion of carbohydrates. 
Severe hypoglycaemia resulting in loss of consciousness should be treated according to best 
available medical practice. 
One case of accidental overdose of oral semaglutide was reported in the NN9924-3692 trial. The 
subject accidentally took the trial product 
 day and was thus treated with 20 mg of 
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oral semaglutide. The subject did not report any symptoms and treatment was continued without 
any change.
One case of accidental overdose has been reported in subjects treated with s.c. semaglutide once 
weekly. 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. No symptoms of hypoglycaemia or any other symptoms or signs 
were noted. 
For further details please see the current edition of the IB for oral administration of semaglutide 
(NN9924), edition 624, and any updates hereof.
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
Event adjudication committee
An independent external event adjudication committee (EAC) is established to perform 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 authorisations to 
impact on 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 12–2 have been selected for adjudication in order to obtain an external 
independent validation of the diagnosis. In addition, cardiovascular events are being adjudicated 
according to U.S. Food and Drug Administration (FDA) requirements42.
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The EAC will review copies in English (translated if necessary) of medical documentation received 
in the adjudication packages (e.g. x-ray, ECGs, ultrasound images, discharge summaries, pathology 
reports and death certificates). The investigator must provide medical documentation as soon as 
possible, when they receive the request from Novo Nordisk or the event adjudication vendor.
The AEs for adjudication are listed in Table 12–2:
Table 12–2
Adverse events for adjudication
Events
Description
Adjudication outcome
Death*
! All-cause death
! Cardiovascular death 
(including undetermined 
cause of death)
! Non-Cardiovascular death
Acute Coronary Syndrome
Acute Coronary Syndrome conditions include: 
! ST-elevation acute myocardial infarction 
(STEMI)
! Non-ST elevation acute myocardial infarction 
(NSTEMI)
! Silent MI 
! Unstable angina pectoris 
! Acute MI (STEMI or 
NSTEMI), silent MI
! Unstable angina pectoris 
requiring hospitalisation
Cerebrovascular event
! Episode of focal or global neurological 
dysfunction caused by brain, spinal cord, or 
retinal vascular injury as a result of 
haemorrhage or infarction
! 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 UNL
! Characteristic findings of acute pancreatitis on 
imaging
Acute pancreatitis
! Mild
! Moderately severe
! Severe
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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 injury43 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 < 0.5 mL/kg/h for 6 hours
! Acute kidney injury
Lactic acidosis
! Lactic acidosis is characterized by increased 
blood lactate level in association with metabolic 
acidosis
! Lactic acidosis
* Death is not a separate event, but an outcome
There are different processes for capturing events for adjudication:
!
Direct reporting by investigator:
–
All AEs need to be assessed by the investigator if any AE category is applicable. If the AE 
category selected is in scope for adjudication, the event specific adjudication form will be 
populated for sites to complete.
–
AEs with fatal outcome.
!
Screening:
–
All AEs will be screened by Novo Nordisk 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.
–
All ECGs will be centrally read. If the central reading conclusion is suggestive of new MI, 
the ECG adjudication form will be populated for sites to complete for all post-baseline 
ECGs.
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!
EAC identified events:
–
The 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.
AEs for adjudication must be reported according to Section 12.2. In addition, the specific 
adjudication form should be completed within 14 calendar days of the investigator’s first 
knowledge of the AE and all relevant predefined documents provided within 4 weeks according to 
instructions in the event adjudication site manual. 
The assessment made by the EAC will be included in the clinical trial report as well as assessments 
made by the investigator. However, the adjudication made by an EAC, given its independent 
analysis of each event, will be attributed with greater importance of the two.
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13 Case report forms 
Novo Nordisk will provide a system for the eCRF. This system and support services to the system 
will be provided by an external supplier.
Ensure that all relevant questions are answered and that no empty data field exists. If a test or an 
assessment has not been done and will not be available, or if the question is irrelevant (e.g. is not 
applicable), indicate this according to the data entry instructions.
The following will be provided as paper CRFs:
–
Pregnancy forms
The following will be provided as paper CRFs to be used when access to the eCRF is revoked or if 
the eCRF is unavailable:
–
AE forms 
–
Safety information forms 
–
Technical complaint forms (also to be used to report complaints that are not subject related
(e.g. discovered at trial site before allocation)).
On the paper CRF forms print legibly, using a ballpoint pen. Ensure that all questions are answered 
and that no empty data blocks exist. Ensure that no information is recorded outside the data blocks. 
If a test/assessment has not been done and will not be available, indicate this by writing “ND” (not 
done) in the appropriate answer field in the CRF. If the question is irrelevant (e.g. is not applicable) 
indicate this by writing “NA” (not applicable) in the appropriate answer field. Further guidance can 
be obtained from the instructions in the CRF.
The investigator must ensure that all information is consistent with the source documentation. By 
electronically signing the case book in the eCRF, the investigator confirms that the information in 
the eCRF and related forms is complete and correct.
13.1
Corrections to case report forms 
Corrections to the eCRF data may be made by the investigator or the investigator’s delegated staff. 
An audit trail will be maintained in the eCRF application containing as a minimum: the old and the 
new data, identification of the person entering the data, date and time of the entry and reason for the 
correction.
If corrections are made by the investigator’s delegated staff after the date the investigator has signed 
the case book, the case book must be signed and dated again by the investigator.
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13.2
Case report form flow 
The investigator must ensure that data is recorded in the eCRF as soon as possible, preferably 
within 5 days after the visit. Once data has been entered, it will be available to Novo Nordisk for 
data verification and validation purposes.
At the end of the trial the investigator must ensure that all remaining data have been entered into the 
eCRF no later than 3 days after LSLV at the site in order to ensure the planned lock of the database.
Site specific eCRF data (in an electronic readable format) will be provided to the trial site before 
access to the eCRF is revoked. This data must be retained at the trial site. When the final clinical 
trial report is available, the data will be archived by Novo Nordisk.
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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 until LSLV at the trial site 
(for trial sites with active subjects (defined as subjects in screening, treatment or follow-up)).
The monitor must be given direct access to all source documents (original documents, data and 
records). Direct access includes permission to examine, analyse, verify and reproduce any record(s) 
and report(s) that are important to the evaluation of the trial. If the electronic medical record does 
not have a visible audit trail, the investigator must provide the monitor with signed and dated 
printouts. In addition the relevant trial site staff should be available for discussions at monitoring 
visits and between monitoring visits (e.g. by telephone).
All data must be verifiable in source documentation other than the eCRF. 
For all data recorded the source document must be defined in a source document agreement at each 
trial site. There must only be one source defined at any time for any data element.
Source data generated by the trial site can be corrected by another person than the person entering 
the source data if accepted by local regulations; any correction must be explained, signed and dated 
by the person making the correction.
The original diaries and/or PROs must not be removed from the trial site, unless they form part of 
the CRF and a copy is kept at the site.
The monitor will ensure that the eCRFs are completed and that paper CRFs are collected.
The following data will be source data verified for screening failures:
!
Date for obtaining informed consent.
!
Reason for screening failure.
Monitors will review the subject's medical records and other source data (e.g. the diaries and PROs) 
to ensure consistency and/or identify omissions compared to the eCRF. If discrepancies are found, 
the investigator must be questioned about these.
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A follow-up letter (paper or electronic) will be sent to the investigator following each monitoring 
visit. This should address any action to be taken.
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15 Data management
Data management is the responsibility of Novo Nordisk. Data management may be delegated under 
an agreement of transfer of responsibilities to a Contract Research Organisation. 
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.
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16 Computerised systems
Novo Nordisk will capture and process clinical data using computerised systems that are described 
in Novo Nordisk Standard Operating Procedures and IT architecture documentation. The use and 
control of these systems are documented.
Investigators working on the trial may use their own electronic systems to capture source data.
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17 Statistical considerations
General considerations
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 two levels of anti-diabetic background 
medication at screening (with and without SU) will be included based on the actual information
collected through the eCRF. In case of missing eCRF information the information collected from 
the IWRS system 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 ½ LLoQ. Number 
of values below LLoQ by treatment and visit will be summarised if deemed relevant.
Results from a statistical analysis will as a minimum be presented by the estimated treatment 
contrasts for oral semaglutide versus sitagliptin comparisons with associated two-sided 95% 
confidence intervals and p-values corresponding to two-sided tests of no difference.
If no statistical analysis is specified, data will be presented using relevant summary statistics.
Primary and secondary estimands
Two estimands addressing different aspects of the trial objective will be defined; a primary de-facto 
(effectiveness) estimand and a secondary de-jure (efficacy) estimand: 
!
Primary estimand
–
de-facto treatment difference (oral semaglutide versus sitagliptin) at week 52 for all 
randomised subjects regardless of adherence to randomised treatment and initiation of 
rescue medication
The primary de-facto estimand assesses the expected glycaemic benefit in a future population that 
results from subjects initiating treatment with oral semaglutide including potential rescue 
medication(s) as compared to initiating treatment with sitagliptin including potential rescue 
medication(s). Generalisation of this estimand depends among other things on the extent to which 
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the use of rescue medication in this trial reflects clinical practice and the adherence to trial product 
administration in this trial reflects the behaviour of the target population. Accordingly, data 
collected regardless of discontinuation of trial product or initiation of rescue medication(s) will be 
used to draw inference.
!
Secondary estimand 
–
de-jure treatment difference (oral semaglutide versus sitagliptin) at week 52 for all 
randomised subjects if all subjects adhered to treatment and did not initiate rescue 
medication
The secondary de-jure estimand assesses the glycaemic benefit a future subject is expected to 
achieve if initiating and continuing treatment with oral semaglutide as compared to sitagliptin. It is 
considered a clinically relevant estimand as it provides information to treating clinicians about the 
expected glycaemic efficacy of oral semaglutide compared to sitagliptin for purposes of treating 
individual subjects. Generalisation of this estimand depends among other things on the extent to 
which the adherence to trial product administration in this trial reflects the behaviour of the target 
population. Accordingly, only data collected prior to discontinuation of trial product or initiation of 
rescue medication will be used to draw inference. This will avoid confounding from rescue 
medication.
Missing data considerations at week 52
When estimating the primary estimand, the proportion of missing data, i.e., data that do not exist 
even though subjects are intended to stay in the trial regardless of treatment status and initiation of 
rescue medication(s), is expected to be maximum 15% . Missing data will mainly be due to 
withdrawal from trial or lost to follow-up.
When estimating the secondary estimand, the proportion of missing data is expected to be higher 
(20-30%) since data collected after discontinuation of trial product or initiation of rescue 
medication(s) will be set to missing. The 20-30% of missing data is based on the sitagliptin phase 3 
trials41, the oral semaglutide phase 2 trial (NN9924-3790), that indicates that a low starting dose 
with gradual dose-escalation diminishes gastrointestinal AEs compared with more aggressive 
dosing regimens. The possibility to reduce the dose due to issues with tolerability is also expected 
to reduce the number of subjects withdrawing from the oral semaglutide arm. Across treatment 
arms the main reasons for missing data are expected to be early treatment discontinuation due to 
gastrointestinal AEs and eventually initiation of rescue medication. Initiation of rescue medication 
is expected to be more frequent in the sitagliptin than in the oral semaglutide arm. A higher 
proportion of subjects are expected to discontinue treatment due to AEs in the oral semaglutide arm, 
compared to the sitagliptin treatment arm. So overall the frequency of missing data is expected to be 
similar across treatment arms.
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Descriptive summaries and graphical representation of extent, reason(s) for and pattern of missing 
data will be presented by treatment arm.
17.1
Sample size calculation
The primary endpoint, if a subject after week 52 achieves (yes/no) HbA1c < 7% (53 mmol/mol) and 
the confirmatory secondary endpoint, change from baseline to week 52 in body weight (kg) are 
planned to be tested for superiority of oral semaglutide versus sitagliptin. 
The sample size calculation is made to ensure at least 90% to confirm superiority of oral 
semaglutide vs. sitagliptin on the primary endpoint, if a subject after week 52 achieves HbA1c < 7% 
(yes/no). Two pre-specified confirmatory hypotheses are shown in Figure 17–1. The hierarchal 
testing strategy is used to control the overall type-1 error at a nominal two-sided 5% level. The 
statistical testing strategy is built on the principle that glycaemic effect will have to be established in 
terms of HbA1c superiority before testing for added benefits in terms of body weight superiority.
The sample size calculation is based on a 5% (two-sided) significance level and Fishers exact test. 
The sample size depends on the proportion of responders and the absolute difference in proportions 
between semaglutide and sitagliptin. Assuming an absolute difference in proportions of 15 
percentage-points (taking the retrieved and imputed data into account) and that the proportion of 
sitagliptin responders are distributed around 20 to 50%, the power for confirming superiority on the 
primary endpoint, if a subject after week 52 achieves (yes/no) HbA1c < 7% (53 mmol/mol) will be 
at least 90% with 250 subjects per arm. In total 500 subjects are planned to be randomised.
Figure 17–1
Graphical illustration of the closed testing procedure
The overall significance level of α = 0.05 (two-sided) is initially allocated to the HbA1c superiority test. The local 
significance level (α-local) will be reallocated to the body weight hypothesis if the first hypothesis is confirmed. The 
sample size is based on the HbA1c hypothesis.
 = 0.05
HbA1c < 7% (yes/no)
Superiority
 = 0
Body weight (kg)
Superiority
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17.2
Definition of analysis sets
The following analysis sets will be defined:
Full analysis set (FAS): Includes all randomised subjects. Subjects in the FAS will contribute to 
the evaluation “as randomised”.
Safety analysis set (SAS): Includes all subjects exposed to at least one dose of trial product. 
Subjects in the SAS will contribute to the evaluation “as treated”.
Data selections and observation periods
Unless subjects withdraw their informed consent, data collection will continue for the full duration 
of the trial. The full duration of the trial is defined as up to and including:
!
the follow-up visit (V11) for subjects on trial product
!
the latest occurring visit of the end-of-treatment visit (V10) or the follow-up premature 
discontinuation visit (V11A), for subjects who have discontinued trial product prematurely
Subjects and data to be used in an analysis will be selected in a two-step manner:
!
Firstly, subjects will be selected based on the specified analysis set
!
Secondly, data points on the selected subjects from the first step will be selected based on the 
specified observation period
Definition of the observation periods:
In-trial: This observation period represents the time period where subjects are considered to be in 
the trial, regardless of discontinuation of trial product or initiation of rescue medication. The in-trial 
observation period starts at randomisation (as registered in the IWRS) and ends at the date of:
!
the last direct subject-site contact, which is scheduled to take place 5 weeks after planned last 
dose of trial product at the follow-up visit (V11)
!
withdrawal for subjects who withdraw their informed consent
!
the last subject-investigator contact as defined by the investigator for subjects who are lost to 
follow-up
!
death for subjects who dies before any of the above 
On-treatment: This observation period represents the time period where subjects are considered 
treated with the trial product. The observation period is a subset of the in-trial observation period. It 
starts at the date of first dose of trial product. Two slightly different end dates will be needed to 
cover all assessments appropriately.
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For adjudicated events, ECGs and AEs including hypoglycaemic episodes, the observation period 
ends at the first date of any of the following:
!
the follow-up visit (V11)
!
the follow-up prematurely discontinuation visit (V11A)
!
the last date on trial product +38 days 
!
the end-date for the in-trial observation period
The follow-up visit (V11/V11A) is scheduled to take place 5 weeks after the last date on trial 
product corresponding to approximately five half-lives of oral semaglutide. The visit window for 
the follow-up visit is +3 days.
For efficacy and other safety assessments (laboratory assessments, physical examination and vital 
signs) the observation period ends at the last date on trial product +3 days. This will be used in 
order to ensure specificity to reversible effects of treatment. 
On-treatment without rescue medication: This observation period is a subset of the on-treatment 
observation period, where subjects are considered treated with trial product, but have not initiated 
any rescue medications. Specifically it starts at date of first dose of trial product and the observation 
period ends at the first date of any of the following:
!
the last dose of trial product +3 days
!
initiation of rescue medication
The in-trial observation period will be the primary observation period when estimating the primary 
estimand. The on-treatment without rescue medication observation period will be the primary 
observation period when estimating the secondary estimand. The on-treatment observation period 
will be considered supportive for evaluating efficacy. Safety will be evaluated based on the in-trial 
and the on-treatment observation periods.
Data points collected outside an observation period will be treated as missing in the analysis. 
Baseline data will always be included in an observation period. For adjudicated events, the onset 
date will be the EAC adjudicated onset date.
Before data are locked for statistical analysis and the randomisation code is broken, a review of all 
data will take place. Any decision to exclude either a subject or single observations from the 
statistical analysis is the joint responsibility of the members of the Novo Nordisk study group. 
Exclusion of data from analyses should be used restrictively, and normally no data should be 
excluded from the FAS. The subjects or observations to be excluded, and the reasons for their 
exclusion must be documented and signed by those responsible before database lock. The subjects 
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and observations excluded from analysis sets, and the reason for this, will be described in the 
clinical trial report.
Confirmatory hypotheses
For the primary HbA1c endpoint the following confirmatory one-sided hypothesis are planned to be 
tested for oral semaglutide versus sitagliptin.
!
H0: OR ≤ 1 against Ha: OR >1
For the confirmatory secondary body weight endpoint the following confirmatory one-sided 
hypothesis are planned to be tested for oral semaglutide versus sitagliptin. 
!
H0: μ ≥ 0.0kg against Ha: μ < 0.0 kg, where μ = (oral semaglutide minus sitagliptin)
Operationally both confirmatory hypotheses will be evaluated by two-sided tests at the 5% 
significance level.
Multiplicity and criteria for confirming hypotheses
The type I error for testing the two confirmatory hypotheses related to the HbA1c and body weight 
endpoints will be preserved in the strong sense at 5 % (two-sided) using an hierarchical testing 
strategy as outlined in Figure 17–1. 
Superiority of the primary hypotheses will be considered confirmed if the odds ratio is supporting 
the corresponding alternative hypothesis and the two-sided p-value from the primary analysis of the 
primary estimand is strictly below the 5% two-sided significance level. This is equivalent to using a 
one-sided p-value (nominal α = 0.025) and a one-sided 2.5 % overall significance level. If the 
primary hypothesis is confirmed, the testing strategy will continue testing the confirmatory 
secondary hypothesis at a 5% two-sided significance level. Superiority of the secondary 
confirmatory hypotheses will then be considered confirmed if the treatment difference is supporting 
the corresponding alternative hypothesis and the two-sided p-value from the primary analysis of the 
primary estimand is strictly below the 5% two-sided significance level.
17.3
Primary endpoint
The primary endpoint is if a subject after week 52 achieves (yes/no) HbA1c < 7% (53 mmol/mol) 
ADA target. 
17.3.1
Primary analysis for the primary estimand 
The primary estimand will be estimated based on the FAS using week 52 measurements from the 
in-trial observation period. The primary statistical analysis will be a logistic regression model with 
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treatment, region, and stratification factor as fixed effects and baseline HbA1c measurement as a 
covariate. Firstly, a pattern mixture model using multiple imputation is used to impute missing 
values for continuous HbA1c assessments assuming that the missing data mechanism is missing at 
random (MAR) within the groups used for imputation. Imputation of missing data at week 52 will 
be done within 4 groups of subjects defined by randomised treatment arm, and whether subjects at 
week 52; (i) have discontinued treatment or initiated rescue medication or (ii) are still on treatment 
and have not initiated  rescue medication. It is hereby assumed that the likely values of what the 
missing data would have been if available are best described by information from subjects who at 
week 52 are similar in terms of randomised treatment arm and treatment adherence/rescue status.
Missing values for each group will be imputed as follows:
!
An analysis of covariance (ANCOVA) with region and stratification factor as categorical fixed 
effects and baseline HbA1c measurement as a covariate will be fitted to observed values of the 
change from baseline to week 52 in HbA1c.
!
The estimated parameters for location and dispersion will be used to impute 100 values for each 
subject with missing week 52 data based on region and stratification factor as categorical fixed 
effects and baseline HbA1c measurement as a covariate. Thus, 100 complete data sets will be 
generated including observed and imputed values.
!
The binary endpoint will be created for each of the 100 complete data sets.
!
A logistic regression model with treatment, region, and stratification factor as fixed effects and 
baseline HbA1c measurement as a covariate is fitted for each of the imputed datasets.
!
The resulting 100 estimates and variances will be combined using Rubin’s rule44, and the 
estimated odds ratio between oral semaglutide and sitagliptin together with two-sided 95 % CI 
and two-sided p-value for testing no difference from one will be presented.
17.3.2
Primary analysis for the secondary estimand
The secondary estimand will be estimated based on the FAS using post-baseline measurements up 
to and including week 52 from the on-treatment without rescue medication observation period. 
Handling of missing data will be determined from the imputed continuous responses. A total of 100 
imputed data sets will be created using a mixed model for repeated measurements (MMRM) based 
analysis. The binary endpoint will be created for each of the 100 complete data sets. The imputed 
complete data sets will be analysed using a logistic regression model with treatment, region, and 
stratification factor as fixed effects, and baseline HbA1c measurement as a covariate. The resulting 
100 estimates and variances will be combined using Rubin’s rule44. The MMRM based analysis will 
use a restricted maximum likelihood (REML) and include all post-baseline HbA1c measurements 
collected at scheduled visits up to and including week 52 as dependent variables. The independent 
effects included in the model will be treatment, region, and stratification factor as categorical fixed 
effects and baseline HbA1c as a covariate, all nested within visit. An unstructured covariance matrix 
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for HbA1c measurements within the same subject will be employed, assuming measurements from 
different subjects are independent.
The MMRM is a well-established method that accounts for the uncertainty pertaining to missing 
data. This analysis assumes that the missing data mechanism is MAR. Under this assumption the 
statistical behaviour of the missing data (given the observed responses and model fixed effects and 
covariates) is assumed to be same as the observed data.
17.3.3
Sensitivity analyses
To investigate the sensitivity of the primary analysis results, complementary and separate analyses 
will be performed for the primary and secondary estimand. In line with European Medicines 
Agency recommendations (CHMP 2010)45 and with a report from the US National Research 
Council (NAS 2010)46, these analyses will primarily evaluate the sensitivity of the results due to the 
impact of missing data.
The evaluation of the robustness of the primary analysis will in all cases be a logistics regression 
model with treatment, region, and stratification factor as fixed effects and baseline HbA1c
measurement as a covariate. However missing data will be based on different pattern mixture model 
approaches using multiple imputation. The binary endpoint will be created using the imputed 
continuous data. An overview of the sensitivity analyses for each of the estimands are specified 
below followed by a more detailed description of the two different pattern mixture models used. 
Finally, an additional sensitivity analyses for the primary analysis will be described that is not based 
on the pattern mixture model approach. 
Sensitivity analyses for the primary estimand
The estimation of the primary estimand will be repeated using the following sensitivity analyses for 
imputing missing continuous HbA1c assessments before testing the binary primary endpoint using 
logistic regression: 
!
A comparator multiple imputation analysis based on FAS using the in-trial observation period
!
A tipping-point multiple imputation analysis based on FAS using the in-trial observation period.
!
A MMRM based analysis implemented in a multiple imputation setting (the primary analysis 
for the secondary estimand) based on FAS using the in-trial observation period
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Sensitivity analyses for the secondary estimand
The estimation of the secondary estimand will be repeated using the following sensitivity analyses:
!
A comparator multiple imputation analysis based on FAS using the on-treatment without rescue 
medication observation period.
!
A comparator multiple imputation analysis based on FAS using the on-treatment observation 
period. This sensitivity analysis aims to compare oral semaglutide versus sitagliptin for subjects 
who adhere to treatment regardless of whether or not rescue medication has been initiated.
!
A tipping-point multiple imputation analysis based on FAS using the on-treatment without 
rescue medication observation period.
17.3.3.1
Pattern mixture models
Common for the two pattern mixture model sensitivity analyses is that they all aim to stress-test the 
primary HbA1c results by changing the assumptions for missing data in the oral semaglutide 
treatment arms, while maintaining the missing at random data assumption for the sitagliptin arm:
!
Comparator multiple imputation analysis: In this sensitivity analysis missing data at week 52 
for all subjects will be imputed to resemble  the distribution of the week 52 values observed in 
the sitagliptin treatment arm. In effect, this imputation approach removes the treatment 
difference between oral semaglutide and sitagliptin for all subjects randomised to oral 
semaglutide, given that oral semaglutide is better than sitagliptin.
!
Tipping-point multiple imputation analysis: In this sensitivity analysis, missing data will first be 
imputed according to the primary analysis. Secondly, for the oral semaglutide treatment arm a 
penalty will be added to the imputed values at week 52. The approach is to gradually increase 
this penalty until a confirmed HbA1c conclusion from the primary analysis is changed. The 
specific value of the penalty that changes the conclusion will be used to evaluate the robustness 
of the primary analysis result.
17.3.3.2
Other sensitivity analysis
The following additional sensitivity analysis will be specified:
!
Last observation carried forward (LOCF) analysis: This sensitivity analysis will be based on 
the FAS using the on-treatment without rescue medication observation period. The statistical 
analysis will be a logistic regression model with treatment, region, and stratification factor as 
fixed effects and baseline HbA1c as a covariate 
Assessment of sensitivity analyses
The results from the sensitivity analyses will be collectively used to interpret the robustness of the 
trial results for HbA1c. Due to the sensitivity analyses inherent conservative nature, it will not be a 
requirement that all confirmatory hypotheses are consistently confirmed across the sensitivity 
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analyses. Thus, no absolute success criteria will be pre-defined for each sensitivity analysis. The 
sensitivity results in totality will be used to substantiate the credibility of the trial results.
17.4
Secondary endpoints
17.4.1
Confirmatory secondary endpoints
Change from baseline to week 52 in body weight (kg) will be a confirmatory secondary endpoint. 
The primary and secondary estimands will be estimated using the same approaches as described for 
the primary HbA1c endpoint without dichotomizing the endpoint and with a linear normal regression 
model instead of the logistic regression model. Baseline body weight will be used as a covariate 
instead of baseline HbA1c in both the multiple imputation and analysis models.
Superiority will be considered confirmed if the mean treatment difference is supporting the 
corresponding hypothesis and the two-sided p-value from the analysis of the primary estimand is 
strictly below its local two-sided significance level resulting from the closed testing procedure in 
Figure 17–1. Sensitivity analyses similar to the ones pre-specified for testing superiority for the 
primary HbA1c endpoint will be made to evaluate the robustness of the body weight results.
17.4.2
Supportive secondary endpoints
17.4.2.1
Efficacy endpoints
The below supportive secondary efficacy endpoints will be evaluated for:
!
the primary estimand based on FAS using the in-trial observation period
!
the secondary estimand based on FAS using the on-treatment without rescue medication 
observation period
No sensitivity analyses are planned for these.
Continuous efficacy endpoints
Change from baseline to week 52 in:
!
HbA1c
!
FPG
!
Body weight (%)
!
BMI
!
Waist circumference
!
Fasting lipid profile (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides)
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BMI will be calculated based on body weight and height based on the formulae:
BMI kg/m2 = body weight (kg)/(height [m] × height [m]) or (kg/m2 = [lb/in2 × 703])
The above continuous endpoints will be analysed separately using similar model approaches as for 
the secondary endpoint with the associated baseline response as a covariate. Fasting lipid profile
endpoints will be log-transformed prior to analysis with the associated log-transformed baseline 
value as a covariate
Binary efficacy endpoints
If a subject after 52 weeks achieves (yes/no):
!
HbA1c ≤6.5% (48 mmol/mol) AACE target
!
HbA1c reduction ≥1%-point (10.9 mmol/mol)
!
Weight loss ≥3% 
!
Weight loss ≥5% 
!
Weight loss ≥10% 
!
HbA1c < 7.0% (53 mmol/mol) without hypoglycaemia (treatment-emergent severe or BG-
confirmed symptomatic hypoglycaemia) and no weight gain
!
HbA1c reduction ≥1%-point (10.9 mmol/mol) and weight loss ≥3%
The above binary endpoints will be analysed separately using similar model approaches as for the 
primary endpoint with the associated baseline response as a covariate. 
Time to event endpoint
!
Time to rescue medication
The endpoint will be analysed based on FAS using both the on-treatment observation period and the 
in-trial observation period. For the analysis based on the on-treatment observation period, subject 
without need for rescue medication during the on-treatment observation period will be censored at 
the time point of the date of last trial product. For the in-trial period subject without need for 
addition of glucose-lowering medication during the in-trial observation period, will be censored at 
the time point of the date of end of the in-trial observation period. For this analysis, the follow-up 
period will be excluded from the in-trial observation period, since subjects will have to stop 
treatment at the end-of-treatment visit and therefore might need addition of glucose-lowering 
medication during the follow-up period.
The endpoint will be described and compared for oral semaglutide versus sitagliptin using 
likelihood ratio tests obtained from a Cox proportional hazards model with treatment, stratification 
factors, the interaction between the two stratification factors and region as categorical fixed effects 
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and baseline HbA1c as a covariate. From this analysis the estimated Hazard ratios between oral 
semaglutide versus sitagliptin will be presented together with 95% confidence intervals and two 
sided p values for test of no difference.
17.4.2.2
Safety endpoints
The safety endpoints will be evaluated based on SAS using the on-treatment observation period and 
based on SAS using the in-trial observation period unless otherwise stated. The following endpoints 
are used to support the safety objectives.
Adverse events 
!
Number of TEAEs during exposure to trial product, assessed up to approximately 57 weeks
All AEs will be coded using the most recent version of the Medical Dictionary for Regulatory 
Activities (MedDRA) coding. 
A treatment-emergent AE is defined as an AE with onset in the on-treatment observation period 
(see definition of observation periods in Section 17.2).
TEAEs 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) for the on-treatment observation period. Supportive 
summaries of AEs will be made for the in-trial observation period. The development over time in 
gastrointestinal AEs will be presented graphically.
Other safety endpoints
Change from baseline to week 52 in:
!
Amylase (part of biochemistry)
!
Lipase (part of biochemistry)
!
Pulse
!
Systolic blood pressure
!
Diastolic blood pressure
The above safety endpoints will be evaluated using the primary analysis for the primary estimand 
based on SAS using the in-trial observation period and using the primary analysis for the secondary 
estimand based on SAS using the on-treatment observation period. Endpoints will be analysed as 
described above for continuous efficacy endpoints. Results will be presented at week 52. Amylase 
and lipase endpoints will be log-transformed prior to analysis with the associated log-transformed 
baseline value as a covariate.
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Change from baseline to week 52 in:
!
Haematology
!
Biochemistry (except for amylase and lipase)
!
Calcitonin
!
ECG category
!
Physical examination
The above safety endpoints will be summarised descriptively by treatment arm and visit. 
Categorical safety endpoints will be summarised as counts and relative frequencies. Calcitonin will 
also be presented by gender.
Hypoglycaemia
!
Number of treatment-emergent severe or BG-confirmed symptomatic hypoglycaemic episodes 
during exposure to trial product, assessed up to approximately 57 weeks
!
Treatment-emergent severe or BG-confirmed symptomatic hypoglycaemic episodes during 
exposure to trial product, assessed up to approximately 57 weeks (yes/no) 
Classification of hypoglycaemia:
Hypoglycaemic episodes will be summarised for the SAS and the on-treatment observation period 
only.
Treatment-emergent: hypoglycaemic episodes will be defined as treatment-emergent if the onset of 
the episode occurs within the on-treatment observation period (see definition of observation periods 
in Section 17.2).
Nocturnal hypoglycaemic episodes: episodes occurring between 00:01 and 05.59 both inclusive.
Hypoglycaemic episodes are classified according to the Novo Nordisk classification of 
hypoglycaemia and the ADA classification of hypoglycaemia (see Figure 17–2).
Novo Nordisk classification of hypoglycaemia
In normal physiology, symptoms of hypoglycaemia occur below a PG level of 3.1 mmol/L 
(56 mg/dL)47. Therefore, Novo Nordisk has included hypoglycaemia with PG levels below this cut-
off point in the definition of BG-confirmed hypoglycaemia.
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Novo Nordisk uses the following classification in addition to the ADA classification:
!
Severe or BG-confirmed symptomatic hypoglycaemia: An episode that is severe according to 
the ADA classification38 or BG-confirmed by a PG value < 3.1 mmol/L (56 mg/dL) with
symptoms consistent with hypoglycaemia.
ADA classification38 of hypoglycaemia
!
Severe hypoglycaemia: An episode requiring assistance of another person to actively administer 
carbohydrate, glucagon, or take other corrective actions. PG concentrations may not be 
available during an event, but neurological recovery following the return of PG to normal is 
considered sufficient evidence that the event was induced by a low PG concentration.
!
Asymptomatic hypoglycaemia: An episode not accompanied by typical symptoms of 
hypoglycaemia, but with a measured PG concentration ≤ 3.9 mmol/L (70 mg/dL).
!
Documented symptomatic hypoglycaemia: An episode during which typical symptoms of 
hypoglycaemia are accompanied by a measured PG concentration ≤ 3.9 mmol/L (70 mg/dL).
!
Pseudo-hypoglycaemia: An episode during which the person with diabetes reports any of the 
typical symptoms of hypoglycaemia with a measured PG concentration > 3.9 mmol/L (70 
mg/dL) but approaching that level.
!
Probable symptomatic hypoglycaemia: An episode during which symptoms of hypoglycaemia 
are not accompanied by a PG determination but that was presumably caused by a PG
concentration ≤ 3.9 mmol/L (70 mg/dL).
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Hypoglycaemic 
episode 
PG ≤ 3.9 mmol/L 
(70 mg/dL) 
or 
Alleviation of 
symptoms 
or
Seizure, coma or 
fatal 
SMPG
measurement
Asymptomatic 
hypoglycaemia
Documented 
symptomatic 
hypoglycaemia
Pseudo-
hypoglycaemia
Probable 
symptomatic 
hypoglycaemia
No
Yes
No measurement 
with symptoms
PG > 3.9 mmol/L 
(70 mg/dL)
with symptoms
PG ≤3.9 mmol/L 
(70 mg/dL)
with symptoms
PG ≤3.9 mmol/L 
(70 mg/dL)
without symptoms
No
Yes
Note: Glucose measurements are performed with capillary blood calibrated to plasma equivalent glucose values
PG: plasma glucose  SMPG: Self-measured plasma glucose  
Subject 
able to 
treat him/
herself
Severe 
hypoglycaemia
(ADA 2013)
Figure 17–2
ADA classification of hypoglycaemia
Data on treatment-emergent hypoglycaemic episodes will be presented in terms of the number of 
subjects with at least one episode, the percentage of subjects with at least one episode (%), the total 
number of episodes and the episode rate per 100 patient years of observation time.
Analysis of severe or BG-confirmed symptomatic hypoglycaemic endpoints
The number of treatment-emergent severe or BG-confirmed symptomatic hypoglycaemic episodes 
during the on-treatment period will be analysed using a negative binomial regression model with a 
log-link function and the logarithm of the duration of the subject’s on-treatment observation period 
as offset. The model will include treatment, stratification factor and region as fixed factors and 
baseline HbA1c as covariate.
The binary endpoint showing whether a subject has at least one treatment-emergent severe or BG-
confirmed symptomatic hypoglycaemic episode will be analysed using a logistic regression model 
with treatment, stratification factor and region as fixed factors and baseline HbA1c as covariate.
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17.5
Interim analysis
No interim analyses or other analyses of unblinded data will be performed before the database is 
locked.
17.6
Patient reported outcomes
Change from baseline to week 52:
!
SF-36v2™ (acute version) health survey: Scores from the 8 domains and the physical 
component score and mental component score summary scores 
!
DTSQ: individual items and treatment satisfaction score (6 of the 8 items summed)
The PRO endpoints will be evaluated using the primary analysis for the primary estimand and using 
the primary analysis for the secondary estimand based on FAS using the on-treatment without 
rescue medication period. All of the above individual items and scores will be analysed separately
as the other continuous efficacy endpoints with the associated baseline response as a covariate.
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18 Ethics
18.1
Benefit-risk assessment of the trial
18.1.1
Risks and precautions
The nonclinical safety programme of oral semaglutide has not revealed any safety issues precluding 
use in humans. 
The sections below describe the important identified and potential risks and precautions associated 
with oral semaglutide treatment. These are based on findings in nonclinical studies 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-adjustment 
every 8 weeks according to HbA1c and tolerability (nausea/vomiting) have been implemented in this
trial. 
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 on 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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Pancreatic cancer
Patients with T2DM have an increased risk of certain types of cancer such as pancreatic cancer. 
There is currently no support from nonclinical studies or clinical trials or post marketing data that 
GLP-1-based therapies increase the risk of pancreatic cancer. However, pancreatic cancer has been 
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 European Medicines Agency.
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.
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. 
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.
SGLT-2 inhibitors, an allowed background medication, 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 ketoacidosis.
Impaired renal function may increase the risk of metformin associated lactic acidosis when GLP-1 
RAs are co-administered with metformin. As a precaution serum creatinine will be measured 
regularly. In subjects treated with metformin who experience prolonged or severe nausea and 
vomiting, the investigator should monitor serum creatinine, and if clinically indicated, withhold 
metformin until resolution of renal dysfunction.
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The use of the background medication should be in accordance with the current approved labels.
Other safety considerations
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 intend to become pregnant or are of childbearing potential and not using an adequate 
contraceptive method will not be enrolled in the trial. In addition, pregnancy tests will be performed 
at all visits, including screening and follow-up and at any time during the trial if a menstrual period 
is missed, or as required by local law.
General precautions 
All subjects will be included after a thorough evaluation with regards to in- and exclusion criteria 
defined in order to ensure that subjects are eligible for trial treatment. 
There are also strict glyacemic rescue criteria in place to ensure acceptable glycaemic control 
during the trial. If rescue medication is required, it should be in accordance with ADA/European 
Association for the Study of Diabetes25, 26 (excluding GLP-1 RAs, DPP-4 inhibitors and amylin 
analogues).
It is the responsibility of the investigator to ensure the best possible care according to the principles 
outlined in Diabetes Care 2016 Standards of Medical Care in Diabetes48.
Further details with regards to safety of trial product are described in the current edition of the IB 
for oral semaglutide (NN9924) edition 624, or any updates thereto.
18.1.1.1
Sitagliptin
The most commonly reported side effects associated with sitagliptin are upper respiratory tract 
infection, nasopharyngitis and headache. Also acute pancreatitis, acute renal failure, 
hypersensitivity reaction, severe and disabling arthralgia and hypoglycaemia have been reported41, 
49.
18.1.2
Benefits 
In this trial, subjects will be randomised to one of two treatment arms involving a treatment regimen 
anticipated to be more efficacious than the treatment they receive at the time of entry into the trial. 
Based on the results of the phase 2 dose finding trial oral semaglutide is expected to provide 
clinically relevant improvements in glycaemic control and body weight in subjects with T2DM.
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Similarly treatment with sitagliptin is expected to provide clinically relevant improvements in 
glycaemic control41. In addition, it is expected that all subjects will benefit from participation 
through close contact with the study site, with close follow-up of their T2DM and a careful medical 
examination; all of which will most likely result in an intensified management of their T2DM.
All subjects in this trial will receive trial products and auxiliary supplies free of charge.
18.1.3
Risk and benefit conclusion 
The safety profile for oral semaglutide 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.
Sitagliptin is already a marketed drug approved for the use in subjects with T2DM. 
Safety and efficacy will be monitored regularly and acceptable glycaemic control will be reinforced 
at all times during the trial.
In conclusion, the potential risk to the subjects in this trial is considered low and acceptable in view 
of the anticipated benefits oral semaglutide/sitagliptin will provide to subjects with T2DM.
18.2
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.
The subjects must be fully informed of their rights and responsibilities while participating in the 
trial as well as possible disadvantages of being treated with the trial products.
The investigator must ensure the subject ample time to come to a decision whether or not to 
participate in the trial.
A voluntary, signed and personally dated informed consent must be obtained from the subject 
before any trial-related activity.
The responsibility for seeking informed consent must remain with the investigator, but the 
investigator may delegate the task to a medically qualified person, in accordance with local 
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requirements. The written informed consent must be signed and personally dated by the person who 
seeks the informed consent before any trial-related activity.
If information becomes available that may be relevant to the subject’s willingness to continue 
participating in the trial, the investigator must inform the subject in a timely manner and a revised 
written subject information must be provided and a new informed consent must be obtained.
In order to avoid missing data, the subjects will be informed about the importance of completing the 
trial also if the subjects discontinue from trial product.
18.3
Data handling
If the subject withdraws from the trial or is lost to follow up, then the subject’s data will be handled 
as follows:
!
Data already collected and any data collected at the end-of-trial visit including follow-up visit 
will be retained by Novo Nordisk, entered into the database and used for the clinical trial report. 
!
Safety events will be reported to Novo Nordisk and regulatory authorities according to 
local/national requirements.
If data is used, it will always be in accordance with local regulations and IRBs/IECs.
18.4
Information to subjects during trial
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.
18.5
Premature termination of the trial and/or trial site
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.
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19 Protocol compliance
19.1
Protocol deviations
Deviations from the protocol should be avoided.
If deviations do occur, the investigator must inform the monitor and the implications of the 
deviation must be reviewed and discussed.
Deviations must be documented and explained in a protocol deviation by stating the reason, date 
and the action(s) taken. Some deviations, for which corrections are not possible, can be 
acknowledged and confirmed via edit checks in the eCRF or via listings from the trial database.
Documentation on protocol deviations must be kept in the investigator’s trial master file and 
sponsor trial master file.
19.2
Prevention of missing data
The importance of subject retention will be addressed by Novo Nordisk in the training and 
communication with the trial sites. 
The subjects will be carefully informed about the trial procedures before signing informed consent, 
so that they know the implications of participating in the trial.  
Close surveillance of subject retention will be performed throughout the trial by Novo Nordisk with 
focus on reasons for premature discontinuation of trial product or withdrawal of consent to secure 
early mitigations in collaboration with the trial sites. 
The investigator will make every effort to ensure that all assessments are performed and data is 
collected. If missing data does occur the reason will be collected via the protocol deviation process, 
see Section 19.1. Novo Nordisk will monitor protocol deviations on an on-going basis throughout 
the trial followed by appropriate actions (e.g. re-training of site staff).
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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.
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21
Critical documents
Before a trial site is allowed to start screening subjects, written notification from Novo Nordisk 
must be received and the following documents must be available to Novo Nordisk:
!
Regulatory approval and/or acknowledgement of notification as required 
!
Approval/favourable opinion from IRBs/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 IB for oral semaglutide and SmPC or similar product information for Januvia®
(sitagliptin)
!
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)
Only applicable for US trial sites: 
!
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
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Novo Nordisk will analyse and report data from all sites together if more than one site is involved in 
the trial.
By signing the protocol agreement, each investigator agrees to comply fully with ICH GCP1, 
applicable regulatory requirements and the Declaration of Helsinki2. 
By signing the protocol agreement, each investigator also agrees to allow Novo Nordisk to make 
investigator’s name and information about site name and address publically available if this is 
required by national or international regulations.
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22 Responsibilities
The investigator is accountable for the conduct of the trial at his/her site and must ensure adequate 
supervision of the conduct of the trial at the trial site. If any tasks are delegated, the investigator 
must maintain a log of appropriately qualified persons to whom he/she has delegated specified trial-
related duties. The investigator must ensure that there is adequate and documented training for all 
staff participating in the conduct of the trial. It is the investigator's responsibility to supervise the 
conduct of the trial and to protect the rights, safety and well-being of the subjects.
A qualified physician, who is an investigator or a sub-investigator for the trial, must be responsible 
for all trial-related medical decisions.
The investigator will follow instructions from Novo Nordisk when processing data.
The investigator is responsible for filing essential documents (i.e. those documents which 
individually and collectively permit evaluation of the conduct of a trial and the quality of the data 
produced) in the investigator trial master file. The documents including the subject identification 
code list must be kept in a secure locked facility, so no unauthorized persons can get access to the 
data. 
The investigator will take all necessary technical and organisational safety measures to prevent 
accidental or wrongful destruction, loss or deterioration of data. The investigator will prevent any 
unauthorised access to data or any other processing of data against applicable law. The investigator 
must be able to provide the necessary information or otherwise demonstrate to Novo Nordisk that 
such technical and organisational safety measures have been taken.
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).
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23 Reports and publications
The information obtained during the conduct of this trial is considered confidential and may be used 
by 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 two investigators will be appointed by Novo Nordisk to review and sign the clinical trial 
report (signatory investigator) on behalf of all participating investigators. The signatory 
investigator(s) will be appointed based upon the criteria defined by the International Committee of 
Medical Journal Editors for research publications50.
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 Disclosure27.
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.
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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 Editors50 (sometimes referred to as the Vancouver 
Criteria). Novo Nordisk will appoint investigator(s) to prepare publications in collaboration with 
Novo Nordisk.
23.1.2
Site-specific publication(s) by investigator(s)
For a multi-centre clinical trial, analyses based on single-site data usually have significant statistical 
limitations and frequently do not provide meaningful information for healthcare professionals or 
subjects and therefore may not be supported by Novo Nordisk. It is a Novo Nordisk policy that such 
individual reports do not precede the primary manuscript and should always reference the primary 
manuscript of the trial.
Novo Nordisk reserves the right to prior review of such publications. Further to allow for the 
primary manuscript to be published as the first, Novo Nordisk asks for deferment of publication of 
individual site results until the primary manuscript is accepted for publication. As Novo Nordisk 
wants to live up to the industry publication policy, submission of a primary publication will take 
place no later than 18 months after trial completion. 
23.2
Investigator access to data and review of results
As owner of the trial database, Novo Nordisk has the discretion to determine who will have access 
to the database. 
Individual investigators will have their own research subjects' data and will be provided with the 
randomisation code after results are available.
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24 Retention of clinical trial documentation and human biosamples
24.1
Retention of clinical trial documentation
Subject’s medical records must be kept for the maximum period permitted by the hospital, 
institution or private practice.
The investigator must agree to archive the documentation (this includes both electronic and paper-
based records) pertaining to the trial in an archive after completion or discontinuation of the trial if 
not otherwise notified. The investigator should not destroy any documents without prior permission 
from Novo Nordisk. If the investigator cannot archive the documents at the trial site, Novo Nordisk 
can refer the investigator to an independent archive provider that has a system in place to allow only 
the investigator to access the files.
The investigator must be able to access his/her trial documents without involving Novo Nordisk in 
any way. Site-specific CRFs and other subject data (in an electronic readable format or as paper 
copies or prints) will be provided to the investigator before access is revoked to the systems and/or 
electronic devices supplied by Novo Nordisk. These data must be retained by the trial site. If the 
provided data (e.g. the CD-ROM) is not readable during the entire storage period, the investigator 
can request a new copy. A copy of all data will be stored by Novo Nordisk.
Novo Nordisk will maintain Novo Nordisk documentation pertaining to the trial for at least 20 years 
after discontinuation of the marketing authorisation, termination of the trial or cancellation of the 
research project, whichever is longest.
The files from the trial site/institution must be retained for 15 years after end of trial as defined in 
Section 7, or longer if required by local regulations or Novo Nordisk. In any case trial files cannot 
be destroyed until the trial site/institution is notified by Novo Nordisk. The deletion process must 
ensure confidentiality of data and must be done in accordance with local regulatory requirements.
24.2
Retention of human biosamples
Antibody samples collected in relation to suspicion of hypersensitivity reaction during the trial may 
be retained at Novo Nordisk until market authorisation in case Health Authorities request further 
characterisation of the antibody response (maximum up to 15 years from end of trial).
For Brazil only: Biological samples from Brazil will be destroyed at the end of the trial.
The subject’s identity will remain confidential and the antibody samples will be identified only by
subject number, visit number and trial identification number. No direct identification of the subject 
will be stored together with the samples. Only Novo Nordisk staff will have access to the stored 
antibody samples. Subjects can contact the investigator if they wish to be informed about results 
derived from stored antibody samples obtained from their own body.
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25 Institutional Review Boards/Independent Ethics Committees and 
regulatory authorities
IRB/IEC:
Written approval or favourable opinion must be obtained from IRB/IEC prior to commencement of 
the trial.
During the trial, the investigator or Novo Nordisk, as applicable, must promptly report the 
following to the IRB/IEC, in accordance with local requirements: updates to IB, unexpected SAEs 
where a causal relationship cannot be ruled out, protocol amendments according to local 
requirements, deviations to the protocol implemented to eliminate immediate hazards to the 
subjects, new information that may affect adversely the safety of the subjects or the conduct of the 
trial (including new benefit-risk analysis in case it will have an impact on the planned follow-up of 
the subjects), annually written summaries of the trial status and other documents as required by the 
local IRB/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.
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26 Indemnity statement
Novo Nordisk carries product liability for its products, and liability as assumed under the special 
laws, acts and/or guidelines for conducting clinical trials in any country, unless others have shown 
negligence.
Novo Nordisk assumes no liability in the event of negligence, or any other liability of the sites or 
investigators conducting the trial, or by persons for whom the said site or investigator are 
responsible.
Novo Nordisk accepts liability in accordance with:
For Austria only: Arzneimittelgesetz (BGBI. Nr. 185/1983) last amended with BGBl Nr. 63/2009. 
For Belgium only: Law concerning experiments on the human person of 07 May 2004 - Article 29: 
§1. Even if without fault, the sponsor is liable for the damage which the subject and/or his rightful 
claimants sustain and which shows either a direct or an indirect connection with the trial.
For Switzerland only: Therapeutic Products Act of 15 December 2000 (Status as of 1 January 
2014) (TPA/HMG) and Ordinance on Clinical Trials in Human Research (ClinO/KlinV) of 20 
September 2013.
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27 References
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human and veterinary use and establishing a European Medicines Agency, article 57. 
Official Journal of the European Communities. 2004.
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Clarke WL, Cox DJ, Gonder-Frederick LA, Julian D, Schlundt D, Polonsky W. Reduced 
awareness of hypoglycemia in adults with IDDM. A prospective study of hypoglycemic 
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Ware JE, Jr., Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. 
Conceptual framework and item selection. Med Care. 1992;30(6):473-83.
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Ware JE, Kosinski M, Dewey JE. How to Score Version Two of the SF-36 Health Survey. 
Edition 3 ed: Lincoln RI: QualityMetric, Incorporated. 2000.
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Turner-Bowker DM, Bartley PJ, Ware JE. SF-36® Health Survey & "SF" Bibliography. 
Lincoln, RI: QualityMetric Incorporated; 2002 Third Edition (1988-2000). 2002.
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Bradley C. The Diabetes Treatment Satisfaction Questionnaire: DTSQ. In: Bradley C, 
editor. Handbook of Psychology and Diabetes: a guide to psychological measurement in 
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
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Trial ID: NN9924-4257
Version:
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Status:
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diabetes research and practice. Chur, Switzerland: Harwood Academic Publishers; 1994. p. 
111-32.
37.
National Kidney F. KDOQI Clinical Practice Guideline for Diabetes and CKD: 2012 
Update. Am J Kidney Dis. 2012;60(5):850-86.
38.
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.
39.
McAulay V, Deary IJ, Frier BM. Symptoms of hypoglycaemia in people with diabetes. 
Diabet Med. 2001;18(9):690-705.
40.
Commission E. The Rules Governing Medicinal Products in the European Union, Volume 4, 
Annex 13, Investigational Medicinal Products. Brussels, February 2010.
41.
Merck Sharp & Dohme Limited. JANUVIA - European Summary of Product Characteristics 
Annex 1. 26 May 2015.
42.
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. 
20 Aug 2014.
43.
KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney international 
supplements. 2012;2(1):1-138.
44.
Little RJA, Rubin DB. Statistical analysis with missing data: New York: John Wiley & 
Sons. 1987.
45.
European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP). 
Guideline on Missing Data in Confirmatory Clinical Trials (EMA/CPMP/EWP/1776/99 
Rev. 1). 2 Jul 2010.
46.
National Academy of Sciences (NAS). The Prevention and Treatment of Missing Data in 
Clinical Trials. Washington D.C.: The National Academies Press. 2010.
47.
Schwartz NS, Clutter WE, Shah SD, Cryer PE. Glycemic thresholds for activation of 
glucose counterregulatory systems are higher than the threshold for symptoms. J Clin Invest. 
1987;79(3):777-81.
48.
Association AD. Standards of medical care in diabetes - 2016. Diabetes Care. 2016;39 
Suppl. 1:S13-S22.
49.
Food and Drug Administration labelling for sitagliptin. 2006.
CONFIDENTIAL


