Conditions: Diabetes Diabetes Mellitus, Type 2
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1864
Healthy volunteers: no

Brief summary:
This trial is conducted globally. The aim of the trial is to investigate efficacy and long-term safety of oral semaglutide versus sitagliptin in subjects with type 2 diabetes.

Detailed description:

Arms:
arm 1: None arm 2: None arm 3: None arm 4: None

Interventions: intervention 1: semaglutide intervention 2: sitagliptin intervention 3: placebo
Intervention descriptions: intervention 1: Oral administration once-daily intervention 2: Oral administration once-daily intervention 3: Oral administration once-daily

Protocol document:
Prot_000.pdf: 
Cover Page for Protocol 
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT02607865 
Sponsor trial ID: 
NN9924-4222 
Official title of study: 
Efficacy and long-term safety of oral semaglutide versus 
sitagliptin in subjects with type 2 diabetes 
Document date: 
21-November-2018 
 


Link
Link
Link
Link
Link
Link
Link
Link
Link
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 ........................................................................................................
Protocol amendment 1 - FR...............................................................................................................
Protocol amendment 2 - FR...............................................................................................................
Protocol amendment 3 - FR...............................................................................................................
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
Oral semaglutide
Trial ID: NN9924-4222
Clinical Trial Report
Appendix 16.1.1
21 November 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:
24 August 2015
Novo Nordisk
Trial ID: NN9924-4222
Version:
2.0
UTN: U1111-1168-4339 
Status:
Final
EudraCT no.: 2015-001351-71 
Page:
1 of 119
Protocol
Trial ID: NN9924-4222
PIONEER 3 - vs. DPP-4 inhibitor
Efficacy and long-term safety of oral semaglutide versus sitagliptin
in subjects with type 2 diabetes
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:
24 August 2015
Novo Nordisk
Trial ID: NN9924-4222
Version:
2.0
UTN: U1111-1168-4339 
Status:
Final
EudraCT no.: 2015-001351-71 
Page:
2 of 119
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 ................................................................................................................................................13
3
Background information and rationale for the trial............................................................................17
3.1
Background information..............................................................................................................17
3.1.1
Type 2 diabetes mellitus ............................................................................................17
3.1.2
Glucagon-like peptide-1 ............................................................................................17
3.1.3
Oral semaglutide........................................................................................................18
3.1.4
Non-clinical data........................................................................................................18
3.1.4.1
Semaglutide.........................................................................................18
3.1.4.2
SNAC ..................................................................................................19
3.1.5
Clinical data oral semaglutide....................................................................................20
3.1.5.1
Pharmacokinetics ................................................................................20
3.1.5.2
Efficacy ...............................................................................................21
3.1.5.3
Safety...................................................................................................21
3.1.6
Sitagliptin...................................................................................................................22
3.2
Rationale for the trial...................................................................................................................22
4
Objective(s) and endpoint(s) ..................................................................................................................23
4.1
Objective(s)..................................................................................................................................23
4.1.1
Primary objective.......................................................................................................23
4.1.2
Secondary objectives .................................................................................................23
4.2
Endpoint(s)...................................................................................................................................23
4.2.1
Primary endpoint........................................................................................................23
4.2.2
Secondary endpoints..................................................................................................23
4.2.2.1
Confirmatory secondary endpoints .....................................................23
4.2.2.2
Supportive secondary endpoints..........................................................24
5
Trial design ..............................................................................................................................................26
5.1
Type of trial .................................................................................................................................26
5.2
Rationale for trial design..............................................................................................................26
5.3
Treatment of subjects...................................................................................................................27
5.3.1
Dosing instructions ....................................................................................................27
5.3.2
Background medication.............................................................................................28
5.4
Treatment after discontinuation of trial product ..........................................................................28
5.5
Rationale for treatment ................................................................................................................28
6
Trial population.......................................................................................................................................29
6.1
Number of subjects......................................................................................................................29
6.2
Inclusion criteria ..........................................................................................................................29
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
24 August 2015
Novo Nordisk
Trial ID: NN9924-4222
Version:
2.0
UTN: U1111-1168-4339 
Status:
Final
EudraCT no.: 2015-001351-71 
Page:
3 of 119
6.3
Exclusion criteria.........................................................................................................................29
6.4
Rescue criteria..............................................................................................................................31
6.5
Premature discontinuation of trial product ..................................................................................32
6.6
Withdrawal criteria ......................................................................................................................32
6.7
Subject replacement.....................................................................................................................33
6.8
Rationale for trial population.......................................................................................................33
7
Milestones.................................................................................................................................................34
8
Methods and assessments .......................................................................................................................35
8.1
Visit procedures...........................................................................................................................35
8.1.1
Screening, visit 1........................................................................................................35
8.1.2
Fasting visits ..............................................................................................................36
8.1.3
Randomisation and trial product administration........................................................36
8.1.4
End-of-treatment (visit 16) and Follow-up (visit 17).................................................37
8.1.5
Premature discontinuation of trial product and Follow-up (visits 16A and 17A)......37
8.1.6
Withdrawals...............................................................................................................37
8.1.7
Investigator assessments............................................................................................38
8.2
Subject related information..........................................................................................................39
8.2.1
Demography...............................................................................................................39
8.2.2
Tobacco use ...............................................................................................................39
8.2.3
Concomitant illness and medical history...................................................................39
8.2.4
Concomitant medication............................................................................................40
8.3
Assessments for efficacy..............................................................................................................40
8.3.1
Blood samples............................................................................................................40
8.3.2
7 -point self-measured plasma glucose profile ..........................................................40
8.3.3
Body weight, height and BMI....................................................................................41
8.3.4
Waist circumference ..................................................................................................42
8.3.5
Patient reported outcomes questionnaires..................................................................42
8.4
Assessments for safety.................................................................................................................43
8.4.1
Physical examination.................................................................................................43
8.4.2
Vital signs ..................................................................................................................43
8.4.3
Eye examination ........................................................................................................44
8.4.4
Electrocardiogram – 12 –lead....................................................................................44
8.4.5
Blood samples............................................................................................................44
8.4.6
Pregnancy test............................................................................................................45
8.4.7
Antibodies..................................................................................................................46
8.4.8
Hypoglycaemic episodes ...........................................................................................47
8.5
Laboratory assessments ...............................................................................................................50
8.5.1
Fasting plasma glucose..............................................................................................51
8.6
Other assessments........................................................................................................................51
8.6.1
Pharmacokinetics.......................................................................................................51
8.6.2
Subject diary ..............................................................................................................51
8.7
Additional safety assessments......................................................................................................51
8.7.1
Assessments in case of suspicion of acute pancreatitis..............................................52
8.7.2
Assessments in case of suspicion of hypersensitivity reactions.................................52
8.7.3
Assessments in case of increased levels of creatine kinase .......................................53
8.7.4
Assessments in case of increased levels of aminotransferases ..................................53
8.8
Subject compliance......................................................................................................................54
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
24 August 2015
Novo Nordisk
Trial ID: NN9924-4222
Version:
2.0
UTN: U1111-1168-4339 
Status:
Final
EudraCT no.: 2015-001351-71 
Page:
4 of 119
9
Trial supplies ...........................................................................................................................................55
9.1
Trial products...............................................................................................................................55
9.2
Labelling......................................................................................................................................55
9.3
Storage .........................................................................................................................................56
9.4
Drug accountability and destruction............................................................................................56
9.5
Auxiliary supplies........................................................................................................................57
10 Interactive web response system............................................................................................................58
11 Randomisation procedure and breaking of blinded codes..................................................................59
11.1
Breaking of blinded codes ...........................................................................................................59
12 Adverse events, technical complaints and pregnancies .......................................................................60
12.1
Definitions ...................................................................................................................................60
12.2
Reporting of adverse events.........................................................................................................64
12.3
Follow-up of adverse events........................................................................................................67
12.4
Technical complaints and technical complaint samples ..............................................................68
12.4.1
Reporting of technical complaints .............................................................................68
12.4.2
Collection, storage and shipment of technical complaint samples ............................68
12.5
Pregnancies in female subjects ....................................................................................................69
12.6
Precautions and/or overdose ........................................................................................................70
12.7
Committees related to safety........................................................................................................71
12.7.1
Novo Nordisk safety committee ................................................................................71
12.7.2
Event adjudication committee....................................................................................71
13 Case report forms....................................................................................................................................74
13.1
Corrections to case report forms..................................................................................................74
13.2
Case report form flow..................................................................................................................74
14 Monitoring procedures ...........................................................................................................................76
15 Data management....................................................................................................................................77
16 Computerised systems.............................................................................................................................78
17 Statistical considerations ........................................................................................................................79
17.1
Sample size calculation................................................................................................................81
17.2
Definition of analysis sets............................................................................................................84
17.3
Primary endpoint..........................................................................................................................86
17.3.1
Primary analysis for the primary estimand ................................................................86
17.3.2
Primary analysis for the secondary estimand.............................................................87
17.3.3
Sensitivity analyses....................................................................................................88
17.3.3.1
Pattern mixture models........................................................................89
17.3.3.2
Other sensitivity analysis ....................................................................90
17.3.3.3
Assessment of sensitivity analyses......................................................90
17.4
Secondary endpoints....................................................................................................................90
17.4.1
Confirmatory secondary endpoints............................................................................90
17.4.2
Supportive secondary endpoints ................................................................................91
17.4.2.1
Efficacy endpoints...............................................................................91
17.4.2.2
Safety endpoints..................................................................................93
17.5
Pharmacokinetic modelling .........................................................................................................96
17.6
Health economics and/or patient reported outcomes...................................................................97
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
24 August 2015
Novo Nordisk
Trial ID: NN9924-4222
Version:
2.0
UTN: U1111-1168-4339 
Status:
Final
EudraCT no.: 2015-001351-71 
Page:
5 of 119
18 Ethics........................................................................................................................................................98
18.1
Benefit-risk assessment of the trial..............................................................................................98
18.1.1
Risks and precautions ................................................................................................98
18.1.1.1
Oral Semaglutide.................................................................................98
18.1.1.2
Sitagliptin ..........................................................................................100
18.1.2
Benefits....................................................................................................................100
18.1.3
Risk and benefit conclusion.....................................................................................100
18.2
Informed consent .......................................................................................................................100
18.3
Data handling.............................................................................................................................101
18.4
Information to subject during trial.............................................................................................101
18.5
Premature termination of the trial and/or trial site.....................................................................102
19 Protocol compliance..............................................................................................................................103
20 Audits and inspections ..........................................................................................................................104
21 Critical documents ................................................................................................................................105
22 Responsibilities......................................................................................................................................107
23 Reports and publications......................................................................................................................108
23.1
Communication of results..........................................................................................................108
23.1.1
Authorship ...............................................................................................................109
23.1.2
Site-specific publication(s) by investigator(s) .........................................................109
23.2
Investigator access to data and review of results.......................................................................109
24 Retention of clinical trial documentation and human biospecimens................................................110
24.1
Retention of clinical trial documentation...................................................................................110
24.2
Retention of human biospecimens.............................................................................................110
25 Institutional Review Boards/Independent Ethics Committees and regulatory authorities............112
26 Indemnity statement .............................................................................................................................113
27 References..............................................................................................................................................115
Attachment I–Global list of key staff and relevant departments and suppliers
Attachment II–Country list of key staff and relevant departments
Appendix A–Calcitonin monitoring
Appendix B–Adverse events requiringadditional data collection
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
24 August 2015
Novo Nordisk
Trial ID: NN9924-4222
Version:
2.0
UTN: U1111-1168-4339 
Status:
Final
EudraCT no.: 2015-001351-71 
Page:
6 of 119
Table of Figures
Page
Figure 5–1
Trial design.............................................................................................................................26
Figure 12–1
Initial reporting of AEs...........................................................................................................66
Figure 17–1
Graphical illustration of the closed testing procedure ............................................................83
Figure 17–2
ADA classification of hypoglycaemia....................................................................................96
Table of Tables
Page
Table 5–1
Treatment of subjects..............................................................................................................27
Table 9–1
Investigational medicinal products.........................................................................................55
Table 9–2
Storage conditions for investigational medicinal products.....................................................56
Table 12–1
Overview of AEs requiring additional data collection and AEs subject to event 
adjudication ............................................................................................................................65
Table 12–2
Adverse events for adjudication .............................................................................................72
Table 17–1
Assumptions for sample size calculation................................................................................82
Table 17–2
Powers for individual hypotheses...........................................................................................82
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
24 August 2015
Novo Nordisk
Trial ID: NN9924-4222
Version:
2.0
UTN: U1111-1168-4339 
Status:
Final
EudraCT no.: 2015-001351-71 
Page:
7 of 119
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
CK
creatine kinase
CKD-EPI
Chronic Kidney Disease Epidemiology 
Collaboration 
CLAE
clinical laboratory adverse event
CoEQ
Control of Eating questionnaire 
CRF
case report form
CTR
clinical trial report
CVD
cardiovascular disease
DDI
drug-drug interaction
DPP-4i
dipeptidyl peptidase 4 inhibitor
DUN
dispensing unit number
EAC
event adjudication committee
ECG
electrocardiogram
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate (CDISC term is 
GFR, estimated)
EMA
European Medicines Agency
FAS
full analysis set
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
24 August 2015
Novo Nordisk
Trial ID: NN9924-4222
Version:
2.0
UTN: U1111-1168-4339 
Status:
Final
EudraCT no.: 2015-001351-71 
Page:
8 of 119
FDA
U.S. Food and Drug Administration
FPG
fasting plasma glucose
FSFV
first subject first visit
FU
follow-up
GCP
Good Clinical Practice
GI
gastrointestinal
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
IEC
independent ethics committee
IMP
investigational medicinal product
IWQoL-Lite
Impact of Weight on Quality of Life questionnaire
IRB
institutional review board
IWRS
interactive web response system
LDL
low density lipoprotein
LSFV
last subject first visit
LSLV
last subject last visit
MAR
missing at random
MEN 2
Multiple Endocrine Neoplasia Type 2
MI
myocardial infarction
MTC
Medullary Thyroid Carcinoma
MMRM
Mixed Model for Repeated Measurements
NIMP
non-investigational medicinal product
NYHA
New York Heart Association
OAD
oral antidiabetic drug
P
phone contact
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
24 August 2015
Novo Nordisk
Trial ID: NN9924-4222
Version:
2.0
UTN: U1111-1168-4339 
Status:
Final
EudraCT no.: 2015-001351-71 
Page:
9 of 119
PG
plasma glucose
PK
pharmacokinetics
PP
per protocol
PRO
patient reported outcome
SAE
serious adverse event
SAP
statistical analysis plan
SAS
safety analysis set
s.c.
subcutaneous(ly)
SF-36v2™ 
Short Form-36 version 2 health survey
SIF
Safety information form
SMPG
self-measured plasma glucose
SmPC
summary of product characteristics
SNAC
sodium N-(8-(2-hydroxybenzoyl) amino) caprylate
SU
sulfonylurea
SUSAR
suspected unexpected serious adverse reaction
T2DM
type 2 diabetes mellitus
TEAE
treatment emergent adverse events
TIA
transient ischemic attack
TMM
Trial Materials Manual
UNL
upper normal level
UTN
Universal Trial Number
V
visit
VLDL
very low density lipoprotein 
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
24 August 2015
Novo Nordisk
Trial ID: NN9924-4222
Version:
2.0
UTN: U1111-1168-4339 
Status:
Final
EudraCT no.: 2015-001351-71 
Page:
10 of 119
1
Summary
Objectives and endpoints:
Primary objective
To compare the effect of once-daily dosing of three dose levels (3 mg, 7 mg and 14 mg) of oral 
semaglutide versus sitagliptin 100 mg once-daily, both in combination with metformin with or 
without sulfonylurea (SU), on glycaemic control in subjects with type 2 diabetes mellitus (T2DM).
Secondary objectives
To compare the effect of once-daily dosing of three dose levels (3 mg, 7 mg and 14 mg) of oral 
semaglutide versus sitagliptin 100 mg once-daily, both in combination with metformin with or 
without SU, on body weight in subjects with T2DM.
To compare the long-term safety and tolerability of once-daily dosing of three dose levels (3 mg, 
7 mg and 14 mg) of oral semaglutide versus sitagliptin 100 mg once-daily, both in combination 
with metformin with or without SU, in subjects with T2DM.
Primary endpoint
Change from baseline to week 26 in HbA1c
Key secondary endpoints
Change from baseline to week 26 in
!
Body weight (kg)
!
Fasting plasma glucose (FPG)
Subjects who after 26 weeks of treatment achieve (yes/no):
!
HbA1c < 7.0% (53 mmol/mol), American Diabetes Association (ADA) target
This endpoint will also be evaluated after week 52 and after week 78.
Change from baseline to week 52 and to week 78 in:
!
HbA1c
!
Body weight (kg)
!
FPG
Number of treatment emergent adverse events (TEAEs) during exposure to trial product, assessed 
up to approximately 83 weeks
Number of treatment emergent severe or blood glucose (BG) confirmed symptomatic 
hypoglycaemic episodes during exposure to trial product, assessed up to approximately 83 weeks
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
24 August 2015
Novo Nordisk
Trial ID: NN9924-4222
Version:
2.0
UTN: U1111-1168-4339 
Status:
Final
EudraCT no.: 2015-001351-71 
Page:
11 of 119
Trial design:
The trial is a 78 week, randomised, double-blind, double-dummy, active-controlled, parallel-group, 
multi-centre, multi-national, four-armed trial.
Subjects with T2DM inadequately controlled with metformin or metformin + sulfonylurea (SU) 
will be randomised in a 1:1:1:1 manner to receive either a dose of 3 mg, 7 mg or 14 mg of oral 
semaglutide once-daily or a dose of 100 mg sitagliptin once-daily.
Total trial duration for the individual subject will be approximately 85 weeks. The trial includes a 2 
week screening period, followed by a 78 week randomised treatment period and a follow-up period 
of 5 weeks. 
Trial population:
It is planned to randomise 1860 subjects.
Key inclusion criteria
!
Male or female, age ≥ 18 years at the time of signing informed consent.
For Japan only: Male or female, age ≥ 20 years at the time of signing informed consent.
!
Diagnosed with T2DM ≥ 90 days prior to day of screening.
!
HbA1c 7.0-10.5 % (53-91 mmol/mol) (both inclusive).
!
Stable daily dose of metformin (≥1500 mg or maximum tolerated dose as documented in 
subject medical record) alone or in combination with SU (≥ half of the maximum approved dose 
according to local label or maximum tolerated dose as documented in subject medical record) 
within 90 days prior to the day of screening.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
24 August 2015
Novo Nordisk
Trial ID: NN9924-4222
Version:
2.0
UTN: U1111-1168-4339 
Status:
Final
EudraCT no.: 2015-001351-71 
Page:
12 of 119
Key exclusion criteria
!
Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing 
potential and not using adequate contraceptive methods (adequate contraceptive measures as 
required by local regulation or practice). 
For certain specific countries: Additional specific requirements apply.
!
Family or personal history of Multiple Endocrine Neoplasia Type 2 (MEN 2) or Medullary 
Thyroid Carcinoma (MTC).
!
History of pancreatitis (acute or chronic).
!
History of major surgical procedures involving the stomach potentially affecting absorption of 
trial product (e.g. subtotal and total gastrectomy, sleeve gastrectomy, gastric bypass surgery).
!
Any of the following: myocardial infarction, stroke or hospitalization for unstable angina and/or 
transient ischaemic attack within the past 180 days prior to the day of screening.
!
Subjects presently classified as being in New York Heart Association (NYHA) Class IV.
!
Planned coronary, carotid or peripheral artery revascularisation known on the day of screening.
!
Renal impairment defined as estimated Glomerular Filtration Rate (eGFR)
< 60 mL/min/1.73 m2 as per Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI).
!
History or presence of malignant neoplasms within the last 5 years (except basal and squamous 
cell skin cancer and in-situ carcinomas).
Key assessments:
Efficacy:
!
HbA1c
!
FPG
!
Body weight
Safety:
!
Adverse events
!
Hypoglycaemic episodes
Trial products:
The following trial products will be supplied by Novo Nordisk A/S, Denmark: 
!
Semaglutide, 3 mg tablet
!
Semaglutide, 7 mg tablet
!
Semaglutide, 14 mg tablet
!
Semaglutide placebo tablet (Placebo I)
!
Sitagliptin (Januvia®), 100 mg tablet
!
Sitagliptin placebo tablet (Placebo II)
CONFIDENTIAL


Protocol
UTN: U1111-1168-4339 
Date:
24 August 2015
Status:
Final
Novo Nordisk
Trial ID: NN9924-4222
EudraCT no.: 2015-001351-71 
Version:
2.0
Page:
13 of 119
2
Flow chart
Trial Periods
Screening1
Randomisation
Treatment
End-of-treatment 
(EoT)
Follow-up2
EoT premature 
discontinuation3
Follow-up 
premature 
discontinuation3
Visit (V), Phone (P)
V1
V2
P3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13
V14
V15
V16
V17
V16A
V17A
Timing of visit (weeks)
Up 
to -2
wks
0
2
4
8
14
20
26
32
38
45
52
59
66
72
78
83
Shortly 
after 
discontinua
-tion of 
trial 
product
5 weeks 
after 
discontinua-
tion of trial 
product (last 
dose)
Visit window (days)
±3
±3
±3
±3
±3
±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
x
x
x
x
x
x
Demography
x
Tobacco use
x
Concomitant illness and 
medical history
x
History of diabetes 
x
History of
cardiovascular disease 
x
History of gallbladder 
disease
x
History of 
gastrointestinal disease
x
Randomisation
x
Withdrawal criteria
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x