Protocol
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Date:
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Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103 
Status:
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50.
International Committee of Medical Journal Editors. Recommendations for the Conduct, 
Reporting, Editing and Publication of Scholarly Work in Medical Journals; current version 
available at www.icmje.org.
CONFIDENTIAL


Global and country key Novo Nordisk staff
Attachments I and II (if applicable) to the protocol are located in the Trial Master File.
Content: Global key staff and Country key staff
CONFIDENTIAL
Date:
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Version:
Status:
Oral semaglutide
Trial ID: NN9924-4257
Clinical Trial Report
Appendix 16.1.1
25 October 2018
1.0
Final
CONFIDENTIAL


Protocol - Appendix A
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Appendix A
Monitoring of Calcitonin
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Protocol - Appendix A
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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
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2
Calcitonin monitoring
A blood sample will be drawn at pre-specified trial visits for measurement of calcitonin.
In case a subject has a calcitonin value ≥ 10 ng/L the algorithm outlined in Figure 1 and described 
below should be followed. The algorithm applies for all calcitonin values in the trial.
Calcitonin < 10ng/L
Calcitonin  ≥ 10 ng/L and 
< 50 ng/L
Calcitonin  ≥ 50 ng/L and 
< 100 ng/L
Calcitonin  ≥ 100 ng/L
Evaluation of 
calcitonin results
Calcitonin  ≥ 10 ng/L and 
last measurement in the 
trial
No action
●Investigate potential confounding 
factors
●Continue sampling of calcitonin 
according to protocol
●Refer to thyroid specialist
●Discontinue trial product
●Refer to thyroid specialist
●Refer to thyroid specialist
Figure 1
Flow of calcitonin monitoring
2.1
Calcitonin ≥ 100 ng/L  
Action: The subject must immediately be referred to a thyroid specialist for further evaluation and 
the trial product must be discontinued (see protocol Section 6.5 premature discontinuation of trial 
CONFIDENTIAL


Protocol - Appendix A
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Trial ID: NN9924-4257
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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 disease.1 Two of these subjects were diagnosed with MTC and two were diagnosed with 
C-cell hyperplasia, resulting in a positive predictive value of a C-cell anomaly of 50%.
Diagnostic evaluation should include: 
!
thyroid ultrasound examination 
!
if available and 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.
CONFIDENTIAL


Protocol - Appendix A
CONFIDENTIAL
Date:
06 April 2016
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Trial ID: NN9924-4257
Version:
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UTN: U1111-1177-5103 
Status:
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Background: Calcitonin values from 20-50 ng/L were found in up to 1% of subjects of the 
population of 5817 patients with thyroid nodular disease1. The predictive value of a C-cell anomaly 
for this calcitonin level was 8.3%. However, the likelihood of having a medullary carcinoma >1 cm 
with calcitonin in this range is extremely low.
For calcitonin values 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 calcitonin > 10 ng/L to screen for C-cell 
disease, but they do not provide sufficient information on patients with basal calcitonin > 10 and <
20 ng/L to allow conclusions.2,3
CONFIDENTIAL


Protocol - Appendix A
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Date:
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Trial ID: NN9924-4257
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3
References
1 Costante G, Meringolo D, Durante C, Bianchi D, Nocera M, Tumino S et al. Predictive value of serum calcitonin 
levels for preoperative diagnosis of medullary thyroid carcinoma in a cohort of 5817 consecutive patients with 
thyroid nodules. J Clin Endocrinol Metab 2007; 92(2):450-455.
2 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


4Protocol - Appendix B
CONFIDENTIAL
Date:
06 April 2016
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Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103
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Final
EudraCT No.: 2015-005593-38
Page:
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Appendix B
Adverse events requiring additional data collection
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4Protocol - Appendix B
CONFIDENTIAL
Date:
06 April 2016
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Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103
Status:
Final
EudraCT No.: 2015-005593-38
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1
Adverse events requiring additional data collection 
For the following AEs additional data collection is required and specific event forms must be 
completed in the eCRF in addition to the AE form:
!
Acute coronary syndrome (myocardial infarction [MI] or hospitalisation for unstable angina)
!
Cerebrovascular event (stroke or transient ischaemic attack [TIA])
!
Heart failure
!
Pancreatitis
!
Neoplasm (excluding thyroid neoplasm)
!
Thyroid disease (including thyroid neoplasm)
!
Renal event
!
Hypersensitivity reaction
!
Acute gallstone disease
!
Medication error (concerning trial products):
!
Administration of wrong drug. 
Note: Use of wrong DUN is not considered a medication error unless it results in 
administration of wrong drug.
!
Wrong route of administration.
!
Administration of an overdose with the intention to cause harm (e.g. suicide attempt)
misuse or abuse of trial product.
!
Accidental administration of a higher dose than intended. A higher dose is a dose of at least 
one tablet 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.
!
Lactic acidosis
!
Creatine kinase (CK) > 10 x upper normal limit (UNL)
!
Hepatic event:
!
alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 5 x UNL and total 
bilirubin ≤ 2 x UNL
!
ALT or AST > 3 x UNL and total bilirubin > 2 x UNL*
!
Hepatic event leading to trial product discontinuation
*Please note that in case of a hepatic event defined as ALT or AST > 3 x UNL and total bilirubin 
> 2 x UNL, where no alternative aetiology exists (Hy’s law), this must be reported as an SAE using 
the important medical event criterion if no other seriousness criteria are applicable.
In case any of these events fulfil the criteria for an SAE, please report accordingly, see protocol 
Section 12.1.2.
CONFIDENTIAL


4Protocol - Appendix B
CONFIDENTIAL
Date:
06 April 2016
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Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103
Status:
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EudraCT No.: 2015-005593-38
Page:
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Some of these events will undergo event adjudication by the event adjudication committee (EAC), 
please see protocol Section 12.7.2 and protocol Table 12-1.
1.1
Acute coronary syndrome
If an event of acute coronary syndrome (ranging from unstable angina pectoris to MI) is observed 
during the trial, 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
!
Use of thrombolytic drugs
!
Revascularisation procedures 
1.2
Cerebrovascular event
If a cerebrovascular event (e.g. TIA, stroke) is observed during the trial, the following additional 
information must be reported if available: 
!
Type of event (e.g. TIA, Stroke)
!
Contributing condition
!
Neurologic signs and symptoms
!
History of neurologic disease
!
Imaging supporting the condition
!
Treatment given for the condition
1.3
Heart failure
If an event of heart failure is observed during the trial, the following additional information must be 
reported if available: 
!
Signs and symptoms of heart failure
!
New York Heart Association (NYHA) Class
!
Supportive imaging
!
Supportive laboratory measurements
!
Initiation or intensification of treatment for this condition
CONFIDENTIAL


4Protocol - Appendix B
CONFIDENTIAL
Date:
06 April 2016
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Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103
Status:
Final
EudraCT No.: 2015-005593-38
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1.4
Pancreatitis
For all confirmed events of pancreatitis 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
1.4.1
Assessments in case of suspicion of acute pancreatitis
Most patients with acute pancreatitis experience severe abdominal pain that is located generally in 
the epigastrium and radiates to the back. The onset of the pain may be swift reaching maximum 
intensity within 30 min, it is frequently unbearable and characteristically persists for more than 24 
hours without relief1. 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 pancreatitis1. In general, serum lipase is thought 
to be more sensitive and specific than serum amylase in the diagnosis of acute pancreatitis. 
In case of suspicion of acute pancreatitis, the trial product should promptly be interrupted (no 
treatment discontinuation call should be made in IWRS before diagnosis of acute pancreatitis is 
confirmed). Appropriate additional examinations must be performed, including local measurement 
of amylase and lipase. 
The diagnosis of acute pancreatitis requires two of the following three features2: 
!
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.
If acute pancreatitis is ruled out, trial product should be re-initiated.
If acute pancreatitis is confirmed, appropriate treatment and careful monitoring of the subject 
should be initiated. The subject must be discontinued from trial product (treatment discontinuation 
call), but should remain in the trial (see protocol Section 6.5 and 8.1.5). 
CONFIDENTIAL


4Protocol - Appendix B
CONFIDENTIAL
Date:
06 April 2016
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Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103
Status:
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EudraCT No.: 2015-005593-38
Page:
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1.5
Neoplasm
All events of neoplasms (excluding thyroid neoplasm, which will be reported under thyroid disease) 
must be reported during the trial and 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 observed during the trial, 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 observed during the trial, the following additional information must be reported if 
available:
!
Signs and symptoms of renal failure
!
Specific laboratory tests supporting the diagnosis 
!
Imaging performed supporting the diagnosis
!
Kidney biopsy results
!
Risk or confounding factors identified including exposure to nephrotoxic agents
CONFIDENTIAL


4Protocol - Appendix B
CONFIDENTIAL
Date:
06 April 2016
Novo Nordisk
Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103
Status:
Final
EudraCT No.: 2015-005593-38
Page:
6 of 9
1.8
Hypersensitivity reaction
All events of hypersensitivity reactions must be reported and 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
!
Treatment given for the reaction
!
Previous history of similar reaction
!
Risk or confounding factors identified
1.8.1
Assessments in case of suspicion of hypersensitivity reaction
In case of suspicion of a severe immediate systemic hypersensitivity reaction3 to the trial product, 
the subject must be discontinued from trial product but should remain in the trial (see protocol 
Section 6.5 and 8.1.5).
If suspicion of a hypersensitivity reaction occurs, the subjects should be instructed to contact the 
site staff as soon as possible for further guidance. 
To assist in the diagnostic evaluation it is recommended to draw a blood sample for measurement of 
tryptase (total and/or mature tryptase, local assessment) within 3 hours of onset of the 
hypersensitivity reaction, and if this is achieved, a tryptase sample should also be drawn at V11A. 
Furthermore, a blood sample for assessment of IgE anti-semaglutide antibodies and anti-
semaglutide antibodies should be drawn as soon as possible after the event and at V11A and sent to 
central laboratory. Tryptase concentrations, if available, should be included in the specific event 
form when reporting the AE.
In case of suspicion of immune complex disease3, the subject must be discontinued from trial 
product but should remain in the trial (see protocol Section 6.5 and 8.1.5). It is recommended to 
draw a blood sample for local assessment of complement levels (C3 and C4) to assist in the 
diagnostic evaluation. Complement level results should be included in the specific event form when 
reporting the AE.
CONFIDENTIAL


4Protocol - Appendix B
CONFIDENTIAL
Date:
06 April 2016
Novo Nordisk
Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103
Status:
Final
EudraCT No.: 2015-005593-38
Page:
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1.9
Acute gallstone disease
If an event of acute gallstone disease or clinical suspicion of this is observed during the trial, the 
following additional information must be reported if available:
!
Signs and symptoms of acute gallstone disease
!
Specific laboratory tests supporting a diagnosis of gallstone
!
Imaging performed and consistency with gallstone disease
!
Treatment given for the condition
!
Relevant risk factors for acute gallstone disease
!
Family history of gallstones
1.10
Medication error
If a medication error is observed during the trial, the following additional information is required 
and must be reported: 
!
Trial product(s) involved 
!
Classification of medication error
!
Wrong drug(s) administered
!
Administration of an overdose
!
Whether the subject experienced any hypoglycaemic episode and/or AE(s) as a result of the 
medication error 
!
Suspected primary reason for the medication error 
For definition of medication error, see protocol Section 12.1.4.
1.11
Lactic acidosis
If an event of lactic acidosis is observed during the trial, the following additional information must 
be reported if available:
!
Signs and symptoms of lactic acidosis
!
Specific laboratory tests describing the event 
!
Possible cause(s) of the event
1.12
Creatine kinase > 10 x UNL
If an event of CK > 10 x UNL is observed during the trial the following additional information must 
be reported if available:
!
Signs and symptoms associated to the event 
!
Recent physical activity
!
Possible cause(s) of the event
CONFIDENTIAL