Protocol
UTN: U1111-1168-4339 
Date:
24 August 2015
Status:
Final
Novo Nordisk
Trial ID: NN9924-4222
EudraCT no.: 2015-001351-71 
Version:
2.0
Page:
14 of 119
Trial Periods
Screening1
Randomisation
Treatment
End-of-treatment 
(EoT)
Follow-up2
EoT premature 
discontinuation3
Follow-up 
premature 
discontinuation3
Visit (V), Phone (P)
V1
V2
P3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13
V14
V15
V16
V17
V16A
V17A
Timing of visit (weeks)
Up 
to -2
wks
0
2
4
8
14
20
26
32
38
45
52
59
66
72
78
83
Shortly 
after 
discontinua
-tion of 
trial 
product
5 weeks 
after 
discontinua-
tion of trial 
product (last 
dose)
Visit window (days)
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+3
+3
EFFICACY
HbA1c
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Fasting plasma glucose
x
x
x
x
x
x
x
x
x
x
x
PK Sampling4
x
x
x
x
x
x
x
x
x
x
x
Lipids
x
x
x
x
x
Body height
x
Body weight, BMI 
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
7-point profile
x
x
x
x
x
PRO questionnaires
x
x
x
x
x
SAFETY
Eye examination5
x
Physical examination
x
x
x
x
Electrocardiogram
x
x
x
x
x
x
x
Vital signs
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Pregnancy test6
x
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
Biochemistry7
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


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UTN: U1111-1168-4339 
Date:
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Status:
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Trial Periods
Screening1
Randomisation
Treatment
End-of-treatment 
(EoT)
Follow-up2
EoT premature 
discontinuation3
Follow-up 
premature 
discontinuation3
Visit (V), Phone (P)
V1
V2
P3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13
V14
V15
V16
V17
V16A
V17A
Timing of visit (weeks)
Up 
to -2
wks
0
2
4
8
14
20
26
32
38
45
52
59
66
72
78
83
Shortly 
after 
discontinua
-tion of 
trial 
product
5 weeks 
after 
discontinua-
tion of trial 
product (last 
dose)
Visit window (days)
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+3
+3
Antibodies8
x
x
x
x
x
x
x
x
x
x
x
Adverse events9
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
Technical complaints
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
TRIAL MATERIAL
IWRS call
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Dispensing of trial 
product
x
x
x
x
x
x
x
x
x
x
x
x
x
Drug accountability
x
x
x
x
x
x
x
x
x
x
x
x
x
x
REMINDERS
Hand out ID card
x
Hand out and instruct in 
BG meter use
x
Dispense and/or collect 
diary
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Attend visit fasting10
x
x
x
x
x
x
x
x
x
x
x


Protocol
UTN: U1111-1168-4339 
Date:
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Status:
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Novo Nordisk
Trial ID: NN9924-4222
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Version:
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Footer
Description
X1
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).
X2
Subjects, who have discontinued trial product prematurely, are not required to attend V17 (Follow-up).
X3
V16A and V17A are only applicable for subjects who have discontinued trial product prematurely.
X4
PK sampling is only applicable for a subset of the subjects.
No PK sampling should be done for visits occurring after V17A (subjects who have discontinued trial product prematurely).
X5
Dilated fundoscopy/fundus photography performed within 90 days prior to randomisation is acceptable if results are available for evaluation at V2, unless worsening of visual 
function since last examination.
X6
For women of child bearing potential: Urine pregnancy test should also be performed at any time during the trial if a menstrual period is missed and/or according to local 
regulations/law.
X7
At V1 only Creatinine and eGFR will be assessed as part of Biochemistry. 
X8
At randomisation, the antibody sampling must be done pre-dose. 
No antibody sampling should be done for visits occurring after V17A (subjects who have discontinued trial product prematurely).
X9
Adverse events reporting, includes adverse events from the first trial-related activity after the subject has signed the informed consent at V1.
X10
Fasting for blood sampling is defined as having consumed only water within the last 8 hours prior to visit.


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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)1and applicable regulatory requirements and in 
accordance with the Declaration of Helsinki2.
For Mexico only: The above will include the following responsibilities for the head of the 
Institution/Health Care Establishment, Ethics, Research and, when applicable, Biosafety 
Committees and sponsor within their scope of responsibility: 
a) Investigation follow-up;
b) Damages to health arising from the investigation development; as well as those arising from 
interruption or advanced suspension of treatment due to non-attributable reasons to the Subject;
c) Timely compliance of the terms in which the authorization of a research for health in human 
beings had been issued;
d) To present in a timely manner the information required by the Health Authority.
In this document, the term investigator refers to the individual responsible for the overall conduct of 
the clinical trial at a trial site.
3.1
Background information
3.1.1
Type 2 diabetes 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 liver.3
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 control.5,6
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 islets.7,8 Subjects 
with T2DM have a decreased incretin effect.9-12 However, the insulinotropic action of GLP-1 and 
thus, the ability to lower BG levels, is preserved when GLP-1 is administered at supra physiological 
levels.13 In addition, supra physiological levels of GLP-1 induces reduction in body weight 14. GLP-
1 is a physiological regulator of appetite and food intake and GLP-1receptors are present in several 
areas of the brain involved in appetite regulation15,16. Physiologically, GLP-1 also has a pronounced 
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inhibitory effect on gastric emptying; however this effect seems to diminish upon chronic exposure
14-16. These mechanisms of action make GLP-1 an attractive pharmacological treatment for 
T2DM.17-19
3.1.3
Oral semaglutide 
Semaglutide is a long-acting GLP-1 receptor agonist (GLP-1 RA) structurally similar to liraglutide 
(Victoza®), a once-daily GLP-1 RA developed by Novo Nordisk and approved worldwide for the 
treatment of T2DM. Compared to human native GLP-1, which has a very short half-life, the 
semaglutide molecule has three minor but important modifications ensuring protraction of its 
action: amino acid substitutions at position 8 (alanine to alfa-aminoisobuztyric 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 26.20The 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 very low when administered orally, semaglutide has been co-formulated with the 
absorption enhancing excipient sodium N-(8-(2-hydroxybenzoyl) amino) caprylate (SNAC) in order 
to increase bioavailability based on the 
 concept developed by 
 
. When semaglutide is co-formulated with SNAC, SNAC has the capacity to 
augment the absorption of semaglutide across the gastrointestinal (GI) epithelium. The absorption 
enhancement by SNAC is dose, size and time-dependent and is believed to take place in close 
proximity of the tablet in the stomach. The absorption process is hampered if dosed with food, 
liquid or in the presence of significant stomach content. Throughout this document oral semaglutide 
will refer to the drug product, that is, semaglutide co-formulated with 300 mg SNAC. 
Novo Nordisk is currently also developing semaglutide for once-weekly subcutaneous (s.c.) 
administration in subjects with T2DM. 
3.1.4
Non-clinical data
3.1.4.1
Semaglutide
The non-clinical programme for semaglutide was designed according to the ICH M3 guideline to 
support the clinical development. The standard non-clinical data package required to support phase 
3 clinical trials has been completed. In addition, 2-year carcinogenicity studies and a pre- and 
postnatal development toxicity study have been completed. Semaglutide was generally well 
tolerated in animals (mice, rats and cynomolgus monkeys). Two potential safety issues have been 
identified and these are detailed below.
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Thyroid C-cell tumours in rodents
Treatment-related non-genotoxic proliferative changes in the thyroid C-cells of mice and rats were 
observed in 2-year carcinogenicity studies with semaglutide; thyroid hyperplasia was preceded by 
an increase in serum calcitonin. C-cell changes have not been observed in long-term studies in non-
human primate. The observed pattern of effects in mice and rats and lack of these effects in the non-
human primate and in man suggest that the mechanism by which semaglutide acts on the thyroid C-
cells in rodents is the same as has been demonstrated for other GLP-1 RAs, including liraglutide. 
According to this mechanism, C-cell hyperplasia is mediated by the GLP-1 receptor and is not 
associated with RET (re-arranged during transfection) gene activation and rodents appear to be 
particularly sensitive, whereas humans are not. The relevance for human subjects is currently 
unknown, but considered to be low21.
Embryo−foetal development toxicity
Semaglutide caused embryo-foetal development toxicity in the rat through a GLP-1 receptor 
mediated effect on the inverted yolk sac placenta leading to impaired nutrient supply to the 
developing embryo. Primates do not have an inverted yolk sac placenta which makes this 
mechanism unlikely to be of relevance to humans and cynomolgus monkeys. In the developmental 
toxicity studies in cynomolgus monkey, a marked pharmacology mediated maternal body weight 
loss coincided with increased early foetal loss; however, there was no indication of a teratogenic 
potential of semaglutide in this species. These data suggest an important species-dependent 
mechanism, whereby semaglutide is teratogenic in rats but not in primates.
A review of results from the non-clinical studies can be found in the investigator’s brochure (IB) for 
Semaglutide (subcutaneous administration), edition 1022 and the IB for Oral administration of 
semaglutide (NN9924), edition 623, 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 
non-clinical programme to support clinical phase 3 development and marketing authorisation 
application (MAA) submission has been conducted including a 26-week carcinogenicity study in 
transgenic rasH2 mice and a 2-year carcinogenicity study in Sprague-Dawley rats.
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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 plasma exposures (AUC) of 2-fold in 
the mouse and up to 44-fold in the rat when compared to the mean human exposure following a 
clinical dose of 300 mg SNAC/day.
A review of results from the non-clinical studies can be found in the IB for Oral administration of 
semaglutide (NN9924), edition 623, or any updates hereof.
3.1.5
Clinical data oral semaglutide
A comprehensive clinical pharmacology programme including 12 trials has been completed, as well 
as a 26-week phase 2 dose-finding trial involving more than 600 subjects with T2DM.
For details on the individual trials, please see the IB for Oral administration of semaglutide 
(NN9924) edition 623, or any updates hereof.
3.1.5.1
Pharmacokinetics
In single dose trials, oral semaglutide has demonstrated a long mean terminal half-life (t½) ranging 
from 153 to 161 hours (~1 week) and a median time to reach maximum observed concentration 
(tmax) ranging from 1 to 2 hours in healthy subjects. 
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 steady 
state plasma exposure.
Data obtained following investigation of different dosing conditions for oral semaglutide have 
demonstrated that subjects should take the oral semaglutide tablet in the morning in a fasting state 
and at least 30 minutes before the first meal of the day. The tablet can be taken with up to half a 
glass of water (approximately 120mL/4 fluid oz).
Drug-drug interaction (DDI) investigations have explored the effect of oral semaglutide on the 
exposure to lisinopril, warfarin, metformin and digoxin as well as the effect of omeprazole on oral 
semaglutide and SNAC. It was demonstrated that oral semaglutide did not change the exposure to 
lisinopril, warfarin or digoxin, but increased the exposure to metformin when taken simultaneously. 
The increase in exposure to metformin may be related to delayed gastric emptying caused by 
semaglutide as observed for other GLP-1 RAs. Based on the wide therapeutic index of metformin, 
the increased exposure to metformin was however not considered clinically relevant. Further, it was 
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demonstrated that the exposure to semaglutide appeared to be slightly higher when administered 
with omeprazole in comparison to semaglutide alone, but the effect was not statistically significant 
or considered clinically relevant.  In subjects with mild to end-stage renal impairment, the exposure 
to semaglutide appeared similar in subjects with normal and impaired renal function, whereas the 
AUC for SNAC was greater in subjects with impaired renal function than in subjects with normal 
renal function. The Cmax of SNAC appeared similar in subjects with normal and impaired renal 
function. The renal clearance of all SNAC metabolites was decreased in subjects with renal 
impairment. 
In subjects with mild to severe hepatic impairment, the exposure to semaglutide appeared to be 
unaffected by the degree of hepatic impairment, whereas the exposure to SNAC (in terms of both 
AUC and Cmax) was increased for subjects with hepatic impairment as compared to subjects with 
normal hepatic function.
All tablets of oral semaglutide contain 300 mg of SNAC. SNAC is rapidly absorbed with a median 
tmax ranging from 0.35−0.5 hours in healthy subjects and from 0.52−1.43 hours in subjects with 
T2DM. It is extensively metabolized 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. 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 HbA1c and body weight. 
Placebo-adjusted reductions in HbA1c were dose-dependent and statistically significant for all oral 
semaglutide treatment arms at week 26 (range: -0.40% to -1.59%). Placebo-adjusted reductions in 
body weight were dose-dependent and statistically significant for oral semaglutide treatment doses 
of 10 mg and above at week 26 (range: -3.61 to -6.98 kg). 
3.1.5.3
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, common
adverse events (AEs) included nausea and vomiting, most of them of mild to moderate severity. In 
line with findings for other GLP-1 RAs, an increase in heart rate and serum levels of lipase and 
amylase has also been observed in subjects exposed to oral semaglutide.
In addition to the 13 completed clinical trials with oral semaglutide, SNAC has been investigated in 
the programme of orally administrated heparin in combination with SNAC (heparin/SNAC). The 
heparin/SNAC programme (
.) included 29 phase 1 trials (SNAC doses 
ranged from 0.172-10.5 g). In three of these trials SNAC alone was investigated (to a maximum 
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dose of 10.5 g). The studies covered formulation development, food effect, hepatic and renal 
impairment, age-effect and drug-drug interaction. The programme also included a total of three 
phase 2 and 3 trials in which the effects of orally delivered heparin solution (with >1.5 g SNAC 
three times a day) 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 623, or 
any updates hereof.
3.1.6
Sitagliptin
The selected active comparator in this trial is sitagliptin, an oral antidiabetic drug (OAD) of the 
DPP-4 inhibitor (DPP-4i) 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 
(GIP), secretion of insulin is increased and release of glucagon is suppressed. 
Further information can be obtained in the locally approved Januvia® label24.
For an assessment of benefits and risks of the trial, see Section 18.1.
3.2
Rationale for the trial
The rationale for the present trial is to compare the efficacy and safety of once-daily dosing with 
three dose levels (3 mg, 7 mg and 14 mg) of oral semaglutide with sitagliptin 100 mg once-daily in 
subjects with T2DM. Furthermore, the trial will ensure that long-term safety data are collected from 
subjects with T2DM exposed to oral semaglutide for a minimum of 18 months, as recommended by 
U.S. Food and Drug Administration (FDA)24.
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4
Objective(s) and endpoint(s)
4.1
Objective(s)
4.1.1
Primary objective
To compare the effect of once-daily dosing of three dose levels (3 mg, 7 mg and 14 mg) of oral 
semaglutide versus sitagliptin 100 mg once-daily, both in combination with metformin with or 
without SU, on glycaemic control in subjects with T2DM.
4.1.2
Secondary objectives
To compare the effect of once-daily dosing of three dose levels (3 mg, 7 mg and 14 mg) of oral 
semaglutide versus sitagliptin 100 mg once-daily, both in combination with metformin with or 
without SU, on body weight in subjects with T2DM.
To compare the long-term safety and tolerability of once-daily dosing of three dose levels (3 mg, 7 
mg and 14 mg) of oral semaglutide versus sitagliptin 100 mg once-daily, both in combination with 
metformin with or without SU, in subjects with T2DM.
4.2
Endpoint(s)
4.2.1
Primary endpoint
Change from baseline to week 26 in HbA1c
4.2.2
Secondary endpoints
4.2.2.1
Confirmatory secondary endpoints
Change from baseline to week 26 in body weight (kg)
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4.2.2.2
Supportive secondary endpoints
Supportive secondary efficacy endpoints
Change from baseline to week 52 and to week 78 in:
!
HbA1c*
!
Body weight (kg)*
Change from baseline to week 26, to week 52 and to week 78 in:
!
Body weight (%)
!
FPG*
!
Self-measured plasma glucose (SMPG), 7 point profile
o
Mean 7 point profile
o
Mean post prandial increment (over all meals)
!
Body mass index (BMI)
!
Waist circumference
!
Fasting lipid profile (total cholesterol, low density lipoprotein (LDL) cholesterol, very low 
density lipoprotein (VLDL) cholesterol, high-density lipoprotein (HDL) cholesterol, 
triglycerides, free fatty acids)
!
Patient reported outcomes
o
Short Form-36 version 2 (SF-36v2™) (acute version) health survey 
o
Impact of Weight on Quality of Life (IWQoL-Lite) Clinical Trial Version
o
Control of Eating questionnaire (CoEQ)
Subjects who after 26 weeks of treatment achieve (yes/no):
!
HbA1c < 7.0 % (53 mmol/mol) ADA target*
!
HbA1c ≤6.5 % (48 mmol/mol) American Association of Clinical Endocrinologists (AACE) 
target
!
HbA1c reduction ≥1 %
!
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 % and weight loss ≥3 %
The above eight endpoints will be evaluated after week 52 and after week 78 as well.
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Time to event endpoint
!
Time to rescue medication
This endpoint will be evaluated after week 26, after week 52 and after week 78.
Supportive secondary safety endpoints
!
Number of TEAEs during exposure to trial product, assessed up to approximately 83 weeks*
!
Number of treatment emergent severe or BG confirmed symptomatic hypoglycaemic episodes
during exposure to trial product, assessed up to approximately 83 weeks*
!
Treatment emergent severe or BG confirmed symptomatic hypoglycaemic episodes during 
exposure to trial product, assessed up to approximately 83 weeks (yes/no) 
Change from baseline to week 78 in:
!
Haematology
!
Biochemistry
!
Calcitonin
!
Pulse
!
Systolic blood pressure
!
Diastolic blood pressure
!
Electrocardiogram (ECG) category
!
Physical examination
Occurrence of anti-semaglutide antibodies (yes/no):
!
Anti-semaglutide binding antibodies
!
Anti-semaglutide neutralising antibodies 
!
Anti-semaglutide binding antibodies cross reacting with native GLP-1
!
Anti-semaglutide neutralising antibodies cross reacting with native GLP-1 
Anti-semaglutide binding antibody levels
Endpoints to be included in PK meta-analyses across phase 3a trials with oral semaglutide
PK-concentrations
!
Semaglutide plasma concentration in a subset of the subjects (approximately 50%) for 
population PK analyses
* Key supportive secondary endpoint prospectively selected for disclosure (e.g. clinicaltrials.gov 
and EudraCT)
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5
Trial design
5.1
Type of trial
The trial is a 78 week, randomised, double-blind, double-dummy, active-controlled, parallel-group, 
multi-centre, multi-national trial with four arms comparing efficacy and safety of oral semaglutide 
3 mg, 7 mg and 14 mg once-daily with sitagliptin 100 mg once-daily. Subjects with T2DM 
inadequately controlled on metformin alone or in combination with SU will be randomised in a 
1:1:1:1-manner to receive either:
!
oral semaglutide 3 mg and sitagliptin placebo
!
oral semaglutide 7 mg and sitagliptin placebo
!
oral semaglutide 14 mg and sitagliptin placebo
!
sitagliptin 100 mg and oral semaglutide placebo
Randomisation will be stratified according to anti-diabetic pre-trial background medication 
(metformin or metformin + SU) to ensure even distribution of the four treatment arms within strata.
To maintain the blinding of the trial, the treatment will consist of two tablets daily as the sitagliptin 
tablet is not visually identical to the oral semaglutide tablets (see Section 9.1).
Total trial duration for the individual subject will be approximately 85 weeks. The trial includes a 
2 week screening period, followed by a 78 week randomised treatment period and a follow-up 
period of 5 weeks.
A schematic diagram of the trial design is shown in Figure 5–1.
Figure 5–1
Trial design
5.2
Rationale for trial design
Parallel treatment arms and a randomised double-blind double-dummy active controlled design 
have been chosen in accordance with trial objectives and to avoid bias in the trial. The primary 
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efficacy endpoint will be evaluated at week 26 (see Section 17). No interim analysis will be done 
and the blinding will remain throughout the trial in order to assess long-term safety and tolerability 
in an un-biased manner (see Section 17). Supportive secondary efficacy endpoints are also included 
at week 52 and week 78.
5.3
Treatment of subjects
Treatment of subjects is summarised in Table 5–1.
Oral semaglutide treatment arms
All subjects randomised to semaglutide will initiate treatment with 3 mg once daily. Subjects 
randomised to maintenance doses of 7 mg or 14 mg will follow a fixed dose-escalation regimen 
with 4 weeks between the dose escalation steps. The maintenance dose of 7 mg once daily will be 
reached after 4 weeks on 3 mg once daily. The maintenance dose of 14 mg once daily will be 
reached after 4 weeks on 3 mg once daily, followed by 4 weeks on 7 mg once daily. In addition, all 
subjects randomised to oral semaglutide will receive sitagliptin placebo once daily. 
Sitagliptin treatment arm
Subjects randomised to sitagliptin will receive 100 mg once daily without dose escalation. In 
addition, all subjects randomised to sitagliptin will receive oral semaglutide placebo once daily. 
Table 5–1
Treatment of subjects
Screening 
Treatment period
1
Treatment period
2
Treatment period
3
Follow-up 
First visit in each period
V1
V2
V4
V5
V16
Duration of each perioda
2 weeks
4 weeks
4 weeks
70 weeks
5 weeks
Treatment arm
oral semaglutide 3 mg
+ sitagliptin placebo
Screening 
3 mg + placebo
3 mg + placebo
3 mg + placebo
Follow-up
oral semaglutide 7 mg 
+ sitagliptin placebo
Screening 
3 mg + placebo
7 mg + placebo
7 mg + placebo
Follow-up 
oral semaglutide 14 mg 
+ sitagliptin placebo
Screening 
3 mg + placebo
7 mg + placebo
14 mg + placebo
Follow-up 
sitagliptin 100 mg 
+ oral semaglutide placebo
Screening 
100 mg + placebo
100 mg + placebo
100 mg + placebo
Follow-up 
ª Please see Section 2 for visit windows.
5.3.1
Dosing instructions
Absorption of oral semaglutide is significantly affected by food and fluid in the stomach, hence 
dosing should be in the morning in fasting state and at least 30 minutes before the first meal of the 
day. Trial products can be taken with up to half a glass of water (approximately 120 ml/4 fluid oz). 
The tablets must be taken whole: do not break or chew (see Table 9–2). Furthermore, other oral 
medication can be taken 30 minutes after trial products.
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5.3.2
Background medication
After inclusion (V1), subjects must continue anti-diabetic pre-trial background medication (i.e. 
metformin alone or in combination with SU) throughout the entire trial. The background medication 
must be maintained at the stable, pre-trial dose and at the same frequency during the whole 
treatment period unless rescue medication is needed (see Section 6.4) 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
!
should be used in accordance with standard of care or local label in the individual country 
!
must not exceed the maximum approved dose in the individual country
 
5.4
Treatment after discontinuation of trial product
When discontinuing trial products 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). After discontinuation of trial product, GLP-1 RAs are not allowed before completion 
of the follow-up visit (see Section 8.1.4 and 8.1.5) which is to take place 5 weeks after the last date 
on trial product (to avoid interference with the antibody analysis).
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. The duration and doses of randomised treatments are 
considered adequate to collect sufficient data on efficacy and safety in accordance with the trial 
objectives.
Sitagliptin has been chosen as comparator since it is an established OAD within the DPP-4i drug 
class.
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6
Trial population
6.1
Number of subjects 
Number of subjects planned to be screened:
3100
Number of subjects planned to be randomised:
1860
Number of subjects expected to complete the trial on or off randomised trial product:
1674
For Japan only: 200 Japanese subjects planned to be randomised with an approximate equal 
distribution across the 4 treatment arms.
For Mexico only: 98 Mexican subjects planned to be randomised.
6.2
Inclusion criteria
For an eligible subject, all inclusion criteria must be answered “yes”. 
1. Informed consent obtained before any trial-related activities. Trial-related activities are any 
procedures that are carried out as part of the trial, including activities to determine suitability for 
the trial. 
2. Male or female, age ≥ 18 years at the time of signing informed consent.
For Japan only: Male or female, age ≥ 20 years at the time of signing informed consent.
3. Diagnosed with type 2 diabetes mellitus ≥90 days prior to day of screening.
4. HbA1c 7.0-10.5% (53-91 mmol/mol) (both inclusive).
5. Stable daily dose of metformin (≥1500 mg or maximum tolerated dose as documented in the 
subject medical record) alone or in combination with SU (≥ half of the maximum approved dose 
according to local label or maximum tolerated dose as documented in the subject medical 
record) within 90 days prior to the day of screening.
6.3
Exclusion criteria
For an eligible subject, all exclusion criteria must be answered "no".
1. Known or suspected hypersensitivity to trial product(s) or related products. 
2. Previous participation in this trial. Participation is defined as signed informed consent.
3. Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing 
potential and not using adequate contraceptive methods (adequate contraceptive measures as 
required by local regulation or practice).
For Germany only: Only highly effective methods of birth control are accepted (i.e. one that 
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results in less than 1% per year failure rate when used consistently and correctly such as 
implants, injectables, combined oral contraceptives, some intrauterine device), or sexual 
abstinence or vasectomised partner.
For United Kingdom only: Adequate contraceptive measures are defined as established use of 
oral, intravaginal, transdermal combined estrogen and progestogen hormonal methods of 
contraception; oral, injected or implanted progestogen only hormonal methods of 
contraception; placement of an intrauterine device or intrauterine hormone releasing system, 
bilateral tubal occlusion, barrier methods of contraception (condom or occlusive cap with 
spermicidal foam/gel/film/cream/suppository), female sterilisation, vasectomised partner (where 
partner is sole partner of subject), or true abstinence (when in line with preferred and usual 
lifestyle).
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 Japan only: Adequate contraceptive measures are abstinence (not having sex), diaphragm, 
condom (by the partner), intrauterine device, sponge, spermicide or oral contraceptives.
4. Receipt of any investigational medicinal product within 90 days before screening.
For Brazil only: Participation in other trials within one year prior to screening visit (visit 1) 
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 hospitalization for unstable angina and/or 
transient ischaemic attack within the past 180 days prior to the day of screening. 
10. Subjects presently classified as being in New York Heart Association (NYHA) Class IV.
11. Planned coronary, carotid or peripheral artery revascularisation known on the day of screening.
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12. Renal impairment defined as estimated Glomerular Filtration Rate (eGFR) <60 mL/min/1.73 m2 
as per Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI).
13. 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.
14. Proliferative retinopathy or maculopathy requiring acute treatment. Verified by fundus 
photography or dilated fundoscopy performed within 90 days prior to randomisation.
15. History or presence of malignant neoplasms within the last 5 years (except basal and squamous 
cell skin cancer and in-situ carcinomas).
6.4
Rescue criteria
Subjects with persistent and unacceptable hyperglycaemia should be offered treatment 
intensification. To allow time for dose escalation and to observe the expected effect of treatment on 
glycaemic parameters, rescue criteria will be applied from week 8 and onwards. If any of the FPG 
values (including fasting SMPG) exceed the limits outlined below and no intercurrent cause of the 
hyperglycaemia can be identified, a confirmatory FPG (at central laboratory) should be obtained by 
calling the subject for a re-test:
!
14.4 mmol/L (260 mg/dL) from week 8 to end of week 13
!
13.3 mmol/L (240 mg/dL) from week 14 to end of week 25
!
11.1 mmol/L (200 mg/dL) from week 26 to end of trial
If the confirmatory FPG also exceeds the values described above, the subject should be offered 
rescue medication (i.e. intensification of existing anti-diabetic background medication and/or 
initiation of new anti-diabetic medication). 
In addition, subject should be offered rescue medication if:
!
HbA1c (at central laboratory) > 8.5% (69.4 mmol/mol) from week 26 to end of trial 
It is important for trial integrity that only subjects actually needing treatment intensification (as 
defined above) are started on rescue medication. Subjects that are started on rescue medication 
should continue to follow the protocol-specified visit schedule. Rescue medication should be 
prescribed 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).  
Rescue medication and any changes hereto should be captured on the concomitant medication form 
in the electronic case report form (eCRF), see Section 8.2.4. Rescue medication is considered to be 
NIMP and will not be provided by Novo Nordisk.
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6.5
Premature discontinuation of trial product
All efforts should be made to keep the subject on trial product.
However, if necessary for safety concerns related to trial product, or unacceptable intolerability, as 
judged by the investigator, treatment with trial product must be discontinued (i.e. a treatment 
discontinuation call must be made in the interactive web response system (IWRS)) and in these 
cases trial product should not be re-initiated. In case the trial product is interrupted due to suspicion 
of acute pancreatitis, please see Section 8.7.1.
Furthermore, the subject must discontinue treatment with trial product if any of the following 
applies:
!
pregnancy
!
intention of becoming pregnant
!
included in the trial in violation of the inclusion and/or exclusion criteria
!
participation in another clinical trial with an investigational medicinal product (IMP)
!
calcitonin ≥ 100 ng/L
Subjects discontinuing treatment with trial product will not be withdrawn from trial and will be 
followed as described in Section 8.1.5.
The primary reason for discontinuation of trial product must be specified in the eCRF.
6.6
Withdrawal criteria
This section refers to withdrawal from the trial. 
The subject may withdraw at will at any time. The subject’s request to withdraw from trial must 
always be respected.
Subjects who agree to attend or provide health status at the planned V16 should not be considered 
withdrawn from the trial.
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 withdrawn from the trial.
Subjects who consider withdrawing informed consent should be encouraged to have procedures 
performed according to the V16A and V17A visits.
See Section 8.1.6 for procedures to be undertaken in case of withdrawal from trial.
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A subject included in the trial in violation of the inclusion and/or exclusion criteria must 
discontinue treatment with trial product, but will not be withdrawn from the trial. The subject will 
be followed as described in Section 8.1.5.
For Mexico only: Should the subject his/her family members parents or legal representative decide 
to withdraw the consent for participation in the trial, the subject will be entitled to receive 
appropriate, free of charge medical care and/or trial drug during the follow up period of the 
protocol when it will be established with certainty that no untoward medical consequences of the 
subject´s participation in the research occurred.
6.7
Subject replacement
Subjects who are withdrawn will not be replaced
6.8
Rationale for trial population
Subjects with T2DM inadequately controlled on metformin alone or in combination with SUs will 
be included in the trial. The eligibility criteria allow for enrolment of a relatively broad trial 
population. This will ensure that the trial population will resemble the target population in common 
practice. However, concomitant conditions which could jeopardise the safety of the subjects or 
compliance with the protocol will preclude subjects from participating (see Section 6.3). 
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7
Milestones
Planned duration of recruitment period FSFV-LSFV
20 weeks
Planned FSFV:
15-Feb-2016
Planned LSLV:
23-Feb-2018
End of trial is defined as LSLV
Recruitment:
The screening and randomisation rate will be followed closely via the IWRS in order to estimate 
when to stop screening. All investigators will be notified immediately when the recruitment period 
ends, after which no further subjects may be screened and the IWRS will be closed for further 
screening.
Trial registration:
Information of the trial will be disclosed at clinicaltrials.gov, novonordisk-trials.com and the 
Clinical Trials Information JapicCTI site clinicaltrials.jp. According to the Novo Nordisk Code of 
Conduct for Clinical Trial 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
Each subject will attend 16 site visits and 1 phone visit. Subjects who prematurely discontinue trial 
product will also be asked to attend V16A and V17A, but will not be asked to attend V17.
For visit numbers, timing of site and phone visits and visit windows during the trial period, please 
refer to the flow chart, Section 2. Planned visits can be re-scheduled within the allowed visit 
window. It is the responsibility of the investigator to ensure that all site visits occur according to the 
flow chart.
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. Subjects will be invited for the next scheduled visit 
according to the visit schedule.
If a subject is unable or unwilling to attend all subsequent visit(s) the investigator should at least 
aim to have the subject attend the V8, V12 and the End-of-treatment visit (V16) as these visits
should be performed for all subjects (except subjects who withdraw informed consent, see 
Section 8.1.6).
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.
8.1.1
Screening, visit 1
The investigator must keep a subject screening log, a subject identification code list and a subject 
enrolment log. The subject screening log and subject enrolment log may be combined in one list. 
In addition, 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.
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 IWRS. Each subject will be assigned a unique 6-digit subject 
number which will remain the same throughout the trial.
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Once all data relating to visit 1 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 CRF must be completed 
with the reason for not continuing in the trial. Serious adverse events (SAEs) from screening 
failures must be transcribed by the investigator into the CRF. Follow-up of SAEs must be carried 
out according to Section 12.
A screening failure session must be made in the IWRS. The case book must be signed.
Re-screening is NOT allowed. However, in case any laboratory samples are not available (e.g. 
haemolysed/lost), re-sampling is allowed.
8.1.2
Fasting visits
The subjects must attend several visits in a fasting state (see Section 2). Fasting for blood sampling 
is defined as having consumed only water within the last 8 hours prior to the visit. Trial 
product must be taken after blood sampling and other oral medication can be taken 30 minutes after 
trial products.
Glucose lowering agents and trial product should not be taken until after blood sampling has been 
performed.
If subjects do not attend the visit in a fasting state they must be asked to attend a re-scheduled visit 
within the visit window to have all planned visit assessments performed. Only AEs should be 
captured in the eCRF at the original visit.
8.1.3
Randomisation and trial product administration
Eligible subjects will be randomised into one of four treatment arms. The randomisation session 
must be performed in the IWRS which will allocate the dispensing unit number (DUN) of trial 
product to be dispensed to the subject.
All visit 2 assessments should be performed before administration of first dose of trial product.
Trial product (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 instructed in the 
dosing requirements at every dispensing visit, please see Section 5.3.1.
Date and time of first administration of trial product will be captured in the eCRF.
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8.1.4
End-of-treatment (visit 16) and Follow-up (visit 17)
Subjects who stay on trial product throughout the trial, must attend the End-of-treatment visit (V16) 
78 weeks after randomisation and the Follow-up visit (V17) 5 weeks after the last date on trial 
product (+3 days visit window). A completion call must be performed in the IWRS after completion 
of visit 16 (see Section 10).
In case the subject cannot be reached (by clinic visit or phone contact) at the scheduled visit 17 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) to collect health status. If no health status can be collected, the subject should be 
considered lost to follow up. 
8.1.5
Premature discontinuation of trial product and Follow-up (visits 16A and 17A)
Subjects who discontinue trial product prematurely should attend visit 16A, scheduled to take place 
shortly after discontinuation of trial product. Visit 17A should be scheduled 5 weeks (+3 days visit 
window) after the last date on trial product. A treatment discontinuation session must be performed
in the IWRS at visit 16A (see Section 10).
Subjects should continue with the originally scheduled site contacts after visit 17A and up to visit 
16. If necessary, in order to retain the subject in the trial, site visits can be replaced by phone 
contacts after V17A. However, as a minimum, these subjects should be asked to attend the 
scheduled V8 at week 26, V12 at week 52 and End-of-treatment (V16) at week 78.
In case the subject cannot be reached (by clinic visit or phone contact) at the scheduled visit 16 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) to collect health status. If no health status can be collected, the subject should be 
considered lost to follow up. 
8.1.6
Withdrawals
If a subject considers withdrawing from the trial, the investigator must aim to undertake procedures 
similar to those for visit 16A as soon as possible and visit 17A 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 from a trial, the 
investigator must make a reasonable effort to ascertain the reason(s), while fully respecting the 
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subject’s rights. Where the reasons are obtained, the primary reason for not completing the trial 
must be specified on the end-of-trial form in the eCRF.
8.1.7
Investigator assessments
Review of diaries, PROs, laboratory reports, ECGs and fundoscopy/fundus photography must be 
documented either on the documents and/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 investigators 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.
In case of abnormal clinically significant findings found as a result of screening procedures 
conducted at visit 1 or assessments revealing baseline conditions at visit 2 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.
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8.2
Subject related information 
8.2.1
Demography
Demography will be recorded in the eCRF at screening and consists of:
!
date of birth or age (according to local regulation)
!
sex
!
race (according to local regulation)
!
ethnicity (according to local regulation)
8.2.2
Tobacco use
Details of smoking status must be recorded at visit 1. Smoking is defined as smoking at least one 
cigarette, cigar or pipe daily. The collected information should include whether or not the subject 
smokes or has smoked. If the subject has smoked, record approximately when the subject stopped 
smoking.
8.2.3
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.
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 (at visit 1) on the disease specific forms only i.e. not 
on the medical history/concomitant illness form:
!
Diabetes history/diabetes complications (e.g. date of diagnosis, diabetic retinopathy, diabetic 
neuropathy, diabetic nephropathy)
!
History of cardiovascular disease (CVD) (e.g. ischaemic heart disease, myocardial infarction, 
heart failure incl. 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).
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8.2.4
Concomitant medication
A concomitant medication is any medication, other than the trial products, which is taken during 
the trial, including the screening and follow-up periods.
Details of any concomitant medication must be recorded at the first visit. For antidiabetic 
medication, the start date of current dose must be recorded at visit 1. Changes in concomitant 
medication must be recorded at each visit as they occur. 
The information collected for each concomitant medication includes
!
trade name or generic name
!
indication
!
start date and stop date or continuation
!
total daily dose (only applicable for antidiabetic 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.
8.3
Assessments for efficacy
8.3.1
Blood samples
Blood samples will be drawn according to 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
Lipids (fasting see Section 8.1.2):
!
Total cholesterol
!
LDL-cholesterol
!
HDL-cholesterol
!
VLDL-cholesterol
!
Free fatty acids
!
Triglycerides
8.3.2
7 -point self-measured plasma glucose profile
At visit 1, subjects will be provided with a blood glucose meter (BG meter) including lancets, 
plasma-calibrated test strips and control solutions as well as instructions for use. The subjects will 
be instructed in how to use the device, the instruction will be repeated as necessary during the trial. 
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The BG meters use test strips calibrated to plasma values. Therefore, all measurements performed 
with capillary blood are automatically calibrated to plasma equivalent glucose values, which will be 
shown on the display.
The subject will be instructed to perform a 7-point SMPG profile four times during the trial period 
(see Section 2) using the BG meter provided for the trial. The 7-point SMPG profile should be 
performed on a day where the subject does not anticipate unusual strenuous exercise. The 7-point 
profile should preferably be taken within a week prior to the visit.
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, the values in the eCRF 
should be corrected.
The record of each SMPG measurement should include the following seven time points:
!
before breakfast
!
90 minutes after start of breakfast
!
before lunch
!
90 minutes after start of lunch
!
before dinner
!
90 minutes after start of dinner
!
at bedtime
8.3.3
Body weight, height and BMI
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.
BMI will be calculated for the investigators convenience at visit 1 in the eCRF but will not be saved 
in the clinical database. The equation used in the eCRF is listed below:
BMI kg/m2 = body weight (kg)/(Height (m) x Height (m)) or (kg/m2 = [lb/in2 x 703])
All BMI calculations will subsequently take place in the clinical database using measurements of 
height and weight according to flowchart 2.
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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 0.5 cm or 
0.2 inches using a non-stretchable measuring tape. The same measuring tape should be used 
throughout the trial (measuring tape will be provided to the sites).
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
Patient reported outcomes questionnaires
PRO will be assessed using the questionnaires:
!
SF-36v2™ (acute version) health survey37-39
!
IWQoL-Lite Clinical Trial Version40,41
!
CoEQ42-45
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 fifteen 
minutes to complete the three questionnaires. Subjects should be given the opportunity to complete 
the questionnaires by themselves without interruption. All results from the PRO questionnaires 
must be transferred into the eCRF.
The questionnaires SF-36v2™and IQWoL-Lite Clinical Trial Version are commonly used PRO 
instruments, also in the T2DM area. The Control of Eating questionnaire has not been developed to 
be used in clinical trials. However, it has previously been included in clinical trials on an item per 
item basis, among others in a T2DM population.
All the questionnaires will be translated to local language before being handed out to the subjects 
participating in the trial. 
SF-36 acute version
SF-36v2™ acute version measures the individual overall health related quality of life on 8 domains; 
Physical functioning, Role functioning, Bodily pain, General health, Vitality, Social functioning, 
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Role emotional and Mental health. The acute version’s questions are based on a recall period of one 
week. SF-36v2™ contains 36 items.
Impact of Weight on Quality of Life questionnaire (IWQoL-Lite) Clinical Trial Version
The IWQoL-Lite for Clinical Trials was adapted from the IWQOL-Lite and measures the health 
related quality of life. The IQWoL- Lite Clinical Trial Version contains 23 items.
Control of Eating Questionnaire (CoEQ)
The CoEQ has its origins in the Food Craving Record. It comprises 21-items designed to assess the 
intensity and type of food cravings, as well as subjective sensations of appetite and mood. For this 
study a version with only 19 items will be included.
8.4
Assessments for safety
8.4.1
Physical examination
A physical examination will be performed by the investigator according to local procedure (see 
Section 2). 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
8.4.2
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.
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8.4.3
Eye examination 
Dilated fundoscopy/fundus photography will be performed as per flow chart (see Section 2) by the 
investigator or according to local practise. Results of the dilated fundoscopy/fundus photography 
will be interpreted by the investigator (see Section 8.1.7).
If dilated fundoscopy/fundus photography 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 dilated fundoscopy/fundus photography 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.
8.4.4
Electrocardiogram – 12 –lead
12-lead ECG will be performed as per 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 
assessment and the investigator must forward the ECGs to the central ECG reader as soon as 
possible.
If the central ECG evaluation of a post-baseline ECG is suggestive of new myocardial infarction 
(MI), the investigator will be notified and, unless already done, the investigator should report this as 
AE or SAE at investigator’s discretion (see Section 12.1).
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).
8.4.5
Blood samples
Blood samples will be drawn according to flow chart (see Section 2) and will be analysed at the 
central laboratory to determine levels of the following safety laboratory parameters:
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Haematology:
!
Haemoglobin
!
Haematocrit
!
Leucocytes
!
Thrombocytes
!
Differential count (eosinophils, neutrophils, basophils, lymphocytes and monocytes)
Biochemistry: 
!
Alanine aminotransferase (ALT)
!
Albumin
!
Alkaline phosphatase (ALP)
!
Amylase
!
Aspartate aminotransferase (AST)
!
Bilirubin, total
!
Calcium, total
!
Creatinine
!
eGFR per CKD-EPI32
!
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.
8.4.6
Pregnancy test
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.
In case a menstrual period is missed or if pregnancy is suspected between the scheduled visits a 
urine pregnancy test should be performed.
Pregnancy testing will not be required (unless required by local law) for women of non-childbearing 
potential defined as, but not limited to, women who have undergone a hysterectomy, bilateral 
oophorectomy or bilateral tubal ligation or who are postmenopausal (i.e. women above the age of 
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50, who have been without menstrual period for at least 1 year). The basis for non-bearing potential 
should be documented in medical records.
Contraceptive methods
Female subjects of childbearing potential must ensure using adequate contraceptive methods until 5 
weeks after the last date on trial product.
For Germany only: Only highly effective methods of birth control are accepted (i.e. one that results 
in less than 1% per year failure rate when used consistently and correctly such as implants, 
injectables, combined oral contraceptives, some intrauterine device), or sexual abstinence or 
vasectomised partner.
For United Kingdom only: Adequate contraceptive measures are defined as established use of oral, 
intravaginal, transdermal combined estrogen and progestogen hormonal methods of contraception; 
oral, injected or implanted progestogen only hormonal methods of contraception; placement of an 
intrauterine device or intrauterine hormone releasing system, bilateral tubal occlusion, barrier 
methods of contraception (condom or occlusive cap with spermicidal 
foam/gel/film/cream/suppository), female sterilisation, vasectomised partner (where partner is sole 
partner of subject), or true abstinence (when in line with preferred and usual lifestyle).
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 Japan only: Adequate contraceptive measures are abstinence (not having sex), diaphragm,
condom (by the partner), intrauterine device, sponge, spermicide or oral contraceptives.
For Argentina only: Birth control methods will be reimbursed by Novo Nordisk Pharma Argentina 
S.A.
8.4.7
Antibodies
Blood samples will be drawn for measurement of serum antibodies to semaglutide at selected visits
(see Section 2). Positive anti-semaglutide binding antibody samples will be further characterised for 
cross reactivity to native GLP-1. Samples which are positive for anti-semaglutide neutralising 
antibodies will be further characterised for in vitro neutralising effect towards semaglutide. In 
addition, samples which are positive for antibodies cross-reacting with native GLP-1 will be further 
analysed for in vitro neutralising effect towards native GLP-1.
Furthermore, samples drawn at randomisation may be used for calculations of the neutralising effect 
in the in vitro neutralising antibody assays. The in vitro neutralising assays will be performed by 
Novo Nordisk.
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At randomisation, the antibody sampling must be done pre-dose. 
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 visit 1 
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) or symptoms have been resolved in 
accordance to current guidelines33.
An 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.
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The record should include the following information: 
!
Start date and time of the hypoglycaemic episode.
!
Stop date and time of hypoglycaemic episode (stop time is the first time the plasma glucose 
value is > 3.9 mmol/L (70 mg/dL and/or symptoms have been resolved)).
If a stop date and time is not reported a hypoglycaemic episode will cover a period of 60 
minutes.
!
The plasma glucose level before treating the episode (if available) and any follow up 
measurements. 
The lowest value measured during the hypoglycaemic episode will be reported as the plasma 
glucose value for the episode, the remaining values will be kept as source data.
!
Whether the episode was symptomatic (Yes/No).
A hypoglycaemic episode starting without symptoms should be updated to symptomatic if the 
subject experience 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.
!
Date, time and dose of last trial product administration and other anti-diabetic treatments prior 
to the episode.
!
Date and time of last main meal (not including snacks) prior to the episode.
!
Whether the episode occurred in relation to physical activity.
!
Change in any concomitant illness.
!
Any sign of fever or other acute disease.
!
Whether the subject was asleep when the episode occurred.
o
If yes, whether the symptoms of the episode woke up the subject.
The answer to the question: "Was subject able to treat him/herself?" must be answered "No" for an 
episode requiring assistance of another person to actively administer carbohydrate, glucagon, or 
take other corrective actions. 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 concentration33.
Oral carbohydrates should not be given if the subject is unconscious.
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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 other 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 changed, medication 
error (i.e. overdose, mix-up between products), other factors not listed or unknown)
!
Did the subject experience seizure?
!
Was the subject unconscious/comatose?
!
Did the subject experience any of the following symptoms34 (layman term used in the diary is 
specified in brackets if different from the protocol term)?
o
Autonomic: sweating, trembling, hunger or palpitations (rapid or irregular heart beat)
o
Neuroglycopenic: confusion, drowsiness, speech difficulty, visual disturbances, odd 
behaviour, impaired balance or incoordination (reduced ability to coordinate 
movement)
o
General malaise: headache or malaise (feeling discomfort/unease)
o
Other symptoms?
The Investigator must review the diary at each contact for low SMPG values not reported as 
hypoglycaemic episodes (see Section 2 for relevant visits). The subject must be questioned whether 
any of the low values were severe i.e. whether the subject was able to self-treat or not. If the subject 
was not able to self-treat it has to be reported as a severe hypoglycaemic episode on a 
hypoglycaemic episode form.
Low SMPG values for non-severe hypoglycaemic episodes not having a hypoglycaemic episode 
form completed within 7 days since the SMPG measurement should be reported on a 
hypoglycaemic episode form with as much information as possible. Novo Nordisk will not query 
for additional data except for the date, SMPG value and whether the subject was able to self-treat 
due to decreased validity of such data 35,36.
The subject must be re-trained in how to report hypoglycaemic episodes if the investigator identifies 
low SMPG values not reported as hypoglycaemic episodes.
If the hypoglycaemic episode fulfils the criteria for an SAE then an AE form and a safety 
information form (SIF) must also be filled in, see Section 12.
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8.5
Laboratory assessments
The laboratory analyses will mainly be performed by a central laboratory. Anti-semaglutide 
antibodies, in vitro neutralising effect, IgE anti-semaglutide antibodies and PK samples will be 
analysed by a special laboratory and Novo Nordisk A/S (see Sections 8.4.7, 8.6.1 and 8.7.2. For
some of the analyses described in Section 8.7.1 and 8.7.1 a local laboratory must be used.
The handling, transportation and storage of biological samples are described in the laboratory 
manual (for central and special 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 and 
the investigator must review all laboratory results for signs of concomitant illness and AEs and 
report these according to Section 8.7 and 12). However, anti-semaglutide antibody and semaglutide 
plasma concentration results will not be available to the investigator during the trial. These results 
will be provided to the investigator upon request after the completion of the clinical trial report 
(CTR).
The laboratory provides results to the trial sites in the units preferred by the trial sites while the 
results that are transferred to the trial database will always be in SI units.
The laboratory equipment may provide analyses not requested in the protocol but produced 
automatically in connection with the requested analyses according to specifications in the laboratory 
standard operating procedures. Such data will not be transferred to the trial database, but abnormal 
values will be reported to the investigator. 
For Brazil only: All laboratory results will be communicated to the investigators.
All laboratory samples will be destroyed at the latest at the completion of the CTR, except samples 
obtained for anti-semaglutide antibody analysis. Antibody samples may be retained until drug 
approval by FDA and/or European Medicines Agency (EMA). The retained antibody samples may 
be used for further characterisation of antibody responses towards drug if required by health 
authorities or for safety reasons, see Section 24.2.
For Brazil only: Biological samples from Brazil will be destroyed at the end of the trial.
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8.5.1
Fasting plasma glucose
FPG is measured in order to evaluate glycaemic control. The subject must attend these visits fasting
(see Section 8.1.2).
Low FPGs reported by a laboratory in connection to trial related visits, i.e. FPG results ≤ 3.9 
mmol/L (70 mg/dL), should not be reported as hypoglycaemic episodes but as an AE (e.g. a FPG 
result of 2.9 mmol/L (52 mg/dL) should be reported as “low plasma glucose of 2.9 mmol/L (52 
mg/dL)”). See Section 12 for reporting of AEs.
8.6
Other assessments
8.6.1
Pharmacokinetics
The blood samples for the population PK will be drawn in a sub population for bioanalysis of
semaglutide plasma concentrations (see Section 2). The sub population will include approximately 
50% of all randomised subjects and the selection of sites to participate will be done in collaboration 
with local Novo Nordisk affiliate. The investigator must record the exact date and time for sampling 
the blood for PK analysis in the eCRF. The date and time of the latest trial product administration 
prior to the visit must be recorded by the subject in the subject diary and transcribed to the eCRF by 
the investigator.
8.6.2
Subject diary
The diaries should be handed out at the visit 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 and time of first trial product administration
!
date and time of last trial product administration prior to visits with PK sampling
!
hypoglycaemic episodes
!
changes in concomitant medication
!
AEs
!
SMPG 7-point profile
8.7
Additional safety assessments
All AEs must be collected and reported according to the procedures described in Section 12.
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8.7.1
Assessments in case of suspicion of acute pancreatitis
Most patients with acute pancreatitis experience abdominal pain that is located generally in the 
epigastrium and radiates to the back. The onset of the pain may be swift reaching maximum 
intensity within 30 min, it is frequently unbearable and characteristically persists for more than 24 
hours without relief.46 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 pancreatitis.46 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 features47: 
!
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 Section 6.5 and 8.1.5). The event should be reported as an 
AE requiring additional data collection (see Section 12.1) and Appendix B) and will undergo 
assessment by the EAC (see Section 12.7.2).
8.7.2
Assessments in case of suspicion of hypersensitivity reactions
In case of suspicion of a severe immediate systemic hypersensitivity reaction48 to the trial product, 
the subject must be discontinued from trial product but should remain in the trial (see Section 6.5
and 8.1.5).
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 V17A. 
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Furthermore, a blood sample for assessment of anti-semaglutide IgE antibodies should be drawn as 
soon as possible after the event and at V17A and sent to central laboratory for analysis. Tryptase 
concentrations, if available, should be included in the specific event form when reporting the AE.
In case of suspicion of immune complex disease48, the subject must be discontinued from trial 
product but should remain in the trial (see 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.
The event should be reported as an AE requiring additional data collection (see Section 12.1 and 
Appendix B).
8.7.3
Assessments in case of increased levels of creatine kinase
In case of CK > 10x upper normal level (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. 
The event should be reported as an AE requiring additional data collection (see Section 12.1 and 
Appendix B).
8.7.4
Assessments in case of increased levels of aminotransferases
In case of
1. ALT or AST >3x UNL and total bilirubin >2x UNL,
the event must be reported as an SAE (see Section 12.1). 
2. ALT or AST >10x UNL and total bilirubin ≤2x UNL, 
the event should be reported as an AE requiring additional data collection(see Section 12.1 and 
Appendix B).
For both events prompt repeat testing (at central laboratory) including ALT, AST, ALP and total 
bilirubin should be done and discontinuation of trial product considered. Thereafter, repeat testing 
(at central laboratory) of ALT, AST, ALP and total bilirubin should be done regularly until the 
abnormalities return to normal or baseline state. Additional clinical information should be gathered 
to seek a possible cause of the observed laboratory test abnormalities.
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8.8
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 and dose packs. 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 subjects medical record.
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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 IMPs and will be provided by Novo Nordisk A/S, 
Denmark:
Table 9–1
Investigational medicinal products
Trial product
Strength
Dosage form
Route of 
administration
Container/
delivery device 
Semaglutide 3 mg tablet 
3 mg
Tablet
Oral
Dose packa
Semaglutide 7 mg tablet
7 mg
Semaglutide 14 mg tablet 
14 mg
Placebo I tablet 
N/A
Sitagliptin (Januvia®) tablet
100 mg
Tablet
Oral
Dose packa
Placebo II tablet
N/A
aOne dose pack contains one blister pack.
Metformin and SU and rescue medication are considered NIMPs and will not be supplied by Novo 
Nordisk. However, metformin and SU will be reimbursed if required by the country’s regulatory 
authority or IRB/IEC.
 