4Protocol - Appendix B
CONFIDENTIAL
Date:
06 April 2016
Novo Nordisk
Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103
Status:
Final
EudraCT No.: 2015-005593-38
Page:
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1.12.1
Assessments in case of increased levels of creatine kinase
In case of CK > 10 x UNL prompt repeat testing (at central laboratory) of CK should be done. 
Repeat testing (at central laboratory) should be done regularly until CK levels return to normal or 
baseline state. Additional clinical information should be gathered to seek possible cause of the 
observed CK elevation. 
1.13
Hepatic events
!
ALT or AST > 5 x UNL and total bilirubin ≤ 2 x UNL
!
ALT or AST > 3 x UNL and total bilirubin > 2 x UNL*
!
Hepatic events leading to trial product discontinuation 
*Please note that risk of liver injury defined as ALT or AST > 3 x UNL and total 
bilirubin > 2 x UNL, where no alternative aetiology exits (Hy’s law), should also be reported as a 
SAE (important medical event, according to protocol Section 12.1.2). 
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 
1.13.1
Assessments in case of increased levels of aminotransferases
Both events should prompt repeat testing (at central laboratory) including ALT, AST, alkaline 
phosphatase (ALP) and total bilirubin and discontinuation of trial product should be 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.
CONFIDENTIAL


4Protocol - Appendix B
CONFIDENTIAL
Date:
06 April 2016
Novo Nordisk
Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103
Status:
Final
EudraCT No.: 2015-005593-38
Page:
9 of 9
2
References
1.
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.
2.
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.
3.
U.S. Department of Health and Human Services, Food and Drug Administration. Guidance 
for Industry: Immunogenicity Assessment for Therapeutic Protein Products. August 2015.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
09 November 2016
Novo Nordisk
Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103
Status:
Final
EudraCT No.: 2015-005593-38
Page:
1 of 17
Protocol Amendment
no 1
to Protocol, final version 1.0
dated 06 April 2016
Trial ID: NN9924-4257
Efficacy and Safety of Oral Semaglutide Using a Flexible Dose
Adjustment Based on Clinical Evaluation versus Sitagliptin in
Subjects with Type 2 Diabetes Mellitus
A 52-week Randomised, Open-label, Active-controlled Trial
Trial phase: 3a
Applicable to all countries
Amendment originator:
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol Amendment
CONFIDENTIAL
Date:
09 November 2016
Novo Nordisk
Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103
Status:
Final
EudraCT No.: 2015-005593-38
Page:
2 of 17
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 on diabetic retinopathy....................3
1.2
Addition of bicarbonate as a part of the biochemistry laboratory assessment...............................4
1.3
Investigator’s responsibility in ensuring evaluation and management of certain risk factors 
and complications ..........................................................................................................................4
1.4
Clarification of the criteria for completion, withdrawal and lost to follow-up..............................4
1.5
Other minor adjustments, clarifications and correction of typographical errors............................4
1.5.1
Statistical considerations..............................................................................................4
1.5.2
Adverse events for Adjudication .................................................................................5
1.5.3
Pregnancies in female partners of male subjects (only applicable for Brazil).............5
2
Changes......................................................................................................................................................6
2.1
Section 2 Flow chart ......................................................................................................................6
2.2
Section 4.2.2.2 Supportive secondary endpoints ...........................................................................8
2.3
Section 6.6 Withdrawal from trial .................................................................................................8
2.4
Section 8.1.4 End-of-treatment (visit 10) and Follow-up (visit 11)...............................................8
2.5
Section 8.1.5 Premature discontinuation of trial product and follow-up (visits 10A and 
11A) ...............................................................................................................................................9
2.6
Section 8.1.6.1 Lost to follow-up ...................................................................................................9
2.7
Section 8.4.1.2 Adverse events requiring additional data collection.............................................9
2.8
Section 8.4.2  Physical examination ............................................................................................10
2.9
Section 8.4.4  Eye examination....................................................................................................11
2.10
Section 8.4.6 Laboratory assessments for safety .........................................................................11
2.11
Section 12.1.5 Adverse events requiring additional data collection............................................11
2.12
Section 12.5 Pregnancies.............................................................................................................12
2.13
Section 12.7.2 Event adjudication committee..............................................................................13
2.14
Section 17.3.1 Primary analysis for the primary estimand ..........................................................13
2.15
Section 17.3.2 Primary analysis for the secondary estimand.......................................................13
2.16
Section 17.4.2.2 Safety endpoints................................................................................................14
2.17
Section 18.1 Benefit-risk assessment of the trial.........................................................................14
2.18
Section 27 References..................................................................................................................15
2.19
Appendix B Section 1 Adverse events requiring additional data collection................................16
2.20
Appendix B, new section.............................................................................................................17
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1
Introduction including rationale for the protocol amendment
This protocol amendment introduces:
1. Additional eye examinations and additional data collection on diabetic retinopathy 
2. Addition of bicarbonate as a part of the biochemistry laboratory assessment
3. Investigator’s responsibility in ensuring evaluation and management of certain risk factors and 
complications
4. Clarification of the criteria for completion, withdrawal and lost to follow-up
5. Other minor adjustments, clarifications and correction of typographical errors
1.1
Additional eye examinations and additional data collection on diabetic retinopathy 
Updated protocol Sections: 2, 4.2.2.2, 8.4.1.2, 8.4.4, 12.1.5, 17.4.2.2, 18.1 and Appendix B.
Transient worsening of diabetic retinopathy is a recognised complication in selected patients with 
diabetes after initiation of intensive antidiabetic treatment1,2,3. 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 placebo4. The 
majority of the related adverse events were moderate in severity and did not lead to premature 
discontinuation of trial product. 
 additional eye examinations 
have been implemented in all trials in the PIONEER programme. Also, to further understand this 
safety signal, additional information will be collected for all diabetic retinopathy events reported 
during the trial. The information will be collected not only from new subjects enrolled by the time 
of this amendment, but also from already enrolled subjects to the extent that the information is 
available. Furthermore, information to the investigators and subjects related to diabetic retinopathy 
has been added to the protocol (see Section 18) and the subject information. 
                                                
1 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.
2 The Diabetes Control and Complications Trial Research Group. Early worsening of diabetic retinopathy in the 
Diabetes Control and Complications Trial. Arch Ophthalmol. 1998;116(7):874-86.
3 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):37-9.
4 Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, et al. Semaglutide and Cardiovascular Outcomes 
in Patients with Type 2 Diabetes. N Engl J Med. 2016.
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1.2
Addition of bicarbonate as a part of the biochemistry laboratory assessment
Updated protocol Section: 8.4.6
 that bicarbonate is added as a routine laboratory test in trials where SGLT2-
inhibitors are used as background medication, because SGLT2-inhibitors have been associated with 
a risk for metabolic acidosis.
1.3
Investigator’s responsibility in ensuring evaluation and management of certain risk 
factors and complications
Updated protocol Section: 8.4.2, 8.4.4 and18.1
 text is added to highlight the investigator’s responsibility in 
relation to further evaluation of potential incidental thyroid nodules discovered at the physical 
examination.
In addition, text is added to highlight the investigator’s responsibility in ensuring evaluation and 
management of cardiovascular risk factors and microvascular complications such as diabetic kidney 
disease and diabetic retinopathy.
1.4
Clarification of the criteria for completion, withdrawal and lost to follow-up
Updated protocol Sections: 6.6, 8.1.4, 8.1.5 and 8.1.6.1
The criteria for subject completion, -withdrawal and -lost to follow-up respectively are clarified and 
have been made consistent across sections. Lost to follow-up is considered a subcategory to 
withdrawal from trial. In addition, it is emphasised that as soon as contact to a subject is lost, efforts 
must be made to regain contact and the efforts must continue until the subjects last planned visit. 
Only if contact is not regained at that time point can the subject be considered lost to follow up. 
Because this trial is not an outcome trial the terminology ‘health status’ is replaced with “relevant 
safety information” - the purpose of which is to follow up on any adverse events or pregnancy, and 
not to determine if a subject completes the trial or not.
1.5
Other minor adjustments, clarifications and correction of typographical errors
1.5.1
Statistical considerations
Updated protocol Sections: 17.3.1 and 17.3.2
For the pattern mixture model using multiple imputation, the number of imputations will be 
increased from 100 to 1000 data sets, to ensure a greater precision of the estimates. 
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1.5.2
Adverse events for Adjudication
Updated protocol Section: 12.7.2 and Appendix B
Table 12-2 has been aligned with Table 12-1 reflecting that unstable angina pectoris requires
hospitalisation to qualify for Event Adjudication.
1.5.3
Pregnancies in female partners of male subjects (only applicable for Brazil)
Updated protocol Section: 12.5
Brazilian National Ethical Committee (CONEP) has requested the use of a local subject 
information/informed consent form for a female partner of male subject. The protocol is updated 
accordingly.
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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
Screening a
Randomisation
Treatment
End-of-treatment 
(EoT)
Follow-up b
EoT premature 
discontinuation c
Follow-up 
premature 
discontinuation c
Visit (V), Phone contact (P)
V1
V2
P3
V4
V5
V6
V7
V8
V9
V10
V11
V10A
V11A
Timing of visit 
(weeks)
Up to -2 
wks
0
4
8
16
24
32
40
48
52
57
Day of 
discontinuation of 
trial product 
5 weeks after 
discontinuation of 
trial product 
Visit window (days)
±3
±3
±3
±3
±3
±3
±3
±3
+3
+3
+3
SAFETY
Eye examinationg
x
x
x


Protocol Amendment
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Date:
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Status:
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Footer
Description
xg
Fundus photography or dilated fundoscopy performed within 90 days before randomisation is acceptable if results are available for 
evaluation at visit 2 and no deterioration in visual function since last examination.
Fundus photography or dilated fundoscopy must be performed again:
!
at V10 or within 5 weeks thereafter for subjects completing treatment
!
at V10A or within 5 weeks thereafter, and again within 5 weeks prior to V10, for subjects who have prematurely 
discontinued trial product


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2.2
Section 4.2.2.2
Supportive secondary endpoints
Supportive secondary safety endpoints
Change from baseline to week 52 in:
!
Haematology
!
Biochemistry
!
Calcitonin
!
Pulse
!
Systolic blood pressure
!
Diastolic blood pressure
!
Electrocardiogram (ECG) category
!
Physical examination 
!
Eye examination category
2.3
Section 6.6
Withdrawal from trial
The subject may withdraw consent at will at any time. The subject’s request to withdraw from the 
trial must always be respected. Only subjects who withdraw consent should be considered as 
withdrawn from trial. A subject who does not complete the trial is also considered withdrawn from 
the trial. Hence a subject is considered withdrawn if the following applies:
!
Subject withdrew consent 
!
Subject is lost to follow-up (only to be used if there is no contact with the subject by the time of 
the subject’s last scheduled visit, see Sections 8.1.4, 8.1.5, 8.1.6 and 8.1.6.1)
!
Other (subject deceased or closure of trial site)
2.4
Section 8.1.4
End-of-treatment (visit 10) and Follow-up (visit 11)
At V10 the subject should be reminded about the importance of attending the follow-up visit (V11). 
If the subject, nonetheless, dose not attend V11, the site should make efforts to obtain contact with 
the subject within the visit window. 
A trial completer is defined as a subject who attends, or is in contact with the site, at the subject’s
last scheduled visit. For subjects who complete treatment, the last scheduled visit is V11. (For 
subjects who discontinue trial product, see Section 8.1.5) 
In case the subject cannot be reached (by clinic visit or phone contact) at the scheduled visit 11, the 
site should consult the contacts provided by the subject (e.g. close relatives), relevant physicians, 
medical records and locator agencies (if allowed according to local law) to collect health status. If 
no health status can be collected, the subject should be considered lost to follow up and this should 
be specified in the end-of-trial form.
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2.5
Section 8.1.5
Premature discontinuation of trial product and follow-up (visits 10A
and 11A)
Subjects, who only agree to attend or provide health status at the planned V10, should not be 
considered withdrawn from the trial. In case the subject cannot be reached (by clinic visit or phone 
contact) at the scheduled V10, the site should consult the contacts provided by the subject (e.g. 
close relatives), relevant physicians, medical records and locator agencies (if allowed according to 
local law) to collect health status. If no health status can be collected, the subject should be 
considered lost to follow-up and this should be specified in the end-of-trial form. 
A subject who prematurely discontinued trial product is still considered a trial completer if the 
subject attends or is in contact with the site, at the subject’s last scheduled visit. For subjects who 
prematurely discontinue trial product, the last scheduled visit is V10 (or V11A if it is scheduled 
after V10). For subjects who complete treatment, see Section 8.1.4.The site should prepare in due 
time to establish contact with the subject within the visit window of the scheduled V10 if the subject 
has agreed to attend this visit.
In summary, subjects should stay in the trial irrespective of lack of adherence to randomised 
treatment, lack of adherence to visit schedule, missing assessments or trial product discontinuation 
for any reason. Only subjects who decline any further contact with the site in relation to the trial 
should be considered as having withdrawn from the trial consent (see Section 8.1.6).
2.6
Section 8.1.6.1
Lost to follow-up
In case contact to the subject is lost during the trial, the site should immediately undertake efforts to 
re-establish contact. If the subject cannot be reached (by clinic visit or phone contact) and the 
subject has consented to it, the site should consult the contacts provided by the subject (e.g. close 
relatives), relevant physicians, medical records and locator agencies (if allowed according to local 
law) in an attempt to regain contact with the subject or to obtain relevant safety information from 
other sources. Efforts to regain contact should continue until the end of the subject’s last scheduled 
visit: V11 for subjects who have completed treatment, whereas for subjects who have discontinued 
trial product prematurely the last visit is V10 (or V11A if it is scheduled after V10). Only if contact 
with the subject is not regained by the end of the visit window of the last scheduled visit can the 
subject be considered lost to follow-up (see Section 6.6).
2.7
Section 8.4.1.2
Adverse events requiring additional data collection 
For the following AEs additional data collection is required and specific event forms must be 
completed in the eCRF in addition to the AE form:
!
Acute coronary syndrome (MI or hospitalisation for unstable angina)
!
Cerebrovascular event (stroke or transient ischaemic attack)
!
Heart failure 
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!
Pancreatitis
!
Neoplasm (excluding thyroid neoplasm)
!
Thyroid disease (including thyroid neoplasm)
!
Renal event
!
Hypersensitivity reaction
!
Acute gallstone disease
!
Medication error
!
Lactic acidosis
!
Creatine kinase (CK) > 10x UNL
!
Hepatic event defined as:
!
ALT or aspartate aminotransferase (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.
!
Diabetic retinopathy and related complications 
*Please note that in case of a hepatic event defined as ALT or AST >3 x UNL and total bilirubin >2 
x UNL, where no alternative aetiology exists (Hy's law), this must be reported as an SAE using the 
important medical event criterion if no other seriousness criteria are applicable.
2.8
Section 8.4.2
Physical examination
A physical examination will be performed by the investigator according to local procedure (see 
Section 2 and 8.1.7). 
A physical examination must include:
!
General appearance
!
Head, ears, eyes, nose, throat, neck
!
Thyroid gland*
!
Respiratory system
!
Cardiovascular system
!
Gastrointestinal system including mouth
!
Musculoskeletal system
!
Central and peripheral nervous system
!
Skin
!
Lymph node palpation
*Please note that the diagnostic evaluation of thyroid nodules should be in accordance with the 
American Thyroid Association Management Guidelines or any updates hereof37, and adapted to 
local treatment guidelines if applicable.
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2.9
Section 8.4.4 
Eye examination 
Fundus photography or dilated fundoscopy will be performed as per the flow chart (see Section 2) 
by the investigator or according to local practice. Fundoscopy requires pharmacological dilation of 
both pupils. Results of the fundus photography or dilated fundoscopy will be interpreted by the 
investigator (see Section 8.1.7).
2.10
Section 8.4.6
Laboratory assessments for safety
Biochemistry:
!
Alanine aminotransferase (ALT)
!
Albumin
!
Alkaline phosphatase (ALP)
!
Amylase
!
Aspartate aminotransferase (AST)
!
Bilirubin, total
!
Calcium, total
!
Creatinine
!
eGFR per CKD-EPI37 38
!
Creatine kinase (CK)
!
Lipase
!
Potassium
!
Sodium
!
Urea
!
Bicarbonate
2.11
Section 12.1.5
Adverse events requiring additional data collection
Table 12-1
Adverse events requiring completion of specific event forms and/or are subject to 
event adjudication [Note: In this document only the additional event is shown, all other events are 
unchanged]
Event
Specific event form
Event adjudication
Diabetic retinopathy and related complications
Yes
No
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2.12
Section 12.5
Pregnancies
12.5.1 
Pregnancies in female subjects
[Note: This section is not changed.]
12.5.2 
Pregnancies in female partners of male subjects (only applicable for Brazil)
Male subjects must be instructed to notify the investigator if their female partner becomes pregnant 
during the trial, except in the screening period. At the last scheduled visit, male subjects must be 
asked if their female partner has become pregnant.
If a female partner has become pregnant during the trial, the investigator must follow-up on the 
pregnancy outcome and until the newborn infant is one month of age, irrespective of whether the 
trial is completed or not. The investigator must ask the male subject and assess, if the pregnancy 
outcome is normal or abnormal.
When the pregnancy outcome is normal this information is recorded in the subject’s medical record 
only, no further information is collected and reported to Novo Nordisk. When the pregnancy
outcome is abnormal (i.e. congenital anomalies, foetal death including spontaneous abortion 
and/or any anomalies of the foetus observed at gross examination or during autopsy), the following 
must be reported by the investigator to Novo Nordisk electronically (e.g. in PDF format) or by fax:
1. Reporting of pregnancy information
Information from the male subject has to be reported on the Paternal Form. Furthermore, 
information from the female partner (including information about the pregnancy outcome and 
health status of the infant until the age of one month) has to be reported on the Maternal Forms 1A, 
1B and 2, after an informed consent has been obtained from the female partner. 
Initial reporting and follow-up information must be reported within 14 calendar days of the 
investigator’s first knowledge of initial or follow-up information.
2. Reporting of AE information
The following AEs in the foetus and newborn infant have to be reported:
!
Non-serious AEs evaluated as possible/probably related to the father’s treatment with the trial 
product(s).
!
SAEs in the foetus and newborn infant - whether or not related to the father’s treatment with the 
trial product(s). This includes an abnormal outcome - such as foetal death (including 
spontaneous abortion) and congenital anomalies (including those observed at gross 
examination or during autopsy of the foetus).
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Forms and timelines for reporting AEs:
See Section 12.5.1, point 2, “Forms and timelines for reporting AEs”.
Any queries or follow-up requests from Novo Nordisk to non-serious AEs, SAEs and pregnancy 
forms must be responded to by the investigator within 14 calendar days from the date of receipt of 
the request, unless otherwise specified in the follow-up request.
2.13
Section 12.7.2
Event adjudication committee
Table 12-2
Adverse events for adjudication [Note: Only shown is the event with updated event 
description, all other events are unchanged]
Events
Description
Adjudication outcome
Acute Coronary Syndrome
Acute Coronary Syndrome conditions include: 
! ST-elevation acute myocardial infarction 
(STEMI)
! Non-ST elevation acute myocardial infarction 
(NSTEMI)
! Silent MI 
! Unstable angina pectoris requiring 
hospitalisation
! Acute MI (STEMI or 
NSTEMI), silent MI
! Unstable angina pectoris 
requiring hospitalisation
2.14
Section 17.3.1
Primary analysis for the primary estimand
Missing values for each group will be imputed as follows:
!
An analysis of covariance (ANCOVA) with region and stratification factor as categorical fixed 
effects and baseline HbA1c measurement as a covariate will be fitted to observed values of the 
change from baseline to week 52 in HbA1c.
!
The estimated parameters for location and dispersion will be used to impute 100 1000 values for 
each subject with missing week 52 data based on region and stratification factor as categorical 
fixed effects and baseline HbA1c measurement as a covariate. Thus, 100 1000 complete data sets 
will be generated including observed and imputed values.
!
The binary endpoint will be created for each of the 100 1000 complete data sets.
!
A logistic regression model with treatment, region, and stratification factor as fixed effects and 
baseline HbA1c measurement as a covariate is fitted for each of the imputed datasets.
!
The resulting 100 1000 estimates and variances will be combined using Rubin’s rule44 45, and 
the estimated odds ratio between oral semaglutide and sitagliptin together with two-sided 95 % 
CI and two-sided p-value for testing no difference from one will be presented.
2.15
Section 17.3.2
Primary analysis for the secondary estimand
The secondary estimand will be estimated based on the FAS using post-baseline measurements 
up to and including week 52 from the on-treatment without rescue medication observation 
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period. Handling of missing data will be determined from the imputed continuous responses. A 
total of 100 1000 imputed data sets will be created using a mixed model for repeated 
measurements (MMRM) based analysis. The binary endpoint will be created for each of the 100
1000 complete data sets. The imputed complete data sets will be analysed using a logistic 
regression model with treatment, region, and stratification factor as fixed effects, and baseline 
HbA1c measurement as a covariate. The resulting 100 1000 estimates and variances will be 
combined using Rubin’s rule4445. The MMRM based analysis will use a restricted maximum 
likelihood (REML) and include all post-baseline HbA1c measurements collected at scheduled 
visits up to and including week 52 as dependent variables. The independent effects included in 
the model will be treatment, region, and stratification factor as categorical fixed effects and 
baseline HbA1c as a covariate, all nested within visit. An unstructured covariance matrix for 
HbA1c measurements within the same subject will be employed, assuming measurements from 
different subjects are independent.
2.16
Section 17.4.2.2
Safety endpoints
Other safety endpoints
Change from baseline to week 52 in:
!
Haematology 
!
Biochemistry (except for amylase and lipase)
!
Calcitonin
!
ECG category
!
Physical examination 
!
Eye examination category
2.17
Section 18.1
Benefit-risk assessment of the trial
Other safety considerations
Diabetic retinopathy complications
A transient worsening of diabetic retinopathy is a recognised complication in selected patients with 
diabetes after initiation of intensive antidiabetic treatment49,50,51. 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 progression52,53 even in intensively treated patients who experienced early 
worsening50. 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 
placebo54. 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 
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retinopathy or maculopathy requiring acute treatment will be excluded. As part of good diabetes 
management the investigator is encouraged to ensure adequate monitoring and treatment of 
diabetic retinopathy in subjects enrolled into the trial55.
General precautions 
It is the responsibility of the investigator to ensure the best possible care of the subject. This 
includes adequate glycaemic control, appropriate risk factor modification such as optimal 
treatment of hypertension, dyslipidaemia and other cardiovascular risk factors, as well as regular 
monitoring and treatment of diabetic kidney disease and diabetic retinopathy according to the 
principles outlined in Diabetes Care 2016 Standards of Medical Care in Diabetes4855.
2.18
Section 27
References 
37.
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.
49.
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.
50.
The Diabetes Control and Complications Trial Research Group. Early worsening of 
diabetic retinopathy in the Diabetes Control and Complications Trial. Arch 
Ophthalmol. 1998;116(7):874-86.
51.
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):37-9.
52.
Intensive blood-glucose control with sulphonylureas or insulin compared with 
conventional treatment and risk of complications in patients with type 2 diabetes 
(UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 
1998;352(9131):837-53, Erratum 1999; 354: 602.
53.
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 
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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.
54.
Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, et al. 
Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl 
J Med. 2016.
55.
American Diabetes Association. Standards of medical care in diabetes - 2016. 
Diabetes Care. 2016;39 (Suppl. 1):S1-S109.
48.
American Diabetes Association. Standards of medical care in diabetes - 2016. 
Diabetes Care. 2016;39 (Suppl. 1):S13-S22.
2.19
Appendix B
Section 1 Adverse events requiring additional data collection
For the following AEs additional data collection is required and specific event forms must be 
completed in the eCRF in addition to the AE form:
!
Acute coronary syndrome (myocardial infarction [MI] or hospitalisation for unstable angina)
!
Cerebrovascular event (stroke or transient ischaemic attack [TIA])
!
Heart failure
!
Pancreatitis
!
Neoplasm (excluding thyroid neoplasm)
!
Thyroid disease (including thyroid neoplasm)
!
Renal event
!
Hypersensitivity reaction
!
Acute gallstone disease
!
Medication error (concerning trial products):
!
Administration of wrong drug. 
Note: Use of wrong DUN is not considered a medication error unless it results in 
administration of wrong drug.
!
Wrong route of administration.
!
Administration of an overdose with the intention to cause harm (e.g. suicide attempt) 
misuse or abuse of trial product.
!
Accidental administration of a higher dose than intended. A higher dose is a dose of at least 
one tablet 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.
!
Lactic acidosis
!
Creatine kinase (CK) > 10 x upper normal limit (UNL)
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
09 November 2016
Novo Nordisk
Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103
Status:
Final
EudraCT No.: 2015-005593-38
Page:
17 of 17
!
Hepatic event:
!
alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 5 x UNL and total 
bilirubin ≤ 2 x UNL
!
ALT or AST > 3 x UNL and total bilirubin > 2 x UNL*
!
Hepatic event leading to trial product discontinuation
!
Diabetic retinopathy and related complications
2.20
Appendix B, new section 
1.14
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 
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
14 March 2017
Novo Nordisk
Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103
Status:
Final
EudraCT No.: 2015-005593-38
Page:
1 of 56
Protocol Amendment
no 2
to Protocol, final version 2.0
dated 11 November 2016
Trial ID: NN9924-4257
PIONEER 7 – Flexible dose adjustment
Efficacy and Safety of Oral Semaglutide Using a Flexible Dose
Adjustment Based on Clinical Evaluation versus Sitagliptin in
Subjects with Type 2 Diabetes Mellitus
A 52-week Randomised, Open-label, Active-controlled Trial
Trial phase: 3a
Applicable to all countries
Amendment originator:
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol Amendment no 2
CONFIDENTIAL
Date:
14 March 2017
Novo Nordisk
Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103
Status:
Final
EudraCT No.: 2015-005593-38
Page:
2 of 56
Table of Contents   
Page
Table of Contents..............................................................................................................................................2
1
Introduction including rationale for the protocol amendment.............................................................4
1.1
Rationale for the amendment.........................................................................................................4
1.2
Design of the extension period ......................................................................................................4
1.3
Subject Information and Informed Consent form..........................................................................5
2
Changes......................................................................................................................................................6
2.1
Protocol sub-title............................................................................................................................6
2.2
Section 1   Summary......................................................................................................................6
2.3
Section 2   Flow Chart .................................................................................................................10
2.4
Section 3.2   Rationale for trial....................................................................................................16
2.5
Section 4.1   Objectives ...............................................................................................................16
2.5.1
Section 4.1.1   Primary objective...............................................................................16
2.5.2
Section 4.1.2   Secondary objectives .........................................................................16
2.6
Section 4.2   Endpoints ................................................................................................................17
2.6.1
Section 4.2.1   Primary endpoint................................................................................17
2.6.2
Section 4.2.2.1   Confirmatory secondary endpoints.................................................17
2.6.3
Section 4.2.2.2   Supportive secondary endpoints .....................................................18
2.7
Section 5.1   Type of trial.............................................................................................................20
2.8
Section 5.2   Rationale for trial design.........................................................................................23
2.9
Section 5.3   Treatment of subjects..............................................................................................24
2.9.1
Section 5.3.1   Oral semaglutide treatment................................................................24
2.9.2
Section 5.3.2   Sitagliptin treatment...........................................................................25
2.9.3
Section 5.3.4   Background medication .....................................................................25
2.10
Section 6.1   Number of subjects .................................................................................................25
2.11
Section 6.2   Inclusion criteria .....................................................................................................25
2.12
Section 6.3   Exclusion criteria ....................................................................................................26
2.13
Section 6.4   Rescue criteria.........................................................................................................26
2.14
Section 6.8   Rationale for trial population..................................................................................26
2.15
Section 7   Milestones..................................................................................................................27
2.16
Section 8.1   Visit procedures ......................................................................................................27
2.16.1
Section 8.1.3   Randomisation and trial products administration ..............................27
2.16.2
Section 8.1.4   End-of-treatment (visit 10) and Follow-up (visit 11).........................28
2.16.3
Section 8.1.5   Premature discontinuation of trial product and follow-up (visits 
10A and 11A).............................................................................................................29
2.16.4
Section 8.1.6   Withdrawal from trial ........................................................................30
2.16.5
Section 8.1.6.1   Lost to follow-up.............................................................................30
2.17
Section 8.3.5   Point-of-care HbA1c measurement.......................................................................31
2.18
Section 8.4.4   Eye examination...................................................................................................31
2.19
Section 8.6.1   Subject diary ........................................................................................................31
2.20
Section 11   Randomisation procedure ........................................................................................31
2.21
Section 12.2   Reporting of adverse events..................................................................................32
2.22
Section 12.7.2   Event adjudication committee............................................................................32
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
14 March 2017
Novo Nordisk
Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103
Status:
Final
EudraCT No.: 2015-005593-38
Page:
3 of 56
2.23
Section 14   Monitoring procedures.............................................................................................32
2.24
Section 17   Statistical considerations..........................................................................................33
2.25
Section 17.1   Sample size calculation.........................................................................................36
2.26
Section 17.2   Definition of analysis sets.....................................................................................39
2.27
Section 17.3.1   Primary analyses for the primary estimand........................................................45
2.28
Section 17.3.2   Primary analysis for the secondary estimand.....................................................45
2.29
Section 17.4.1   Confirmatory secondary endpoints....................................................................45
2.29.1
Section 17.4.2.1   Efficacy endpoints ........................................................................46
2.29.2
Section 17.4.2.2   Safety endpoints............................................................................49
2.30
Section 17.5   Interim analysis.....................................................................................................53
2.31
Section 17.6   Patient-reported outcomes ....................................................................................53
2.32
Section 18.1.1   Risks and precautions ........................................................................................54
2.33
Section 18.1.2   Benefits ..............................................................................................................54
2.34
Section 27   References................................................................................................................54
3
Changes in Appendices...........................................................................................................................55
3.1
Appendix B, Section 1.8.1   Assessments in case of suspicion of hypersensitivity reaction.......55
4
Changes in protocol Attachments..........................................................................................................56
4.1
Attachment I – Global list of key staff and relevant departments and suppliers of clinical 
relevance......................................................................................................................................56
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
14 March 2017
Novo Nordisk
Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103
Status:
Final
EudraCT No.: 2015-005593-38
Page:
4 of 56
1
Introduction including rationale for the protocol amendment
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
1.1
Rationale for the amendment
This protocol amendment introduces a 52-week extension period to the trial in order to assess:
a) Sustainability of glycaemic control and long-term safety in subjects exposed to oral semaglutide 
using flexible dose adjustment in combination with 1-2 oral antidiabetics for a period of up to 
104 weeks
b) Effect of switching from sitagliptin to oral semaglutide on glycaemic control and safety for a 
period of up to 52 weeks
The protocol sections 1-8, 11-12, 14, 17, 18, 27 (see Section 2 of this amendment) and Appendix B, 
Section 1.8.1 (see Section 3.1 of this amendment) have been updated due to the inclusion of the 
52-week extension phase. 
In addition, minor clarifications and corrections are included in this amendment and Attachment I 
(see Section 4.1 of this amendment) has been updated.
1.2
Design of the extension period
After 52 weeks of participation in the main phase of the trial, subjects who are on randomised 
treatment will be offered to enter the additional 52-week extension phase.
The extension phase will consist of two parts (three treatment arms):
a) Extension phase (sustainability): 
!
Subjects randomised to oral semaglutide in the main phase of the trial will continue to 
receive oral semaglutide at unchanged conditions (flexible dose adjustment) throughout the 
extension phase
b) Extension phase (switch): Subjects randomised to sitagliptin in the main phase of the trial will 
be re-randomised to receive either oral semaglutide or sitagliptin in the extension phase. 
!
Subjects re-randomised to oral semaglutide will initiate treatment with the 3 mg dose for the 
first 8 weeks, followed by a flexible dose adjustment every 8 weeks throughout the 
extension phase.
!
Subjects re-randomised to sitagliptin will continue unchanged on the 100 mg dose 
throughout the extension phase
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
14 March 2017
Novo Nordisk
Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103
Status:
Final
EudraCT No.: 2015-005593-38
Page:
5 of 56
For subjects continuing in the extension phase, additional 52 weeks treatment will be added and the 
total trial duration will be approximately 111 weeks (2 weeks screening, 104 weeks treatment and 
5 weeks follow-up). 
No new parameters will be introduced to be measured or evaluated during the extension phase.
1.3
Subject Information and Informed Consent form
An addendum to the master Subject Information and Informed Consent form has been prepared for 
those subjects who are eligible and wish to continue in the extension phase of the trial.
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
14 March 2017
Novo Nordisk
Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103
Status:
Final
EudraCT No.: 2015-005593-38
Page:
6 of 56
2
Changes
2.1
Protocol sub-title
A 52-week Randomised, Open-label, Active-controlled Trial with a 52-week Extension Phase
2.2
Section 1   Summary
Primary objective
Main phase
To compare the effect of once-daily dosing of oral semaglutide using a flexible dose adjustment 
based on clinical evaluation versus sitagliptin once daily, both in combination with 1-2 oral anti-
diabetic drugs (OADs) on glycaemic control in subjects with Type 2 diabetes mellitus (T2DM).
Secondary objectives
Main phase
!
To compare the effect of once-daily dosing of oral semaglutide using a flexible dose 
adjustment based on clinical evaluation versus sitagliptin once daily, both in combination 
with 1-2 OADs on body weight in subjects with T2DM.
!
To compare the safety and tolerability of once-daily dosing of oral semaglutide using a 
flexible dose adjustment based on clinical evaluation versus sitagliptin once daily, both in 
combination with 1-2 OADs in subjects with T2DM.
Extension phase (sustainability)
!
To evaluate the sustainability of glycaemic control and body weight reduction of once-daily 
dosing of oral semaglutide using a flexible dose adjustment based on clinical evaluation in 
subjects with T2DM.
!
To evaluate the long term safety of once-daily dosing of oral semaglutide using a flexible dose 
adjustment based on clinical evaluation in subjects with T2DM.
Extension phase (switch)
!
To compare the effect on glycaemic control of switching to once-daily dosing of oral 
semaglutide using a flexible dose adjustment based on clinical evaluation versus staying on 
once-daily sitagliptin in subjects with T2DM. 
!
To compare the effect on body weight of switching to once-daily dosing of oral semaglutide 
using a flexible dose adjustment based on clinical evaluation versus staying on once-daily 
sitagliptin in subjects with T2DM.
!
To compare the safety and tolerability of switching to once-daily dosing of oral semaglutide 
using a flexible dose adjustment based on clinical evaluation versus staying on once-daily 
sitagliptin in subjects with T2DM.
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
14 March 2017
Novo Nordisk
Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103
Status:
Final
EudraCT No.: 2015-005593-38
Page:
7 of 56
Primary endpoint
Main phase
If a subject after week 52 achieves (yes/no) glycosylated haemoglobin (HbA1c) < 7% (53 
mmol/mol) American Diabetes Association target.
Key secondary endpoints
Main phase
.....
Number of treatment-emergent adverse events during exposure to trial product, assessed up to 
approximately 57 52 weeks.
Number of treatment-emergent severe or blood glucose-confirmed symptomatic hypoglycaemic 
episodes during exposure to trial product, assessed up to approximately 57 52 weeks.
Extension phase (sustainability)
If a subject after week 104 achieves (yes/no) HbA1c < 7% (53 mmol/mol) American Diabetes 
Association target.
Change from baseline to week 104 in:
!
Body weight (kg)
!
HbA1c
!
Fasting plasma glucose (FPG)
Number of treatment-emergent adverse events during exposure to trial product, assessed up to 
approximately 109 weeks.
Number of treatment-emergent severe or blood glucose-confirmed symptomatic hypoglycaemic 
episodes during exposure to trial product, assessed up to approximately 109 weeks. 
Extension phase (switch)
If a subject after week 104 achieves (yes/no) HbA1c < 7% (53 mmol/mol) American Diabetes 
Association target.
Change from week 52 to week 104 in:
!
Body weight (kg)
!
HbA1c
!
Fasting plasma glucose (FPG)
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
14 March 2017
Novo Nordisk
Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103
Status:
Final
EudraCT No.: 2015-005593-38
Page:
8 of 56
Number of treatment-emergent adverse events during exposure to trial product, assessed from
week 52 up to approximately 109 weeks.
Number of treatment-emergent severe or blood glucose-confirmed symptomatic hypoglycaemic 
episodes during exposure to trial product, assessed from week 52 up to approximately 109 weeks. 
Trial design:
The trial consists of two 52-week treatment periods. The first 52-week treatment period is referred 
to as the main phase and the second 52-week treatment period as the extension phase. The 
extension phase consists of two parts; these are referred to as extension phase (switch) and 
extension phase (sustainability).
Main phase
The main phase This is a 52-week randomised, open-label, active-controlled, parallel-group, multi-
centre, multi-national treatment phase trial with two arms comparing the efficacy and safety of oral 
semaglutide using a flexible dose adjustment versus sitagliptin, in subjects with T2DM treated with 
1-2 OADs. 
Subjects will be randomised 1:1 to receive one of the following treatments as add-on to their anti-
diabetic background medication:
!
flexible dosing (3, 7 or 14 mg) of oral semaglutide once daily
!
100 mg sitagliptin once daily
Extension phase
The extension phase is a 52-week open-label, 3-arm, parallel-group treatment period following the 
main phase. The extension phase (switch) is active-controlled.
Subjects randomised to oral semaglutide in the main phase and who are still on trial product will 
continue treatment with oral semaglutide using a flexible dose adjustment in the 52-week extension 
phase (sustainability).
Subjects randomised to sitagliptin in the main phase and who are still on trial product will be 
re-randomised 1:1 at week 52 to receive one of the following two treatments in the 52-week 
extension phase (switch) as add-on to their anti-diabetic background medication:
!
flexible dosing (3, 7 or 14 mg) of oral semaglutide once daily
!
100 mg sitagliptin once daily
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
14 March 2017
Novo Nordisk
Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103
Status:
Final
EudraCT No.: 2015-005593-38
Page:
9 of 56
Main and extension phase
In this trial the dosing of oral semaglutide is flexible, following predefined dose adjustment criteria 
which are based on the subject’s individual HbA1c and tolerability (nausea/vomiting). Sitagliptin 
should be taken once-daily on at a fixed dose of 100 mg throughout the trial.
The total trial duration of the main phase for the individual subject will be either approximately 
54 weeks or approximately 59 weeks depending on whether or not the subject continues into the 
extension phase. The trial includes a 2-week screening period, a 52-week treatment period and for 
subjects not continuing in the extension phase, a 5-week follow-up period. For subjects continuing 
in the extension phase, 52 additional weeks will be added and the total trial duration will be 
approximately 111 weeks (2 week screening, 104 week treatment and 5 week follow up). The trial is 
designed to have visits every 8 weeks, including and a phone contact at week 4 and week 56.
Trial population:
Main phase: Number of subjects planned to be randomised: 500
Extension phase: Number of subjects planned to continue in the extension phase: 380
Key inclusion criteria
Main phase
!
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.
…..
Extension phase
!
Informed consent for the extension phase obtained before any trial-related activities for the 
extension phase. 
!
On randomised treatment with or without rescue medication at week 52.
Key exclusion criteria
Main phase
!
Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing 
potential and not using an adequate contraceptive method (adequate contraceptive measure as 
required by local regulation or practice).
…..
Extension phase
There are no new exclusion criteria for the extension phase.
CONFIDENTIAL