For Japan only: During the treatment period, all anti diabetic medication including pre-trial OADs 
will  be reimbursed by Novo Nordisk Japan according to the local requirement.
Oral semaglutide and the corresponding placebo tablets are white to light yellow oval shaped tablets 
embossed with "M8" on one side. The comparator sitagliptin and the corresponding placebo tablets 
are beige, round, convex tablets engraved with "277" on one side. For both semaglutide and 
sitagliptin, respectively, the active drug and the corresponding placebo tablets are identical with 
regard to visual appearance and all semaglutide tablets are visually identical to each other, 
irrespective of dose levels.
9.2
Labelling
The trial products will be labelled in accordance with Annex 1349, local regulations and trial 
requirements.
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Each trial site will be supplied with sufficient trial product 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.
Table 9–2
Storage conditions for investigational medicinal products
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
Placebo I tablet
Sitagliptin (Januvia®) 100 mg tablet
Do not store above 30ºC
(86ºF)
Do not freeze
Do not refrigerate
Store in the original package
Must not be used if tablets 
appear damaged, if the blister 
pack is broken or unsealed 
before use
Placebo II tablet
The investigator must ensure the availability of proper storage conditions and also record and 
evaluate the temperature. The investigator must inform Novo Nordisk immediately if any trial 
product has been stored outside specified conditions (e.g. outside temperature range).
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.
For Japan only: The head of the study site or the trial product storage manager if assigned by the 
head of the study site must ensure the availability of proper storage conditions, record and evaluate 
the temperature.
9.4
Drug accountability and destruction
Drug accountability is the responsibility of the investigator.
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Subjects must be instructed to return all used, partly used and unused trial products including empty 
packaging material at each dispensing visit.
Returned trial product (used/partly used or unused including empty packaging material) can be 
stored at room temperature and must be stored separately from non-allocated trial product.
Drug accountability is performed by using the IWRS. Only dispensed DUNs returned by the subject 
(used/partly used or unused) are accounted for. Drug accountability should be done on tablet level.
Destruction will be done according to local procedures after accountability is finalised and verified 
by the monitor. Destruction of products must be documented and recorded in IWRS including 
destruction confirmation.
9.5
Auxiliary supplies
The following will be provided by Novo Nordisk A/S in accordance with the TMM:
•
BG meters and BG meter auxiliaries 
For Japan only: The trial sites are allowed to purchase and supply themselves with auxiliary 
supplies, if possible. BG meters must be the same model as supplied by Novo Nordisk.
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10
Interactive web response system
A trial-specific IWRS will be set up which can be accessed at any time via the internet or telephone. 
Access to the IWRS must be restricted to and controlled by authorised persons. 
IWRS is used for: 
!
Screening
!
Screening failure
!
Randomisation
!
Medication arrival
!
Dispensing
!
Treatment discontinuation
!
Completion
!
Code break
!
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 and breaking of blinded codes
The trial is a double-blinded trial. A randomisation session will be carried out for all subjects using 
IWRS. 
At the randomisation visit (visit 2) subjects meeting all eligibility criteria will be randomised to one
of four parallel treatment arms as described in Section 5.1.
11.1
Breaking of blinded codes
The IWRS will notify Novo Nordisk (monitor and the Global Safety department) immediately after 
the code is broken.
The code for a particular subject may be broken in a medical emergency if knowing the actual 
treatment would influence the treatment of the subject. Whenever a code is broken the person 
breaking the code must print the Code Break Confirmation Notification generated by the IWRS, 
record the reason and sign and date the document.
When the code is broken, the treatment allocation will be accessible to the investigator and the 
Novo Nordisk Global Safety department. If IWRS is not accessible at the time of code break the 
IWRS helpdesk should be contacted. Contact details are listed in Attachment I. If the code has been 
broken the subject should discontinue treatment with trial product but be asked to continue in the 
trial (see Section 8.1.5). A treatment discontinuation session must be completed in IWRS.
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12 Adverse events, technical complaints and pregnancies
12.1
Definitions
Adverse event 
An adverse event (AE) is any untoward medical occurrence in a subject administered a product and 
which does not necessarily have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom or disease temporally associated with the use of a product, whether or not 
considered related to the product.
An AE includes:
!
A clinically significant worsening of a concomitant illness.
!
A clinical laboratory adverse event (CLAE): a clinical laboratory abnormality which is 
clinically significant, i.e. an abnormality that suggests a disease and/or organ toxicity and is of a 
severity that requires active management. Active management includes active treatment or 
further investigations, for example change of medicine dose or more frequent follow-up due to 
the abnormality.
The following should not be reported as AEs:
!
Pre-existing conditions, including those found as a result of screening procedures (pre-existing 
conditions should be reported as medical history or concomitant illness).
!
Pre-planned procedures unless the condition for which the procedure was planned has worsened 
from the first trial related activity after the subject has signed the informed consent.
!
Non-serious hypoglycaemia is an AE, but is reported on a hypoglycaemic episode form instead 
of on an AE form, see Section 8.4.8. 
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.
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. 
Suspicion of transmission of infectious agents via the trial product must always be considered 
an SAE. 
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 dyscrasiasis or convulsions that do not result in hospitalisation, or development of drug 
dependency or drug abuse.
Trial specific serious adverse event
The following laboratory abnormalities must be reported as an SAE:
!
ALT or AST >3x UNL and total bilirubin >2x UNL
Additional assessments should be made for events meeting the above criterion (see Section 8.7.4).
Non-serious adverse event
A non-serious AE is any AE which does not fulfil the definition of an SAE.
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Adverse events requiring additional data collection
Adverse events requiring additional data collection are events which, in the evaluation of safety, 
have a special focus (e.g. required by the health authorities). The AEs requiring additional data 
collection are:
!
Acute coronary syndrome (myocardial infarction or hospitalisation for unstable angina)
!
Cerebrovascular event (stroke or transient ischaemic attack (TIA))
!
Heart failure requiring hospitalisation
!
Pancreatitis 
!
Neoplasm (excluding thyroid neoplasm)
!
Thyroid disease (including thyroid neoplasm)
!
Renal event 
!
Hypersensitivity reactions
!
Acute gallstone disease
!
Medication error (concerning trial products):
o
Administration of wrong drug. 
Note: Use of wrong DUN is not considered a medication error.
o
Wrong route of administration.
o
Administration of an overdose with the intention to cause harm (e.g. suicide 
attempt).
o
Accidental administration of a higher dose than intended. 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) > 10x UNL
!
Hepatotoxicity events:
o
ALT or AST > 10x UNL and total bilirubin ≤ 2x UNL
o
Hepatotoxicity leading to trial product discontinuation 
Technical complaint
A technical complaint is any written, electronic, or oral communication that alleges product 
(medicine or device) defects. The technical complaint may be associated with an AE, but does not 
concern the AE itself.
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Examples of technical complaints:
!
The physical or chemical appearance of trial products (e.g. discoloration, particles or 
contamination)
!
The packaging material (e.g. cracks or errors in labelling text)
12.2
Reporting of adverse events
All events meeting the definition of an AE must be collected and reported. This includes events 
from the first trial-related activity after the subject has signed the informed consent until the end of 
the post-treatment follow-up period (V17) for subjects on trial product OR until the end of trial 
(V16 or V17A, whichever comes last) for the subjects who have discontinued trial product 
prematurely. 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. Novo Nordisk assessment of expectedness is performed according to the following 
reference documents: 
!
IB for Oral administration of semaglutide (NN9924), edition 623 and any updates hereof. 
!
Summary of Product Characteristics (SmPC) for Januvia® (sitagliptin)50 and any updates hereof.
All AEs must be recorded by the investigator on an AE form. The investigator should report the 
diagnosis, if available. If no diagnosis is available, the investigator should record each sign and 
symptom as individual AEs using separate AE forms.
For SAEs, a SIF must be completed in addition to the AE form. A SIF is a form to collect 
supplementary clinical information. If several symptoms or diagnoses occur as part of the same 
clinical picture, one SIF 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 event specific forms 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.
Some events will undergo event adjudication by the Event Adjudication Committee (EAC), please 
refer to Section 12.7.2. For AEs qualifying for event adjudication, the Event Adjudication Form will 
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also have to be completed in the eCRF. The Event Adjudication Form is a checklist of clinical data
to be provided from the site.
For an overview of AEs requiring additional data collection and AEs that will undergo event 
adjudication, please see Table 12–1.
Table 12–1
Overview of AEs requiring additional data collection and AEs subject to event 
adjudication
Event
AEs requiring additional 
data collection
Event adjudication
Death
No
Yes
Acute coronary syndrome (myocardial infarction or 
hospitalisation for unstable angina)
Yes
Yes
Cerebrovascular event (stroke or transient ischaemic 
attack)
Yes
Yes
Heart failure requiring hospitalisation
Yes
Yes
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 reactions
Yes
No
Acute gallstone disease
Yes
No
Medication error
Yes
No
Lactic acidosis
Yes
Yes
Creatine kinase (CK) > 10x UNL
Yes
No
Hepatotoxicity events
Yes
No
Timelines for initial reporting of AEs:
The investigator must complete the following forms in the eCRF within the specified timelines:
!
SAEs: The AE form within 24 hours and the SIF within 5 calendar days of the investigator's 
first knowledge of the SAE.
Both forms must be signed within 7 calendar days from the date the information was entered in 
the eCRF. 
!
SAEs fulfilling criteria for additional data collection: In addition to above, the corresponding 
specific event form within 14 calendar days of investigators knowledge of the event.
!
Events for adjudication: Specific Event Adjudication Form must be completed within 14 
calendar days. The investigator should preferably provide the medical documentation within 4 
weeks of event identification.
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If the eCRF is unavailable, the concerned AE information must be reported on paper forms and sent 
to Novo Nordisk by fax, e-mail or courier within the same timelines as stated above. When the 
eCRF becomes available again, the investigator must enter the information on the appropriate forms 
in the eCRF.
The AE form for a non-serious AE should be signed when the event is resolved or at the end of the 
trial.
Contact details (fax, telephone, e-mail and address) are provided in the investigator trial master file.
An AE is observed 
and reported 
Fulfilling seriousness 
criteria?
It is an SAE
complete:
! AE form ≤ 24 hours
! SIF ≤ 5 calendar days
It is a non-serious AE
complete:
! AE form
Requiring 
additional data 
collection?
Requiring 
additional data 
collection?
Complete:
! Specific event form ≤ 14  calendar days
Yes
Complete: 
! Specific event form
Yes
No
Yes
Complete:
! Adjudication form ≤ 14 calendar days
Yes
AE: adverse event
SAE: serious adverse event
SIF: safety information form
All timelines are from the investigator’s
first knowledge of the event
Events for adjudication are described in chapter 12.7.2
Is the event to 
be adjudicated?
Is the event to 
be adjudicated?
Complete:
! Adjudication form  ≤ 14 calendar days
Yes
Figure 12–1
Initial reporting of AEs
Reporting of trial product-related SUSARs by Novo Nordisk:
Novo Nordisk will notify the investigator of trial product-related suspected unexpected serious 
adverse reactions (SUSARs) in accordance with local requirements and GCP.1 In addition, the 
investigator will be informed of any trial-related SAEs that may warrant a change in any trial 
procedure.
In accordance with regulatory requirements, Novo Nordisk will inform the regulatory authorities, 
including EMA, of trial product-related SUSARs. In addition, Novo Nordisk will inform the 
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IRBs/IECs of trial product-related SUSARs in accordance with local requirement and GCP1, unless 
locally this is an obligation of the investigator.
Novo Nordisk products used as concomitant medication:
If an SAE is considered to have a causal relationship with a Novo Nordisk marketed product used 
as concomitant medication in the trial, it is important that the suspected relationship is reported to 
Novo Nordisk, e.g. in the alternative aetiology section on the SIF. Novo Nordisk may need to report 
this AE to relevant regulatory authorities.
12.3
Follow-up of adverse events
The investigator must record follow-up information by updating the 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 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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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/7 mg/14 mg or placebo I tablets
!
Sitagliptin 100 mg or placebo II tablets
which occur from the time of first usage of the product until the time of the last usage of the 
product, must be collected and reported to Customer Complaint Center, Novo Nordisk.
Contact details (fax, e-mail and address) are provided in Attachment I to the protocol.
The investigator must assess whether the technical complaint is related to any AEs or SAEs.
Technical complaints must be reported on a separate technical complaint form. A technical 
complaint form for each code number or for each DUN must be completed.
The investigator must complete the technical complaint form in the eCRF within the following 
timelines of the trial site obtaining knowledge of the technical complaint:
!
Technical complaint assessed as related to an SAE within 24 hours
!
All other technical complaints within 5 calendar days
If the eCRF is unavailable or when reporting a technical complaint that is not subject related, the 
information must be provided on a paper form by fax, e-mail or courier to Customer Complaint 
Center, Novo Nordisk, within the same timelines as stated above. When the eCRF becomes 
available again, the investigator must enter the information on the technical complaint form in the 
eCRF.
12.4.2
Collection, storage and shipment of technical complaint samples
The investigator must collect the technical complaint sample and notify the monitor within 5 
calendar days of obtaining the sample at trial site. The monitor must coordinate the shipment to 
Customer Complaint Center, Novo Nordisk (the address is provided in Attachment I) and ensure 
that the sample is sent as soon as possible. A print or copy of the technical complaint form must be 
sent with the sample.
The investigator must ensure that the technical complaint sample contains the code number and, if 
available, the DUN.
If the technical complaint sample is unobtainable, the investigator must specify on the technical 
complaint form why it is unobtainable.
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Storage of the technical complaint sample must be done in accordance with the conditions 
prescribed for the product. The shipment of the technical complaint sample should be done in 
accordance with the same conditions as for storage (see Section 9).
12.5
Pregnancies in female subjects
Female subjects must be instructed to notify the investigator immediately if they become pregnant 
during the trial. The investigator must report any pregnancy in subjects who have received trial 
product(s).
The investigator must follow the pregnancy until the pregnancy outcome and 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. 
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.
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Forms and timelines for reporting AEs:
Non-serious AEs: 
–
Paper AE form* within 14 calendar days of the investigator's first knowledge of the initial 
or follow-up information to the non-serious AE.
SAEs: 
–
Paper AE form* within 24 hours of the investigator's first knowledge of the SAE.
–
Paper SIF within 5 calendar days of the investigator's first knowledge of the SAE.
–
SAE follow-up information to the AE form and/or SIF within 24 hours of the 
investigator's first knowledge of the follow-up information.
*
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.
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 (mild/moderate) include: hunger, slight headache, 
nausea, light-headedness, palpitations and sweating. Severe hypoglycaemia may produce loss of 
consciousness. Symptoms of non-severe hypoglycaemia should be treated by ingestion of 
carbohydrates.
Severe hypoglycaemia resulting in loss of consciousness should be treated at the investigator’s 
discretion according to best available medical practise.
One case of accidental overdose of oral semaglutide was reported in the NN9924-3692 trial in a 
subject treated with 
 mg oral semaglutide once daily. The subject accidentally took the trial 
product 
. No AEs were reported at the same time. The medication error 
was discovered at the next scheduled visit. The subject did not report any symptoms and treatment 
was continued without any change.
One case of accidental overdose has been reported in s.c. semaglutide once weekly treated subjects. 
The case classified as moderate in severity and considered to be probably related to semaglutide 
was reported by a subject enrolled in the trial NN9535-1821. No hospitalisation was needed. The 
subject inadvertently injected  mg of semaglutide instead of 0.4 mg, which corresponds to a 
fold higher dose than the maximum dose included in that trial. After 
 hours the subject felt 
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nauseated, vomited and had a headache. The subject was instructed to drink sufficient amounts of 
fluids. 
 the subject wished to continue in the 
trial. PG levels, blood pressure and pulse were monitored during the following days and no 
symptoms of hypoglycaemia or any other symptoms or signs were noted. The subject was 
withdrawn from the trial after 
 days of treatment due to an AE (diarrhoea).
For further details please see the current edition of the IB for Oral administration of semaglutide 
(NN9924), edition 623, 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. The oral semaglutide safety committee may recommend unblinding of any data 
for further analysis and in this case an independent ad hoc group will be established in order to 
maintain the blinding of the trial personnel.
12.7.2
Event adjudication committee
An independent external event adjudication committee (EAC) is established to perform qualitative 
or quantitative validation of selected AEs according to pre-defined diagnostic criteria. The
validation is based on review of pre-defined clinical source 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 EACs 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 FDA requirements51.
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 
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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 assessments made by the EAC will be included in the clinical trial report as well as assessments 
made by the investigator. However, the adjudication made by an EAC, given its independence and 
in-depth analysis of each event, will be attributed with greater importance of the two. The outcome 
of adjudication will be kept in the clinical trial database.
The following AEs will be adjudicated in this trial:
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 (UAP)
!
Acute myocardial 
infarction (STEMI or 
NSTEMI), silent MI
!
Unstable angina pectoris
requiring hospitalisation
Cerebrovascular 
events
!
Episode of focal or global neurological 
dysfunction caused by brain, spinal cord, or retinal 
vascular injury as a result of haemorrhage or 
infarction
!
Transient Ischaemic Attack (TIA) is defined as a 
transient episode (< 24 hours) of focal 
neurological dysfunction caused by brain, spinal 
cord, or retinal ischaemia, without acute infarction
!
Ischaemic stroke
!
Haemorrhagic stroke
!
Undetermined stroke
!
TIA
Heart failure 
requiring 
hospitalisation
!
Hospitalisation with a primary diagnosis of heart 
failure (new episode or worsening of existing heart 
failure)
!
Heart failure requiring 
hospitalisation
Acute pancreatitis
The diagnosis of acute pancreatitis requires two of the 
following three features:
!
Abdominal pain consistent with acute pancreatitis 
(acute onset of a persistent, severe, epigastric pain 
often radiating to the back)
!
Serum lipase activity (and/or amylase activity) at 
least three times greater than the upper limit of 
normal
!
Characteristic findings of acute pancreatitis on 
imaging
Acute pancreatitis
!
Mild
!
Moderate 
!
Severe
Malignant 
neoplasm
Malignant neoplasms are defined as
!
neoplasms in which abnormal cells divide without 
control and can invade nearby tissues and/or 
!
Malignant neoplasm
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spread to other parts of the body through the blood 
and lymph systems
Thyroid neoplasms are excluded in this event category
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 injury52 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
All AEs will be screened for potential missed events for adjudication and if needed, the investigator 
will be asked to provide additional information such as an alternative aetiology, underlying cause(s) 
and/or clinical details.
The event adjudication vendor or EAC can decide to have an AE adjudicated even if not initially 
reported as an event for adjudication by the investigator.
Event adjudication will be performed for AEs in randomised subjects including AEs with an onset 
date during the screening period. Event adjudication will not be performed for AEs in screening 
failures.
AEs for adjudication must be reported according to Section 12.2. In addition the specific event 
adjudication form should be completed within 14 calendar days of the investigator's first knowledge 