Protocol Amendment no 2
UTN: U1111-1177-5103
Date:
14 March 2017
Status:
Final
Novo Nordisk
Trial ID: NN9924-4257
EudraCT No.: 2015-005593-38
Version:
1.0
Page:
10 of 56
2.3
Section 2   Flow Chart
Trial Periods
Screening a
Randomisation
Treatment (main phase)
End-of-treatment (EoT)/
Start of extension phase k
Follow-up b
EoT premature 
discontinuation c
Follow-up premature 
discontinuation c
Treatment (extension phase)
End-of-treatment 
Follow-up b
EoT premature 
discontinuation c
Follow-up premature 
discontinuation c
Visit (V), Phone contact (P)
V1
V2
P3
V4
V5
V6
V7
V8
V9
V10
V11
V10A
V11A
P12
V13
V14
V15
V16
V17
V18
V19
V20
V19A
V20A
Timing of visit 
(weeks)
Up to -2 
weeks
0
4
8
16
24
32
40
48
52
57
Day of disc. of 
trial product
5 weeks after 
disc. of trial 
product
56
60
68
76
84
92
100
104
109
Day of disc. of 
trial product
5 weeks after 
disc. of trial 
product
Visit window (days)
±3
±3
±3
±3
±3
±3
±3
±3
+3
+3
+3
±3
±3
±3
±3
±3
±3
±3
±3
+3
+3
+3
SUBJECT RELATED
INFO/ASSESSMENTS
Informed consent
x
x*
In/exclusion criteria
x
x
x*
Concomitant medication
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Concomitant illness and 
medical history
x
Demography
x
Diagnosis of 
diabetes/diabetes 
complication
x
Hypoglycaemia unawareness
x
Tobacco use
x
History of cardiovascular 
disease
x


Protocol Amendment no 2
UTN: U1111-1177-5103
Date:
14 March 2017
Status:
Final
Novo Nordisk
Trial ID: NN9924-4257
EudraCT No.: 2015-005593-38
Version:
1.0
Page:
11 of 56
Trial Periods
Screening a
Randomisation
Treatment (main phase)
End-of-treatment (EoT)/
Start of extension phase k
Follow-up b
EoT premature 
discontinuation c
Follow-up premature 
discontinuation c
Treatment (extension phase)
End-of-treatment 
Follow-up b
EoT premature 
discontinuation c
Follow-up premature 
discontinuation c
Visit (V), Phone contact (P)
V1
V2
P3
V4
V5
V6
V7
V8
V9
V10
V11
V10A
V11A
P12
V13
V14
V15
V16
V17
V18
V19
V20
V19A
V20A
Timing of visit 
(weeks)
Up to -2 
weeks
0
4
8
16
24
32
40
48
52
57
Day of disc. of 
trial product
5 weeks after 
disc. of trial 
product
56
60
68
76
84
92
100
104
109
Day of disc. of 
trial product
5 weeks after 
disc. of trial 
product
Visit window (days)
±3
±3
±3
±3
±3
±3
±3
±3
+3
+3
+3
±3
±3
±3
±3
±3
±3
±3
±3
+3
+3
+3
History of gallbladder 
disease
x
History of gastrointestinal 
disease
x
Randomisation
x
x*
Criteria for premature 
discontinuation of trial 
product
x
x
x
x
x
x
x
x*
x
x
x
x
x
x
x
EFFICACY
Height
x
Body weight
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Waist circumference
x
x
x
x
x
x
x
x
x
x
PRO questionnaires
x
x
x
x
x
x
x
x
x
x
x
Dose adjustment criteriad
x
x
x
x
x
x
x*
x
x
x
x
x
x
Fasting plasma glucose
x
x
x
x
x
x
x
x
HbA1c
e
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x


Protocol Amendment no 2
UTN: U1111-1177-5103
Date:
14 March 2017
Status:
Final
Novo Nordisk
Trial ID: NN9924-4257
EudraCT No.: 2015-005593-38
Version:
1.0
Page:
12 of 56
Trial Periods
Screening a
Randomisation
Treatment (main phase)
End-of-treatment (EoT)/
Start of extension phase k
Follow-up b
EoT premature 
discontinuation c
Follow-up premature 
discontinuation c
Treatment (extension phase)
End-of-treatment 
Follow-up b
EoT premature 
discontinuation c
Follow-up premature 
discontinuation c
Visit (V), Phone contact (P)
V1
V2
P3
V4
V5
V6
V7
V8
V9
V10
V11
V10A
V11A
P12
V13
V14
V15
V16
V17
V18
V19
V20
V19A
V20A
Timing of visit 
(weeks)
Up to -2 
weeks
0
4
8
16
24
32
40
48
52
57
Day of disc. of 
trial product
5 weeks after 
disc. of trial 
product
56
60
68
76
84
92
100
104
109
Day of disc. of 
trial product
5 weeks after 
disc. of trial 
product
Visit window (days)
±3
±3
±3
±3
±3
±3
±3
±3
+3
+3
+3
±3
±3
±3
±3
±3
±3
±3
±3
+3
+3
+3
Lipids
x
x
x
x
x
x
SAFETY
Adverse eventsf
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
ECG
x
x
x
x
x
x
x
x
x
x
x
Eye examinationg
x
x
x
x
x
Physical examination
x
x
x
x
x
Vital signs
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Biochemistryh
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Haematology
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Calcitonin
x
x
x
x
x
x
x
x
x
x
x
Pregnancy testi
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Technical complaints
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Hypoglycaemic episodes
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
TRIAL MATERIAL
Dispensing visit
x
x
x
x
x
x
x
x*
x
x
x
x
x
x


Protocol Amendment no 2
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Trial Periods
Screening a
Randomisation
Treatment (main phase)
End-of-treatment (EoT)/
Start of extension phase k
Follow-up b
EoT premature 
discontinuation c
Follow-up premature 
discontinuation c
Treatment (extension phase)
End-of-treatment 
Follow-up b
EoT premature 
discontinuation c
Follow-up premature 
discontinuation c
Visit (V), Phone contact (P)
V1
V2
P3
V4
V5
V6
V7
V8
V9
V10
V11
V10A
V11A
P12
V13
V14
V15
V16
V17
V18
V19
V20
V19A
V20A
Timing of visit 
(weeks)
Up to -2 
weeks
0
4
8
16
24
32
40
48
52
57
Day of disc. of 
trial product
5 weeks after 
disc. of trial 
product
56
60
68
76
84
92
100
104
109
Day of disc. of 
trial product
5 weeks after 
disc. of trial 
product
Visit window (days)
±3
±3
±3
±3
±3
±3
±3
±3
+3
+3
+3
±3
±3
±3
±3
±3
±3
±3
±3
+3
+3
+3
Drug accountability
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
IWRS call
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
REMINDERS
Attend visit fastingj
x
x
x
x
x
x
x
x
Handout and instruct in BG 
meter use
x
Handout ID card
x
Training in dosing 
instructions
x
x
x
x
x
x
x
x
x
x*
x
x
x
x
x
x
x
Dispense and/or collect diary
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x


Protocol Amendment no 2
UTN: U1111-1177-5103
Date:
14 March 2017
Status:
Final
Novo Nordisk
Trial ID: NN9924-4257
EudraCT No.: 2015-005593-38
Version:
1.0
Page:
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Footer
Description
xa
Subject can be randomised as soon as all inclusion and exclusion criteria are confirmed. The screening assessments must not exceed 2 weeks prior to randomisation (V2).
xb
Only subjects who have completed treatment in the main phase and are not continuing in the extension phase are required to attend V11.
Subjects who have discontinued trial product prematurely are not required to attend V11 (Follow-up) in the main phase or V20 (Follow-up) in the extension phase.
xc
V10A and V11A in the main phase and V19A and V20A in the extension phase are only applicable for subjects who have discontinued trial product prematurely.
xd
Dose adjustment criteria are subject's HbA1c (measured by point-of-care device) and tolerability (nausea/vomiting).
!
at V10 the dose adjustment criteria are only relevant for subjects on oral semaglutide in the main phase and are continuing on oral semaglutide in the extension phase.
In addition, for stratification purpose at V10, HbA1c (measured by point-of-care device) is also applicable for subjects on sitagliptin in the main phase continuing in the 
extension phase (see Section 8.3.5 and 11)
!
at V4-V9 and V13-V18, HbA1c (measured by point-of-care device) is only applicable for subjects on oral semaglutide
xe
Assessed at central laboratory.
xf
Adverse events reporting includes adverse events from the first trial-related activity after the subject has signed the informed consent at V1. Pre-existing conditions identified as 
a result of the screening procedures should be reported as medical history.
xg
Fundus photography or dilated fundoscopy performed within 90 days before randomisation is acceptable if results are available for evaluation at visit 2 and no deterioration in 
visual function since last examination.
Fundus photography or dilated fundoscopy must be performed for all subjects again:
!
at V10 or within 5 weeks thereafter for subjects completing treatment
!
at V10A or within 5 weeks thereafter, and again within 5 weeks prior to V10, for subjects who have prematurely discontinued trial product
In the extension phase:
!
at V19 or within 5 weeks thereafter for subjects completing treatment
!
at V19A or within 5 weeks thereafter, and again within 5 weeks prior to V19, for subjects who have prematurely discontinued trial product
xh
At V1, only ALT, creatinine and eGFR will be assessed as part of Biochemistry.
xi
For women of child-bearing potential: Urine pregnancy test should also be performed at any time during the trial if menstrual period is missed, and/or according to local 
regulations/law. For details regarding local regulations/law see Section 6.3.


Protocol Amendment no 2
UTN: U1111-1177-5103
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xj
Fasting for blood sampling is defined as no food or liquid within the last 8 hours prior to blood sampling, however water is allowed up until 2 hours prior to blood sampling. 
Trial product must be taken after blood sampling. Other oral medication can be taken 30 minutes after trial product (for subjects randomised to oral semaglutide only). Injectable 
medications can be administered after blood sampling.
xk
For subjects not continuing in the extension phase: V10 is the end-of-treatment (EoT) visit. 
For subjects continuing in the extension phase:
!
subjects on semaglutide in the main phase: V10 is a treatment visit
!
subjects on sitagliptin in the main phase: V10 is a combined re-randomisation and treatment visit
x*
Activities at V10 marked with x* are NOT applicable for patients who will not continue in the extension phase. 
Additional activities at V10 applicable for patients who have signed the addendum to the informed consent and are continuing in the extension phase (see Section 8.1.3):
!
inclusion criteria for the extension phase must be assessed
!
HbA1c (measured by point-of-care device) is applicable for all subjects at V10 continuing in the extension phase. The dose adjustment criteria are only relevant for subjects 
randomised to oral semaglutide in the main phase and are continuing in the extension phase (see Section 5.3.1). For subjects on sitagliptin in the main phase, the HbA1c
value will be used for stratification of the re-randomisation (see Section 5.2 and 11)
!
subjects randomised to sitagliptin in the main phase, will at V10 be re-randomised in IWRS to one of the two parallel treatment arms as described in Section 5.1 and 5.2 
!
dispense diary (for extension phase) and trial product. All V10 assessments must be performed before administration of trial product in the extension phase


Protocol Amendment no 2
CONFIDENTIAL
Date:
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Trial ID: NN9924-4257
Version:
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2.4
Section 3.2   Rationale for trial
Rationale for the 52-week extension phase
1. Extension phase (sustainability): Evaluate the sustainability of glycaemic control and long-
term safety of once-daily oral semaglutide using flexible dose adjustment based on clinical 
evaluation over a period of 104 weeks (in subjects randomised to oral semaglutide flexible 
dosing in the main phase and continuing on oral semaglutide flexible dosing in the extension 
phase).
2. Extension phase (switch): Evaluate the switch from sitagliptin to oral semaglutide in subjects 
randomised to sitagliptin in the main phase and re-randomised at week 52 to either switch to 
once-daily oral semaglutide flexible dosing or continue on once-daily sitagliptin in the 
extension phase.
2.5
Section 4.1   Objectives
2.5.1
Section 4.1.1   Primary objective
Main phase
To compare the effect of once-daily dosing of oral semaglutide using a flexible dose adjustment 
based on clinical evaluation versus sitagliptin once daily, both in combination with 1-2 OADs on 
glycaemic control in subjects with T2DM.
2.5.2
Section 4.1.2   Secondary objectives
Main phase
!
To compare the effect of once-daily dosing of oral semaglutide using a flexible dose adjustment 
based on clinical evaluation versus sitagliptin once daily, both in combination with 1-2 OADs 
on body weight in subjects with T2DM.
!
To compare the safety and tolerability of once-daily dosing of oral semaglutide using a flexible 
dose adjustment based on clinical evaluation versus sitagliptin once daily, both in combination 
with 1-2 OADs in subjects with T2DM.
Extension phase (sustainability)
!
To evaluate the sustainability on glycaemic control and body weight reduction of once-daily 
dosing of oral semaglutide using a flexible dose adjustment based on clinical evaluation in 
subjects with T2DM.
!
To evaluate the long term safety of once-daily dosing of oral semaglutide using a flexible dose 
adjustment based on clinical evaluation in subjects with T2DM.
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
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Trial ID: NN9924-4257
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Extension phase (switch)
!
To compare the effect on glycaemic control of switching to once-daily dosing of oral 
semaglutide using a flexible dose adjustment based on clinical evaluation versus staying on 
once-daily sitagliptin in subjects with T2DM. 
!
To compare the effect on body weight of switching to once-daily dosing of oral semaglutide 
using a flexible dose adjustment based on clinical evaluation versus staying on once-daily 
sitagliptin in subjects with T2DM.
!
To compare the safety and tolerability of switching to once-daily dosing of oral semaglutide 
using a flexible dose adjustment based on clinical evaluation versus staying on once-daily 
sitagliptin in subjects with T2DM.
2.6
Section 4.2   Endpoints
Baseline refers to randomisation at V2 (in the main phase), and week 52 refers to 52 weeks after 
randomisation at V2, and week 104 refers to 104 weeks after randomisation at V2.
The endpoints will be evaluated based on the following time periods and treatment arms, see more 
details in Section 17.
Main phase, baseline to week 52:
!
Oral semaglutide (3, 7 or 14 mg)
!
Sitagliptin (100 mg)
Extension phase (sustainability), baseline to week 104:
!
Oral semaglutide (3, 7 or 14 mg) during 104 weeks
Extension phase (switch), week 52 to week 104:
!
Oral semaglutide (3, 7 or 14 mg) switching from sitagliptin (100 mg) at week 52
!
Sitagliptin (100 mg) continuing on sitagliptin (100 mg) after week 52
2.6.1
Section 4.2.1   Primary endpoint
Main phase 
If a subject after week 52 achieves (yes/no) HbA1c < 7% (53 mmol/mol) American Diabetes 
Association (ADA) target.
2.6.2
Section 4.2.2.1   Confirmatory secondary endpoints
Main phase 
Change from baseline to week 52 in body weight (kg)
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
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Version:
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Extension phase (switch)
Change from week 52 to week 104 in HbA1c
Change from week 52 to week 104 in body weight (kg)
2.6.3
Section 4.2.2.2   Supportive secondary endpoints
Key supportive secondary endpoints prospectively selected for disclosure (e.g. clinicaltrials.gov and 
EudraCT) are marked with an asterisk (*).
Supportive secondary efficacy endpoints
Main phase
Change from baseline to week 52 in:
!
HbA1c*
!
Fasting plasma glucose (FPG)*
.....
Extension phase (sustainability)
Change from baseline to week 104 in:
!
HbA1c
!
Fasting plasma glucose (FPG)
!
Body weight (kg)
!
Body weight (%)
!
Body mass index (BMI)
!
Waist circumference
!
Patient-reported outcomes (PROs):
o
Short Form (SF-36v2TM) (acute version) health survey
o
Diabetes Treatment Satisfaction Questionnaire (DTSQs)
If a subject after week 104 achieves (yes/no):
!
HbA1c < 7% (53 mmol/mol) American Diabetes Association (ADA) target
!
HbA1c ≤6.5% (48 mmol/mol) American Association of Clinical Endocrinologists (AACE) target 
!
HbA1c reduction ≥1%-point (10.9 mmol/mol)
!
HbA1c < 7% (53 mmol/mol) or HbA1c reduction ≥1%-point (10.9 mmol/mol)
!
Weight loss ≥5%
!
HbA1c < 7.0% (53 mmol/mol) without hypoglycaemia (treatment-emergent severe or 
BG-confirmed symptomatic hypoglycaemic episodes) and no weight gain
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
14 March 2017
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Trial ID: NN9924-4257
Version:
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UTN: U1111-1177-5103
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Extension phase (switch)
Change from week 52 to week 104 in:
!
Fasting plasma glucose (FPG)
!
Body weight (%)
!
Body mass index (BMI)
!
Waist circumference
!
Patient-reported outcomes (PROs):
o
Short Form (SF-36v2TM) (acute version) health survey 
o
Diabetes Treatment Satisfaction Questionnaire (DTSQs)
If a subject after week 104 achieves (yes/no):
!
HbA1c < 7% (53 mmol/mol) American Diabetes Association (ADA) target
!
HbA1c ≤6.5% (48 mmol/mol) American Association of Clinical Endocrinologists (AACE) target
!
HbA1c reduction ≥1%-point (10.9 mmol/mol) compared to week 52
!
Weight loss ≥5% compared to week 52
!
HbA1c < 7.0% (53 mmol/mol) without hypoglycaemia (treatment-emergent severe or 
BG-confirmed symptomatic hypoglycaemic episodes) after week 52 and no weight gain
compared to week 52
!
HbA1c < 7% (53 mmol/mol) and no need for rescue medication after week 52
!
No need for rescue medication after week 52
Time to event: 
!
Time to rescue medication after week 52
Supportive secondary safety endpoints
Main phase
!
Number of treatment-emergent adverse events (TEAEs) during exposure to trial product, 
assessed up to approximately 57 52 weeks
!
Number of treatment-emergent severe or BG-confirmed symptomatic hypoglycaemic episodes 
during exposure to trial product, assessed up to approximately 57 52 weeks
!
Treatment-emergent severe or BG-confirmed symptomatic hypoglycaemic episodes during 
exposure to trial product, assessed up approximately 57 52 weeks (yes/no)
Extension phase (sustainability)
!
Number of treatment-emergent adverse events (TEAEs) during exposure to trial product, 
assessed up to approximately 109 weeks
!
Number of treatment-emergent severe or BG-confirmed symptomatic hypoglycaemic episodes 
during exposure to trial product, assessed up to approximately 109 weeks
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
14 March 2017
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Trial ID: NN9924-4257
Version:
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UTN: U1111-1177-5103
Status:
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EudraCT No.: 2015-005593-38
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!
Treatment-emergent severe or BG-confirmed symptomatic hypoglycaemic episodes during 
exposure to trial product, assessed up to approximately 109 weeks (yes/no)
Extension phase (switch)
!
Number of treatment-emergent adverse events (TEAEs) during exposure to trial product, 
assessed from week 52 up to approximately 109 weeks
!
Number of treatment-emergent severe or BG-confirmed symptomatic hypoglycaemic episodes 
during exposure to trial product, assessed from week 52 up to approximately 109 weeks
!
Treatment-emergent severe or BG-confirmed symptomatic hypoglycaemic episodes during 
exposure to trial product, assessed from week 52 up to approximately 109 weeks (yes/no)
Main phase 
Change from baseline to week 52 in:
…..
Extension phase (sustainability)
Change from baseline to week 104 in:
!
Haematology
!
Biochemistry
!
Calcitonin
!
Pulse
!
Systolic blood pressure
!
Diastolic blood pressure
!
Eye examination category
Extension phase (switch)
Change from week 52 to week 104 in:
!
Haematology
!
Biochemistry
!
Calcitonin
!
Pulse
!
Systolic blood pressure
!
Diastolic blood pressure
!
Eye examination category
2.7
Section 5.1   Type of trial
The trial consists of two 52-week treatment periods. The first 52-week treatment period is referred 
to as the main phase and the second 52-week treatment period as the extension phase. The 
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Protocol Amendment no 2
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extension phase consists of two parts; these are referred to as the extension phase (sustainability) 
and the extension phase (switch).
Main phase
The main phaseThis is a 52-week randomised, open-label, active-controlled, parallel-group, multi-
centre, multi-national treatment phase trial with two arms comparing the efficacy and safety of oral 
semaglutide using a flexible dose adjustment versus sitagliptin 100 mg once-daily, in subjects with 
T2DM treated with 1-2 OADs (metformin, sulfonylureas [SU], thiazolidinediones [TZD], sodium 
glucose co-transporter 2 [SGLT-2] inhibitors). 
Subjects will be randomised 1:1 to receive one of the following treatments as add-on to their anti-
diabetic background medication:
!
flexible dosing (3, 7 or 14 mg) of oral semaglutide once daily
!
100 mg sitagliptin once daily
Extension phase
The extension phase is a 52-week open-label, 3-arm, parallel-group treatment period following the 
main phase. The extension phase (switch) is active-controlled.
Extension phase (sustainability)
Subjects randomised to oral semaglutide in the main phase and still on trial product will continue 
treatment with oral semaglutide using a flexible dose adjustment in the 52-week extension phase. 
Extension phase (switch)
Subjects randomised to sitagliptin in the main phase and still on trial product will be re-randomised 
1:1 at week 52 to receive one of the following treatments in the 52-week extension phase as add-on 
to their anti-diabetic background medication: 
!
flexible dosing (3, 7 or 14 mg) of oral semaglutide once daily
!
100 mg sitagliptin once daily
Trial duration
The total trial duration of the main phase for the individual subject will be either approximately 
54 weeks or approximately 59 weeks depending on whether or not the subject continues into the 
extension phase. The trial includes a 2-week screening period, a 52-week treatment period and, for 
subjects not continuing in the extension phase, a 5-week follow-up period. For subjects continuing 
in the extension phase, additional 52 weeks will be included and the total trial duration will be 
approximately 111 weeks (2 weeks screening, 104 weeks treatment and 5 weeks follow-up). The 
trial is designed to have visits every 8 weeks, including and a phone contact at week 4 and week 56.
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
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Trial ID: NN9924-4257
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A schematic illustration of the trial design is shown in Figure 5-1.
* Subjects who have completed treatment in the main phase and are not continuing in the extension phase must 
attend the Follow-up visit (Week 57) 5 week after the last date on trial product.
Figure 5–1
Trial design
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
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Trial ID: NN9924-4257
Version:
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2.8
Section 5.2   Rationale for trial design
Main phase
The main phase of the trial has been designed as an open-label, parallel-group, 2-arm superiority 
trial, where oral semaglutide will be compared with the DPP-4 inhibitor sitagliptin. 
…..
Extension phase 
The extension phase of this trial has been designed as an additional 52-week open-label extension 
phase after completion of 52 weeks of treatment in the main phase. Subjects randomised to oral 
semaglutide in the main phase and still on trial product at week 52 will continue on oral 
semaglutide in the extension phase. Subjects randomised to sitagliptin in the main phase and still 
on trial product at week 52 will be re-randomised in a 1:1 manner to either switch to oral 
semaglutide or continue on sitagliptin.
Overall, the extension phase consists of 3 treatment arms:
1. subjects continuing on oral semaglutide
2. subjects randomised to sitagliptin in the main phase and re-randomised to oral semaglutide
3. subjects randomised to sitagliptin in the main phase and re-randomised to sitagliptin
The trial design will allow for the evaluation of the sustainability of the effect and safety of the 
flexible dosing of once-daily oral semaglutide during a 104-week period as well as of the switch 
from once-daily sitagliptin to once-daily oral semaglutide. Subjects are only eligible to continue in 
the extension phase if they are still on the randomised treatment at week 52, regardless of use of 
rescue medication. The re-randomisation in the sitagliptin arm will be stratified according to HbA1c
below 7% (yes/no) and if the subject is currently on prescribed rescue medication and continuing 
on the same medication in the extension phase (yes/no). This is to ensure an even distribution in the 
two treatment arms in the extension phase (switch). 
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
14 March 2017
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Trial ID: NN9924-4257
Version:
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UTN: U1111-1177-5103
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2.9
Section 5.3   Treatment of subjects
Table 5-1
Treatment of subjects
Treatment of subjects in the main phase:
Trial periods
Screening
Treatment main phase (52 weeks)
period 1  Treatment period 2  Treatment period 3
Follow-up*
(V11)
First visit in each period
V1
V2
V4
V5
V11
Duration of each period
2 weeks
8 weeks
8 weeks
36 weeks
5 weeks
Treatment arm
N
Oral semaglutide
250
Screening 
3 mg
flexible dosing
(3 or 7 mg)
flexible dosing
(3, 7 or 14 mg)
Follow-up
Sitagliptin
250
Screening 
100 mg
100 mg100 mg
Follow-up 
* Only applicable for subjects not continuing in the extension phase
Treatment of subjects continuing in the extension phase:
Trial periods
Treatment extension phase (52 weeks)
Follow-up
(V20)
First visit in each period
V10
V13
V14
Duration of each period
8 weeks
8 weeks
36 weeks
5 weeks
Treatment arm
N**
Oral semaglutide (sustainability)
190
flexible dosing 
(3, 7 or 14 mg)
Follow-up
Sitagliptin (switch)***
95
100 mg
Follow-up 
Oral semaglutide (switch)***
95
3 mg
flexible dosing
(3 or 7 mg)
flexible dosing
(3, 7 or 14 mg)
Follow-up
** Only estimated numbers
*** Subjects on sitagliptin in the main phase continuing in the extension phase will be re-randomised (1:1) at V10 to sitagliptin 
or oral semaglutide
2.9.1
Section 5.3.1   Oral semaglutide treatment
Extension phase (sustainability)
Subjects randomised to oral semaglutide in the main phase will continue to receive oral 
semaglutide in the extension phase using the same clinical criteria as applied in the main phase for 
oral semaglutide. Starting from V10, the point-of-care device must be used to measure the subject’s 
HbA1c level prior to evaluation of the dose-adjustment criteria (see Section 2 and 8.1.3). 
Extension phase (switch)
Subjects randomised to sitagliptin in the main phase and re-randomised at week 52 to oral 
semaglutide in the extension phase will initiate treatment with 3 mg of oral semaglutide without any 
wash-out of sitagliptin, and the dose of oral semaglutide will starting from V13 be adjusted using 
the same clinical criteria as applied in the main phase. 
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
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Trial ID: NN9924-4257
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2.9.2
Section 5.3.2   Sitagliptin treatment
Main phase
The selected active comparator 
....
Extension phase (switch)
Subjects randomised to sitagliptin in the main phase and re-randomised at week 52 to sitagliptin in 
the extension phase will continue with once-daily sitagliptin 100 mg.
2.9.3
Section 5.3.4   Background medication
After signing the informed consent, subjects must continue using their anti-diabetic background 
medication throughout the entire trial. The background medication must be maintained at the same 
dose level as given at trial entrance (V1) and with the same frequency during the entire treatment 
period unless rescue medication is needed (see Section 6.4), any safety concerns related to the 
background medication arises or if the subject has unacceptable hypoglycaemia on a background of 
SU in which case the dose of SU can be reduced. 
For the two treatment arms in the extension phase (switch), the current prescribed rescue 
medication (at V10) in the main phase will be treated as background medication in the extension 
phase. During the extension phase the anti-diabetic background medication must be maintained at 
the same dose level as given at V10 and with the same frequency during the entire treatment period 
unless rescue medication is needed (see Section 6.4), any safety concerns related to the background 
medication arise or if the subject has unacceptable hypoglycaemia on a background of SU or 
insulin in which case the dose of SU or insulin can be reduced.
2.10
Section 6.1   Number of subjects
Main phase
…..
Number of subjects expected to complete the first 52 weeks of the trial on or off trial product:
425
Extension phase
Planned number of subjects to continue into the extension phase:
380
Number of subjects expected to complete the trial 
(including the extension phase) on or off trial product:
323
2.11
Section 6.2   Inclusion criteria
Inclusion criteria for the main phase:
For an eligible subject, all inclusion criteria must be answered “yes”. The inclusion criteria for the 
main phase are not re-assessed for the extension phase.
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Protocol Amendment no 2
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Trial ID: NN9924-4257
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Inclusion criteria for the extension phase:
7. Informed consent for the extension phase obtained before any trial-related activities for the 
extension phase.
8. On randomised treatment with or without rescue medication at week 52.
2.12
Section 6.3   Exclusion criteria
Exclusion criteria for the main phase:
For an eligible subject, all exclusion criteria must be answered “no”. The exclusion criteria for the 
main phase are not re-assessed for the extension phase.
Exclusion criteria for extension phase:
There are no new exclusion criteria for the extension phase.
2.13
Section 6.4   Rescue criteria
Subjects with persistent and unacceptable hyperglycaemia should be offered treatment 
intensification with rescue medication. It is important for trial integrity that only subjects actually 
needing treatment intensification (i.e. intensification of existing anti-diabetic medication and/or 
initiation of new anti-diabetic medication) are started on rescue medication. For subjects who are 
re-randomised at week 52 to switch from sitagliptin to oral semaglutide in the extension phase, the 
dose of oral semaglutide should be increased to the maximal tolerated dose before initiation of 
rescue medication.
2.14
Section 6.8   Rationale for trial population
Main phase
Subjects with T2DM inadequately controlled on 1-2 OADs (metformin, SU, TZD, SGLT-2 
inhibitors) will be included in the trial.
…..
Extension phase (sustainability)
To investigate the sustainability of glycaemic effect and safety of oral semaglutide flexible dosing, 
all subjects treated with oral semaglutide at week 52 in the main phase are invited to continue 
treatment with oral semaglutide flexible dosing in the extension phase independent of their level of 
glycaemic control and whether or not rescue medication has been initiated. 
Extension phase (switch)
To investigate the effect and safety of switching from sitagliptin to oral semaglutide flexible dosing, 
all subjects treated with sitagliptin at week 52 in the main phase are invited to be re-randomised to 
either switch to oral semaglutide flexible dosing or continue sitagliptin in the extension phase 
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Protocol Amendment no 2
CONFIDENTIAL
Date:
14 March 2017
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Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103
Status:
Final
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independent of glycaemic control and whether rescue medication has been initiated. No wash-out 
period will be included.
2.15
Section 7   Milestones
Planned LSLV for the main phase:
19-Mar Apr-2018
Planned LSLV for the complete trial (including the extension phase):
Apr-2019
Primary Completion Date for the main phase of the trial is 52 weeks (visit 10) after the date of 
randomisation of the last randomised subject in the main phase.
End of trial is defined as: LSLV for the complete trial.
The results from the trial will be reported in two clinical trial reports; the first clinical trial report 
will report the results from the main phase and the second clinical trial report will report the 
results of the entire trial period, including the extension phase. 
2.16
Section 8.1   Visit procedures
Each subject will have 10 site visits and 1 phone contact if only completing the main phase of the 
trial. Eligible subjects who accept to continue in extension phase will not attend follow-up V11 but 
will continue with 8 additional visits and 1 phone contact.
2.16.1
Section 8.1.3   Randomisation and trial products administration
Main phase
…..
The investigator must document that subjects are trained in the dosing instructions at every 
dispensing visit, see Section 5.3.31.
Extension phase (visit 10)
Subjects are considered eligible to continue in the extension phase if they are still on the 
randomised treatment at V10 (regardless of use of rescue medication) and have consented to 
continue in the extension phase. Subjects who have prematurely discontinued trial product are not 
eligible for the extension phase. The inclusion and exclusion criteria for the main phase are not 
re-assessed at week 52 before entering the extension phase.
Eligible subjects, who have signed the addendum to the informed consent, will continue in the 
extension phase at V10. The first trial-related activity only for subjects continuing in the extension 
phase is the measurement of HbA1c at V10 using the point-of-care device (see Section 2 and 8.3.5).
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
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Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103
Status:
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Page:
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Subjects randomised to oral semaglutide in the main phase will continue to receive oral 
semaglutide in the extension phase using the same clinical criteria as applied in the main phase
(See Section 5.1). The point-of-care device must be used to measure the subject’s HbA1c prior to 
evaluation of the dose-adjustment criteria at V10 (see Section 5.3.1 and 8.3.5).
Subjects randomised to sitagliptin in the main phase will be re-randomised at week 52 to either oral 
semaglutide or sitagliptin in the extension phase (see Section 5.1, 5.2 and 11). The 
re-randomisation will be stratified according to HbA1c below 7% (yes/no) measured by a point-of-
care device, and if the subject is currently on prescribed rescue medication and continuing on the 
same medication in the extension phase (yes/no). Rescue medication is defined as intensification of 
existing background anti-diabetic medication compared to V1 and/or initiation of new anti-diabetic 
medication. A dispensing session and re-randomisation must be made in the IWRS which will 
allocate the DUN of trial product to be dispensed to the subject.
All V10 assessments must be performed before administration of first dose of trial product in the 
extension phase.
Trial products (see Section 9) will be dispensed to the subject in the extension phase by the site, 
hospital pharmacy or equivalent at each site visit during the trial from V10 to last visit before the 
end-of-treatment visit (see Section 2). The investigator must document that subjects are trained in 
the dosing instructions at every dispensing visit, see Section 5.3.3.
For the subjects in the sitagliptin arm re-randomised to oral semaglutide, the date of first 
semaglutide administration will be captured in the eCRF.
2.16.2
Section 8.1.4   End-of-treatment (visit 10) and Follow-up (visit 11)
For subjects only completing the main phase
Subjects, who stay on trial product throughout the main phase trial, must attend the end-of-
treatment visit (V10) 52 weeks after randomisation and the follow-up visit (V11) 5 weeks after the 
last date on trial product (+3 days visit window). The end-of-trial form in the eCRF must be 
completed if subjects are not continuing in the extension phase. Throughout the protocol, last date 
on trial product is defined as date of the subject’s last dosage of trial product. A completion call 
must be performed in the IWRS after completion of V10 (see Section 10). 
At V10 the subject should be reminded about the importance of attending the follow-up visit (V11). 
If the subject, nonetheless, dose does not attend V11, the site should make efforts to obtain contact 
with the subject within the visit window. 
A trial completer of the main phase is defined as a subject who attends, or is in contact with the site, 
at the subject’s last scheduled visit. For subjects who complete treatment in the main phase and do 
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
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Novo Nordisk
Trial ID: NN9924-4257
Version:
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UTN: U1111-1177-5103
Status:
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Page:
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not continue in the extension phase, the last scheduled visit is V11. (For subjects who discontinue 
trial product, see Section 8.1.5).
For subjects continuing in and completing the extension phase
Subjects who continue in the extension phase and stay on trial product throughout the trial must 
attend the end-of-treatment visit V19 and the follow-up visit V20 5 weeks after the last date on trial 
product (+3 days visit window). The end-of-trial form in the eCRF must be completed. A completion 
call must be performed in the IWRS after completion of V19 (see Section 10). 
At V19, the subject should be reminded about the importance of attending the follow-up visit V20. If 
the subject, nonetheless, does not attend V20, the site should make efforts to obtain contact with the 
subject within the visit window. 
A completer of the extension phase is defined as a subject who attends or is in contact with the site 
at the subject’s last scheduled visit. For subjects who complete treatment in the extension phase, the 
last scheduled visit is V20 (for subjects who discontinue trial product prematurely, see 
Section 8.1.5).
2.16.3
Section 8.1.5   Premature discontinuation of trial product and follow-up (visits 10A 
and 11A)
In general subjects should stay in the trial irrespective of lack of adherence to randomised 
treatment, lack of adherence to visit schedule, missing assessments or trial product discontinuation 
for any reason. Only subjects who decline any further contact with the site in relation to the trial 
should be considered as having withdrawn consent (see Section 8.1.6).
Subjects not continuing in the extension phase
…..
A subject who prematurely discontinued trial product is still considered a trial completer of the 
main phase if the subject attends or is in contact with the site, at the subject’s last scheduled visit. 
For subjects who prematurely discontinue trial product, the last scheduled visit is V10 (or V11A if 
it is scheduled after V10). For subjects who complete treatment in the main phase, see 
Section 8.1.4. The site should prepare in due time to establish contact with the subject within the 
visit window of the scheduled V10 if the subject has agreed to attend this visit.
Subjects continuing in the extension phase
Subjects who discontinue trial product prematurely in the extension phase should attend V19A, 
which is scheduled to take place on the day of discontinuation of trial product (+3 days visit 
window). V20A should be scheduled 5 weeks (+3 days visit window) after the last date on trial 
product. The primary reason for premature discontinuation of trial product must be specified in the 
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
14 March 2017
Novo Nordisk
Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103
Status:
Final
EudraCT No.: 2015-005593-38
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end-of-trial form in the eCRF, and final drug accountability must be performed. A treatment 
discontinuation session must be made in the IWRS at V19A (see Section 10).
If premature discontinuation of trial product is decided during a scheduled visit, the visit will be 
converted into a V19A and trial procedures must be performed accordingly.
Subjects should continue with the originally scheduled site contacts after V20A, up to and including 
V19. If necessary, to retain the subject in the trial, site visits can be replaced by phone contacts 
after V20A. However, if a subject is unable or unwilling to attend all subsequent visit(s), the 
investigator should at least aim to have the subject attend V19 (end-of-treatment) at week 104, 
because this visit should be performed for all subjects if at all possible (except subjects who 
withdraw informed consent, see Section 8.1.6).
A subject who prematurely discontinued trial product is still considered a completer of the 
extension phase if the subject attends or is in contact with the site, at the subject’s last scheduled 
visit. For subjects who prematurely discontinue trial product, the last scheduled visit is V19 (or 
V20A if it is scheduled after V19). For subjects who complete treatment, see Section 8.1.4. In due 
time, the site should prepare to establish contact with the subject within the visit window of the 
scheduled V19 if the subject has agreed to attend this visit.
In summary, subjects should stay in the trial irrespective of lack of adherence to randomised 
treatment, lack of adherence to visit schedule, missing assessments or trial product discontinuation 
for any reason. Only subjects who decline any further contact with the site in relation to the trial 
should be considered as having withdrawn consent (see Section 8.1.6). 
2.16.4
Section 8.1.6   Withdrawal from trial
If a subject considers withdrawing from the trial, the investigator must aim to undertake procedures 
for V10A (main phase)/V19A (extension phase) as soon as possible and V11A (main phase)/V20A 
(extension phase) should be scheduled 5 weeks (+3 days visit window) after the last date on trial 
product, if the subject agrees to it.
2.16.5
Section 8.1.6.1   Lost to follow-up
In case contact to the subject is lost during the trial, the site should immediately undertake efforts to 
re-establish contact. If the subject cannot be reached (by clinic visit or phone contact) and the 
subject has consented to it, the site should consult the contacts provided by the subject (e.g. close 
relatives), relevant physicians, medical records and locator agencies (if allowed according to local 
law) in an attempt to regain contact with the subject or to obtain relevant safety information from 
other sources. 
Efforts to regain contact should continue until the end of the subject’s last scheduled visit.:
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Protocol Amendment no 2
CONFIDENTIAL
Date:
14 March 2017
Novo Nordisk
Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103
Status:
Final
EudraCT No.: 2015-005593-38
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For subjects not continuing in the extension phase:
!
V11 for subjects who have completed treatment, whereas for subjects who have discontinued 
trial product prematurely the last visit is V10 (or V11A if it is scheduled after V10).
For subjects continuing in the extension phase:
!
V20 for subjects who have completed treatment, whereas for subjects who have discontinued 
trial product prematurely the last visit is V19 (or V20A if it is scheduled after V19)
Only if contact with the subject is not regained by the end of the visit window of the last scheduled 
visit can the subject be considered lost to follow-up (see Section 6.6).
2.17
Section 8.3.5   Point-of-care HbA1c measurement
In addition, the point-of-care device should be used to assess the HbA1c at V10 for subjects 
randomised to sitagliptin in the main phase and continuing in the extension phase as this value will 
be used to stratify (according to whether or not the subject had an HbA1c < 7.0% at week 52) the
re-randomisation of the subjects.
2.18
Section 8.4.4   Eye examination
If fundus photography or dilated fundoscopy has been performed within 90 days prior to 
randomisation at V2, the procedure does not need to be repeated, unless worsening of visual 
function since the last examination. The results must be available prior to randomisation at V2. 
2.19
Section 8.6.1   Subject diary
!
For subjects switching from sitagliptin to oral semaglutide at V10 in the extension phase:
date of first semaglutide administration
2.20
Section 11   Randomisation procedure 
The trial is an open-label trial. A randomisation session will be made at V2 for all eligible subjects 
using IWRS.
At V2, eligible subjects will be randomised to one of the two parallel treatment arms as described in 
Section 5.1 and Section 5.2. Randomisation will be stratified (two strata) according to anti-diabetic 
background medication at screening (with and without SU).
Subjects randomised to sitagliptin at V2 who are still on trial product at V10 and decide to continue 
in the extension phase will be re-randomised to one of the two parallel treatment arms as described 
in Section 5.1 and Section 5.2. The re-randomisation in the sitagliptin arm will be stratified 
according to HbA1c below 7% (yes/no) and if the subject is currently on prescribed rescue 
medication and continuing on the same medication in the extension phase (yes/no). This is to ensure 
an even distribution in the two treatment arms in the extension phase (switch). 
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
14 March 2017
Novo Nordisk
Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103
Status:
Final
EudraCT No.: 2015-005593-38
Page:
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2.21
Section 12.2   Reporting of adverse events 
All events meeting the definition of an AE must be collected and reported. This includes events 
occurring from the first trial-related activity after the subject has signed the informed consent until 
the last planned visit.
Subjects not continuing in the extension phase:
!
V11 for subjects completing treatment
!
V10 (or V11A if it is scheduled after V10) for subjects who prematurely discontinue trial 
product
Subjects continuing in the extension phase:
!
V20 for subjects completing treatment
!
V19 (or V20A if it is scheduled after V19) for subjects who prematurely discontinue trial 
product
end of the post-treatment follow-up period (V11) for subjects on trial product or until the end of 
trial (V10 or V11A, whichever comes last) for the subjects who have discontinued trial product 
prematurely. 
2.22
Section 12.7.2   Event adjudication committee
Event adjudication will be performed for AEs in randomised subjects including AEs with an onset 
date during the screening period. Event adjudication will not be performed for AEs in screening 
failures. The adjudication process will be the same throughout the trial, including the extension 
phase. 
2.23
Section 14   Monitoring procedures
Monitoring will be conducted under a risk based approach including risk assessment, monitoring 
plans, centralised monitoring and visits to trial sites. 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 centralised remote monitoring of the 
eCRFs (remote assessment of data by Novo Nordisk), the trial site’s recruitment rate and the 
compliance of the trial site to the protocol and GCP, but will not exceed 12 weeks until LSLV at the 
trial site (for trial sites with active subjects (defined as subjects in screening, treatment or 
follow-up)).
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
14 March 2017
Novo Nordisk
Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103
Status:
Final
EudraCT No.: 2015-005593-38
Page:
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2.24
Section 17   Statistical considerations
The results from the trial will be reported in two clinical trial reports; the first clinical trial report 
will report the results from the main phase and the second clinical trial report will report the 
results of the entire trial period, including the extension phase. 
A database lock for the main phase will be performed when all subjects have completed the main 
phase to be able to report the results in the first clinical trial report. After completion of the 
extension phase, there will be a second database lock followed by the reporting of the results of the 
entire trial in the second clinical trial report.
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 for the main phase.
Data from all sites will be analysed and reported together. The data from the different dose levels 
for each oral semaglutide arm will be pooled as one oral semaglutide arm and not analysed by dose 
level. However, the two oral semaglutide arms in the extension phase will not be pooled.
In statistical analyses where stratification is included, the two levels of anti-diabetic background 
medication at screening (with and without SU) stratification factors will be included based on the 
actual information collected through the eCRF via the concomitant medication form and the central 
laboratory results for HbA1c (extension phase only). The stratification factor in the main phase will 
be anti-diabetic background medication at screening (with and without SU). In case of missing 
eCRF information for the anti-diabetic background medication the information collected from the 
IWRS system will be used. The stratification factors in the extension phase will be HbA1c below 7% 
(yes/no) and if the subject is currently on prescribed rescue medication and continuing on the same 
medication in the extension phase (yes/no). Rescue medication is defined as intensification of 
existing background anti-diabetic medication compared to V1 and/or initiation of new anti-diabetic 
medication.
The latest available measurement, at or prior to the randomisation visit, for the main phase and the 
extension phase (switch) respectively, 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 ½ LLoQ. Number 
of values below LLoQ by treatment and visit will be summarised if deemed relevant.
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Protocol Amendment no 2
CONFIDENTIAL
Date:
14 March 2017
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Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103
Status:
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The results will be presented as follows. 
Main phase
Results from a statistical analysis will as a minimum be presented by the estimated treatment 
contrasts for oral semaglutide versus sitagliptin comparisons with associated two-sided 95% 
confidence intervals and p-values corresponding to two-sided tests of no difference.
!
Oral semaglutide (3, 7 or 14 mg)
!
Sitagliptin (100 mg)
If no statistical analysis is specified, data will be presented using relevant summary statistics.
Extension phase (sustainability)
Relevant descriptive statistics will be presented, including graphical presentations, to evaluate the 
data from the below treatment arm for subjects randomised to oral semaglutide and continuing on 
oral semaglutide in the extension phase. 
!
Oral semaglutide (3, 7 or 14 mg) during 104 weeks
Extension phase (switch)
The results from the extension phase (switch) will be presented as for the main phase; however, the 
comparison will be between the below two treatment arms in which subjects were randomised to 
sitagliptin at trial entry and re-randomised at week 52 to either continue on sitagliptin or switch to 
oral semaglutide. 
!
Oral semaglutide (3, 7 or 14 mg), switching from sitagliptin at week 52
!
Sitagliptin (100 mg), continuing on sitagliptin after week 52
Primary and secondary estimands
Two estimands addressing different aspects of the trial objective will be defined; a primary de-facto 
(effectiveness) estimand and a secondary de-jure (efficacy) estimand: 
!
Primary estimand
–
de-facto treatment effect difference (oral semaglutide versus sitagliptin) at week 52 for all 
randomised subjects regardless of adherence to randomised treatment and initiation of 
rescue medication
The primary de-facto estimand assesses the expected glycaemic benefit in a future population that 
results from subjects initiating treatment with oral semaglutide including potential rescue 
medication(s) as compared to initiating treatment with sitagliptin including potential rescue 
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
14 March 2017
Novo Nordisk
Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103
Status:
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medication(s). Generalisation of this estimand depends among other things on the extent to which 
the use of rescue medication in this trial reflects clinical practice and the adherence to trial product 
administration in this trial reflects the behaviour of the target population. Accordingly, data 
collected regardless of discontinuation of trial product or initiation of rescue medication(s) will be 
used to draw inference.
!
Secondary estimand 
–
de-jure treatment effectdifference (oral semaglutide versus sitagliptin) at week 52 for all 
randomised subjects if all subjects adhered to treatment and did not initiate rescue 
medication
The secondary de-jure estimand assesses the glycaemic benefit a future subject is expected to 
achieve if initiating and continuing treatment with oral semaglutide as compared to sitagliptin. It is 
considered a clinically relevant estimand as it provides information to treating clinicians about the 
expected glycaemic efficacy of oral semaglutide compared to sitagliptin for purposes of treating 
individual subjects. Generalisation of this estimand depends among other things on the extent to 
which the adherence to trial product administration in this trial reflects the behaviour of the target 
population. Accordingly, only data collected prior to discontinuation of trial product or initiation of 
rescue medication will be used to draw inference. For the two treatment arms in the extension 
phase (switch), the current prescribed rescue medication (at V10) in the main phase will be treated 
as background medication in the extension phase and only data collected after initiation of rescue 