of the AE and all relevant predefined documents provided according to instructions in the event 
adjudication site manual.
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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 case report forms (CRF):
!
Pregnancy forms
In addition paper AE forms and paper SIFs will be provided. These must be used when access to the 
eCRF is revoked or if the eCRF is unavailable. The paper technical complaint form must also be 
used for complaints that are not subject specific.
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 CRF data may be made by the investigator or the investigator's delegated staff.
An audit trail will be maintained in the CRF application containing as a minimum: the old and the 
new data, identification of the person entering the data, date and time of the entry and reason for the 
correction.
If corrections are made by the investigator's delegated staff after the date the investigator has signed 
the case book, the case book must be signed and dated again by the investigator.
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.
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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 CTR is 
available, the data will be archived by Novo Nordisk.
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14 Monitoring procedures 
During the course of the trial, the monitor will visit the trial site to ensure that the protocol is 
adhered to, that all issues have been recorded, to perform source data verification and to monitor 
drug accountability. The first monitoring visit will be performed as soon as possible after FSFV at 
the trial site and no later than 4 weeks after. The monitoring visit intervals will depend on the 
outcome of the remote monitoring of the CRFs, the trial site's recruitment rate and the compliance 
of the trial site to the protocol and GCP, but will not exceed 12 weeks for trial sites with active 
subjects (defined as subjects in screening, treatment or follow-up).
The monitor must be given direct access to source documents (original documents, data and 
records). Direct access includes permission to examine, analyse, verify and reproduce any record(s) 
and report(s) that are important to the evaluation of the trial. If the electronic medical record does 
not have a visible audit trail, the investigator must provide the monitor with signed and dated 
printouts. In addition the relevant trial site staff should be available for discussions at monitoring 
visits and between monitoring visits (e.g. by telephone).
All data must be verifiable in source documentation other than the CRF (BMI and age are not 
source data verified as they are calculated in EDC).
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 CRFs 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 must 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 CRF. If discrepancies are 
found, the investigator must be questioned about these.
A follow-up letter (paper or electronic) will be sent to the investigator following each monitoring 
visit. This should address any action to be taken.
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15 Data management
Data management is the responsibility of Novo Nordisk. Data management may be delegated under 
an agreement of transfer of responsibilities to another data management unit within Novo Nordisk 
or an external 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
The blinding of the randomised treatments will be maintained until the database has been released 
for statistical analysis. No interim analyses or other analyses of unblinded data will be performed 
before the database is locked.
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 combinations (metformin; 
metformin+SU) will be included based on the actual information collected through the eCRF. In 
case of missing eCRF information the information collected from 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 ½LLoQ. Number of 
values below LLoQ by treatment and visit will be summarised if deemed relevant.
The primary and confirmatory efficacy endpoints will be confirmed at week 26. This approach will 
result in a lower proportion of missing data compared to the expected proportion of missing data at 
week 52 and week 78 and therefore a more reliable estimate of efficacy. 
Results from a statistical analysis will as a minimum be presented by the estimated treatment 
contrasts for the below three comparisons at week 26, week 52 and week 78 with associated two-
sided 95% confidence intervals and p-values corresponding to two-sided tests of no difference:
!
oral semaglutide 14 mg vs. sitagliptin 100 mg
!
oral semaglutide 7 mg vs. sitagliptin 100 mg
!
oral semaglutide 3 mg vs. sitagliptin 100 mg
If no statistical analysis is specified, data will be presented using relevant summary statistics.
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Primary and secondary estimands
Two estimands adressing different aspect of the trial objective will be defined; a primary de-facto 
(effectiveness) estimand and a secondary de-jure (efficacy) estimand: 
!
Primary estimand
o
de-facto treatment difference at week 26 for all randomised subjects
!
Secondary estimand 
o
de-jure treatment difference at week 26 for all randomised subjects if all subjects 
adhered to treatment and did not initiate rescue medication
The primary de-facto estimand assesses the average effect in a future population that results from 
initiating treatment with oral semaglutide including potential rescue medication(s) as compared to 
initiating treatment with sitagliptin 100 mg including potential rescue medication(s). Generalisation 
of this estimand depends among other things on the extent to which the use of rescue medication 
and treatment adherence in this trial reflects clinical practice. All post-baseline scheduled visit data 
will be included in the analysis, including data collected after discontinuation of trial product or 
initiation of rescue medication(s).
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 100 
mg. 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 100 mg for 
purposes of treating individual subjects. Generalisation of this estimand depends among other 
things on the extent to which the compliance to trial product administration in this trial reflects 
clinical practice. Only post-baseline scheduled visit data collected prior to discontinuation of trial 
product or initiation of rescue medication will be included in the analysis. This will avoid 
confounding from rescue medication. 
Missing data considerations at week 26
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), when estimating the 
primary estimand , is expected to be maximum 10% based on the oral semaglutide phase 2 trial 
(NN9924-3790). Thus, missing data will be due to withdrawal from trial or lost to follow-up.
The proportion of missing data when estimating the secondary estimand is expected to be higher 
(20%) since data collected after discontinuation of trial product or initiation of rescue medication(s) 
will be set to missing. The 20% of missing data is based on the sitagliptin phase 3 trials50 the oral 
semaglutide phase 2 trial (NN9924-3790) and the indication that a low starting dose with gradual 
dose escalation diminishes GI AEs compared with more aggressive dosing regimens. Across 
treatment arms the main reasons for missing data are expected to be early treatment discontinuation 
due to GI AEs and eventually initiation of rescue medication. Initiation of rescue medication is 
expected to be more frequent in the sitagliptin 100 mg arm and in the oral semaglutide 3 mg arm
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than for the two highest dose levels of oral semaglutide. A higher proportion of subjects are 
expected to discontinue treatment due to AEs in the oral semaglutide 14 mg arm, compared to the 
other treatment arms. So overall the frequency of missing data is expected to be similar across 
treatment arms.
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 is change from baseline to week 26 in HbA1c. For HbA1c both non-inferiority 
and superiority versus sitagliptin 100 mg are planned to be tested at each dose level. The 
confirmatory secondary endpoint is change from baseline to week 26 in body weight (kg). For body 
weight, superiority versus sitagliptin 100 mg is planned to be tested at each dose level. The sample 
size calculation is based on jointly meeting the below three out of the nine pre-specified 
confirmatory hypotheses shown in Figure 17–1. The closed testing procedure described in Bretz et 
al 201153 is used to control the overall type-1 error at a nominal two-sided 5% level. The three 
hypotheses are
!
HbA1c superiority of oral semaglutide 14 mg vs. sitagliptin 100 mg
!
HbA1c superiority of oral semaglutide 7 mg vs. sitagliptin 100 mg
!
HbA1c non-inferiority of oral semaglutide 3 mg vs. sitagliptin 100 mg (margin 0.3%) 
The statistical testing strategy is based on the following two principles:
!
Within a dose level, glycaemic efficacy must be established by HbA1c non-inferiority before 
testing for added benefits in terms of superiority for HbA1c and/or superiority of body weight. 
!
Glycaemic efficacy by HbA1c non-inferiority must be established on all higher dose levels 
before continuing testing hypotheses on lower dose levels.
The sample size is calculated using the calcPower function in the R package, gMCP54 using 10000 
simulations. All of the nine pre-specified confirmatory tests are assumed to be independent. Since 
positive correlations among the tests are expected, the assumption of independence is viewed as 
conservative.
The sample size assumptions for treatment effects (TE), adjusted treatment effects and the common 
standard deviation (SD) used across dose levels are given in Table 17–1. These are based on the 
oral semaglutide phase 2 results (NN9924-3790), sitagliptin phase 3a trial results50 and supported 
by results from the s.c. semaglutide phase 2 trial (NN9535-1821).
Since the equalising effect of rescue medication will be included in the primary analysis as well as a 
conservative approach for handling of missing data will be performed, an adjustment in treatment 
effect will be implemented for the 10% of subjects who discontinue trial product or initiate rescue 
medication and for the 10% of subjects with missing data. The treatment effects used in the sample 
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size calculation will be adjusted according to a 75% smaller effect in these subjects. In addition, the 
non-inferiority margin of 0.3 % for HbA1c is used, when testing for non-inferiority. The adjusted 
treatment effects for testing non-inferiority (HbA1c only) and superiority are as described below:
!
Non-inferiority 
o
0.8*TE + 0.2*TE*0.25 + non-inferiority margin*0.1
!
Superiority
o
0.8*TE + 0.2*TE*0.25 
Table 17–1
Assumptions for sample size calculation
Semaglutide vs. sitagliptin 
HbA1c
Body weight
Treatment dose
14 mg
7 mg
3 mg
14 mg
7 mg
3 mg
Treatment effect (TE)
-0.5%
-0.3%
-0.1%
-3.0 kg
-2.0 kg
-1.0 kg
Adjusted TE, non-inferiority
-0.395%
-0.225%
-0.055%
-2.52 kg
-1.67 kg
-0.82 kg
Adjusted TE, superiority
-0.425%
-0.255%
-0.085%
-2.55 kg
-1.70 %
-0.85%
Standard deviation 
1.1%
1.1%
1.1%
4.0 kg
4.0 kg
4.0 kg
With the above assumptions, allocating 465 subjects to each of the semaglutide treatment arms and 
sitagliptin 100 mg provides 90 % power to jointly confirm HbA1c superiority of semaglutide 14 mg 
vs. sitagliptin 100 mg, HbA1c superiority of semaglutide 7 mg vs. sitagliptin 100 mg and HbA1c
non-inferiority of semaglutide 3 mg vs. sitagliptin 100 mg. Calculated powers for selected 
individual hypotheses are presented in Table 17–2. In total 4×465 = 1860 subjects are planned to be 
randomised.
Table 17–2
Powers for individual hypotheses
Statistical test
HbA1c superiority
Body weight superiority
HbA1c non-inferiority 
(margin = 0.3 %)
Treatment dose
14 mg
7 mg
3 mg
14 mg
7 mg
3 mg
3 mg
Power (%)
> 99
90
19
> 99
> 99
89
> 99
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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 non-
inferiority test of semaglutide 14 mg vs. sitagliptin 100 mg. The local significance level (α-local) 
will be reallocated if a hypothesis is confirmed according to the weight given by the directed edges 
between nodes (hypotheses).
 = 0.05
HbA1c (%)
Non-inferiority
 = 0
HbA1c (%)
Superiority
 = 0
HbA1c (%)
Non-inferiority
 = 0
Body weight (kg)
Superiority
1 3
⁄
1 2
⁄
1 3
⁄
1 3
⁄
1 2
⁄
1 2
⁄
1 2
⁄
 = 0
HbA1c (%)
Superiority
 = 0
HbA1c (%)
Non-inferiority
 = 0
Body weight (kg)
Superiority
1 3
⁄
1 2
⁄
1 3
⁄
1 3
⁄
1 2
⁄
1 2
⁄
1 2
⁄
 = 0
Body weight (kg)
Superiority
 = 0
HbA1c (%)
Superiority
1
1
semaglutide 7 mg
vs. sitagliptin 100 mg
semaglutide 3 mg
vs. sitagliptin 100 mg
semaglutide 14 mg
vs. sitagliptin 100 mg
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Protocol
CONFIDENTIAL
Date:
24 August 2015
Novo Nordisk
Trial ID: NN9924-4222
Version:
2.0
UTN: U1111-1168-4339 
Status:
Final
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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 
evaluation “as randomised”.
Safety analysis set (SAS): includes all subjects exposed to at least one dose of trial product. 
Subjects in the SAS will contribute to the evaluation based on the trial product received for the 
majority of the period where they were on treatment. This will be referred to as contributing to the 
evaluation “as treated”.
Per protocol (PP) analysis set: includes all subjects in the full analysis set who fulfils the 
following criteria
!
have not violated any inclusion criteria
!
have not fulfilled any exclusion criteria
!
have a baseline HbA1cmeasurement
!
is exposed to trial product and have at least one HbA1c measurement at or after week 14
Subjects in the PP analysis set will contribute to the analysis “as treated”.
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 will be used restrictively and normally no subjects will be excluded 
from the FAS. If any subjects or observations are to be excluded from the analysis sets or the 
observation periods defined below, this, together with the reasons for their exclusion, will be 
documented and signed by those responsible before database lock. A description of these exclusions 
will be included in the clinical trial report.
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 (V17) for subjects on trial product
!
the End-of-treatment visit (V16) or the follow-up premature discontinuation visit (V17A), 
whichever comes last, 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.
!
First, subjects will be selected based on the specified analysis set
!
Next, data points on the selected subjects from first step will be selected based on the specified 
observation period
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Protocol
CONFIDENTIAL
Date:
24 August 2015
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Trial ID: NN9924-4222
Version:
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UTN: U1111-1168-4339 
Status:
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In this trial, three observation periods will be defined, as described below. 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, onset date will be the EAC adjudicated 
onset date.
Definition of the observation periods:
!
In-trial: This observation period will include information assessed at or after date of 
randomisation (as registered in the IWRS system) and up to and including the last direct 
subject-site contact, which is scheduled to take place 5 weeks (+3 days visit window) after the  
planned last dose on trial product at a follow-up visit. For subjects who withdraw their informed 
consent, the in-trial observation period ends at their date of withdrawal. If a subject is lost to 
follow-up, the end of the in-trial period is defined as the date of the last subject-investigator 
contact (site or phone visit). In the case a subject dies during the trial the date of death will be 
the end-date of the in-trial observation period regardless of the above defined end-dates. This 
observation period will be the primary observation period for estimating the primary estimand 
used for evaluating safety.
!
On-treatment: This observation period is a subset of the in-trial observation period and 
represents the time period in which a subject is considered exposed to trial product. For 
adjudicated events, ECGs, anti-semaglutide antibodies and AEs including hypoglycaemic 
episodes information collected on or after the first date of trial product up to and including the 
first date of (i) the follow-up visit V17, (ii) the follow-up prematurely discontinuation visit 
V17A, (iii) the last date on trial product +38 days or (iv) the end-date for the in-trial observation 
period will be used. The follow-up visit is scheduled to take place 5 weeks after the last date on 
trial product corresponding to approximately five half-lives of oral semaglutide. In addition, the 
ascertainment window includes the follow-up visit window of +3 days after last date on trial 
product. For efficacy and other safety assessments (laboratory assessments, physical 
examination and vital signs) information collected on or after the first date of trial product up to 
and including the last date on trial product +3 days will be used in order to ensure specificity to 
reversible effects of treatment. The end-date for all assessments in the on-treatment observation 
period will be before or the same date as the end-date for the in-trial observation period. This 
observation period will be considered supportive for evaluating efficacy and used for evaluating 
safety. 
!
On-treatment without rescue medication: This observation period is a subset of the on-
treatment observation period. To avoid potential confounding from rescue medications, 
information that is collected after initiation of rescue medication will be excluded from this 
observation period. Specifically, it includes information collected at or after date of first dose on 
trial product up to and including the first date of; (i) last date on trial product +3 days or 
(ii) initiation of rescue medication. Thus, an ascertainment window of 3 days for subjects not 
initiating rescue medication. This observation period will be the primary observation period for 
estimating the secondary estimand.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
24 August 2015
Novo Nordisk
Trial ID: NN9924-4222
Version:
2.0
UTN: U1111-1168-4339 
Status:
Final
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17.3
Primary endpoint 
The primary endpoint is change from baseline to week 26 in HbA1c.
17.3.1
Primary analysis for the primary estimand 
The primary estimand will be estimated based on the FAS using week 26 measurements from the 
in-trial observation period. The primary statistical analysis will be a pattern mixture model using 
multiple imputation to handle missing data assuming that the missing data mechanism is missing at 
random (MAR). Imputation of missing data at week 26 will be done within 16 groups of subjects 
defined by randomised treatment arm, stratification factor and whether subjects at week 26; (i) have 
discontinued treatment or initiated rescue medication or (ii) 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 26 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 as a categorical fixed effect and baseline 
HbA1c measurement as a covariate will be fitted to observed values of the change from baseline 
in HbA1c at week 26.
!
The estimated parameters for location and dispersion will be used to impute 100 values for each 
subject with missing week 26 data based on region and baseline HbA1c. Thus, 100 complete 
data sets will be generated including observed and imputed values.
Analysis used for confirming superiority versus sitagliptin at week 26:
For each of the 100 (now complete) imputed data sets the change from baseline to week 26 will be 
analysed using an ANCOVA with treatment, stratification factor and region as categorical fixed 
effects and baseline HbA1c as covariate. The results obtained from analysing the datasets will be 
combined using Rubin’s rule55 to draw inference.
From this analysis the estimated treatment differences between each of the oral semaglutide dose 
levels and sitagliptin 100 mg together with associated two-sided 95 % CIs and unadjusted two-sided 
p-values for testing no difference from zero will be presented.
Analysis used for confirming non-inferiority versus sitagliptin at week 26:
Prior to analysing the data using the same model and approach as used for confirming superiority 
(see above) a value of 0.3 % (the non-inferiority margin) will be added to imputed values at week 
26 for the oral semaglutide treatment arms only (Koch 2008)56. For evaluating non-inferiority 
versus sitagliptin 100 mg unadjusted two sided p-values for testing no difference from the non-
inferiority margin will be presented.
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Protocol
CONFIDENTIAL
Date:
24 August 2015
Novo Nordisk
Trial ID: NN9924-4222
Version:
2.0
UTN: U1111-1168-4339 
Status:
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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 26 from the on-treatment without rescue observation period. The primary 
analysis for the secondary estimand will be a Mixed Model for Repeated Measurements (MMRM). 
A restricted maximum likelihood (REML) will be used. The model will include all post baseline 
HbA1c measurements collected at scheduled visits up to and including week 26 as dependent 
variables. The independent effects included in the model will be treatment, stratification factor and 
region 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. For subjects who have no post-
baseline scheduled assessments available, the baseline value will be carried forward to the first 
scheduled visit to ensure that all randomised subjects will contribute to the statistical analysis.
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. Even if the assumption of MAR is not 
satisfied, this analysis is not expected to bias the estimated HbA1c treatment effect for the secondary 
estimand in favour of oral semaglutide to any important degree. This is supported by the oral 
semaglutide phase 2 results (NN9924-3790) that showed that subjects who discontinue oral 
semaglutide do not have better outcome on average than those who remain on treatment.
Primary hypotheses 
For the primary HbA1c endpoint the following two confirmatory one-sided hypotheses are planned 
to be tested at each dose level of oral semaglutide versus sitagliptin 100 mg. Let the mean treatment 
difference be defined as μ = (oral semaglutide minus sitagliptin 100 mg):
!
Non-inferiority, using a non-inferiority margin of 0.3 %
o
H0: μ ≥0.3 % against Ha: μ < 0.3 %
!
Superiority
o
H0: μ ≥0.0 % against Ha: μ < 0.0 %
Operationally the hypotheses will be evaluated by two-sided tests.
Multiplicity and criteria for confirming hypotheses
The Type-I error for testing the nine confirmatory hypotheses related to the HbA1c and body weight 
endpoints (see Section 17.1) will be preserved in the strong sense at 5 % (two-sided) using the 
weighted Bonferroni-based closed testing procedure described in Bretz et al 201153 and outlined in 
Figure 17–1. The first hypothesis to be tested is non-inferiority of HbA1c at the highest dose level. It 
will be tested at the overall significance level (5 %) while allocating 0 % local significance level to 
the remaining of the hypotheses. For this hypothesis, and in general, if a hypothesis is confirmed the 
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Protocol
CONFIDENTIAL
Date:
24 August 2015
Novo Nordisk
Trial ID: NN9924-4222
Version:
2.0
UTN: U1111-1168-4339 
Status:
Final
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significance level will be reallocated according to the weight and the direction of the edges going 