medication in the extension phase will be excluded. This will avoid confounding from rescue 
medication.
Main phase
For both estimands, the treatment effect refers to an odds ratio (OR) for the primary endpoint of 
achieving HbA1c < 7.0% at week 52 (yes/no). The treatment effect refers to a treatment difference 
for the confirmatory secondary endpoint; change from baseline to week 52 in body weight. 
Extension phase (switch) 
For both estimands, the treatment effect refers to a treatment difference for both confirmatory 
secondary endpoints; change from week 52 to week 104 in HbA1c and in body weight. 
Missing data considerations at week 52 and at week 104
When estimating the primary estimand, the proportion of missing data, i.e., data that do not exist 
even though subjects are intended to stay in the trial regardless of treatment status and initiation of 
rescue medication(s), is expected to be maximum 15%. Missing data will mainly be due to 
withdrawal from trial or lost to follow-up.
When estimating the secondary estimand, the proportion of missing data is expected to be higher 
(20-30%) since data collected after discontinuation of trial product or initiation of rescue 
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
14 March 2017
Novo Nordisk
Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103
Status:
Final
EudraCT No.: 2015-005593-38
Page:
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medication(s) will be set to missing. The 20-30% of missing data is based on the sitagliptin phase 3 
trials42, and the oral semaglutide phase 2 trial (NN9924-3790), that indicates that a low starting 
dose with gradual dose-escalation diminishes gastrointestinal AEs compared with more aggressive 
dosing regimens. The possibility to reduce the dose due to issues with tolerability is also expected 
to reduce the number of subjects withdrawing from the oral semaglutide arm. Across treatment 
arms the main reasons for missing data are expected to be early treatment discontinuation due to 
gastrointestinal AEs and eventually initiation of rescue medication. Initiation of rescue medication 
is expected to be more frequent in the sitagliptin than in the oral semaglutide arm. A higher 
proportion of subjects are expected to discontinue treatment due to AEs in the oral semaglutide arm, 
compared to the sitagliptin treatment arm. So overall the frequency of missing data is expected to be 
similar across treatment arms.
The proportion of missing data from week 52 to week 104 is expected to be similar as for the first 
52 weeks in the two treatment arms of re-randomised subjects. The rate of missing data is expected 
to decline over time in the oral semaglutide arm in which subjects were randomised to oral 
semaglutide at baseline due to decreased tolerability issues over time.
It is expected that 190 subjects will enter the extension phase (switch). This is based on the 
assumption that maximum 25% of the subjects do not continue in the extension phase (switch) due 
to withdrawal from trial or they are lost to follow up, off treatment or unwilling to continue.
Descriptive summaries and graphical representation of extent, reason(s) for and pattern of missing 
data will be presented by treatment arm.
2.25
Section 17.1   Sample size calculation
The primary endpoint, if a subject after week 52 achieves (yes/no) HbA1c < 7% (53 mmol/mol) and 
the confirmatory secondary endpoint, change from baseline to week 52 in body weight (kg) are 
planned to be tested for superiority of oral semaglutide versus sitagliptin. 
The following four hypotheses are planned to be tested:
Main phase:
!
Superiority of HbA1c < 7% (yes/no)  at week 52 
!
Superiority of  change from baseline to week 52 in body weight
Extension phase (switch):
!
Superiority of change from week 52 to week 104 in HbA1c
!
Superiority of change from week 52 to week 104 in body weight
The sample size calculation is made to ensure at least 90% power to confirm superiority of 
HbA1c < 7% (yes/no) at week 52 of oral semaglutide versus sitagliptin. The sample size calculation 
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Protocol Amendment no 2
CONFIDENTIAL
Date:
14 March 2017
Novo Nordisk
Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103
Status:
Final
EudraCT No.: 2015-005593-38
Page:
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is made to ensure at least 90% to confirm superiority of oral semaglutide vs. sitagliptin on the 
primary endpoint, if a subject after week 52 achieves HbA1c < 7% (yes/no). TwoThe four pre-
specified confirmatory hypotheses are shown in Figure 17-1. The hierarchal testing strategy is used 
to control the overall type-1 error at a nominal two-sided 5% level for the four confirmatory tests.
The statistical testing strategy is built on the principle that glycaemic effect will have to be 
established in terms of HbA1c superiority before testing for added benefits in terms of body weight 
superiority. The hypotheses related to the main phase will be tested and reported in the first clinical
trial report. If these confirmatory hypotheses are confirmed, the two confirmatory hypotheses 
related to the extension phase (switch) will be tested in the hierarchical order shown in Figure 17-1 
and reported in the final clinical trial report.
The assumptions used in the sample size calculation are based on the oral semaglutide phase 2 
results (trial NN9924-3790)24, sitagliptin phase 3a trial results42, and supported by results from the 
s.c. semaglutide phase 3 trial, SUSTAIN 245.
The sample size calculation is based on a 5% (two-sided) significance level and Fishers exact test. 
The sample size depends on the proportion of responders and the absolute difference in proportions 
between semaglutide and sitagliptin. Assuming an absolute difference in proportions of 15 
percentage-points (taking the retrieved and imputed data into account) and that the proportion of 
sitagliptin responders are distributed around 20 to 50%, the power for confirming superiority on the 
primary endpoint, if a subject after week 52 achieves (yes/no) HbA1c < 7% (53 mmol/mol) will be 
at least 90% with 250 subjects per arm. In total 500 subjects are planned to be randomised.
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
14 March 2017
Novo Nordisk
Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103
Status:
Final
EudraCT No.: 2015-005593-38
Page:
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Figure 17-1 Graphical illustration of the closed testing procedure
The overall significance level of α = 0.05 (two-sided) is initially allocated to the HbA1c superiority test at week 52. The 
local significance level (α-local) will be reallocated to the body weight second hypothesis if the first hypothesis is 
confirmed and so on. The sample size is based on the first HbA1c hypothesis (main phase).
The sample size assumptions for treatment effects (TE), adjusted TE and the standard deviations 
(SD) used to calculate the power for the additional three confirmatory hypotheses are presented in 
Table 17-1.
Because the equalising effect of rescue medication will be included in the analyses and because a 
conservative approach for handling of missing data will be applied, an adjustment of the TE will be 
implemented for the 15% of subjects who are expected to either discontinue trial product 
prematurely or initiate rescue medication as well as for the 15% of subjects who are expected to 
have missing data. The TEs used in the sample size calculation will be adjusted according to a 75% 
smaller effect in these subjects. The adjusted TE is calculated as follows:
0.7×TE + 0.3×TE×0.25
The calculated marginal and conditional powers for each of the four tests are also presented in 
Table 17-1. All the confirmatory hypotheses are assumed to be independent. Because positive 
correlation amongst the test is expected, the assumption of independence is viewed as conservative.
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
14 March 2017
Novo Nordisk
Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103
Status:
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EudraCT No.: 2015-005593-38
Page:
39 of 56
Table 17-1
Assumptions used in sample size and power calculation
Endpoint
Treatment effect 
(TE)
Adjusted 
TE
SD
Number of 
subjects
Marginal 
power
Conditional 
power
Main phase:
HbA1c < 7% (yes/no)
15%-point difference
500
90%
90%
Change in body weight (kg)
2.5
1.94
4.0
500
>99%
90%
Extension phase (switch):
Change in HbA1c (%-point)
0.4
0.31
1.1
190
49%
44%
Change in body weight (kg)
2.5
1.94
4.0
190
91%
40%
2.26
Section 17.2   Definition of analysis sets
The following analysis sets will be defined:
Main phase
Full analysis set (FAS): Includes all randomised subjects. Subjects in the FAS will contribute to 
the evaluation “as randomised”.
Safety analysis set (SAS): Includes all subjects exposed to at least one dose of trial product. 
Subjects in the SAS will contribute to the evaluation “as treated”.
Extension phase (sustainability)
Extension (sustainability) FAS: Includes all subjects randomised to oral semaglutide in the main 
phase and continuing on oral semaglutide in the extension phase. Subjects in the extension 
(sustainability) FAS will contribute to the evaluation “as randomised”.
Extension (sustainability) SAS: Includes all subjects randomised to oral semaglutide in the main 
phase and exposed to at least one dose of oral semaglutide in the extension phase. Subjects in the 
extension (sustainability) SAS will contribute to the evaluation “as treated”.
Extension phase (switch)
Extension (switch) FAS: Includes all subjects randomised to sitagliptin in the main phase and re-
randomised to either continue on sitagliptin or switch to oral semaglutide in the extension phase. 
Subjects in the extension (switch) FAS will contribute to the evaluation “as randomised”.
Extension (switch) SAS: Includes all subjects randomised to sitagliptin in the main phase and re-
randomised and exposed with at least one dose of either sitagliptin or oral semaglutide in the 
extension phase. Subjects in the extension (switch) SAS will contribute to the evaluation “as 
treated”.
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
14 March 2017
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Trial ID: NN9924-4257
Version:
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UTN: U1111-1177-5103
Status:
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EudraCT No.: 2015-005593-38
Page:
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Data selections and observation periods
Unless subjects withdraw their informed consent, data collection will continue for the full duration 
of the trial. The full duration of the trial is defined as up to and including:
!
the follow-up visit (V11) for subjects on trial product
!
the latest occurring visit of the end-of-treatment visit (V10) or the follow-up premature 
discontinuation visit (V11A), for subjects who have discontinued trial product prematurely
!
the follow-up visit V11 for subjects who do not discontinue trial product in the main phase, but 
decide not to continue in the extension phase
!
the latest occurring visit of the end-of-treatment visit V10 or the follow-up premature treatment 
discontinuation visit V11A for subjects who discontinue trial product prematurely in the main 
phase
!
the follow-up visit V20 for subjects who continue in the extension phase and do not discontinue 
trial product in the extension phase
!
the latest occurring visit of the end-of-treatment visit V19 or the follow-up premature treatment 
discontinuation visit V20A for subjects who discontinue trial product prematurely in the 
extension phase
Subjects and data to be used in an analysis will be selected in a two-step manner:
!
Firstly, subjects will be selected based on the specified analysis set
!
Secondly, data points on the selected subjects from the first step will be selected based on the 
specified observation period
Definition of the observation periods:
In-trial: This observation period represents the time period where subjects are considered to be in 
the trial, regardless of discontinuation of trial product or initiation of rescue medication. 
Main phase
The in-trial observation period starts at randomisation (as registered in the IWRS) and ends at the 
date of:
!
the last direct subject-site contact, which is scheduled to take place 5 weeks after planned last 
dose of trial product at the follow-up visit V11 for subjects who decide not to continue in the 
extension phase
!
V10 for subjects who continue in the extension phase
!
withdrawal for subjects who withdraw their informed consent
!
the last subject-investigator contact as defined by the investigator for subjects who are lost to 
follow-up
!
death for subjects who dies before any of the above
Extension phase (sustainability)
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
14 March 2017
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Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103
Status:
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EudraCT No.: 2015-005593-38
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The in-trial observation period starts at randomisation in main phase (as registered in the IWRS) 
and ends at the date of:
!
the last direct subject-site contact, which is scheduled to take place 5 weeks after planned last 
dose of trial product at the follow-up visit V20 for subjects who continue in the extension phase
!
withdrawal for subjects who withdraw their informed consent
!
the last subject-investigator contact as defined by the investigator for subjects who are lost to 
follow-up
!
death for subjects who dies before any of the above
Extension phase (switch)
The in-trial observation period starts at re-randomisation (as registered in the IWRS) planned at 
V10 and ends at the date of:
!
the last direct subject-site contact, which is scheduled to take place 5 weeks after planned last 
dose of trial product at the follow-up visit V20 for subjects who continue in the extension phase
!
withdrawal for subjects who withdraw their informed consent
!
the last subject-investigator contact as defined by the investigator for subjects who are lost to 
follow-up
!
death for subjects who dies before any of the above
On-treatment: This observation period represents the time period where subjects are considered 
treated with the trial product. The observation period is a subset of the in-trial observation period. 
Main phase
The on-treatment observation period It starts at the date of first dose of trial product. Two slightly 
different end dates will be needed to cover all assessments appropriately.
For adjudicated events, ECGs, eye examination category and AEs including hypoglycaemic 
episodes, the observation period ends at the first date of any of the following: 
!
the follow-up visit V11 for subjects on trial product who decide not to continue in the extension 
phase
!
the follow-up prematurely discontinuation visit V11A
!
the last date on trial product +38 days
!
the end-date for the in-trial observation period
For efficacy and other safety assessments (laboratory assessments, physical examination and vital 
signs) the observation period ends at the last date on trial product +3 days. This will be used in 
order to ensure specificity to reversible effects of treatment. 
Extension phase (sustainability)
The on-treatment observation period starts at the date of first dose of trial product.
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
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Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103
Status:
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EudraCT No.: 2015-005593-38
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For adjudicated events, ECGs, eye examination, and AEs including hypoglycaemic episodes, the 
observation period ends at the first date of any of the following:
!
the follow-up visit V20 for subjects on trial product who continue in the extension phase
!
the follow-up prematurely discontinuation visit V20A
!
the last date on trial product +38 days
!
the end-date for the in-trial observation period
For efficacy and other safety assessments (laboratory assessments, physical examination and vital 
signs) the observation period ends at the last date on trial product +3 days. 
Extension phase (switch)
The on-treatment observation period starts at the date of first dose of trial product in the extension 
phase planned at V10.
For adjudicated events, ECGs, eye examination, and AEs including hypoglycaemic episodes, the 
observation period ends at the first date of any of the following:
!
the follow-up visit V20 for subjects on trial product who continue in the extension phase
!
the follow-up prematurely discontinuation visit V20A
!
the last date on trial product +38 days 
!
the end-date for the in-trial observation period
For efficacy and other safety assessments (laboratory assessments, physical examination and vital 
signs) the observation period ends at the last date on trial product +3 days. 
The follow-up visit (V11/V11A/V20/V20A) is scheduled to take place 5 weeks after the last date on 
trial product corresponding to approximately five half-lives of oral semaglutide. The visit window 
for the follow-up visit is +3 days.
For efficacy and other safety assessments (laboratory assessments, physical examination and vital 
signs) the observation period ends at the last date on trial product +3 days. This will be used in 
order to ensure specificity to reversible effects of treatment. 
On-treatment without rescue medication: This observation period is a subset of the on-treatment 
observation period, where subjects are considered treated with trial product, but have not initiated 
any rescue medications. 
Main phase
The on-treatment without rescue medication observation period Specifically it starts at the date of 
first dose of trial product and ends at the first date of any of the following:
!
the last dose of trial product +3 days
!
initiation of rescue medication
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
14 March 2017
Novo Nordisk
Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103
Status:
Final
EudraCT No.: 2015-005593-38
Page:
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Extension phase (sustainability)
The on-treatment without rescue medication observation period starts at the date of first dose of 
trial product and ends at the first date of any of the following:
!
the last dose of trial product +3 days
!
initiation of rescue medication
Extension phase (switch)
For the two treatment arms in the extension phase (switch), the current prescribed rescue 
medication (at V10) in the main phase will be treated as background medication in the extension 
phase and only data collected after initiation of rescue medication in the extension phase will be 
excluded.
Specifically the on-treatment without rescue medication observation period starts at the date of first 
dose of trial product in the extension phase, planned at V10, and ends at the first date of any of the 
following:
!
the last dose of trial product +3 days
!
initiation of rescue medication in the extension phase
The in-trial observation period will be the primary observation period when estimating the primary 
estimand. The on-treatment without rescue medication observation period will be the primary 
observation period when estimating the secondary estimand. The on-treatment observation period 
will be considered supportive for evaluating efficacy the secondary estimand. Safety will be 
evaluated based on the in-trial and the on-treatment observation periods.
Data points collected outside an observation period will be treated as missing in the analysis. 
Baseline data will always be included in an observation period. For adjudicated events, the onset 
date will be the EAC adjudicated onset date.
Before data are locked for statistical analysis and the randomisation code is broken, a review of all 
available data will take place. Any decision to exclude either a subject or single observations from 
the statistical analysis is the joint responsibility of the members of the Novo Nordisk study group. 
Exclusion of data from analyses should be used restrictively, and normally no data should be 
excluded from the FAS. The subjects or observations to be excluded, and the reasons for their 
exclusion must be documented and signed by those responsible before database lock. The subjects 
and observations excluded from analysis sets, and the reason for this, will be described in the 
clinical trial report.
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
14 March 2017
Novo Nordisk
Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103
Status:
Final
EudraCT No.: 2015-005593-38
Page:
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Confirmatory hypotheses
For the primary HbA1c endpoint the following confirmatory one-sided hypothesis are planned to be 
tested where OR refers to the odds ratio for oral semaglutide versus sitagliptin.
!
H0: OR ≤ 1 against Ha: OR >1
For the confirmatory secondary body weight endpoint in the main phase (change from baseline to 
week 52 in body weight), the following hypothesis is planned to be tested, where μ refers to the 
treatment difference between for oral semaglutide minus sitagliptin.
!
H0: μ ≥ 0.0 kg against Ha: μ < 0.0 kg, where μ = (oral semaglutide minus sitagliptin)
For the two confirmatory endpoints in the extension phase (switch; change from week 52 to 
week 104 in HbA1c and change from week 52 to week 104 in body weight), the following 
confirmatory one-sided hypotheses are planned to be tested for oral semaglutide versus sitagliptin. 
!
H0: μ ≥ 0.0 %-point against Ha: μ < 0.0 %-point
!
H0: μ ≥ 0.0 kg against Ha: μ < 0.0 kg
Operationally both the confirmatory hypotheses will be evaluated by two-sided tests at the 5% 
significance level.
Multiplicity and criteria for confirming hypotheses
The type I error for testing the twofour confirmatory hypotheses related to the HbA1c and body 
weight endpoints will be preserved in the strong sense at 5% (two-sided) using an hierarchical 
testing strategy as outlined in Figure 17-1. 
Superiority of the primary hypotheses will be considered confirmed if the odds ratio is supporting 
the corresponding alternative hypothesis and the two-sided p-value from the primary analysis of the 
primary estimand is strictly below the 5% two-sided significance level. This is equivalent to using a 
one-sided p-value (nominal α = 0.025) and a one-sided 2.5% overall significance level. If the 
primary hypothesis is confirmed, the testing strategy will continue by testing the following
confirmatory secondary hypothesis at a 5% two-sided significance level. Superiority of the 
following secondary confirmatory hypotheses will then be considered confirmed if the treatment 
difference is supporting the corresponding alternative hypothesis and the two-sided p-value from 
the primary analysis of the primary estimand is strictly below the 5% two-sided significance level 
and so on. If for any of the four confirmatory hypotheses, superiority is not confirmed the testing 
will terminate.
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
14 March 2017
Novo Nordisk
Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103
Status:
Final
EudraCT No.: 2015-005593-38
Page:
45 of 56
2.27
Section 17.3.1   Primary analyses for the primary estimand
The primary estimand for the primary endpoint will be estimated based on the FAS using week 52 
measurements from the in-trial observation period. 
…..
2.28
Section 17.3.2   Primary analysis for the secondary estimand
The secondary estimand for the primary endpoint will be estimated based on the FAS using post-
baseline measurements up to and including week 52 from the on-treatment without rescue 
medication observation period. 
…..
2.29
Section 17.4.1   Confirmatory secondary endpoints
Main phase
Change from baseline to week 52 in body weight (kg) will be confirmatory secondary endpoint.
The primary and secondary estimands will be estimated using the same approaches as described for 
the primary HbA1c endpoint without dichotomizing the endpoint and with a linear normal regression 
model instead of the logistic regression model. Baseline body weight will be used as a covariate 
instead of baseline HbA1c for the endpoints related to body weight in both the multiple imputation 
and analysis models.
Extension phase (switch)
Change from week 52 to week 104 in HbA1c
Change from week 52 to week 104 in body weight (kg)
The primary estimand will be based on extension phase (switch) FAS using the in-trial extension 
phase (switch) observation period. Whereas, the secondary estimand will be based on extension 
phase (switch) FAS using the on-treatment without rescue medication, extension phase (switch) 
observation period. 
The estimands will be estimated using the same approaches as described for the primary HbA1c
endpoint without dichotomizing the endpoint and with a linear normal regression model instead of 
the logistic regression model. Baseline body weight will be used as a covariate instead of baseline 
HbA1c, in the analyses of the body weight endpoint, in both the multiple imputation and analysis 
models.
The stratification factors, HbA1c below 7% (yes/no) and if the subject is currently on prescribed 
rescue medication and continuing rescue medication in the extension phase (yes/no), and the 
interaction of these will be included as fixed effects in the analyses.
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
14 March 2017
Novo Nordisk
Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103
Status:
Final
EudraCT No.: 2015-005593-38
Page:
46 of 56
Superiority will be considered confirmed if the mean treatment difference is supporting the 
corresponding hypothesis and the two-sided p-value from the analysis of the primary estimand is 
strictly below its local two-sided significance level resulting from the closed testing procedure in 
Figure 17-1. Sensitivity analyses similar to the ones pre-specified for testing superiority for the 
primary HbA1c endpoint will be made to evaluate the robustness of the confirmatory body weight 
results for the main phase. The tipping point analysis will be used as a sensitivity analysis for the 
confirmatory results for the extension phase (switch).
2.29.1
Section 17.4.2.1   Efficacy endpoints
Main phase
!
the primary estimand based on FAS using the in-trial observation period
…..
Extension phase (sustainability)
!
extension phase (sustainability) FAS using the in-trial extension phase (sustainability) 
observation period
!
extension phase (sustainability) FAS using the on-treatment without rescue medication, 
extension phase (sustainability) observation period
Extension phase (switch)
!
the primary estimand based on extension phase (switch) FAS using the in-trial extension phase 
(switch) observation period
!
the secondary estimand based on extension phase (switch) FAS using the on-treatment without 
rescue medication, extension phase (switch) observation period
No sensitivity analyses are planned for these.
Continuous efficacy endpoints
Main phase
Change from baseline to week 52 in: 
!
HbA1c
…..
Extension phase (sustainability)
Change from baseline to week 104 in:
!
HbA1c
!
FPG
!
Body weight (kg)
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
14 March 2017
Novo Nordisk
Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103
Status:
Final
EudraCT No.: 2015-005593-38
Page:
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!
Body weight (%)
!
BMI
!
Waist circumference
Extension phase (switch)
Change from week 52 to week 104 in:
!
FPG
!
Body weight (%)
!
BMI
!
Waist circumference
Main and extension phase (switch)
The above continuous endpoints will be analysed separately using similar model approaches as for 
the confirmatory secondary endpoints for the main phase and the extension phase (switch), 
respectively, with the associated baseline response as a covariate. Fasting lipid profile endpoints 
(main phase only) will be log-transformed prior to analysis with the associated log-transformed 
baseline value as a covariate.
Extension phase (sustainability)
The endpoints will be summarised descriptively by visit. 
Furthermore, the change from baseline to week 52 in HbA1c and in body weight will be presented 
using both the main phase FAS and the extension phase (sustainability) FAS to explore differences 
in HbA1c and in body weight for subjects not continuing in the extension phase (sustainability).     
Binary efficacy endpoints
Main phase
If a subject after 52 weeks achieves (yes/no):
!
HbA1c ≤ 6.5% (48 mmol/mol) AACE target
…..
Extension phase (sustainability)
If a subject after 104 weeks achieves (yes/no):
!
HbA1c < 7% (53 mmol/mol) ADA target
!
HbA1c ≤ 6.5% (48 mmol/mol) AACE target
!
HbA1c reduction ≥ 1%-point (10.9 mmol/mol) 
!
HbA1c < 7% (53 mmol/mol) or HbA1c reduction ≥ 1%-point (10.9 mmol/mol)
!
Weight loss ≥ 5% 
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
14 March 2017
Novo Nordisk
Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103
Status:
Final
EudraCT No.: 2015-005593-38
Page:
48 of 56
!
HbA1c < 7% (53 mmol/mol) without treatment-emergent severe or BG-confirmed symptomatic 
hypoglycaemic episodes and no weight gain 
Extension phase (switch)
If a subject after 104 weeks achieves (yes/no):
!
HbA1c < 7% (53 mmol/mol) ADA target
!
HbA1c ≤ 6.5% (48 mmol/mol) AACE target
!
HbA1c reduction ≥ 1%-point (10.9 mmol/mol) compared to week 52
!
Weight loss ≥ 5% compared to week 52
!
HbA1c < 7% (53 mmol/mol) without treatment-emergent severe or BG-confirmed symptomatic 
hypoglycaemic episodes after week 52 and no weight gain compared to week 52
!
HbA1c < 7% (53 mmol/mol) and no need for rescue medication after week 52
!
No need for rescue medication after week 52
Main and extension phase (switch)
The above binary endpoints will be analysed separately using similar model approaches as for the 
primary endpoint with the associated baseline response, HbA1c or body weight, as a covariate. The 
analysis of the endpoint for rescue medication in extension phase (switch) will not include a 
baseline covariate as rescue medication in the main phase (yes/no) is used as a stratification factor 
in the model.
Extension phase (sustainability) 
The endpoints will be summarised descriptively by visit.
Time to event endpoint
Main phase
!
Time to rescue medication
The above time to event endpoint will be analysed based on FAS using both the on-treatment 
observation period and the in-trial observation period. For the analysis based on the on-treatment 
observation period, subjects without need for rescue medication during the on-treatment observation 
period will be censored at the time point of the date of last trial product. Switch to rescue 
medication at the date of last trial product will be considered as an event. For the in-trial period 
subjects without need for addition of rescue medication during the in-trial observation period, will 
be censored at the time point of the date of end of the in-trial observation period. For this analysis, 
the follow-up period will be excluded from the in-trial observation period, since subjects will have 
to stop treatment at the end-of-treatment visit and therefore might need addition of rescue 
medication during the follow-up period. 
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
14 March 2017
Novo Nordisk
Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103
Status:
Final
EudraCT No.: 2015-005593-38
Page:
49 of 56
The time to event endpoint will be described and compared for oral semaglutide versus sitagliptin 
using likelihood ratio tests obtained from a Cox proportional hazards model with treatment, 
stratification factors, the interaction between the two stratification factors and region as categorical 
fixed effects and baseline HbA1c as a covariate. From this analysis the estimated Hhazard ratios 
between oral semaglutide versus sitagliptin will be presented together with 95% confidence 
intervals and two sided p-values for test of no difference. 
Extension phase (switch)
!
Time to rescue medication after week 52
The endpoint will be analysed based on extension phase (switch) FAS using both the on-treatment 
extension phase (switch) observation period and the in-trial extension phase (switch) observation 
period. For the extension phase (switch), rescue medication initiated in the main phase will be 
treated as background medication in the extension phase and only addition of rescue medication 
after week 52 (V10) will be counted in the analyses. The same analyses approach as for the main 
phase will be performed.
2.29.2
Section 17.4.2.2   Safety endpoints
The safety endpoints for the main phase in the first clinical trial report will be evaluated based on 
SAS using the on-treatment observation period and based on SAS using the in-trial observation 
period unless otherwise stated. 
The safety endpoints for the extension phase in the second clinical trial report will be evaluated 
based on extension phase (switch) and (sustainability) SAS using the on-treatment extension phase 
(switch) and (sustainability) observation period and based on extension phase (switch) and 
(sustainability) SAS using the in-trial extension phase (switch) and (sustainability) observation 
period unless otherwise stated. 
The following endpoints are used to support the safety objectives.
Adverse events 
Main phase
!
Number of TEAEs during exposure to trial product, assessed up to approximately 57 52 weeks 
Extension phase (sustainability)
!
Number of TEAEs during exposure to trial product, assessed up to approximately 109 weeks
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
14 March 2017
Novo Nordisk
Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103
Status:
Final
EudraCT No.: 2015-005593-38
Page:
50 of 56
Extension phase (switch)
!
Number of TEAEs during exposure to trial product, assessed from week 52 up to approximately 
109 weeks
…..
Supportive summaries of AEs will be made for the in-trial observation period. The development 
over time in gastrointestinal AEs will be presented graphically.
Main phase
In addition, events reported from week 52 (V10) to week 57 (V11) in subjects who complete 
treatment in the main phase and do not continue in the extension phase will be listed separately.  
Other safety endpoints
Main phase
Change from baseline to week 52 in:
!
Amylase (part of biochemistry)
…..
Extension phase (sustainability)
Change from baseline to week 104 in:
!
Amylase (part of biochemistry)
!
Lipase (part of biochemistry)
!
Pulse
!
Systolic blood pressure
!
Diastolic blood pressure
Extension phase (switch)
Change from week 52 to week 104 in:
!
Amylase (part of biochemistry)
!
Lipase (part of biochemistry)
!
Pulse
!
Systolic blood pressure
!
Diastolic blood pressure
Main and extension phase (switch)
The above safety endpoints will be evaluated using the primary analysis for the primary estimand 
based on SAS using the in-trial observation period and using the primary analysis for the secondary 
estimand based on SAS using the on-treatment observation period. Endpoints will be analysed as 
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
14 March 2017
Novo Nordisk
Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103
Status:
Final
EudraCT No.: 2015-005593-38
Page:
51 of 56
described above for continuous efficacy endpoints. Results will be presented at week 52. Amylase 
and lipase endpoints will be log-transformed prior to analysis with the associated log-transformed 
baseline value as a covariate.
Extension phase (sustainability)
The endpoints will be summarised descriptively by visit.
The following other safety endpoints will be calculated similarly as for the above other safety 
endpoints:
Change from baseline to week 52 in:
Main phase
The safety endpoint for the main phase will furthermore be calculated for the following:
!
Haematology
!
Biochemistry (except for amylase and lipase)
!
Calcitonin
!
ECG category
!
Physical examination
!
Eye examination category
Extension phase
The safety endpoints for the extension phase (switch) and extension phase (sustainability) will 
furthermore be calculated for the following:
!
Haematology
!
Biochemistry (except for amylase and lipase)
!
Calcitonin
!
Eye examination category
The main and extension phase above safety endpoints will be summarised descriptively by 
treatment arm and visit. Categorical safety endpoints will be summarised as counts and relative 
frequencies. Calcitonin will also be presented by gender.
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
14 March 2017
Novo Nordisk
Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103
Status:
Final
EudraCT No.: 2015-005593-38
Page:
52 of 56
Hypoglycaemia
Main phase
!
Number of treatment-emergent severe or BG-confirmed symptomatic hypoglycaemic episodes 
during exposure to trial product, assessed up to approximately 57 52 weeks
!
Treatment-emergent severe or BG-confirmed symptomatic hypoglycaemic episodes during 
exposure to trial product, assessed up to approximately 57 52 weeks (yes/no)
Extension phase (sustainability)
!
Number of treatment-emergent severe or BG-confirmed symptomatic hypoglycaemic episodes 
during exposure to trial product, assessed up to approximately 109 weeks
!
Treatment-emergent severe or BG-confirmed symptomatic hypoglycaemic episodes during 
exposure to trial product, assessed up to approximately 109 weeks (yes/no)
Extension phase (switch)
!
Number of treatment-emergent severe or BG-confirmed symptomatic hypoglycaemic episodes 
during exposure to trial product, assessed from week 52 up to approximately 109 weeks
!
Treatment-emergent severe or BG-confirmed symptomatic hypoglycaemic episodes during 
exposure to trial product, assessed from week 52 up to approximately 109 weeks (yes/no)
Classification of hypoglycaemia
Hypoglycaemic episodes will be summarised for the SAS, extension phase (sustainability) SAS and 
extension phase (switch) SAS, using only and the on-treatment extension phase (sustainability) and 
on-treatment extension phase (switch) observation period, respectively (referred to as the on-
treatment observation periods in the following)only.
….
Analysis of severe or BG-confirmed symptomatic hypoglycaemic endpoints episodes
Main and extension phase (switch)
The endpoints related to number of treatment-emergent severe or BG-confirmed symptomatic 
hypoglycaemic episodes during the on-treatment period will be analysed using a negative binomial 
regression model with a log-link function and the logarithm of the duration of the subject’s on-
treatment observation period as offset. The model will include treatment, stratification factor and 
region as fixed factors and baseline HbA1c as covariate.
The binary endpoints showing whether a subject has at least one treatment-emergent severe or BG-
confirmed symptomatic hypoglycaemic episode will be analysed using a logistic regression model 
with treatment, stratification factor and region as fixed factors and baseline HbA1c as covariate.
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In addition, treatment-emergent severe or BG-confirmed symptomatic hypoglycaemic episodes 
reported from week 52 (V10) to week 57 (V11) in subjects who complete treatment in the main 
phase and do not continue in the extension phase will be listed separately.  
Extension phase (sustainability)
The endpoints will be summarised descriptively.
2.30
Section 17.5   Interim analysis
No interim analyses or other analyses of unblinded data will be performed before the database for 
the main phase is locked.
A database lock for the main phase will be performed when all subjects have completed the main 
phase to be able to report the results in the first clinical trial report. After completion of the 
extension phase, there will be a second database lock followed by the reporting of the results of the 
entire trial in the second clinical trial report.
2.31
Section 17.6   Patient-reported outcomes
Main phase
Change from baseline to week 52 in:
!
SF-36v2™ (acute version) health survey: Sscores from the 8 domains and the physical 
component score and mental component score summary scores 
!
DTSQs: individual items and treatment satisfaction score (6 of the 8 items summed)
Extension phase (sustainability)
Change from baseline to week 104 in:
!
SF-36v2™ (acute version) health survey: scores from the 8 domains and the physical 
component score and mental component score summary scores 
!
DTSQs: individual items and treatment satisfaction score (6 of the 8 items summed)
Extension phase (switch)
Change from week 52 to week 104 in:
!
SF-36v2™ (acute version) health survey: scores from the 8 domains and the physical 
component score and mental component score summary scores 
!
DTSQs: individual items and treatment satisfaction score (6 of the 8 items summed)
The PRO endpoints will be evaluated using the primary analysis for the primary estimand and using 
the primary analysis for the secondary estimand based on FAS, extension phase (sustainability) FAS 
and the extension phase (switch) FAS, using the on-treatment without rescue medication, 
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on-treatment without rescue medication extension phase (sustainability) and on-treatment without 
rescue medication extension phase (switch) observation periods, respectively.
Main and extension phase (switch)
All of the above individual items and scores will be analysed separately as the other supportive 
continuous efficacy endpoints with the associated baseline response as a covariate. 
Extension phase (sustainability)
The endpoints will be summarised descriptively by visit.
2.32
Section 18.1.1   Risks and precautions
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-adjustment 
every 8 weeks according to HbA1c and tolerability (nausea/vomiting) have been implemented in this 
trial. This is also applicable for subjects switching from sitagliptin to oral semaglutide in the 
extension phase to mitigate possible gastrointestinal AEs related to oral semaglutide.
2.33
Section 18.1.2   Benefits 
In this trial, subjects will be randomised to one of two treatment arms involving a treatment regimen 
anticipated to be more efficacious than the treatment they receive at the time of entry into the trial. 
2.34
Section 27   References
1. International Conference on Harmonisation. ICH Harmonised Tripartite Guideline. Guideline 
for Good Clinical Practise E6(R2), Step 4. 09 Nov 2016.(R1), Step 4. 10 June 1996.
24. Novo Nordisk A/S. Investigator's Brochure for oral semaglutide (NN9924), edition 8 or any 
updates hereof. 2017. Edition 6 or any updates hereof. 2015.
45. Ahrén B, Comas LM, Kumar H, Sargin M, Derving Karsbøl J, Jacobsen SH, et al. Efficacy and 
Safety of Once-weekly Semaglutide vs Sitagliptin as add-on to Metformin and/or 
Thiazolidinediones After 56 Weeks in Subjects With Type 2 Diabetes (SUSTAIN 2). European 
Association for the Study of Diabetes, 52nd meeting, ePoster #767 2016.
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Protocol Amendment no 2
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3
Changes in Appendices
3.1
Appendix B, Section 1.8.1   Assessments in case of suspicion of hypersensitivity 
reaction
To assist in the diagnostic evaluation it is recommended to draw a blood sample for measurement of 
tryptase (total and/or mature tryptase, local assessment) within 3 hours of onset of the 
hypersensitivity reaction, and if this is achieved, a tryptase sample should also be drawn five weeks 
after the event at V11A.
Furthermore, a blood sample for assessment of IgE anti-semaglutide antibodies and anti-
semaglutide antibodies should be drawn as soon as possible after the event and again five weeks 
after the event at V11A and sent to central laboratory.
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4
Changes in protocol Attachments
4.1
Attachment I – Global list of key staff and relevant departments and suppliers of 
clinical relevance
Sponsor’s global medical 
expert:
Name:
Title:
Address:
Tel:
E-mail:
International Trial Manager:
Name:
Address:
Tel:
E-mail:
CONFIDENTIAL

SAP_001.pdf: 
Cover Page for Statistical Analysis Plan  
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT02849080 
Sponsor trial ID: 
NN9924-4257 
Official title of study: 
PIONEER 7 – Flexible dose adjustment. Efficacy and Safety 
of Oral Semaglutide Using a Flexible Dose Adjustment Based 
on Clinical Evaluation versus Sitagliptin in Subjects with Type 
2 Diabetes Mellitus 
Document date: 
25 October 2018 
 


Link
Link
List of contents
Statistical analysis plan......................................................................................................................
Pre-defined MedDRA search – list of preferred terms...................................................................
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Date:
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Oral semaglutide
Trial ID: NN9924-4257
Clinical Trial Report
Appendix 16.1.9
25 October 2018
1.0
Final
16.1.9 Documentation of statistical methods
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Includes redaction of personal identifiable information only. 
. 


Statistical Analysis Plan
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Statistical Analysis Plan
Trial ID: NN9924-4257
Efficacy and Safety of Oral Semaglutide Using a Flexible Dose 
Adjustment Based on Clinical Evaluation versus Sitagliptin in 
Subjects with Type 2 Diabetes Mellitus
A 52-week Randomised, Open-label, Active-controlled Trial with a 52-week Extension Phase
CONFIDENTIAL
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.
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
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Table of contents   
Page
Table of contents.........................................................................................................................................2
List of abbreviations ...................................................................................................................................3
1
Introduction .........................................................................................................................................5
1.1
Trial information.......................................................................................................................5
1.1.1
Main phase ..............................................................................................................5
1.1.2
Extension phase.......................................................................................................5
1.1.2.1
Extension phase (sustainability)..........................................................5
1.1.2.2
Extension phase (switch)....................................................................5
1.2
Trial duration ............................................................................................................................6
1.3
Objectives.................................................................................................................................6
1.3.1
Primary objective.....................................................................................................6
1.3.1.1
Main phase.........................................................................................6
1.3.2
Secondary objectives ...............................................................................................6
1.3.2.1
Main phase.........................................................................................6
1.3.2.2
Extension phase (sustainability)..........................................................7
1.3.2.3
Extension phase (switch)....................................................................7
1.4
Scope of the statistical analysis plan..........................................................................................7
2
Statistical considerations .....................................................................................................................8
2.1
Sample size calculation ...........................................................................................................11
2.2
Definition of analysis sets........................................................................................................13
2.3
Primary endpoint.....................................................................................................................19
2.3.1
Primary analysis for the primary estimand..............................................................19
2.3.2
Primary analysis for the secondary estimand ..........................................................20
2.3.3
Sensitivity analyses................................................................................................20
2.3.3.1
Pattern mixture models.....................................................................21
2.4
Secondary endpoints ...............................................................................................................22
2.4.1
Confirmatory secondary endpoints.........................................................................22
2.4.2
Supportive secondary endpoints .............................................................................23
2.4.2.1
Efficacy endpoints............................................................................23
2.4.2.2
Safety endpoints and safety assessments...........................................28
2.5
Interim analysis.......................................................................................................................33
2.6
Patient reported outcomes .......................................................................................................33
2.6.1
SF-36v2® (acute version) health survey.................................................................34
2.6.2
Diabetes Treatment Satisfaction Questionnaire – status version (DTSQs)...............36
2.6.3
Responder analyses................................................................................................37
3
Changes to the statistical analyses planned in the protocol..............................................................38
4
References ..........................................................................................................................................39
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Statistical Analysis Plan
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List of abbreviations
AACE
American Association of Clinical Endocrinologists
ADA
American Diabetes Association
AE
adverse event
ANCOVA
analysis of covariance
ATC
anatomical therapeutic chemical
BG
blood glucose
BMI
body mass index
BP
bodily pain
CHMP
European Medicines Agency
CI
confidence interval
CRF
case report form
DTSQs
Diabetes Treatment Satisfaction Questionnaire status version
EAC
event adjudication committee
ECG
electrocardiogram
eCRF
electronic case report form
FAS
full analysis set
FPG
fasting plasma glucose
GH
general health
HbA1c
glycosylated  haemoglobin
HRQoL
health-related quality of life 
IWRS
interactive web response system
LLoQ
lower limit of quantification
LOCF
last observation carried forward
MAR
missing at random
MCMC
Markov Chain Monte Carlo
MCS
mental component score 
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
mixed model repeated measures
MNAR
missing not at random
MH
mental health
NA
not applicable
NAS
US National Research Council
NBS
norm-based score
OAD
oral anti-diabetic drug
OR
odds ratio
PCS
physical component score 
PF
physical functioning
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Statistical Analysis Plan
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PG
plasma glucose
PRO
patient reported outcome
RE
role-emotional
RP
role-physical
SAP
statistical analysis plan
SAS
safety analysis set
s.c.
subcutaneous
SD
standard deviation
SF
social functioning
SF-36v2
Short Form-36 version 2
SGLT-2
sodium glucose co-transporter 2
SU
sulfonylureas
T2DM
Type 2 diabetes mellitus
TE
treatment effect
TEAE
treatment-emergent adverse event
TZD
thiazolidinediones
VT
vitality
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Statistical Analysis Plan
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1
Introduction
1.1
Trial information
The trial consists of two 52-week treatment periods. The first 52-week treatment period is referred 
to as the main phase and the second 52-week treatment period as the extension phase. The extension 
phase consists of two parts; these are referred to as the extension phase (sustainability) and the 
extension phase (switch).
1.1.1
Main phase
The main phase is a 52 week randomised, open-label, active-controlled, parallel-group, multi-
centre, multi-national treatment phase with two arms comparing the efficacy and safety of oral 
semaglutide using a flexible dose adjustment versus sitagliptin 100 mg once-daily, in subjects with 
T2DM treated with 1-2 OADs (metformin, sulfonylureas [SU], thiazolidinediones [TZD], sodium 
glucose co-transporter 2 [SGLT-2] inhibitors). 
Subjects will be randomised 1:1 to receive one of the following treatments as add-on to their anti-
diabetic background medication:
!
flexible dosing (3, 7 or 14 mg) of oral semaglutide once-daily
!
100 mg sitagliptin once-daily
1.1.2
Extension phase
The extension phase is a 52-week open-label, 3-arm, parallel-group treatment period following the 
main phase. The extension phase (switch) is active-controlled.
1.1.2.1
Extension phase (sustainability)
Subjects randomised to oral semaglutide in the main phase and still on trial product will continue 
treatment with oral semaglutide using a flexible dose adjustment in the 52-week extension phase. 
1.1.2.2
Extension phase (switch)
Subjects randomised to sitagliptin in the main phase and still on trial product will be re randomised 
1:1 at week 52 to receive one of the following treatments in the 52-week extension phase as add-on 
to their anti-diabetic background medication: 
!
flexible dosing (3, 7 or 14 mg) of oral semaglutide once daily
!
100 mg sitagliptin once daily
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Statistical Analysis Plan
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1.2
Trial duration
The total trial duration of the main phase for the individual subject will be either approximately 54 
weeks or approximately 59 weeks depending on whether or not the subject continues into the 
extension phase. The trial includes a 2 week screening period, a 52 week treatment period and, for 
subjects not continuing in the extension phase, a 5 week follow-up period. For subjects continuing 
in the extension phase, additional 52 weeks will be included and the total trial duration will be 
approximately 111 weeks (2 weeks screening, 104 weeks treatment and 5 weeks follow-up). The 
trial is designed to have visits every 8 weeks and a phone contact at week 4 and week 56.
A schematic illustration of the trial design is shown in Figure 1–1
* Subjects who have completed treatment in the main phase and are not continuing in the extension phase must attend 
the Follow-up visit (Week 57) 5 week after the last date on trial product.
Figure 1–1
Trial design
1.3
Objectives
1.3.1
Primary objective
1.3.1.1
Main phase
To compare the effect of once-daily dosing of oral semaglutide using a flexible dose adjustment 
based on clinical evaluation versus sitagliptin once daily, both in combination with 1-2 OADs on 
glycaemic control in subjects with T2DM.
1.3.2
Secondary objectives
1.3.2.1
Main phase
To compare the effect of once-daily dosing of oral semaglutide using a flexible dose adjustment 
based on clinical evaluation versus sitagliptin once daily, both in combination with 1-2 OADs on 
body weight in subjects with T2DM.
CONFIDENTIAL