from the confirmed hypothesis to the next hypotheses as specified in Figure 17–1. Each of the 
following hypotheses will be tested at their local significance level (α-local). This process will be 
repeated until no further hypotheses can be confirmed.
Non-inferiority and/or superiority will be considered confirmed if the mean 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 its local two-sided significance level as defined by 
the closed testing procedure in Figure 17–1. This is equivalent to using a one-sided p-value 
(nominal alpha = 0.025) and a one-sided 2.5 % overall significance level in the closed testing 
procedure.
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 EMA recommendations57
and with a report from the US National Research Council58, these analysis will primary evaluate the 
sensitivity of the results due to the impact of missing data. Since conservatism, i.e. avoiding bias in 
favour of semaglutide, depends on the context, separate sensitivity analyses will be made for non-
inferiority and superiority testing.
The evaluation of the robustness of the primary analysis results will primarily be based on a pattern 
mixture model approach using multiple imputation. An overview of the sensitivity analyses for each 
of the estimands are specified below followed by a more detailed description of the three different 
pattern mixture models used. Finally, three additional sensitivity analyses for the primary analysis 
will be described that are 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: 
!
A comparator multiple imputation analysis based on FAS using the in-trial observation period
(superiority).
!
A comparator multiple imputation analysis based on FAS using the on-treatment observation 
period (superiority). This sensitivity analysis aims to compare oral semaglutide versus 
sitagliptin 100 mg for subjects who adhere to treatment regardless of whether or not rescue 
medication has been initiated.
!
A comparator multiple imputation analysis differentiating between reasons for discontinuing 
treatment prematurely based on FAS using the in-trial observation period (superiority).
!
A tipping-point multiple imputation analysis based on FAS using the in-trial observation period
(non-inferiority and superiority).
!
A MMRM analysis (the primary for the secondary estimand) based on FAS using the in-trial 
observation period (non-inferiority and superiority).
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Protocol
CONFIDENTIAL
Date:
24 August 2015
Novo Nordisk
Trial ID: NN9924-4222
Version:
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UTN: U1111-1168-4339 
Status:
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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 (superiority).
!
A comparator multiple imputation analysis differentiating between reasons for discontinuing 
treatment prematurely based on FAS using the on-treatment without rescue medication 
observation period (superiority).
!
A tipping-point multiple imputation analysis based on FAS using the on-treatment without 
rescue medication observation period (non-inferiority and superiority).
17.3.3.1
Pattern mixture models
Common for the three pattern mixture model sensitivity analyses is that they all aim to stress-test 
the primary HbA1c results by changing the assumptions for part or all missing data in the oral 
semaglutide treatment arms, while maintaining the missing data assumption for the sitagliptin 100 
mg arm. The analyses will all be implemented using multiple imputation as described for the 
primary analysis of the primary estimand:
!
Comparator multiple imputation analysis: In this sensitivity analysis missing data at week 26 
for all subjects will be imputed to resemble in distribution the week 26 values observed in the 
sitagliptin 100 mg treatment arm. In effect this imputation approach removes the treatment 
difference between oral semaglutide and sitagliptin 100 mg for all subjects randomised to oral 
semaglutide, given that oral semaglutide is better than sitagliptin 100 mg. Due to the potential 
lack of sensitivity for testing non-inferiority this sensitivity analysis will only be used to 
evaluate the robustness of HbA1c superiority conclusions.
!
Comparator multiple imputation analysis differentiating between reasons for discontinuing 
treatment prematurely: In this sensitivity analysis missing data at week 26 for subjects who 
discontinue oral semaglutide treatment due to treatment related AE(s) will be imputed to 
resemble in distribution the week 26 values observed in the sitagliptin 100 mg treatment arm. 
Treatment related AEs are defined as AEs classified as possible or probable related to trial 
product as reported by the investigator. In effect this imputation approach removes the treatment 
difference between oral semaglutide and sitagliptin 100 mg for this selected group of subjects 
randomised to oral semaglutide. This sensitivity analysis is less conservative as compared to the 
first sensitivity analysis. Due to the potential lack of sensitivity for testing non-inferiority this 
sensitivity analysis will only be used to evaluate the robustness of HbA1c superiority 
conclusions.
!
Tipping-point multiple imputation analysis: In this sensitivity analysis, missing data will first be 
imputed according to the primary analysis. Second, for all oral semaglutide treatment arms a 
penalty will be added to the imputed values at week 26. The approach is to gradually increase 
this penalty until all confirmed HbA1c conclusions from the primary analysis are reversed. For 
each hypothesis tested the specific value of the penalty that reverses the conclusion will be used 
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Protocol
CONFIDENTIAL
Date:
24 August 2015
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Trial ID: NN9924-4222
Version:
2.0
UTN: U1111-1168-4339 
Status:
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to evaluate the robustness of the primary analysis results. This sensitivity analysis will be used 
for evaluating the robustness of the HbA1c non-inferiority and superiority conclusions.
17.3.3.2
Other sensitivity analysis
The following additional sensitivity analysis will be specified
!
Per-protocol analysis: This sensitivity will be based on the per-protocol analysis set. Data from 
the in-trial observation period will be analysed using the primary analysis approach for the 
primary estimand. This sensitivity analysis will be used to evaluate the robustness of the HbA1c 
non-inferiority conclusions.
!
Complete case analysis: This sensitivity analysis will be based on the on-treatment without 
rescue medication observation period and include subjects in the FAS who have a valid HbA1c 
measurement at week 26. The change from baseline to week 26 in HbA1c will be analysed by a 
linear normal model (ANCOVA) with treatment, stratification factor and region as categorical 
fixed effects and baseline HbA1c as a covariate. This sensitivity analysis will be used to evaluate 
the robustness of the HbA1c non-inferiority conclusions. 
!
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 change from 
baseline to week 26 in HbA1c will be analysed by a linear normal model (ANCOVA) with 
treatment, stratification factor and region as categorical fixed effects and baseline HbA1c as a 
covariate. This sensitivity analysis will be used for evaluating the robustness of the HbA1c non-
inferiority and superiority conclusions.
17.3.3.3
Assessment of sensitivity analyses
The results from the sensitivity analyses will be collectively used to interpret the robustness of the 
trial results for HbA1c and body weight. Due to the large number of sensitivity analyses and their 
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. 
17.4
Secondary endpoints
17.4.1
Confirmatory secondary endpoints
Change from baseline to week 26 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. Body weight will only be tested for superiority. Baseline body weight 
will be used as a covariate instead of baseline HbA1c in both the imputation and analysis model.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
24 August 2015
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Trial ID: NN9924-4222
Version:
2.0
UTN: U1111-1168-4339 
Status:
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From the analyses the three estimated treatment differences between each of the oral semaglutide 
dose levels and sitagliptin 100 mg will be presented together with associated two-sided 95 % CIs 
and unadjusted two-sided p-values for testing no difference from zero.
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
Continuous efficacy endpoints
Change from baseline to week 52 and 78 in:
!
HbA1c
!
Body weight (kg)
Change from baseline to week 26, 52 and 78 in:
!
Body weight (%)
!
FPG
!
BMI
!
Waist circumference
!
Fasting lipid profiles (total cholesterol, LDL cholesterol, VLDL cholesterol, HDL cholesterol, 
triglycerides, free fatty acids)
Change from baseline to week 26, 52 and 78 in the below derived endpoints from the 7-point 
profile:
!
Mean of the 7-point profile, defined as the area under the profile, calculated using the 
trapezoidal method, divided by the measurement time
!
Mean increment over all meals
The above continuous endpoints will be analysed separately using similar model approaches as for 
the primary endpoint with the associated baseline response as a covariate. Fasting lipid profile 
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Protocol
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Date:
24 August 2015
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Trial ID: NN9924-4222
Version:
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UTN: U1111-1168-4339 
Status:
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endpoints will be log-transformed prior to analysis with the associated log-transformed baseline 
value as a covariate.
For evaluation of the primary estimand the analysis will be performed separately for week 26, 52 
and 78. For the analysis at week 52 and at week 78, the imputation of missing data will be further 
differentiated by whether subjects have discontinued trial product or initiated rescue medication 
prior to week 26 or at or after week 26. This will result in imputation of missing data within 32 
groups of subjects instead of the 16 groups as described for the week 26 evaluation in 
Section 17.3.1. The frequency of missing data is expected to be slightly larger at week 52 and week 
78 compared to week 26. The rate of missing data is expected to decline over time. 
For evaluation of the secondary estimand the MMRM based primary analysis will include all 
scheduled post-baseline measurement up to and including week 78. From this model the estimated 
treatment differences (ratios) will be presented at week 26 (except for HbA1c and body weight), 52 
and 78 with 95 % confidence intervals and two-sided p-values for test of no difference.
Binary efficacy endpoints
Subjects who after 26 weeks of treatment achieve (yes/no):
!
HbA1c < 7.0 % (53 mmol/mol) (ADA) target*
!
HbA1c ≤6.5 % (48 mmol/mol) (AACE) target
!
HbA1c reduction ≥1 %
!
Weight loss ≥3 %
!
Weight loss ≥5 %
!
Weight loss ≥10 %
!
HbA1c < 7.0 % (53 mmol/mol) without confirmed hypoglycaemia (treatment emergent severe or 
BG confirmed symptomatic hypoglycaemic episodes) and no weight gain
!
HbA1c reduction ≥1 % and weight loss ≥3 %
The above eight endpoints will be evaluated after week 52 and after week 78 as well.
Handling of missing data for the response status of the above categorical endpoints will be 
determined from the imputed continuous responses. A total of 100 imputed data sets will be created 
based on the same models as used to analyse HbA1c and body weight. For the secondary estimand 
the MMRM based analysis will be implemented in a MI setting. The imputed complete data sets 
will be analysed using a logistic regression model with treatment, stratification factor and region as 
categorical fixed effects and baseline response as covariate (i.e. baseline HbA1c for binary HbA1c 
endpoints, baseline weight for binary weight endpoints and both baseline HbA1c and body weight 
for the binary endpoint that combines both parameters). Inference comparing treatments will be
drawn using Rubin’s rule55.
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Protocol
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Date:
24 August 2015
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Trial ID: NN9924-4222
Version:
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UTN: U1111-1168-4339 
Status:
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Time to event endpoint
!
Time to rescue medication
Subjects completing the study without need for rescue medication will be censored at the time point 
of actual date of last trial product. Start time is date of first trial product. Time to rescue medication 
will be described and compared for each of the oral semaglutide dose level versus sitagliptin 100 
mg using likelihood ratio tests obtained from a proportional Cox hazards model. From this analysis 
the estimated Hazard ratios between each dose levels and sitagliptin will be presented together with 
95 % confidence intervals and two-sided p-values for test of no difference. This endpoint will be 
evaluated after week 26, after week 52 and after week 78.
17.4.2.2
Safety endpoints
The safety endpoints will be evaluated based on SAS using the on-treatment observation period and 
based on FAS 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 83 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. 
Other safety endpoints
Change from baseline to week 78 in:
!
Amylase
!
Lipase
!
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 
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separately as described above for continuous efficacy endpoints. Results will be presented at week 
26, 52 and 78. Amylase and lipase endpoints will be log-transformed prior to analysis with the 
associated log-transformed baseline value as a covariate.
Change from baseline to week 78 in:
!
Haematology 
!
Biochemistry (except for amylase and lipase)
!
Calcitonin
!
Electrocardiogram (ECG) evaluation
!
Physical examination
Occurrence of anti-semaglutide antibodies (positive/negative):
!
Anti-semaglutide binding antibodies
!
Anti-semaglutide neutralising antibodies 
!
Anti-semaglutide binding antibodies cross reacting with native GLP-1
!
Anti-semaglutide neutralising antibodies cross reacting with native GLP-1
Anti-semaglutide binding antibody levels
The above 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. 
Pharmacokinetics 
Please refer to Section 17.5.
Hypoglycaemia
!
Number of treatment emergent severe or BG confirmed symptomatic hypoglycaemic episodes
during exposure to trial product, assessed up to approximately 83 weeks
!
Treatment emergent severe or BG confirmed symptomatic hypoglycaemic episodes during 
exposure to trial product, assessed up to approximately 83 weeks (yes/no) 
Classification of Hypoglycaemia:
Hypoglycaemic episodes will be summarised for the SAS and the on-treatment observation period 
only.
Treatment emergent: hypoglycaemic episode 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).
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Date:
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Version:
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A treatment emergent hypoglycaemic episode is defined as a hypoglycaemic episode with onset in 
the on-treatment observation period (see definition of observation periods in Section 17.2).
Nocturnal hypoglycaemic episodes: are episodes occurring between 00:01 and 05.59 both inclusive.
Hypoglycaemic episodes are classified according to the Novo Nordisk classification of 
hypoglycaemia 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)59. 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:
!
Severe or BG confirmed symptomatic hypoglycaemia: An episode that is severe according to 
the ADA classification33 or BG confirmed by a PG value < 3.1 mmol/L (56 mg/dL) with
symptoms consistent with hypoglycaemia. 
ADA classification33 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
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 
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 factors for 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.
17.5
Pharmacokinetic modelling
Exploratory population PK modelling will be used to evaluate semaglutide exposure and the effects 
of pre-specified covariates on the exposure. As a minimum, the covariates sex, body weight at 
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baseline and age at baseline will be explored. The modelling will include data from approximately 
50 % of randomised subjects that were exposed to semaglutide in this trial and will be performed as 
a meta-analysis across phase 3a trials. Actual time points for dose administration and PK sampling 
will be used. Results will be presented using criteria which will be pre-specified in a modelling 
analysis plan that is to be finalised before DBL. The modelling will be performed by Quantitative 
Clinical Pharmacology at Novo Nordisk A/S and will be reported separately from the CTR.
Covariate analysis 
Covariates will be tested on CL/F. Covariates for inclusion:
!
Body weight
!
Age group (< 65, 65-75 and ≥75 years)
!
Sex (Male/Female)
!
Race (White/ Black or African American/ Asian/ Hawaiian or Pacific Islander/ Other)
!
Ethnicity (Hispanic or Latino/ not Hispanic or Latino)
!
Upper GI comorbidity (Yes/No)
17.6
Health economics and/or patient reported outcomes
PROs
Change from baseline to week 26, 52 and 78 in:
!
SF-36v2™(acute version) health survey: Total score and scores from the 8 domains
!
IWQoL-Lite Clinical Trial Version: Total score of the 23 items
!
CoEQ: Scores from the 4 domains and scores from 19 individual items
The PRO questionnaires, SF-36v2™, IWQOL and Control of Eating questionnaire will be used to 
evaluate the objective regarding Quality of Life. The PRO endpoints will be analysed separately as 
the other continuous efficacy endpoints using a similar model approaches as for the primary 
endpoint 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
18.1.1.1
Oral Semaglutide
The non-clinical safety programme of oral semaglutide has not revealed any safety issues 
precluding use in humans (see Section 3.1.4).
The sections below describe identified and potential risks associated with oral semaglutide 
treatment. The identified/potential risks are based on findings in non-clinical and clinical trials with 
oral semaglutide as well as other GLP-1 RAs. For each of these risks, mitigating actions have been 
implemented to minimise the risks for subjects enrolled in this trial.
Thyroid C-cell tumours
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 guidance for investigators of further evaluation and action on 
elevated calcitonin concentrations is included in Appendix A. This will ensure appropriate and 
consistent handling of elevated calcitonin levels.
Teratogenicity (embryo-foetal development toxicity)
Semaglutide caused embryo-foetal malformations in the rat through a GLP-1 receptor mediated 
effect on the inverted yolk sac placenta leading to impaired nutrient supply to the developing 
embryo. Primates do not have an inverted yolk sac placenta which makes this mechanism unlikely 
to be of relevance to humans. However, as a precaution, females who are pregnant, breast-feeding 
or intends to become pregnant or are of childbearing potential and not using an adequate 
contraceptive method will not be enrolled in the trial. In addition, throughout the trial, pregnancy 
tests will be done at site visits.
Gastrointestinal adverse events
Consistent with findings with other GLP-1 RAs, the most frequently reported AEs in clinical trials 
with oral semaglutide have been GI disorders (nausea, vomiting, diarrhoea, dyspepsia and 
constipation). Clinical trials have indicated that a low starting dose with gradual dose escalation 
diminishes GI AEs compared with more aggressive dosing regimens. Consequently, a low starting 
dose and gradual dose escalation with 4 weeks between dose-escalation steps have been 
implemented in the trial in order to mitigate GI side effects.
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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 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 
SU or insulin. The risk for development of hypoglycaemia with oral semaglutide in combination 
with SU and insulin is unknown due to limited data. In this trial subjects can be on anti-diabetic 
background medication with SU, but not insulin (however, if rescue medication is needed insulin 
can be prescribed as add-on to randomised treatment). If a subject on SU develops unacceptable 
hypoglycaemia the dose of SU can be reduced.
Acute renal impairment
In subjects treated with GLP-1 RAs including oral semaglutide GI AEs such as nausea, vomiting 
and diarrhoea may lead to significant dehydration and secondary acute renal impairment. Subjects 
with adverse GI events should be recommended to drink plenty of fluids in order to avoid 
dehydration. Also serum creatinine and urea will be measured throughout the trial and eGFR will be 
calculated.
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 the renal dysfunction.
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 measured throughout the trial.
General precautions 
All subjects will be included after a thorough evaluation in regards to in- and exclusion criteria 
defined in order to ensure that subjects are eligible for trial treatment. There are also strict 
glycaemic 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 
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Diabetes25,26 (excluding GLP-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 2014 Standards of Medical Care in Diabetes60.
18.1.1.2
Sitagliptin
The most commonly reported side effects are upper respiratory tract infection, nasopharyngitis and 
headache. Also acute pancreatitis, acute renal failure, hypersensitivity reactions and hypoglycaemia 
have been reported50. 
18.1.2
Benefits 
In this trial subjects will be randomised to one of four 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 significant improvements in glycaemic control and body weight. 
Similarly treatment with sitagliptin is expected to provide clinically significant improvements in 
glycaemic control50.
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 of oral semaglutide generated from the non-clinical and clinical development 
programme has not revealed any safety issues that would prohibit administration of doses in 
accordance with the planned clinical trial. The phase 2 results indicate that oral semaglutide will 
provide clinically significant improvements in glycaemic control and body weight. Sitagliptin is 
already a marketed drug approved for the use in subjects with T2DM. 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.
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Before any trial-related activity, the investigator must give the subject verbal and written 
information about the trial and the procedures involved in a form that the subject can read and 
understand.
The subjects must be fully informed of their rights and responsibilities while participating in the 
trial as well as possible disadvantages of being treated with the trial products.
The investigator must ensure the subject ample time to come to a decision whether or not to 
participate in the trial.
A voluntary, signed and personally dated informed consent must be obtained from the subject 
before any trial-related activity.
The responsibility for seeking informed consent must remain with the investigator, but the 
investigator may delegate the task to a medically qualified person, in accordance with local 
requirements. The written informed consent must be signed and personally dated by the person who 
seeks the informed consent before any trial-related activity.
If information becomes available that may be relevant to the subject’s willingness to continue 
participating in the trial, the investigator must inform the subject in a timely manner and a revised 
written subject information must be provided and a new informed consent must be obtained.
In order to avoid missing data, the subjects will be informed about the importance of completing the 
trial also if the subjects discontinue from trial product.
18.3
Data handling
If the subject is withdrawn from the trial or lost to follow up, then the subject’s data will be handled 
as follows:
!
Data already collected and data collected at the end-of-trial visit will be retained by Novo 
Nordisk, entered into the database and used for the trial report. 
!
Safety events will be reported to Novo Nordisk and regulatory authorities according to 
local/national requirements.
If data is used, it will always be in accordance with local regulations and IRBs/IECs.
18.4
Information to subject 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.
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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 a trial is suspended or prematurely terminated, the investigator must inform the subjects promptly 
and ensure appropriate therapy and follow-up. The investigator and/or Novo Nordisk must also 
promptly inform the regulatory authorities and IRBs/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
Deviations from the protocol should be avoided.
If deviations do occur, the investigator must inform the monitor and the implications of the 
deviation must be reviewed and discussed.
Deviations must be documented and explained in a protocol deviation by stating the reason, date
and the action(s) taken. Some deviations, for which corrections are not possible, can be 
acknowledged and confirmed via edit checks in the eCRF or via listings from the clinical database.
Documentation on protocol deviations must be kept in the investigator's trial master file and 
sponsor trial master file.
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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, 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 and SmPC or local label of comparator
!
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
For Japan only: A seal is accepted as signature.
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
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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
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, each investigator agrees to comply fully with ICH GCP1, applicable 
regulatory requirements and the Declaration of Helsinki2.
By signing the protocol, each investigator also agrees to allow Novo Nordisk to make investigator's 
name and information about site name and address publically available if this is required by 
national or international regulations.
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22 Responsibilities
The investigator is accountable for the conduct of the trial at his/her site. If any tasks are delegated, 
the investigator must maintain a log of appropriately qualified persons to whom he/she has 
delegated specified trial-related duties. The investigator must ensure that there is adequate training 
for all staff participating in the conduct of the trial. It is the investigator's responsibility to supervise 
the conduct of the trial and to protect the rights, safety and well-being of the subjects.
A qualified physician, who is an investigator or a sub-investigator for the trial, must be responsible 
for all trial-related medical decisions.
The investigator must ensure adequate supervision of the conduct of the trial at the trial site. 
The investigator will follow instructions from Novo Nordisk when processing data.
The investigator is responsible for filing essential documents (i.e. those documents which 
individually and collectively permit evaluation of the conduct of a trial and the quality of the data
produced) in the investigator trial master file. The documents including the subject identification 
code list should be kept in a secure locked facility, so no 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 publications61.
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 Disclosure4.
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 Editors61 (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 biospecimens
24.1
Retention of clinical trial documentation
Subject's medical records must be kept for the maximum period permitted by the hospital, 
institution or private practice.
The investigator must agree to archive the documentation (this includes both electronic and paper-
based records) pertaining to the trial in an archive after completion or discontinuation of the trial if 
not otherwise notified. The investigator should not destroy any documents without prior permission 
from Novo Nordisk. If the investigator cannot archive the documents at the trial site, Novo Nordisk 
can refer the investigator to an independent archive provider that has a system in place to allow only 
the investigator to access the files.
The investigator must be able to access his/her trial documents without involving Novo Nordisk in 
any way. Site-specific CRFs and other subject data (in an electronic readable format or as paper 
copies or prints) will be provided to the investigator before access is revoked to the systems and/or 
electronic devices supplied by Novo Nordisk. These data must be retained by the trial site. If the 
provided data (e.g. the CD-ROM) is not readable during the entire storage period, the investigator 
can request a new copy. A copy of all data will be stored by Novo Nordisk.
Novo Nordisk will maintain Novo Nordisk documentation pertaining to the trial for as long as the 
product is on the market plus 20 years. 
The files from the trial site/institution must be retained for 15 years after the completion of the trial, 
or longer if required by local regulations or Novo Nordisk. In any case trial files cannot be 
destroyed until the trial site/institution is notified by Novo Nordisk. The deletion process must 
ensure confidentiality of data and must be done in accordance with local regulatory requirements.
24.2
Retention of human biospecimens
Antibody samples may be stored at the special laboratory until market authorisation in case Health 
Authorities requests further characterisation of the antibody response (maximum up to 15 years 
from end of trial).
Semaglutide PK samples will be stored at the specialised laboratory until final CTR in case Novo 
Nordisk request further analysis of the PK samples.
None of the data will be identified by name. Antibody samples and semaglutide PK samples will be 
identified only by a subject number, a visit number and a trial identification number. The trial staff 
is responsible for maintaining a code list which links to the subject number. The code list must be 
kept for at least 15 years. The code list may be reviewed by Novo Nordisk staff including auditors 
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or representatives from regulatory authorities, but Novo Nordisk staff will not make any copies of 
this list if names are included.
In the event that the blood samples collected for antibody analysis will be used in the future, the 
investigator will become directly informed by Novo Nordisk about the results if the findings are 
deemed clinically relevant. In such case, a written summary of the findings, including listings of 
subject specific values, will be provided once a firm conclusion from the results has been drawn by 
Novo Nordisk. Subjects may at any time contact the investigator if they wish to be informed about 
results derived from stored antibody samples obtained from their own body.
For Brazil only: Biological samples from Brazil will be destroyed at the end of the trial.
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Trial ID: NN9924-4222
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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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Date:
24 August 2015
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Trial ID: NN9924-4222
Version:
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UTN: U1111-1168-4339 
Status:
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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 Russia only: Federal law of 12 April 2010 No. 61-FZ ‘On Medicinal Drugs’ Circulation.
For Germany only: German Drug Law dated August 24, 1976, last amended by article 3 of the law 
dated December 17, 2014 (Federal Law Gazette I p. 2222)
For France only: The French Public Health Code article L 1121-10 (law n° 2004-806 of 9 August 
2004 art. 88 I, IX Journal Officiel of 11 August 2004. "The sponsor is responsible for identification 
of the harmful consequences of the biomedical research for the person lending himself thereto and 
for indemnification of his beneficiaries, except in case of proof, incumbent on it, that the prejudice 
is not attributable to his fault of or the fault of any intervening party, without the sponsor's being 
entitled to call on acts by a third party or the voluntary withdrawal of the person who had initially 
consented to cooperating in the research.
For Mexico only: 
a) Novo Nordisk carries product liability for its products assumed under the special laws, 
acts/and/or guidelines for conducting trials in any country, including those applicable 
provisions on the Mexican United States.   If the subject feels that something goes wrong during 
the course of this trial, the subject should contact the trial staff in the first instance.
b) If during their participation in the trial the subject experiences a disease or injury that, 
according to the trial doctor and the sponsor, is directly caused by the study medication and/or 
a study procedure that otherwise would not have been part of his/her regular medical care, the 
subject will receive from the Institution or Medical Care Establishment and free of charge, the 
appropriate medical treatment as required. In this case, the costs resulting from such treatment  
as well as the costs of any indemnification established by law will be covered by the trial 
sponsor in accordance with the terms provided by all applicable regulations; even if the  subject 
discontinues his/her participation in the study by his own will or by a decision from the 
investigator.
c)
By signing the informed consent, the  subject will not renounce to any compensation or 
indemnification he/she may be entitled to by law, nor will he/she will incur  any additional 
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expense as a result of his/her participation in the trial; any additional expense resulting from 
the subject’s participation in the trial  will be covered by the trial sponsor.
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Trial ID: NN9924-4222
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27 References
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4 UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with 
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5 Chuang LM, Tsai ST, Huang BY, Tai TY, Diabcare A. The status of diabetes control in Asia--a 
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6 Ford ES, Li C, Little RR, Mokdad AH. Trends in A1C concentrations among U.S. adults with 
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8 Kieffer TJ, Habener JL. The glucagon-like peptides. Endocr Rev 1999; 20(6):876-913.
9 Bagger JI, Knop FK, Lund A, Vestergaard H, Holst JJ, Vilsboll T. Impaired regulation of the 
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10 Nauck M, Stockmann F, Ebert R, Creutzfeldt W. Reduced incretin effect in type 2 (non-insulin-
dependent) diabetes. Diabetologia 1986; 29(1):46-52.
11 Nauck MA, Vardarli I, Deacon CF, Holst JJ, Meier JJ. Secretion of glucagon-like peptide-1 
(GLP-1) in type 2 diabetes: what is up, what is down? Diabetologia 2011; 54:10-18.
12 Perley MJ, Kipnis DM. Plasma insulin responses to oral and intravenous glucose: studies in 
normal and diabetic subjects. J Clin Invest 1967; 46(12):1954-1962.
13 Højberg PV, Vilsbøll T, Rabøl R, Knop FK, Bache M, Krarup T et al. Four weeks of near-
normalisation of blood glucose improves the insulin response to glucagon-like peptide-1 and 
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24 August 2015
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Version:
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glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes. Diabetologia 2009; 
52:199-207.
14 Meier JJ. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nat 
Rev Endocrinol 2012; 8(12):728-742.
15 Flint A, Raben A, Astrup A, Holst JJ. Glucagon-like peptide 1 promotes satiety and suppresses 
energy intake in humans. J Clin Invest 1998; 101(3):515-520.
16 Nauck MA, Niedereichholz U, Ettler R, Holst JJ, Orskov C, Ritzel R et al. Glucagon-like 
peptide 1 inhibition of gastric emptying outweighs its insulinotropic effects in healthy humans. Am 
J Physiol 1997; 273(5:PART 1):E981-E988.
17 Nauck MA, Kleine N, Orskov C, Holst JJ, Willms B, Creutzfeldt W. Normalization of fasting 
hyperglycaemia by exogenous glucagon-like peptide 1 (7-36 amide) in type 2 (non-insulin-
dependent) diabetic patients. Diabetologia 1993; 36(8):741-744.
18 Nauck MA. Incretin based therapies for type 2 diabetes mellitus: properties, functions, and 
clinical implications. Am J Med 2011; 124 (1 Suppl):S3-S18.
19 Toft-Nielsen MB, Damholt MB, Madsbad S, Hilsted LM, Hughes TE, Michelsen BK et al. 
Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients. J Clin 
Endocrinol Metab 2001; 86(8):3717-3723.
20 Nauck MA, Petrie JR, Sesti G, Mannucci E, Courreges JP, Atkin S et al. The once-weekly 
human GLP-1 analogue semaglutide provides significant reductions in HbA1c and body weight in 
patients with type 2 diabetes. EASD abstract . 2012. 
21 Waser B, Blank A, Karamitopoulou E, Perren A, Reubi JC. Glucagon-like-peptide-1 receptor 
expression in normal and diseased human thyroid and pancreas. Mod Pathol 2014;1-12.
22 Investigators Brochure for s.c. Semaglutide (NN9535), Edition 10 or any updates hereof.  2015. 
23 Investigators Brochure for oral Semaglutide (NN9924), Edition 6 or any updates hereof. 2015.
24 Guidance for Industry Diabetes Mellitus - Evaluating Cardiovascular Risk in New Antidiabetic 
Therapies to Treat Type 2 Diabetes. Food and Drug Administration, December 2008.  
25 Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M et al. Management 
of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the 
American Diabetes Association (ADA) and the European Association for the Study of Diabetes 
(EASD). Diabetes Care 2012; 35(6):1364-1379.
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Date:
24 August 2015
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Trial ID: NN9924-4222
Version:
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UTN: U1111-1168-4339 
Status:
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26 Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M et al. Management 
of hyperglycaemia in type 2 diabetes, 2015: a patient-centred approach. Update to a position 
statement of the American Diabetes Association and the European Association for the Study of 
Diabetes. Diabetologia 2015; 58(3):429-442.
27 Novo Nordisk. http://www.novonordisk-trials.com/website/content/how-we-disclose-trial-
information.aspx.  2015. 
28 De Angelius C., Drazen JM, Frizelle FA, Haug C, Hoey J, Horton R et al. Clinical Trial 
Registration: A statement from the International Committee of Medical Journal Editors. N Engl J 
Med 2004; 351:1250-1251.
29 Food and Drug Administration Amendments Act of 2007. 11 Oct 2007.
30 The European Parliament and the Council of the European Council. Directive 2001/20/EC of 
the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, 
regulations and administrative provisions of the Member States relating to the implementation of 
good clinical practice in the conduct of clinical trials on medicinal products for human use, article 
11. Official Journal of the European Communities May 2001.
31 The European Parliament and the Council of the European Council. Regulation (EC) No 
726/2004 of the European Parliament and of the Council of 31 March 2004 laying down 
Community procedures for the authorisation and supervision of medicinal products for human and 
veterinary use and establishing a European Medicines Agency, article 57. Official Journal of the 
European Communities April 2001.
32 KDOQI Clinical practice guideline for diabetes and CKD: 2012 update. Am J Kidney Dis -
2012; 60(5):850-886.
33 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(May):1384-1395.
34 McAulay V, Deary IJ, Frier BM. Symptoms of hypoglycaemia in people with diabetes. Diabet 
Med 2001; 18(9):690-705.
35 Food and Drug Administration Center for Drug Evaluation and Research (CDER). Guidance for 
Industry - Patient-Reported Outcome Measures: Use in Medical Product Development to Support 
Labeling Claims. Dec 2009.
36 Stull DE, Leidy NK, Parasuraman B, Chassany O. Optimal recall periods for patient-reported 
outcomes: challenges and potential solutions. Curr Med Res Opin 2009; 25(4):929-942.
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Date:
24 August 2015
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Version:
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Status:
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37 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):473-483.
38 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.
39 Turner-Bowker DM BPWJJ. SF-36® Health Survey & "SF" Bibliography.  2002.  Lincoln, RI: 
QualityMetric Incorporated. 
40 Kolotkin RL, Crosby RD, Kosloski KD, Williams GR. Development of a brief measure to 
assess quality of life in obesity. Obes Res 2001; 9(2):102-111.
41 Adaptation of the Impact of Weight on Quality of Life-Lite for Use in Clinical Trials - Draft 
Instrument Adaptation Report. RTI Health Solutions. 22 May 2015.
42 Hill AJ. The psychology of food craving. Proc Nutr Soc 2007; 66(2):277-285.
43 Hill AJ, Heaton-Brown L. The experience of food craving: a prospective investigation in 
healthy women. J Psychosom Res 1994; 38(8):801-814.
44 Hill AJ, Weaver CF, Blundell JE. Food craving, dietary restraint and mood. Appetite 1991; 
17(3):187-197.
45 Hill AJ, Rogers PJ, Blundell JE. Techniques for the experimental measurement of human eating 
behaviour and food intake: a practical guide. Int J Obes Relat Metab Disord 1995; 19(6):361-375.
46 Banks PA, Freeman ML. Practice guidelines in acute pancreatitis. Am J Gastroenterol 2006; 
101(10):2379-2400.
47 Banks PA, Bollen TL, Dervenis C, Gooszen HG, Johnson CD, Sarr MG et al. Classification of 
acute pancreatitis--2012: revision of the Atlanta classification and definitions by international 
consensus. Gut 2013; 62(1):102-111.
48 Food and Drug Administration. Guidance for Industry: Immunogenicity Assessment for 
Therapeutic Protein Products  . Aug 2015.
49 The rules governing medicinal products in the European Union, volume 4, Annex 13, 
Manufacture of Investigational Medicinal Products - Brussel. European Commission. Feb 2010.
50 Merck Sharp & Dohme Limited. JANUVIA - European Summary of Product Characteristics 
Annex 1. 26 May 2015.
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24 August 2015
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51 Hicks KA, Hung HMJ, Mahaffey KW, Mehran R, Nissen SE, Strockbridge NL et al. 
Standardized Definitions for Cardiovascular and Stroke End Point Events in Clinical Trials 
(DRAFT).  20 Aug 2014. 
52 KDIGO. KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney international 
supplements 2012; 2(1):1-138.
53 Bretz F, Posch M, Glimm E, Klinglmueller F, Maurer W, Rohmeyer K. Graphical approaches 
for multiple comparison procedures using weighted Bonferroni, Simes, or parametric tests. Biom J 
2011; 53(6):894-913.
54 Rohmeyer, K. and Klinglmueller, F. gMCP: Graph Based Multiple Test Procedures. R package 
version 0.8-8. 3 Oct 2014.
55 Little RJA, Rubin DB. Statistical analysis with missing data. New York: John Wiley & Sons, 
1987.
56 Koch GG. Comments on 'Current issues in non-inferiority trials' by Thomas R. Fleming, 
Statistics in Medicine, DOI: 10.1002/sim.2855. Stat Med 2008; 27(3):333-342.
57 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). 
EMA . 2 Jul 2010. 
58 National Academy of Sciences (NAS). The Prevention and Treatment of Missing Data in 
Clinical Trials. Washington D.C.: The National Academies Press, 2010.
59 Schwartz NS, Clutter WE, Shah SD, Cryer PE. Glycemic thresholds for activation of glucose 
counterregulatory systems are higher than the threshold for symptoms. Journal of clinical 
investigation 1987; 79(3):777-781.
60 Standards of medical care in diabetes--2015. Diabetes Care 2015; 38 Suppl 1:S4-85.:S4-S85.
61 International Committee of Medical Journal Editors. Recommendations for the Conduct, 
Reporting, Editing and Publication of Scholarly Work in Medical Journals. Dec 2014.
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Global and country key Novo Nordisk staff
Attachments I and II (if applicable) to the protocol are located in the Trial Master File.
Content: Global key staff and Country key staff
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
Oral semaglutide
Trial ID: NN9924-4222
Clinical Trial Report
Appendix 16.1.1
21 November 2018
1.0
Final
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Protocol - Appendix A
CONFIDENTIAL
Date:
24 August 2015
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Version:
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Appendix A
Monitoring of Calcitonin
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol - Appendix A
CONFIDENTIAL
Date:
24 August 2015
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Trial ID: NN9924-4222
Version:
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Status:
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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.
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Protocol - Appendix A
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Date:
24 August 2015
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Trial ID: NN9924-4222
Version:
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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
CONFIDENTIAL
Date:
24 August 2015
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Trial ID: NN9924-4222
Version:
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UTN: U1111-1168-4339 
Status:
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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 disease1. Two of these subjects were diagnosed with MTC and two were diagnosed with 
C-cell hyperplasia, resulting in a positive predictive value of a C-cell anomaly of 50%.
Diagnostic evaluation should include: 
!
thyroid ultrasound examination 
!
if available and there are no contraindication, a pentagastrin stimulation test should be done. For 
subjects with positive pentagastrin stimulation test, surgery should be considered.
!
if pentagastrin stimulation test is not available, thyroid ultrasound and fine needle aspiration 
biopsy may add important clinical information about the need for surgery.
2.3
Calcitonin ≥ 10 and < 50 ng/L
Action: The subject can continue in the trial on trial product. Continue sampling of calcitonin 
according to the protocol.
If the value is from the last sample taken in the trial, the subject should be referred to a thyroid 
specialist for further evaluation.
CONFIDENTIAL