Statistical Analysis Plan
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To compare the safety and tolerability of once-daily dosing of oral semaglutide using a flexible 
dose adjustment based on clinical evaluation versus sitagliptin once daily, both in combination with 
1-2 OADs in subjects with T2DM.
1.3.2.2
Extension phase (sustainability)
To evaluate the sustainability on glycaemic control and body weight reduction of once-daily dosing 
of oral semaglutide using a flexible dose adjustment based on clinical evaluation in subjects with 
T2DM.
To evaluate the long term safety of once-daily dosing of oral semaglutide using a flexible dose 
adjustment based on clinical evaluation in subjects with T2DM.
1.3.2.3
Extension phase (switch)
To compare the effect on glycaemic control of switching to once-daily dosing of oral semaglutide 
using a flexible dose adjustment based on clinical evaluation versus staying on once-daily 
sitagliptin in subjects with T2DM. 
To compare the effect on body weight of switching to once-daily dosing of oral semaglutide using a 
flexible dose adjustment based on clinical evaluation versus staying on once-daily sitagliptin in 
subjects with T2DM.
To compare the safety and tolerability of switching to once-daily dosing of oral semaglutide using a 
flexible dose adjustment based on clinical evaluation versus staying on once-daily sitagliptin in 
subjects with T2DM.
1.4
Scope of the statistical analysis plan
This SAP is based on the protocol “Efficacy and Safety of Oral Semaglutide Using a Flexible Dose 
Adjustment Based on Clinical Evaluation versus Sitagliptin in Subjects with Type 2 Diabetes 
Mellitus - A 52-week Randomised, Open-label, Active-controlled Trial with a 52-week Extension 
Phase”, version 3.0.
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Statistical Analysis Plan
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2
Statistical considerations
General considerations
The results from the trial will be reported in two clinical trial reports; the first clinical trial report 
will report the results from the main phase and the second clinical trial report will report the results 
of the entire trial period for subjects who continued in the extension phase. The analyses from the 
main phase will not be repeated in the second clinical trial report.
A database lock for the main phase will be performed when all subjects have completed the main 
phase to be able to report the results in the first clinical trial report. After completion of the 
extension phase, there will be a second database lock followed by the reporting of the results of the 
entire trial in the second clinical trial report for subjects who continued in the extension phase.
Data from all sites will be analysed and reported together. The data from the different dose levels 
for each oral semaglutide arm will be pooled as one oral semaglutide arm and not analysed by dose 
level. However, the two oral semaglutide arms in the extension phase will not be pooled.
In statistical analyses where stratification is included, the stratification factors will be included 
based on the actual information collected through the eCRF via the concomitant medication form 
and the central laboratory results for HbA1c (extension phase only). The stratification factor in the 
main phase will be anti-diabetic background medication at screening (with and without SU). In case 
of missing eCRF information for the anti-diabetic background medication the information collected 
from the IWRS system will be used. The stratification factors in the extension phase will be HbA1c
below 7% (yes/no) and if the subject is currently on prescribed rescue medication and continuing on 
the same medication in the extension phase (yes/no). Rescue medication is defined as intensification 
of existing background anti-diabetic medication compared to V1 and/or initiation of new anti-
diabetic medication.
The latest available measurement, at or prior to the randomisation visit, for the main phase and the 
extension phase (switch) respectively, 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 ½ LLoQ. Number 
of values below LLoQ by treatment and visit will be summarised if deemed relevant.
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Statistical Analysis Plan
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The results will be presented as follows. 
Main phase
Results from a statistical analysis will as a minimum be presented by the estimated treatment 
contrasts for oral semaglutide versus sitagliptin comparisons with associated two-sided 95% 
confidence intervals and p-values corresponding to two-sided tests of no difference.
!
Oral semaglutide (3, 7 or 14 mg)
!
Sitagliptin (100 mg)
If no statistical analysis is specified, data will be presented using relevant summary statistics.
Extension phase (sustainability)
Relevant descriptive statistics will be presented, including graphical presentations, to evaluate the 
data from the below treatment arm for subjects randomised to oral semaglutide and continuing on 
oral semaglutide in the extension phase. 
!
Oral semaglutide (3, 7 or 14 mg) during 104 weeks
Extension phase (switch)
The results from the extension phase (switch) will be presented as for the main phase; however, the 
comparison will be between the below two treatment arms in which subjects were randomised to 
sitagliptin at trial entry and re-randomised at week 52 to either continue on sitagliptin or switch to 
oral semaglutide. 
!
Oral semaglutide (3, 7 or 14 mg), switching from sitagliptin at week 52
!
Sitagliptin (100 mg), continuing on sitagliptin after week 52
Primary and secondary estimands
Two estimands addressing different aspects of the trial objective will be defined; a primary de-facto 
(effectiveness) estimand and a secondary de-jure (efficacy) estimand: 
!
Primary estimand
–
de-facto treatment effect for all randomised subjects regardless of adherence to randomised 
treatment and initiation of rescue medication
The primary de-facto estimand assesses the expected glycaemic benefit in a future population that 
results from subjects initiating treatment with oral semaglutide including potential rescue 
medication(s) as compared to initiating treatment with sitagliptin including potential rescue 
medication(s). Generalisation of this estimand depends among other things on the extent to which 
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Statistical Analysis Plan
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the use of rescue medication in this trial reflects clinical practice and the adherence to trial product 
administration in this trial reflects the behaviour of the target population. Accordingly, data 
collected regardless of discontinuation of trial product or initiation of rescue medication(s) will be 
used to draw inference.
!
Secondary estimand 
–
de-jure treatment effect for all randomised subjects if all subjects adhered to treatment and 
did not initiate rescue medication
The secondary de-jure estimand assesses the glycaemic benefit a future subject is expected to 
achieve if initiating and continuing treatment with oral semaglutide as compared to sitagliptin. It is 
considered a clinically relevant estimand as it provides information to treating clinicians about the 
expected glycaemic efficacy of oral semaglutide compared to sitagliptin for purposes of treating 
individual subjects. Generalisation of this estimand depends among other things on the extent to 
which the adherence to trial product administration in this trial reflects the behaviour of the target 
population. Accordingly, only data collected prior to discontinuation of trial product or initiation of 
rescue medication will be used to draw inference. For the two treatment arms in the extension phase 
(switch), the current prescribed rescue medication (at V10) in the main phase will be treated as 
background medication in the extension phase and only data collected after initiation of rescue 
medication in the extension phase will be excluded. This will avoid confounding from rescue 
medication.
Main phase
For both estimands, the treatment effect refers to an odds ratio (OR) for the primary endpoint of 
achieving HbA1c < 7.0% at week 52 (yes/no). The treatment effect refers to a treatment difference 
for the confirmatory secondary endpoint; change from baseline to week 52 in body weight. 
Extension phase (switch) 
For both estimands, the treatment effect refers to a treatment difference for both confirmatory 
secondary endpoints; change from week 52 to week 104 in HbA1c and in body weight. 
Missing data considerations at week 52 and at week 104
When estimating the primary estimand, the proportion of missing data, i.e., data that do not exist 
even though subjects are intended to stay in the trial regardless of treatment status and initiation of 
rescue medication(s), is expected to be maximum 15%. Missing data will mainly be due to 
withdrawal from trial or lost to follow-up.
When estimating the secondary estimand, the proportion of missing data is expected to be higher 
(20-30%) since data collected after discontinuation of trial product or initiation of rescue 
medication(s) will be set to missing. The 20-30% of missing data is based on the sitagliptin phase 3 
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trials3, and the oral semaglutide phase 2 trial (NN9924-3790), that indicates that a low starting dose 
with gradual dose-escalation diminishes gastrointestinal AEs compared with more aggressive 
dosing regimens. The possibility to reduce the dose due to issues with tolerability is also expected 
to reduce the number of subjects withdrawing from the oral semaglutide arm. Across treatment 
arms the main reasons for missing data are expected to be early treatment discontinuation due to 
gastrointestinal AEs and initiation of rescue medication. Initiation of rescue medication is expected 
to be more frequent in the sitagliptin than in the oral semaglutide arm. A higher proportion of 
subjects are expected to discontinue treatment due to AEs in the oral semaglutide arm, compared to 
the sitagliptin treatment arm. So overall the frequency of missing data is expected to be similar 
across treatment arms.
The proportion of missing data from week 52 to week 104 is expected to be similar as for the first 
52 weeks in the two treatment arms of re-randomised subjects. The rate of missing data is expected 
to decline over time in the oral semaglutide arm in which subjects were randomised to oral 
semaglutide at baseline due to decreased tolerability issues over time.
It is expected that 190 subjects will enter the extension phase (switch). This is based on the 
assumption that maximum 25% of the subjects do not continue in the extension phase (switch) due 
to withdrawal from trial or they are lost to follow up, off treatment or unwilling to continue.
Descriptive summaries and graphical representation of extent, reason(s) for and pattern of missing 
data will be presented by treatment arm.
2.1
Sample size calculation
The following four hypotheses are planned to be tested:
Main phase:
Superiority of HbA1c < 7% (yes/no) at week 52 
Superiority of change from baseline to week 52 in body weight
Extension phase (switch):
Superiority of change from week 52 to week 104 in HbA1c
Superiority of change from week 52 to week 104 in body weight
The sample size calculation is made to ensure at least 90% power to confirm superiority of 
HbA1c< 7% (yes/no) at week 52 of oral semaglutide versus sitagliptin. The four pre-specified 
confirmatory hypotheses are shown in Figure 2–1. The hierarchal testing strategy is used to control 
the overall type-1 error at a nominal two-sided 5% level for the four confirmatory tests. 
The statistical testing strategy is built on the principle that glycaemic effect will have to be 
established in terms of HbA1c superiority before testing for added benefits in terms of body weight 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
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Novo Nordisk
Trial ID: NN9924-4257
Version:
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UTN: U1111-1177-5103
Status:
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superiority. The hypotheses related to the main phase will be tested and reported in the first clinical 
trial report. If these confirmatory hypotheses are confirmed, the two confirmatory hypotheses 
related to the extension phase (switch) will be tested in the hierarchical order shown in Figure 2–1
and reported in the final clinical trial report.
The assumptions used in the sample size calculation are based on the oral semaglutide phase 2 
results (trial NN9924-3790)1, sitagliptin phase 3a trial results3, and supported by results from the 
s.c. semaglutide phase 3 trial, SUSTAIN 24.
The sample size calculation is based on a 5% (two-sided) significance level and Fishers exact test. 
The sample size depends on the proportion of responders and the absolute difference in proportions 
between semaglutide and sitagliptin. Assuming an absolute difference in proportions of 15 
percentage-points (taking the retrieved and imputed data into account) and that the proportion of 
sitagliptin responders are distributed around 20 to 50%, the power for confirming superiority on the 
primary endpoint, if a subject after week 52 achieves (yes/no) HbA1c < 7% (53 mmol/mol) will be 
at least 90% with 250 subjects per arm. In total 500 subjects are planned to be randomised. 
Figure 2–1
Graphical illustration of the closed testing procedure
The overall significance level of α = 0.05 (two-sided) is initially allocated to the HbA1c superiority test at week 52. The 
local significance level will be reallocated to the second hypothesis if the first hypothesis is confirmed and so on. The 
sample size is based on the first HbA1c hypothesis (main phase).
The sample size assumptions for treatment effects (TE), adjusted TE and the standard deviations 
(SD) used to calculate the power for the additional three confirmatory hypotheses are presented in
Table 2–1.
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Statistical Analysis Plan
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Date:
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Trial ID: NN9924-4257
Version:
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UTN: U1111-1177-5103
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Because the equalising effect of rescue medication will be included in the analyses and because a 
conservative approach for handling of missing data will be applied, an adjustment of the TE will be 
implemented for the 15% of subjects who are expected to either discontinue trial product 
prematurely or initiate rescue medication as well as for the 15% of subjects who are expected to 
have missing data. The TEs used in the sample size calculation will be adjusted according to a 75% 
smaller effect in these subjects. The adjusted TE is calculated as follows:
0.7×TE + 0.3×TE×0.25
The calculated marginal and conditional powers for each of the four tests are also presented in 
Table 2–1. All the confirmatory hypotheses are assumed to be independent. Because positive 
correlation amongst the test is expected, the assumption of independence is viewed as conservative.
Table 2–1
Assumptions used in sample size and power calculation
Endpoint
Treatment effect 
(TE)
Adjusted 
TE
SD
Number of 
subjects
Marginal 
power
Conditional 
power
Main phase:
HbA1c < 7% (yes/no)
15%-point difference
500
90%
90%
Change in body weight (kg)
2.5
1.94
4.0
500
>99%
90%
Extension phase (switch):
Change in HbA1c (%-point)
0.4
0.31
1.1
190
49%
44%
Change in body weight (kg)
2.5
1.94
4.0
190
91%
40%
2.2
Definition of analysis sets
The following analysis sets will be defined:
Main phase
Full analysis set (FAS): Includes all randomised subjects. Subjects in the FAS will contribute to 
the evaluation “as randomised”.
Safety analysis set (SAS): Includes all subjects exposed to at least one dose of trial product. 
Subjects in the SAS will contribute to the evaluation “as treated”.
Extension phase (sustainability)
Extension (sustainability) FAS: Includes all subjects randomised to oral semaglutide in the main 
phase and continuing on oral semaglutide in the extension phase. Subjects in the extension 
(sustainability) FAS will contribute to the evaluation “as randomised”.
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Statistical Analysis Plan
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Trial ID: NN9924-4257
Version:
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Extension (sustainability) SAS: Includes all subjects randomised to oral semaglutide in the main 
phase and exposed to at least one dose of oral semaglutide in the extension phase. Subjects in the 
extension (sustainability) SAS will contribute to the evaluation “as treated”.
Extension phase (switch)
Extension (switch) FAS: Includes all subjects randomised to sitagliptin in the main phase and re-
randomised to either continue on sitagliptin or switch to oral semaglutide in the extension phase. 
Subjects in the extension (switch) FAS will contribute to the evaluation “as randomised”.
Extension (switch) SAS: Includes all subjects randomised to sitagliptin in the main phase and re-
randomised and exposed with at least one dose of either sitagliptin or oral semaglutide in the 
extension phase. Subjects in the extension (switch) SAS will contribute to the evaluation “as 
treated”.
Data selections and observation periods
Unless subjects withdraw their informed consent, data collection will continue for the full duration 
of the trial. The full duration of the trial is defined as up to and including:
!
the follow-up visit V11 for subjects who do not discontinue trial product in the main phase, but 
decide not to continue in the extension phase
!
the latest occurring visit of the end-of-treatment visit V10 or the follow-up premature treatment 
discontinuation visit V11A for subjects who discontinue trial product prematurely in the main 
phase
!
the follow-up visit V20 for subjects who continue in the extension phase and do not discontinue 
trial product in the extension phase
!
the latest occurring visit of the end-of-treatment visit V19 or the follow-up premature treatment 
discontinuation visit V20A for subjects who discontinue trial product prematurely in the 
extension phase
Subjects and data to be used in an analysis will be selected in a two-step manner:
!
Firstly, subjects will be selected based on the specified analysis set
!
Secondly, data points on the selected subjects from the first step will be selected based on the 
specified observation period
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Statistical Analysis Plan
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Trial ID: NN9924-4257
Version:
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Definition of the observation periods:
In-trial: This observation period represents the time period where subjects are considered to be in 
the trial, regardless of discontinuation of trial product or initiation of rescue medication. 
Main phase
The in-trial observation period starts at randomisation (as registered in the IWRS) and ends at the 
date of:
!
the last direct subject-site contact, which is scheduled to take place 5 weeks after planned last 
dose of trial product at the follow-up visit V11 for subjects who decide not to continue in the 
extension phase
!
V10 for subjects who continue in the extension phase
!
withdrawal for subjects who withdraw their informed consent
!
the last subject-investigator contact as defined by the investigator for subjects who are lost to 
follow-up
!
death for subjects who dies before any of the above
Extension phase (sustainability)
The in-trial observation period starts at randomisation in main phase (as registered in the IWRS) 
and ends at the date of:
!
the last direct subject-site contact, which is scheduled to take place 5 weeks after planned last 
dose of trial product at the follow-up visit V20 for subjects who continue in the extension phase
!
withdrawal for subjects who withdraw their informed consent
!
the last subject-investigator contact as defined by the investigator for subjects who are lost to 
follow-up
!
death for subjects who dies before any of the above
Extension phase (switch)
The in-trial observation period starts at re-randomisation (as registered in the IWRS) planned at 
V10 and ends at the date of:
!
the last direct subject-site contact, which is scheduled to take place 5 weeks after planned last 
dose of trial product at the follow-up visit V20 for subjects who continue in the extension phase
!
withdrawal for subjects who withdraw their informed consent
!
the last subject-investigator contact as defined by the investigator for subjects who are lost to 
follow-up
!
death for subjects who dies before any of the above
On-treatment: This observation period represents the time period where subjects are considered 
treated with the trial product. The observation period is a subset of the in-trial observation period. 
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Trial ID: NN9924-4257
Version:
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Main phase
The on-treatment observation period starts at the date of first dose of trial product. Two slightly 
different end dates will be needed to cover all assessments appropriately.
For adjudicated events, ECGs, eye examination category and AEs including hypoglycaemic 
episodes, the observation period ends at the first date of any of the following: 
!
the follow-up visit V11 for subjects on trial product who decide not to continue in the extension 
phase
!
the follow-up prematurely discontinuation visit V11A
!
the last date on trial product +38 days
!
the end-date for the in-trial observation period
For efficacy and other safety assessments (laboratory assessments, physical examination and vital 
signs) the observation period ends at the last date on trial product +3 days. This will be used in 
order to ensure specificity to reversible effects of treatment. 
Extension phase (sustainability)
The on-treatment observation period starts at the date of first dose of trial product.
For adjudicated events, ECGs, eye examination, and AEs including hypoglycaemic episodes, the
observation period ends at the first date of any of the following:
!
the follow-up visit V20 for subjects on trial product who continue in the extension phase
!
the follow-up prematurely discontinuation visit V20A
!
the last date on trial product +38 days
!
the end-date for the in-trial observation period
For efficacy and other safety assessments (laboratory assessments, physical examination and vital 
signs) the observation period ends at the last date on trial product +3 days. 
Extension phase (switch)
The on-treatment observation period starts at the date of first dose of trial product in the extension 
phase planned at V10.
For adjudicated events, ECGs, eye examination, and AEs including hypoglycaemic episodes, the 
observation period ends at the first date of any of the following:
!
the follow-up visit V20 for subjects on trial product who continue in the extension phase
!
the follow-up prematurely discontinuation visit V20A
!
the last date on trial product +38 days 
!
the end-date for the in-trial observation period
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Statistical Analysis Plan
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Date:
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Trial ID: NN9924-4257
Version:
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UTN: U1111-1177-5103
Status:
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For efficacy and other safety assessments (laboratory assessments, physical examination and vital 
signs) the observation period ends at the last date on trial product +3 days. 
The follow-up visit (V11/V11A/V20/V20A) is scheduled to take place 5 weeks after the last date on 
trial product corresponding to approximately five half-lives of oral semaglutide. The visit window 
for the follow-up visit is +3 days.
On-treatment without rescue medication: This observation period is a subset of the on-treatment 
observation period, where subjects are considered treated with trial product, but have not initiated 
any rescue medications. 
Main phase
The on-treatment without rescue medication observation period starts at the date of first dose of trial 
product and ends at the first date of any of the following:
!
the last dose of trial product +3 days
!
initiation of rescue medication
Extension phase (sustainability)
The on-treatment without rescue medication observation period starts at the date of first dose of trial 
product and ends at the first date of any of the following:
!
the last dose of trial product +3 days
!
initiation of rescue medication
Extension phase (switch)
For the two treatment arms in the extension phase (switch), the current prescribed rescue 
medication (at V10) in the main phase will be treated as background medication in the extension 
phase and only data collected after initiation of rescue medication in the extension phase will be 
excluded.
Specifically the on-treatment without rescue medication observation period starts at the date of first 
dose of trial product in the extension phase, planned at V10, and ends at the first date of any of the 
following:
!
the last dose of trial product +3 days
!
initiation of rescue medication in the extension phase
The in-trial observation period will be the primary observation period when estimating the primary 
estimand. The on-treatment without rescue medication observation period will be the primary 
observation period when estimating the secondary estimand. The on-treatment observation period 
will be considered supportive for evaluating the secondary estimand. Safety will be evaluated based 
on the in-trial and the on-treatment observation periods.
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Statistical Analysis Plan
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Trial ID: NN9924-4257
Version:
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Data points collected outside an observation period will be treated as missing in the analysis. 
Baseline data will always be included in an observation period. For adjudicated events, the onset 
date will be the EAC adjudicated onset date.
Before data are locked for statistical analysis and the randomisation code is broken, a review of all 
available data will take place. Any decision to exclude either a subject or single observations from 
the statistical analysis is the joint responsibility of the members of the Novo Nordisk study group. 
Exclusion of data from analyses should be used restrictively, and normally no data should be 
excluded from the FAS. The subjects or observations to be excluded, and the reasons for their 
exclusion must be documented and signed by those responsible before database lock. The subjects 
and observations excluded from analysis sets, and the reason for this, will be described in the 
clinical trial report.
Confirmatory hypotheses
For the primary HbA1c endpoint the following confirmatory one-sided hypothesis are planned to be 
tested where OR refers to the odds ratio for oral semaglutide versus sitagliptin.
!
H0: OR ≤ 1 against Ha: OR >1
For the confirmatory secondary endpoint in the main phase (change from baseline to week 52 in 
body weight), the following hypothesis is planned to be tested, where μ refers to the treatment 
difference between oral semaglutide minus sitagliptin.
!
H0: μ ≥ 0.0 kg against Ha: μ < 0.0 kg
For the two confirmatory endpoints in the extension phase (switch; change from week 52 to 
week 104 in HbA1c and change from week 52 to week 104 in body weight), the following 
confirmatory one-sided hypotheses are planned to be tested for oral semaglutide versus sitagliptin. 
!
H0: μ ≥ 0.0 %-point against Ha: μ < 0.0 %-point
!
H0: μ ≥ 0.0 kg against Ha: μ < 0.0 kg
Operationally the confirmatory hypotheses will be evaluated by two-sided tests at the 5% 
significance level.
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Statistical Analysis Plan
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Date:
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Trial ID: NN9924-4257
Version:
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UTN: U1111-1177-5103
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Multiplicity and criteria for confirming hypotheses
The type I error for testing the four confirmatory hypotheses related to the HbA1c and body weight 
endpoints will be preserved in the strong sense at 5% (two-sided) using an hierarchical testing 
strategy as outlined in Figure 2–1. 
Superiority of the primary hypotheses will be considered confirmed if the odds ratio is supporting 
the corresponding alternative hypothesis and the two-sided p-value from the primary analysis of the 
primary estimand is strictly below the 5% two-sided significance level. This is equivalent to using a 
one-sided p-value (nominal α = 0.025) and a one-sided 2.5% overall significance level. If the 
primary hypothesis is confirmed, the testing strategy will continue by testing the following 
confirmatory secondary hypothesis at a 5% two-sided significance level. Superiority of the 
following secondary confirmatory hypotheses will then be considered confirmed if the treatment 
difference is supporting the corresponding alternative hypothesis and the two-sided p-value from 
the primary analysis of the primary estimand is strictly below the 5% two-sided significance level 
and so on. If for any of the four confirmatory hypotheses, superiority is not confirmed the testing 
will terminate.
2.3
Primary endpoint
The primary endpoint is if a subject after week 52 achieves (yes/no) HbA1c < 7% (53 mmol/mol) 
ADA target. 
2.3.1
Primary analysis for the primary estimand 
The primary estimand for the primary endpoint will be estimated based on the FAS using week 52 
measurements from the in-trial observation period. The primary statistical analysis will be a logistic 
regression model with treatment, region, and stratification factor as fixed effects and baseline HbA1c
measurement as a covariate. Firstly, a pattern mixture model using multiple imputation is used to 
impute missing values for continuous HbA1c assessments assuming that the missing data 
mechanism is missing at random (MAR) within the groups used for imputation. Imputation of 
missing data at week 52 will be done within 4 groups of subjects defined by randomised treatment 
arm, and whether subjects at week 52; (i) have discontinued treatment or initiated rescue medication 
or (ii) are still on treatment and have not initiated  rescue medication. It is hereby assumed that the 
likely values of what the missing data would have been if available are best described by 
information from subjects who at week 52 are similar in terms of randomised treatment arm and 
treatment adherence/rescue status.
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Statistical Analysis Plan
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Trial ID: NN9924-4257
Version:
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Missing values for each group will be imputed as follows:
!
An analysis of covariance (ANCOVA) with region and stratification factor as categorical 
fixed effects and baseline HbA1c measurement as a covariate will be fitted to observed 
values of the change from baseline to week 52 in HbA1c.
!
The estimated parameters for location and dispersion will be used to impute 1000 values for 
each subject with missing week 52 data based on region and stratification factor as 
categorical fixed effects and baseline HbA1c measurement as a covariate. Thus, 1000 
complete data sets will be generated including observed and imputed values.
!
The binary endpoint will be created for each of the 1000 complete data sets.
!
A logistic regression model with treatment, region, and stratification factor as fixed effects 
and baseline HbA1c measurement as a covariate is fitted for each of the imputed datasets.
!
The resulting 1000 estimates and variances will be combined using Rubin’s rule5, and the 
estimated odds ratio between oral semaglutide and sitagliptin together with two-sided 95 % 
CI and two-sided p-value for testing no difference from one will be presented.
2.3.2
Primary analysis for the secondary estimand
The secondary estimand for the primary endpoint will be estimated based on the FAS using post-
baseline measurements up to and including week 52 from the on-treatment without rescue 
medication observation period. The primary statistical analysis will be a logistic regression model 
with treatment, region, and stratification factor as fixed effects and baseline HbA1c measurement as 
covariate. First; intermittent missing values for continuous HbA1c assessments will be imputed 
using Markov Chain Monte Carlo (MCMC) method to obtain a monotone missing data pattern. This 
imputation is done for each treatment group separately and 1000 copies of the dataset will be 
generated. Second; based on these 1000 datasets the remaining missing values will be imputed 
sequentially. For each treatment group an analysis of covariance model will be used to impute 
missing values at each planned visit. The model will include region and stratification factor as 
categorical effects and baseline and post-baseline HbA1c values prior to the visit in question as 
covariates. Third; the binary endpoint will be created, analysed and the resulting 1000 estimates and 
variances will be combined using Rubin’s rule46. 
2.3.3
Sensitivity analyses
To investigate the sensitivity of the primary analysis results, complementary and separate analyses 
will be performed for the primary and secondary estimand. In line with European Medicines 
Agency recommendations (CHMP 2010)6 and with a report from the US National Research Council 
(NAS 2010)7, these analyses will primarily evaluate the sensitivity of the results due to the impact 
of missing data.
The evaluation of the robustness of the primary analysis will in all cases be a logistic regression 
model with treatment, region, and stratification factor as fixed effects and baseline HbA1c
measurement as a covariate. However missing data will be based on different pattern mixture model 
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Statistical Analysis Plan
CONFIDENTIAL
Date:
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Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103
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approaches using multiple imputation. The binary endpoint will be created using the imputed 
continuous data. An overview of the sensitivity analyses for each of the estimands are specified 
below followed by a more detailed description of the different pattern mixture models used. 
Sensitivity analyses for the primary estimand
The estimation of the primary estimand will be repeated using the following sensitivity analyses for 
imputing missing continuous HbA1c assessments before testing the binary primary endpoint using 
logistic regression: 
!
A comparator multiple imputation analysis based on FAS using the in-trial observation 
period
!
A tipping-point multiple imputation analysis based on FAS using the in-trial observation 
period.
Sensitivity analyses for the secondary estimand
The estimation of the secondary estimand will be repeated using the following sensitivity analyses:
!
A tipping-point multiple imputation analysis based on FAS using the on-treatment without 
rescue medication observation period.
2.3.3.1
Pattern mixture models
Common for the pattern mixture model sensitivity analyses is that they all aim to stress-test the 
primary HbA1c results by changing the assumptions for missing data in the oral semaglutide 
treatment arms, while maintaining the missing at random data assumption for the sitagliptin arm:
!
Comparator multiple imputation analysis: In this sensitivity analysis missing data at week 
52 for all subjects will be imputed to resemble  the distribution of the week 52 values 
observed in the sitagliptin treatment arm. In effect, this imputation approach removes the 
treatment difference between oral semaglutide and sitagliptin for all subjects randomised to 
oral semaglutide, given that oral semaglutide is better than sitagliptin.
!
Tipping-point multiple imputation analysis: In this sensitivity analysis, missing data will 
first be imputed according to the primary analysis. Secondly, for the oral semaglutide 
treatment arm a penalty will be added to the imputed values at week 52. The approach is to 
gradually increase this penalty until a confirmed HbA1c conclusion from the primary 
analysis is changed. The specific value of the penalty that changes the conclusion will be 
used to evaluate the robustness of the primary analysis result.
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Statistical Analysis Plan
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Version:
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UTN: U1111-1177-5103
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Assessment of sensitivity analyses
The results from the sensitivity analyses will be collectively used to interpret the robustness of the 
trial results for HbA1c. Due to the sensitivity analyses inherent conservative nature, it will not be a 
requirement that all confirmatory hypotheses are consistently confirmed across the sensitivity 
analyses. Thus, no absolute success criteria will be pre-defined for each sensitivity analysis. The 
sensitivity results in totality will be used to substantiate the credibility of the trial results.
2.4
Secondary endpoints
2.4.1
Confirmatory secondary endpoints
Main phase
Change from baseline to week 52 in body weight (kg)
The primary estimand will be estimated using the same approaches as described for the primary 
HbA1c endpoint without dichotomizing the endpoint and with a linear normal regression model 
instead of the logistic regression model. Baseline body weight will be used as a covariate instead of 
baseline HbA1c for the endpoints related to body weight in both the multiple imputation and 
analysis models.
The analyses for the secondary estimand will be a mixed model for repeated measure (MMRM). 
The MMRM based analysis will use a restricted maximum likelihood (REML) and include all post-
baseline measurements collected at scheduled visits up to and including week 52 as dependent 
variables. The independent effects included in the model will be treatment, region, and stratification 
factor as categorical fixed effects and baseline value as a covariate, all nested within visit. An 
unstructured covariance matrix for measurements within the same subject will be employed, 
assuming measurements from different subjects are independent.
The MMRM is a well-established method that accounts for the uncertainty pertaining to missing 
data. This analysis assumes that the missing data mechanism is MAR. Under this assumption the 
statistical behaviour of the missing data (given the observed responses and model fixed effects and 
covariates) is assumed to be same as the observed data.
Extension phase (switch)
Change from week 52 to week 104 in HbA1c
Change from week 52 to week 104 in body weight (kg)
The primary estimand will be based on extension phase (switch) FAS using the in-trial extension 
phase (switch) observation period. Whereas, the secondary estimand will be based on extension 
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Statistical Analysis Plan
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Date:
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Trial ID: NN9924-4257
Version:
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UTN: U1111-1177-5103
Status:
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phase (switch) FAS using the on-treatment without rescue medication, extension phase (switch) 
observation period. 
The estimands will be estimated using the same approaches as described for the primary HbA1c
endpoint without dichotomizing the endpoint and with a linear normal regression model instead of 
the logistic regression model. Baseline body weight will be used as a covariate instead of baseline 
HbA1c, in the analyses of the body weight endpoint, in both the multiple imputation and analysis 
models.
The stratification factors, HbA1c below 7% (yes/no) and if the subject is currently on prescribed 
rescue medication and continuing rescue medication in the extension phase (yes/no), and the 
interaction of these will be included as fixed effects in the analyses.
Superiority will be considered confirmed if the mean treatment difference is supporting the 
corresponding hypothesis and the two-sided p-value from the analysis of the primary estimand is 
strictly below its local two-sided significance level resulting from the closed testing procedure in 
Figure 2–1. Sensitivity analyses similar to the ones pre-specified for testing superiority for the 
primary HbA1c endpoint will be made to evaluate the robustness of the confirmatory body weight 
results for the main phase. The tipping point analysis will be used as a sensitivity analysis for the 
confirmatory results for the extension phase (switch).
2.4.2
Supportive secondary endpoints
2.4.2.1
Efficacy endpoints
The below supportive secondary efficacy endpoints will be evaluated for:
Main phase
!
the primary estimand based on FAS using the in-trial observation period
!
the secondary estimand based on FAS using the on-treatment without rescue medication 
observation period
Extension phase (sustainability)
!
extension phase (sustainability) FAS using the in-trial extension phase (sustainability) 
observation period
!
extension phase (sustainability) FAS using the on-treatment without rescue medication, 
extension phase (sustainability) observation period
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
11 May 2018
Novo Nordisk
Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103
Status:
Final
EudraCT No.: 2015-005593-38
Page:
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Extension phase (switch)
!
the primary estimand based on extension phase (switch) FAS using the in-trial extension phase 
(switch) observation period
!
the secondary estimand based on extension phase (switch) FAS using the on-treatment without 
rescue medication, extension phase (switch) observation period
No sensitivity analyses are planned for these.
Continuous efficacy endpoints
Main phase
Change from baseline to week 52 in: 
!
HbA1c
!
FPG
!
Body weight (%)
!
BMI
!
Waist circumference
!
Fasting lipid profile (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides)
Extension phase (sustainability)
Change from baseline to week 104 in:
!
HbA1c
!
FPG
!
Body weight (kg)
!
Body weight (%)
!
BMI
!
Waist circumference
Extension phase (switch)
Change from week 52 to week 104 in:
!
FPG
!
Body weight (%)
!
BMI
!
Waist circumference
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
11 May 2018
Novo Nordisk
Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103
Status:
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EudraCT No.: 2015-005593-38
Page:
25 of 39
BMI will be calculated based on body weight and height based on the formulae:
BMI kg/m2 = body weight (kg)/(height [m] × height [m]) or (kg/m2 = [lb/in2 × 703])
Main and extension phase (switch)
The above continuous endpoints will be analysed separately using similar model approaches as for 
the confirmatory secondary endpoints for the main phase and the extension phase (switch), 
respectively, with the associated baseline response as a covariate. Fasting lipid profile endpoints 
(main phase only) will be log-transformed prior to analysis with the associated log-transformed 
baseline value as a covariate.
Extension phase (sustainability)
The endpoints will be summarised descriptively by visit. 
Furthermore, the change from baseline to week 52 in HbA1c and in body weight will be presented 
using both the main phase FAS and the extension phase (sustainability) FAS to explore differences 
in HbA1c and in body weight for subjects not continuing in the extension phase (sustainability).     
Binary efficacy endpoints
Main phase
If a subject after 52 weeks achieves (yes/no):
!
HbA1c ≤ 6.5% (48 mmol/mol) AACE target
!
Weight loss ≥ 5% 
!
Weight loss ≥ 10% 
!
HbA1c < 7.0% (53 mmol/mol) without hypoglycaemia (treatment-emergent severe or BG-
confirmed symptomatic hypoglycaemia) and no weight gain
!
HbA1c reduction ≥ 1%-point (10.9 mmol/mol) and weight loss ≥ 3%
Extension phase (sustainability)
If a subject after 104 weeks achieves (yes/no):
!
HbA1c < 7% (53 mmol/mol) ADA target
!
HbA1c ≤ 6.5% (48 mmol/mol) AACE target
!
HbA1c < 7% (53 mmol/mol) or HbA1c reduction ≥ 1%-point (10.9 mmol/mol)
!
Weight loss ≥ 5% 
!
HbA1c < 7% (53 mmol/mol) without treatment-emergent severe or BG-confirmed symptomatic 
hypoglycaemic episodes and no weight gain 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
11 May 2018
Novo Nordisk
Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103
Status:
Final
EudraCT No.: 2015-005593-38
Page:
26 of 39
Extension phase (switch)
If a subject after 104 weeks achieves (yes/no):
!
HbA1c < 7% (53 mmol/mol) ADA target
!
HbA1c ≤ 6.5% (48 mmol/mol) AACE target
!
Weight loss ≥ 5% compared to week 52
!
HbA1c < 7% (53 mmol/mol) without treatment-emergent severe or BG-confirmed symptomatic 
hypoglycaemic episodes after week 52 and no weight gain compared to week 52
!
HbA1c < 7% (53 mmol/mol) and no need for rescue medication after week 52
!
No need for rescue medication after week 52
Main and extension phase (switch)
The above binary endpoints will be analysed separately using similar model approaches as for the 
primary endpoint with the associated baseline response, HbA1c or body weight, as a covariate. 
When addressing the primary estimand for the composite endpoint the ‘without hypoglycaemic 
episodes’ component will include non-treatment-emergent events of severe or BG-confirmed 
symptomatic hypoglycaemia as data collected regardless of discontinuation of trial product or 
initiation of rescue medication(s) is used. 
The analysis of the endpoint for rescue medication in extension phase (switch) will not include a 
baseline covariate as rescue medication in the main phase (yes/no) is used as a stratification factor 
in the model.
Extension phase (sustainability) 
The endpoints will be summarised descriptively by visit.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
11 May 2018
Novo Nordisk
Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103
Status:
Final
EudraCT No.: 2015-005593-38
Page:
27 of 39
Time to event endpoint
The analyses of time to event endpoints will be based on the below two definitions:
!
Additional anti-diabetic medication: New anti-diabetic medication and/or intensification of 
anti-diabetic medication initiated at or after randomisation and before (planned) end-of-
treatment
!
Rescue medication: New anti-diabetic medication and/or intensification of anti-diabetic 
medication initiated at or after randomisation and before last date on trial product. This is a 
subset of the additional anti-diabetic medication.
The following rules will be applied based on the concomitant medication data reported by the 
investigator, to determine whether or not the recorded anti-diabetic medication is either 1) new anti-
diabetic medication or 2) intensification of anti-diabetic medication 
1. New anti-diabetic medication: Anti-diabetic medication (4th-level ATC code) that is 
initiated after randomisation and is new compared to the anti-diabetic background 
medication at randomisation and with a dosing duration of more than 21 days 
2. Intensification of anti-diabetic medication: A more than 20% increase in the dose of 
anti-diabetic medication after randomisation as compared to the anti-diabetic medication 
dose at randomisation (5th-level ATC code not changed) and with a dosing duration of 
more than 21 days. 
Main phase
!
Time to event
For the primary estimand the above time to event endpoint will be analysed based on FAS using the 
in-trial observation period. Additional anti-diabetic medication will be considered an event 
regardless of treatment adherence. Time from randomisation to additional anti-diabetic medication 
will be analysed using a Cox proportional hazards model with treatment, region and stratification 
factor as categorical fixed effects and baseline HbA1c as a covariate. From this analysis the 
estimated hazard ratios between oral semaglutide and sitagliptin together with associated two-sided 
95% CIs and unadjusted two-sided p-values will be presented. The analysis aims to address the 
need of additional anti-diabetic medication regardless of if this is due to lack of effect or 
tolerability. Switch to other anti-diabetic treatment is therefore also considered an event and 
withdrawn subjects or subjects lost to follow-up will be considered as having an event on the day of 
withdrawal. Subjects will be censored on the day before planned end-of-treatment visit.
For the secondary estimand the above time to event endpoint will be analysed based on FAS using 
the on-treatment without rescue medication observation period. Time from first dose of trial product 
to initiation of rescue medication will be analysed using the same model as described above. The 
analysis aims to address lack of effect and only initiation of rescue medication as add-on to 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
11 May 2018
Novo Nordisk
Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103
Status:
Final
EudraCT No.: 2015-005593-38
Page:
28 of 39
randomised treatment is considered an event. Switch to other anti-diabetic treatment is not 
considered an event and as a consequence subjects will be censored on the day before last date on 
trial product. Events occurring between randomisation and first date on trial product will be 
included in the analysis as events at day 0, in order to count all events of rescue medication. 
Extension phase (switch)
!
Time to event after week 52
For the primary estimand the above time to event endpoint will be analysed based on FAS using the 
in-trial extension phase (switch) observation period. Additional anti-diabetic medication will be 
considered an event regardless of treatment adherence. Time from re-randomisation to additional 
anti-diabetic medication will be analysed using a Cox proportional hazards model with treatment, 
region, stratification factors and the interaction between the two stratification factors as categorical 
fixed effects and baseline HbA1c as a covariate. 
For the secondary estimand the above time to event endpoint will be analysed based on FAS using 
the on-treatment without rescue medication extension phase (switch) observation period. Time from 
first dose of trial product in the extension phase to initiation of rescue medication will be analysed 
using the same model as described above. For the extension phase (switch), rescue medication 
initiated in the main phase will be treated as background medication in the extension phase and only 
addition of rescue medication after week 52 (V10) will be counted in the analyses.
2.4.2.2
Safety endpoints and safety assessments
The safety endpoints and safety assessments for the main phase in the first clinical trial report will 
be evaluated based on SAS using the on-treatment observation period and based on SAS using the 
in-trial observation period unless otherwise stated. 
The safety endpoints and safety assessments for the extension phase in the second clinical trial 
report will be evaluated based on extension phase (switch) and (sustainability) SAS using the on-
treatment extension phase (switch) and (sustainability) observation period and based on extension 
phase (switch) and (sustainability) SAS using the in-trial extension phase (switch) and 
(sustainability) observation period unless otherwise stated. 
The following endpoints and assessments are used to support the safety objectives.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
11 May 2018
Novo Nordisk
Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103
Status:
Final
EudraCT No.: 2015-005593-38
Page:
29 of 39
Adverse events 
Main phase
!
Number of TEAEs during exposure to trial product, assessed up to approximately 52 weeks 
Extension phase (sustainability)
!
Number of TEAEs during exposure to trial product, assessed up to approximately 109 weeks
Extension phase (switch)
!
Number of TEAEs during exposure to trial product, assessed from week 52 up to approximately 
109 weeks
All AEs will be coded using the most recent version of the Medical Dictionary for Regulatory 
Activities (MedDRA) coding. 
A treatment-emergent AE is defined as an AE with onset in the on-treatment observation period 
(see definition of observation periods in Section 2.2).
TEAEs 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) for the on-treatment observation period. Supportive 
summaries of AEs will be made for the in-trial observation period. The development over time in 
gastrointestinal AEs will be presented graphically.
Other safety endpoints
Main phase
Change from baseline to week 52 in:
!
Amylase (part of biochemistry)
!
Lipase (part of biochemistry)
!
Pulse
!
Systolic blood pressure
!
Diastolic blood pressure
Extension phase (sustainability)
Change from baseline to week 104 in:
!
Amylase (part of biochemistry)
!
Lipase (part of biochemistry)
!
Pulse
!
Systolic blood pressure
!
Diastolic blood pressure
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
11 May 2018
Novo Nordisk
Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103
Status:
Final
EudraCT No.: 2015-005593-38
Page:
30 of 39
Extension phase (switch)
Change from week 52 to week 104 in:
!
Amylase (part of biochemistry)
!
Lipase (part of biochemistry)
!
Pulse
!
Systolic blood pressure
!
Diastolic blood pressure
Main and extension phase (switch)
The above safety endpoints will be analysed as described above for continuous efficacy endpoints.  
Amylase and lipase endpoints will be log-transformed prior to analysis with the associated log-
transformed baseline value as a covariate.
Extension phase (sustainability)
The endpoints will be summarised descriptively by visit.
The following safety assessments will be calculated similarly as for the above other safety 
endpoints:
Main phase
The safety assessments for the main phase will furthermore be calculated for the following:
!
Haematology
!
Biochemistry (except for amylase and lipase)
!
Calcitonin
!
ECG category
!
Physical examination
!
Eye examination category
Extension phase
The safety endpoints for the extension phase (switch) and extension phase (sustainability) will 
furthermore be calculated for the following:
!
Haematology
!
Biochemistry (except for amylase and lipase)
!
Calcitonin
!
Eye examination category
The main and extension phase safety assessments will be summarised descriptively by treatment 
arm and visit. Categorical safety endpoints will be summarised as counts and relative frequencies. 
Calcitonin will also be presented by gender.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
11 May 2018
Novo Nordisk
Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103
Status:
Final
EudraCT No.: 2015-005593-38
Page:
31 of 39
Hypoglycaemia
Main phase
!
Number of treatment-emergent severe or BG-confirmed symptomatic hypoglycaemic episodes 
during exposure to trial product, assessed up to approximately 52 weeks 
!
Treatment-emergent severe or BG-confirmed symptomatic hypoglycaemic episodes during 
exposure to trial product, assessed up to approximately 52 weeks (yes/no)
Extension phase (sustainability)
!
Number of treatment-emergent severe or BG-confirmed symptomatic hypoglycaemic episodes 
during exposure to trial product, assessed up to approximately 109 weeks
!
Treatment-emergent severe or BG-confirmed symptomatic hypoglycaemic episodes during 
exposure to trial product, assessed up to approximately 109 weeks (yes/no)
Extension phase (switch)
!
Number of treatment-emergent severe or BG-confirmed symptomatic hypoglycaemic episodes 
during exposure to trial product, assessed from week 52 up to approximately 109 weeks
!
Treatment-emergent severe or BG-confirmed symptomatic hypoglycaemic episodes during 
exposure to trial product, assessed from week 52 up to approximately 109 weeks (yes/no)
Classification of hypoglycaemia
Hypoglycaemic episodes will be summarised for the SAS (main phase), extension phase 
(sustainability) SAS and extension phase (switch) SAS, using only the on-treatment (main phase), 
on-treatment extension phase (sustainability) and on-treatment extension phase (switch) observation 
period, respectively (referred to as the on-treatment observation periods in the following).
Treatment-emergent: hypoglycaemic episodes will be defined as treatment-emergent if the onset of 
the episode occurs within the on-treatment observation period (see definition of observation periods 
in Section 2.2).
Nocturnal hypoglycaemic episodes: episodes occurring between 00:01 and 05.59 both inclusive.
Hypoglycaemic episodes are classified according to the Novo Nordisk classification of 
hypoglycaemia and the ADA classification of hypoglycaemia (see Figure 2–2).
Novo Nordisk classification of hypoglycaemia
In normal physiology, symptoms of hypoglycaemia occur below a PG level of 3.1 mmol/L 
(56 mg/dL)8. Therefore, Novo Nordisk has included hypoglycaemia with PG levels below this cut-
off point in the definition of BG-confirmed hypoglycaemia.
Novo Nordisk uses the following classification in addition to the ADA classification:
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
11 May 2018
Novo Nordisk
Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103
Status:
Final
EudraCT No.: 2015-005593-38
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Severe or BG-confirmed symptomatic hypoglycaemia: An episode that is severe according to the 
ADA classification2 or BG-confirmed by a PG value < 3.1 mmol/L (56 mg/dL) with symptoms 
consistent with hypoglycaemia.
ADA classification2 of hypoglycaemia
Severe hypoglycaemia: An episode requiring assistance of another person to actively administer 
carbohydrate, glucagon, or take other corrective actions. PG concentrations may not be 
available during an event, but neurological recovery following the return of PG to normal is 
considered sufficient evidence that the event was induced by a low PG concentration.
Asymptomatic hypoglycaemia: An episode not accompanied by typical symptoms of 
hypoglycaemia, but with a measured PG concentration ≤ 3.9 mmol/L (70 mg/dL).
Documented symptomatic hypoglycaemia: An episode during which typical symptoms of 
hypoglycaemia are accompanied by a measured PG concentration ≤ 3.9 mmol/L (70 mg/dL).
Pseudo-hypoglycaemia: An episode during which the person with diabetes reports any of the typical 
symptoms of hypoglycaemia with a measured PG concentration > 3.9 mmol/L (70 mg/dL) but 
approaching that level.
Probable symptomatic hypoglycaemia: An episode during which symptoms of hypoglycaemia are 
not accompanied by a PG determination but that was presumably caused by a PG concentration 
≤ 3.9 mmol/L (70 mg/dL).
Hypoglycaemic 
episode 
PG ≤ 3.9 mmol/L 
(70 mg/dL) 
or 
Alleviation of 
symptoms 
or
Seizure, coma or 
fatal 
SMPG
measurement
Asymptomatic 
hypoglycaemia
Documented 
symptomatic 
hypoglycaemia
Pseudo-
hypoglycaemia
Probable 
symptomatic 
hypoglycaemia
No
Yes
No measurement 
with symptoms
PG > 3.9 mmol/L 
(70 mg/dL)
with symptoms
PG ≤3.9 mmol/L 
(70 mg/dL)
with symptoms
PG ≤3.9 mmol/L 
(70 mg/dL)
without symptoms
No
Yes
Note: Glucose measurements are performed with capillary blood calibrated to plasma equivalent glucose values
PG: plasma glucose  SMPG: Self-measured plasma glucose  
Subject 
able to 
treat him/
herself
Severe 
hypoglycaemia
(ADA 2013)
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
11 May 2018
Novo Nordisk
Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103
Status:
Final
EudraCT No.: 2015-005593-38
Page:
33 of 39
Figure 2–2
ADA classification of hypoglycaemia
Data on treatment-emergent hypoglycaemic episodes will be presented in terms of the number of 
subjects with at least one episode, the percentage of subjects with at least one episode (%), the total 
number of episodes and the episode rate per 100 patient years of observation time.
Analysis of severe or BG-confirmed symptomatic hypoglycaemic episodes
Main and extension phase (switch)
The endpoints related to number of treatment-emergent severe or BG-confirmed symptomatic 
hypoglycaemic episodes during the on-treatment period will be analysed using a negative binomial 
regression model with a log-link function and the logarithm of the duration of the subject’s on-
treatment observation period as offset. The model will include treatment, stratification factor and 
region as fixed factors and baseline HbA1c as covariate.
The binary endpoints showing whether a subject has at least one treatment-emergent severe or BG-
confirmed symptomatic hypoglycaemic episode will be analysed using a logistic regression model 
with treatment, stratification factor and region as fixed factors and baseline HbA1c as covariate.
Extension phase (sustainability)
The endpoints will be summarised descriptively.
2.5
Interim analysis
No interim analyses or other analyses of unblinded data will be performed before the database for 
the main phase is locked.
A database lock for the main phase will be performed when all subjects have completed the main 
phase to be able to report the results in the first clinical trial report. After completion of the 
extension phase, there will be a second database lock followed by the reporting of the results of the 
entire trial in the second clinical trial report.
2.6
Patient reported outcomes
Main phase
Change from baseline to week 52 in:
!
SF-36v2® Health Survey (acute version) (SF-36v2 (acute version)): scores from the 8 domains 
and the physical component score and mental component score summary scores 
!
Diabetes Treatment Satisfaction Questionnaire – status (DTSQs): individual items and total
treatment satisfaction score (6 of the 8 items summed)
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
11 May 2018
Novo Nordisk
Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103
Status:
Final
EudraCT No.: 2015-005593-38
Page:
34 of 39
Extension phase (sustainability)
Change from baseline to week 104 in:
!
SF-36v2 (acute version): scores from the 8 domains, the physical component summary score 
and mental component summary scores 
!
DTSQs: individual items and total treatment satisfaction score (6 of the 8 items summed)
Extension phase (switch)
Change from week 52 to week 104 in:
!
SF-36v2 (acute version): scores from the 8 domains, the physical component summary score 
and mental component summary scores 
!
DTSQs: individual items and total treatment satisfaction score (6 of the 8 items summed)
The PRO endpoints will be based on FAS, extension phase (sustainability) FAS and the extension 
phase (switch) FAS, using the on-treatment without rescue medication, on-treatment without rescue 
medication extension phase (sustainability) and on-treatment without rescue medication extension 
phase (switch) observation periods, respectively. 
Main and extension phase (switch)
All of the above individual items and scores will be analysed separately as the other supportive 
continuous efficacy endpoints with the associated baseline response as a covariate. For SF-36v2 the 
primary analysis for the hypothetical estimand will be reported in a report separate from the CTR. 
Extension phase (sustainability)
The endpoints will be summarised descriptively by visit.
2.6.1
SF-36v2® (acute version) health survey
The SF-36v2® Health Survey (SF-36v2) (acute version) instrument is a commonly used generic 
instrument measuring health-related quality of life (HRQoL)/general health status across disease 
areas including diabetes9. The SF-36v2 (acute version) for adults with a 1-week recall period
contains 36 items. A total of 35 items measure eight domains of functional health and well-being as 
well as two component summary scores: physical functioning (10 items), role limitation due to 
physical health problems (4 items), bodily pain (2 items), general health perceptions (5 items), 
vitality (4 items), social functioning (2 items), role limitations due to emotional problems (3 items) 
and general mental health (5 items), mental component summary (MCS) score, physical component 
summary (PCS) score. There is an additional single item giving information on health change over 
the past week.
Norm-based scores (NBS) will be derived using the QualityMetric Health Outcomes™ Scoring 
Software9 including the 2009 US general population norm. The most recent version of the 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
11 May 2018
Novo Nordisk
Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103
Status:
Final
EudraCT No.: 2015-005593-38
Page:
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QualityMetric Health Outcomes™ Scoring Software available at time of licensing was used for the 
specific trial (version 4.5 for PIONEER 7). Table 2–2 provides an overview of the domains. NBS 
standardises domain and component scores into T-scores using the means and standard deviations 
from the US general population. Higher scores on all domains and component summary measures 
(PCS and MCS) indicate better HRQoL/general health status. Item 2 (i.e. Question 2 in CRF) is not 
included in any score. 
Table 2–2
Overview of domains for SF-36v2 (acute version)
Domain
Items numbers of items 
included in domain
Comment
Physical Functioning (PF)
Items 3a-j
Role Limitations Due to Physical Health (Role-Physical; RP)
Items 4a-d
Bodily Pain (BP)
Items 7, 8
Both item scores reversed 
General Health Perceptions (General Health; GH)
Items 1, 11a-d
Item scores 1, 11b and 11d reversed
Vitality (VT)
Items 9a, 9e, 9g, 9i
Item scores 9a and 9e reversed 
Social Functioning (SF)
Items 6, 10
Item score 6 reversed 
Role Limitations Due To Emotional Problems (Role-
Emotional; RE)
Items 5a-c
Mental Health (MH)
Items 9b, 9c, 9d, 9f, 9h
Item scores 9d and 9h reversed 
Physical component summary (PCS)
NA
The PCS score is a weighted average of 
the 8 domain scores. 
Mental component summary (MCS)
NA
The MCS score is also a weighted 
average of the 8 domain scores. 
Weights differ from PCS to MCS. 
Missing data at instrument level will be handled using the Maximum Data Recovery method: The 
method applies a value to a domain item rendered missing if at least one of the items in that domain 
has valid data. A domain score is considered missing if all item values in the domain are missing. 
PCS and MCS are calculated when at least seven of the eight domains have valid data, either actual 
or estimated. However, to calculate PCS, the PF domain must be one of the seven domains having 
valid data. Also, to calculate MCS, the MH domain must be one of the seven domains having valid 
data.
The responder threshold values, in terms of T-score points for change from baseline are defined in
Table 2–3.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
11 May 2018
Novo Nordisk
Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103
Status:
Final
EudraCT No.: 2015-005593-38
Page:
36 of 39
Table 2–3
Responder thresholds for SF-36v2 (acute version)
Domain
Responder threshold
Physical Functioning (PF)
4.3
Role Limitations Due to Physical Health (Role-Physical; RP)
4.0
Bodily Pain (BP)
5.5
General Health Perceptions (General Health; GH)
7.0
Vitality (VT)
6.7
Social Functioning (SF)
6.2
Role Limitations Due To Emotional Problems (Role-Emotional; RE)
4.6
Mental Health (MH)
6.7
Physical component summary (PCS)
3.8
Mental component summary (MCS)
4.6
Responder analyses will be based on the responder threshold values and are described in section
2.6.3.
2.6.2
Diabetes Treatment Satisfaction Questionnaire – status version (DTSQs)
The DTSQs questionnaire will be used to assess subject’s treatment satisfaction. This questionnaire 
contains 8 items that measures the treatment satisfaction for subjects’ diabetes treatment in terms of 
convenience, flexibility and general feelings regarding treatment.
The DTSQs items are scored on a 7-point graded response scale ranging from 6 to 0. Higher scores 
indicate higher levels of treatment satisfaction for DTSQs items 1, 4 -8. For items 2 and 3 a higher 
score indicates a higher patient perceived experience of hyperglycaemia and hypoglycaemia, 
respectively. Thus, lower scores indicate a perception of blood glucose levels being “none of the 
time” unacceptably high (item 2) or low (item 3). If data are missing for an item, the item score is 
treated as missing. No reversal of item scores will be done.
The domain score of total treatment satisfaction (total treatment sat isfaction score) is computed by 
adding the six items scores 1, 4-8. The score has a minimum of zero and a maximum of 36. A 
higher treatment satisfaction score indicates a higher level of treatment satisfaction. No reversals of 
items are necessary prior to computing the treatment satisfaction score.
Missing data at instrument level will be handled in the following way. For computing the total 
treatment satisfaction score consisting of six items, missing data from one item is allowed. 
Scoring algorithm:
!
Step 1: Sum the existing item scores (i.e. either 5 or 6 item scores)
!
Step 2: Divide this sum by the number of existing item scores
!
Step 3: Multiply by 6 (the number of items in the total treatment satisfaction scale)
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Statistical Analysis Plan
CONFIDENTIAL
Date:
11 May 2018
Novo Nordisk
Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103
Status:
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EudraCT No.: 2015-005593-38
Page:
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Half of a standard deviation (SD) of the baseline DTSQs item and domain scores per trial were used 
as distribution-based approach defining the responder thresholds. The thresholds are derived from 
baseline DTSQs data across trial arms per trial. Responder analyses will be based on the responder 
threshold values and are described in section 2.6.3.
2.6.3
Responder analyses
Responder analyses will be conducted for both estimands, for the same time points that are defined 
for the analyses of PRO endpoints (see protocols) and separately for each score.
For descriptive statistics the following subject responder categorization is applied for all relevant 
time points and scores:
!
Responder - improvement: Individual change from baseline in score ≥ positive responder 
threshold 
!
Non-responder - no change: Individual change from baseline in score  > negative responder 
threshold value and < positive responder threshold value
!
Non-responder - worsening: Individual change from baseline in score  ≤ negative responder 
threshold value
The following binary subject responder definition is applied for all relevant time points and scores:
!
Responder: Individual change from baseline in score ≥ positive responder threshold
!
Non-responder: Individual change from baseline in score < positive responder threshold
The binary responder endpoints will be analysed as the other supportive secondary binary efficacy 
endpoints. Estimated proportions and differences in proportions will be reported in addition to odds 
and odds ratios.
The responder analyses will not be included in the CTR, but in a separate PRO report.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
11 May 2018
Novo Nordisk
Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103
Status:
Final
EudraCT No.: 2015-005593-38
Page:
38 of 39
3
Changes to the statistical analyses planned in the protocol
In section 2 it has been specified in more detail what the second CTR will include.
In section 2.3.2 the analyses for the secondary estimand was specified incorrectly. The correct 
analysis has been described.
In section 2.3.3 the amount of sensitivity analyses has reduced for the trial. The tipping point 
analysis has been kept for both the primary and the secondary estimand as an approach for 
performing a sensitivity analysis under the missing at not random (MNAR) assumption. In other 
words, the tipping point approach is like a progressive stress-testing to assess how severe departures 
from missing at random (MAR) must be in order to overturn conclusions from the primary analysis. 
This sensitivity analysis is considered sufficient to stress-test the secondary estimand. In addition to 
the tipping point analysis one sensitivity analyses for primary estimand is included, to get a better 
understanding of the primary results.
In regards to other sensitivity analysis, the LOCF analysis will not be performed anyway. This 
analysis is not judged to add additional value to the evaluation of the effect as it seems unrealistic 
that data from a subject with missing data, would have been stable from the point of dropout to trial 
completion.
In section 2.4.2.1 the statistical analyses of the two binary effect endpoints (HbA1c reduction ≥ 1%-
point (10.9 mmol/mol) and body weight loss ≥ 3%) have been omitted, because they are being 
analysed as a part of the two composite binary effect endpoints. The analyses of the composite 
endpoints including the ‘without hypoglycaemic episodes’ component and the analyses of the time 
to event endpoints have been described in more detail.
In section 2.4.2.2 the listings of adverse events and hypoglycaemic episodes reported from week 52 
(V10) to week 57 (V11) for subjects not continuing into extension has been removed. All adverse 
events and hypoglycaemic episodes for these subjects are a subset of other listings, hence all events 
are included.
In section 2.6 details on the analyses of PRO endpoints have been included.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
11 May 2018
Novo Nordisk
Trial ID: NN9924-4257
Version:
1.0
UTN: U1111-1177-5103
Status:
Final
EudraCT No.: 2015-005593-38
Page:
39 of 39
4
References
1. Novo Nordisk A/S. Investigator's Brochure for oral semaglutide (NN9924), edition 8 or any 
updates hereof. 2017.
2. 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.
3. Merck Sharp & Dohme Limited. JANUVIA - European Summary of Product Characteristics 
Annex 1. 26 May 2015.
4. Ahrén B, Comas LM, Kumar H, Sargin M, Derving Karsbøl J, Jacobsen SH, et al. Efficacy 
and Safety of Once-weekly Semaglutide vs Sitagliptin as add-on to Metformin and/or 
Thiazolidinediones After 56 Weeks in Subjects With Type 2 Diabetes (SUSTAIN 2).  
European Association for the Study of Diabetes, 52nd meeting, ePoster #767 2016.
5. Little RJA, Rubin DB. Statistical analysis with missing data: New York: John Wiley & 
Sons. 1987.
6. European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP). 
Guideline on Missing Data in Confirmatory Clinical Trials (EMA/CPMP/EWP/1776/99 
Rev. 1). 2 Jul 2010.
7. National Academy of Sciences (NAS). The Prevention and Treatment of Missing Data in 
Clinical Trials. Washington D.C.: The National Academies Press. 2010.
8. Schwartz NS, Clutter WE, Shah SD, Cryer PE. Glycemic thresholds for activation of 
glucose counterregulatory systems are higher than the threshold for symptoms. J Clin Invest. 
1987;79(3):777-81.
9. Maruish, M. E. (2011). User’s manual for the SF-36v2 Health Survey (3rd ed.). Lincoln, RI: 
QualityMetric Incorporated.
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Oral Semaglutide
PIONEER 1-10
Clinical Trial Report
Appendix 16.1.9
CONFIDENTIAL
Date:
19 June 2018
Novo Nordisk
Version:
1.0
Status:
Final
Page:
1 of 211
16.1.9.1 Pre-defined MedDRA search – list of preferred terms
Table of contents
Page
16.1.9.1 Pre-defined MedDRA search – list of preferred terms......................................................................2
CONFIDENTIAL


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