Protocol - Appendix A
CONFIDENTIAL
Date:
24 August 2015
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Trial ID: NN9924-4222
Version:
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UTN: U1111-1168-4339 
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 CT > 10 ng/L to screen for C-cell 
disease, but they do not provide sufficient information on patients with basal CT > 10 and < 20 ng/L 
to allow conclusions.2,3
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Protocol - Appendix A
CONFIDENTIAL
Date:
24 August 2015
Novo Nordisk
Trial ID: NN9924-4222
Version:
2.0
UTN: U1111-1168-4339 
Status:
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3
References
1 Costante G, Meringolo D, Durante C, Bianchi D, Nocera M, Tumino S et al. Predictive value of serum calcitonin 
levels for preoperative diagnosis of medullary thyroid carcinoma in a cohort of 5817 consecutive patients with 
thyroid nodules. J Clin Endocrinol Metab 2007; 92(2):450-455.
2 Scheuba C, Kaserer K, moritz A, drosten R. Sporadic hypercalcitoninemia: clinica and therapeutic consequences. 
Endocrine Related Cancer 2009; 16(1):243-253.
3 Verga U, Ferrero S, Vicentini L, Brambilla T, Cirello V, Muzza M et al. Histopathological and molecular studies in 
patients with goiter and hypercalcitoninemia: reactive or neoplastic C-cell hyperplasia? Endocr Relat Cancer 2007; 
14(2):393-403.
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
24 August 2015
Novo Nordisk
Trial ID: NN9924-4222
Version:
2.0
UTN: U1111-1168-4339 
Status:
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Appendix B
Adverse events requiring additional data collection
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol - Appendix B
CONFIDENTIAL
Date:
24 August 2015
Novo Nordisk
Trial ID: NN9924-4222
Version:
2.0
UTN: U1111-1168-4339 
Status:
Final
EudraCT No.: 2015-001351-71 
Page:
2 of 6
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 or hospitalisation for unstable angina)
!
Cerebrovascular event (stroke or TIA)
!
Heart failure requiring hospitalisation
!
Pancreatitis
!
Neoplasm (excluding thyroid neoplasm)
!
Thyroid disease (including thyroid neoplasm)
!
Renal event
!
Hypersensitivity reactions
!
Acute gallstone disease
!
Medication error (concerning trial products):
o
Administration of wrong drug. 
Note: Use of wrong DUN is not considered a medication error.
o
Wrong route of administration.
o
Administration of an overdose with the intention to cause harm (e.g. suicide 
attempt).
o
Accidental administration of a higher dose than intended. 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) > 10x UNL
!
Hepatotoxicity  events:
o
ALT or AST > 10x UNL and total bilirubin ≤ 2x UNL
o
Hepatotoxicity leading to trial product discontinuation
In case any of these events fulfil the criteria for an SAE, please report accordingly, see Section 12.2.
Some of these events will undergo event adjudication by the Event Adjudication Committee (EAC), 
please see Section 12.7.2 and Table 12-1.
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
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Trial ID: NN9924-4222
Version:
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UTN: U1111-1168-4339 
Status:
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EudraCT No.: 2015-001351-71 
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1.1
Acute coronary syndrome
If an event of acute coronary syndrome (ranging from unstable angina pectoris to myocardial 
infarction) 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 requiring hospitalisation 
If an event of heart failure requiring hospitalisation (admission to an in-patient unit or a visit to an 
emergency department that results in at least a 24 hour stay) is observed during the trial the 
following additional information must be reported if available: 
!
Signs and symptoms of heart failure
!
NYHA Class
!
Supportive imaging
!
Supportive laboratory measurements
!
Initiation or intensification of treatment for this condition
1.4
Pancreatitis
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:
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
24 August 2015
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Trial ID: NN9924-4222
Version:
2.0
UTN: U1111-1168-4339 
Status:
Final
EudraCT No.: 2015-001351-71 
Page:
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!
Imaging performed and consistency with pancreatic disease
!
Treatment for and complications of the event
!
Relevant risk factors for pancreatic disease
!
Family history of pancreatic disease
Please see Section 8.7.1 for further details on assessments in case of suspicion of acute pancreatitis.
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 test supporting the diagnosis 
!
Imaging performed supporting the diagnosis
!
Kidney biopsy results
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
24 August 2015
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Trial ID: NN9924-4222
Version:
2.0
UTN: U1111-1168-4339 
Status:
Final
EudraCT No.: 2015-001351-71 
Page:
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!
Risk or confounding factors identified including exposure to nephrotoxic agents
1.8
Hypersensitivity reactions
If suspicion of a hypersensitivity reaction occurs the subjects should be instructed to contact the site 
staff as soon as possible for further guidance.
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 reactions
!
Risk or confounding factors identified
Please see Section 8.7.2 for further details on assessments in case of suspicion of hypersensitivity
reactions.
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 test 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
o
Wrong drug(s) administered
o
Wrong dose administered
!
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 
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
24 August 2015
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Trial ID: NN9924-4222
Version:
2.0
UTN: U1111-1168-4339 
Status:
Final
EudraCT No.: 2015-001351-71 
Page:
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For definition of medication error, see Section 12.1.
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 test results describing the event 
!
Possible cause(s) of the event
1.12
Creatine kinase (CK) > 10x UNL
!
If an event of CK > 10x 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
Please see Section 8.7.3 for further details on assessments in case of increased levels of CK.
1.13
Hepatotoxicity events
o
ALT or AST > 10x UNL and total bilirubin ≤ 2x UNL
o
Hepatotoxicity leading to trial product discontinuation
If one of the above events is observed during the trial the following additional information must be 
reported if available:
!
Signs and symptoms associated to the event 
!
Risk factors
!
Relevant laboratory test results 
!
Diagnostic imaging performed 
!
Possible cause(s) of the event 
Please see Section 8.7.4 for further details on assessments in case of increased levels 
aminotransferases.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
10 November 2015
Novo Nordisk
Trial ID: NN9924-4222
Version:
1.0
UTN:U1111-1168-4339
Status:
Final
EudraCT No.: 2015-001351-71
Page:
1 of 11
Protocol Amendment
no 1
to Protocol, final version 2
dated 24 August 2015
Trial ID:NN9924-4222
PIONEER 3 - vs. DPP-4 inhibitor
Efficacy and long-term safety of oral semaglutide versus sitagliptin
in subjects with type 2 diabetes
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:
10 November 2015
Novo Nordisk
Trial ID: NN9924-4222
Version:
1.0
UTN:U1111-1168-4339
Status:
Final
EudraCT No.: 2015-001351-71
Page:
2 of 11
Table of Contents   
Page
Table of Contents..............................................................................................................................................2
1
Introduction including rationale for the protocol amendment.............................................................3
1.1
Section 2 Flowchart .......................................................................................................................3
1.2
Section 4.2.2.2 Supportive secondary endpoints ...........................................................................3
1.3
Section 8.1.5 Premature discontinuation of trial product and Follow-up (visits 16A and 
17A) ...............................................................................................................................................3
1.4
Section 8.4.4 Electrocardiogram – 12 -lead...................................................................................3
1.5
Section 8.4.7 Antibodies................................................................................................................3
1.6
Sections 8.7.4 Assessments in case of increased levels of aminotransferases, 12.1 
definitions, Appendix B Section 1 Adverse Events requiring additional data collection and 
Appendix B Section 1.13 Hepatotoxicity events ...........................................................................3
1.7
Section 9.4 Drug accountability and destruction ...........................................................................4
1.8
Section 12.2 Reporting of adverse events......................................................................................4
1.9
Sections 17 Statistical considerations, 17.3.1 Primary analysis for the primary estimand, 
17.4.2.1 Efficacy endpoints and 17.4.2.2 Safety endpoints...........................................................4
2
Changes......................................................................................................................................................5
2.1
Section 2 Flowchart .......................................................................................................................5
2.2
Section 4.2.2.2 Supportive secondary endpoints ...........................................................................5
2.3
Section 8.1.5 Premature discontinuation of trial product and Follow-up (visits 16A and 
17A) ...............................................................................................................................................5
2.4
Section 8.4.4 Electrocardiogram – 12 – Lead................................................................................5
2.5
Section 8.4.7 Antibodies................................................................................................................6
2.6
Section 8.5 Laboratory assessments ..............................................................................................6
2.7
Section 8.7.4 Assessments in case of increased levels of aminotransferases ................................6
2.8
Section 9.4 Drug accountability and destruction ...........................................................................6
2.9
Section 12.1 Definitions ................................................................................................................7
2.10
Section 12.2 Reporting of adverse events......................................................................................8
2.11
Section 17 Statistical considerations..............................................................................................9
2.12
Section 17.3.1 Primary analysis for the primary estimand ..........................................................10
2.13
Section 17.4.2.1 Efficacy endpoints ............................................................................................10
2.14
Section 17.4.2.2 Safety endpoints................................................................................................11
2.15
Appendix B: Section 1 Adverse Events requiring additional data collection..............................11
2.16
Appendix B: Section 1.13 Hepatotoxicity events........................................................................11
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
10 November 2015
Novo Nordisk
Trial ID: NN9924-4222
Version:
1.0
UTN:U1111-1168-4339
Status:
Final
EudraCT No.: 2015-001351-71
Page:
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1
Introduction including rationale for the protocol amendment
In addition to the below, minor inconsistencies and errors have been corrected.
1.1
Section 2 Flowchart
In the flowchart the timing of visit 16A (V16A) and the visit window of +3 days has been added for 
clarity. 
An ‘x’ at visit 2 (Randomisation) for drug accountability has been added as the site should enter the 
date of dispensing the trial product in the interactive web response system (IWRS).
1.2
Section 4.2.2.2 Supportive secondary endpoints
Time to rescue medication will only be analysed at the end of the trial and the text describing 
different time points for assessment has  been deleted.
1.3
Section 8.1.5 Premature discontinuation of trial product and Follow-up (visits 16A 
and 17A)
The timing of V16A and visit window of +3 days has been added for clarity. 
1.4
Section 8.4.4 Electrocardiogram – 12 -lead
A confirmatory ECG is required for all post-baseline ECGs suggestive of a new myocardial 
infarction (MI), as assessed by the central ECG reader. The rationale for this confirmatory ECG is 
to confirm that the ECG findings suggestive of a new MI are valid.
1.5
Section 8.4.7 Antibodies
Anti-semaglutide neutralising antibodies has been changed to anti-semaglutide binding antibodies
in Section 8.4.7 as it does not make sense to characterise neutralising antibodies for neutralising 
effect, however, it does make sense to characterise binding antibodies for neutralising effect. 
Binding antibodies should be seen as all antibodies binding to the drug (semaglutide), a fraction of 
these antibodies may be neutralising.
1.6
Sections 8.7.4 Assessments in case of increased levels of aminotransferases, 12.1
definitions, Appendix B Section 1 Adverse Events requiring additional data collection 
and Appendix B Section 1.13 Hepatotoxicity events
The cut off level for repeat testing of increased levels of aminotransferases has been updated from 
ALT/AST >10x UNL to >5x UNL in section 8.7.4. The rationale is to prompt follow-up of potential 
clinical significant aminotransferase levels.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
10 November 2015
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Trial ID: NN9924-4222
Version:
1.0
UTN:U1111-1168-4339
Status:
Final
EudraCT No.: 2015-001351-71
Page:
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Definition of elevated liver enzymes to be reported as adverse events (AEs) requiring additional 
data collection has been updated in section 12.1 and appendix B to align with 8.7.4 and ensure that 
all potential hepatotoxicity events are captured and can be assessed appropriately.
Suspicion of transmission of infectious agents via the trial product and events fulfilling Hy’s law 
are included underneath the defined seriousness criteria in section 12.1 to clarify that these are 
specific AEs that always fulfil the seriousness criteria. 
The definition of Hy’s law in section 12.1 has been updated to align with the FDA guidance 
document “Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation”.
1.7
Section 9.4 Drug accountability and destruction
To ensure proper trial product accountability sites are requested to account for non-allocated trial 
product as well.
1.8
Section 12.2 Reporting of adverse events
Figure 12-1 has been updated as the previous AE flow did not contain the full AE process flow as 
described in the protocol text.
1.9
Sections 17 Statistical considerations, 17.3.1 Primary analysis for the primary 
estimand, 17.4.2.1 Efficacy endpoints and 17.4.2.2 Safety endpoints
The text regarding stratification factors in the statistical section 17 has been updated to make it
more clear how these are included in the statistical analyses.
Two wrong units have been corrected and irrelevant data removed from Table 17.1.
For the primary analysis to the primary estimand, missing data will not be imputed based on the 
stratification factor, but only treatment and treatment adherence/rescue status  i.e. 16 groups are 
change to 8 groups. In the analysis after 52 weeks 32 groups has been changed to 16 due to the 
same decision. The stratification factor has instead been added as a categorical fixed effect in the 
ANCOVA analysis.
The text below the time to event endpoint has been removed from the statistical section as well, 
since the endpoint will only be analysed at the end of the trial.
In Section 17.4.2.2 treatment emergent hypoglycaemic events are defined twice by mistake, thus the 
second paragraph on the definition is deleted.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
10 November 2015
Novo Nordisk
Trial ID: NN9924-4222
Version:
1.0
UTN:U1111-1168-4339
Status:
Final
EudraCT No.: 2015-001351-71
Page:
5 of 11
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 Flowchart
For V16A: 
Visit window (days): +3 days for Visit 16A
Shortly after Day of discontinuation of trial product
For V2:
‘x’ in Drug accountability.
2.2
Section 4.2.2.2 Supportive secondary endpoints
[…]
Time to event endpoint
!
Time to rescue medication
This endpoint will be evaluated after week 26, after week 52 and after week 78.
2.3
Section 8.1.5 Premature discontinuation of trial product and Follow-up (visits 16A 
and 17A)
Subject who discontinue trial product prematurely should attend visit 16A, scheduled to take place 
shortly after discontinuation of trial product (+3 days visit window).
2.4
Section 8.4.4 Electrocardiogram – 12 – Lead
12-lead ECGs will be performed as per 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 
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 myocardial infarction 
(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 myocardial infarction 
(MI), the investigator will be notified and a confirmatory ECG should be performed., uUnless
already done, the investigator should report this as AE or SAE at investigator’s discretion (see 
Section 12.1).
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
10 November 2015
Novo Nordisk
Trial ID: NN9924-4222
Version:
1.0
UTN:U1111-1168-4339
Status:
Final
EudraCT No.: 2015-001351-71
Page:
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2.5
Section 8.4.7 Antibodies
Samples which are positive for anti-semaglutide neutralising binding antibodies […]
2.6
Section 8.5 Laboratory assessments
For some of the analyses described in Section 8.7.1 and 8.7.1 8.7.2 a local laboratory must be used.
2.7
Section 8.7.4 Assessments in case of increased levels of aminotransferases
In case of
1. ALT or AST >3x UNL and total bilirubin >2x UNL,
the event must be reported as an SAE (see Section 12.1). 
2. ALT or AST >105x UNL and total bilirubin ≤2x UNL, 
the event should be reported as an AE requiring additional data collection (see Section 12.1 and 
Appendix B).
For both events prompt repeat testing (at central laboratory) including ALT, AST, ALP and total 
bilirubin should be done and discontinuation of trial product considered. Thereafter, repeat testing 
(at central laboratory) of ALT, AST, ALP and total bilirubin should be done regularly until the 
abnormalities return to normal or baseline state. Additional clinical information such as related 
symptoms, risk factors and contributing conditions (e.g. viral hepatitis, autoimmune hepatitis, 
alcoholic hepatitis, hepatobiliary or pancreatic disorders) should be gathered to seek a possible 
cause of the observed laboratory test abnormalities.
2.8
Section 9.4 Drug accountability and destruction
Drug accountability 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 or unused including empty packaging material) can be 
stored at room temperature and must be stored separately from non-allocated trial product. Non-
allocated trial product (expired, damaged and available) must be accounted as unused at the latest 
at closure of the trial site.
Drug accountability is performed by using the IWRS. Only dispensed DUNs returned by the subject 
(used/partly used or unused) are accounted for. Drug accountability should be done on tablet level.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
10 November 2015
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Trial ID: NN9924-4222
Version:
1.0
UTN:U1111-1168-4339
Status:
Final
EudraCT No.: 2015-001351-71
Page:
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Destruction will be done according to local procedures after accountability is finalised and verified 
by the monitor. Destruction of products must be documented and recorded in IWRS including 
destruction confirmation.
2.9
Section 12.1 Definitions
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. 
Suspicion of transmission of infectious agents via the trial product must always be 
considered an SAE. 
[…]
Trial specific serious adverse event
The following laboratory abnormalities must be reported as an SAE:
!
ALT or AST >3x UNL and total bilirubin >2x UNL
Additional assessments should be made for events meeting the above criterion (see Section 8.7.4).
The following adverse events must always be reported as an SAE using the important medical event 
criteria if no other seriousness criteria are applicable:
!
suspicion of transmission of infectious agents via the trial product
!
risk of liver injury defined as alanine aminotransferase (ALT) or aspartate aminotransferase 
(AST) >3x UNL and total bilirubin >2x UNL, where no alternative aetiology exists (Hy's 
law).
[…]
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
10 November 2015
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Trial ID: NN9924-4222
Version:
1.0
UTN:U1111-1168-4339
Status:
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EudraCT No.: 2015-001351-71
Page:
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Adverse events requiring additional data collection
Adverse events requiring additional data collection are events which, in the evaluation of safety, 
have a special focus (e.g. required by the health authorities). The AEs requiring additional data 
collection are:
[…]
!
Hepatotoxicity events:
o
ALT or AST > 105x UNL and total bilirubin ≤ 2x UNL
o
ALT or AST > 3x UNL and total bilirubin > 2 UNL
o
Hepatic eventHepatotoxicity leading to trial product discontinuation 
2.10
Section 12.2 Reporting of adverse events
[…]
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 specific forms and the additional 
information to report).
[…]
An AE is observed 
and reported 
Fulfilling seriousness 
criteria?
It is an SAE
complete:
! AE form ≤ 24 hours
! SIF ≤ 5 calendar days
It is a non-serious AE
complete:
! AE form
Requiring 
additional data 
collection?
Requiring 
additional data 
collection?
Complete:
! Specific event form ≤ 14  calendar days
Yes
Complete: 
! Specific event form
Yes
No
Yes
Complete:
! Adjudication form ≤ 14 calendar days
Yes
AE: adverse event
SAE: serious adverse event
SIF: safety information form
All timelines are from the investigator’s
first knowledge of the event
Events for adjudication are described in chapter 12.7.2
Is the event to 
be adjudicated?
Is the event to 
be adjudicated?
Complete:
! Adjudication form  ≤ 14 calendar days
Yes
Figure 12-1 Initial reporting of AEs
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
10 November 2015
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Trial ID: NN9924-4222
Version:
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Status:
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EudraCT No.: 2015-001351-71
Page:
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AE identified
Is additional data 
collection required?
Is the AE to be 
adjudicated and/or 
is the outcome fatal?
AE form ≤  24 hours
SIF ≤5 calendar days
Specific event form (AEs 
and SAEs)
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
AE: adverse event
SAE: serious adverse event
SIF: safety information form 
AEs for adjudication are described in the protocol section 12.7.2
All timelines are from investigators first knowledge of the event
No additional action
No additional action
No
Figure 12-1 Initial reporting of AEs
2.11
Section 17 Statistical considerations
General considerations
[…]
The randomisation is stratified based on pre-trial therapy at screening (metformin or 
metformin+SU) and descent (Japanese subjects/non-Japanese subjects). In the statistical analyses 
descent is a part of region and pre-trial therapy at screening is referred to as stratification factor.
In statistical analyses where stratification is included,tThe two combinations (metformin;
metformin+SU) in the stratification factor will be included based on the actual information
collected through the eCRF. In case of missing eCRF information the information collected from 
IWRS system will be used.
Table 17–1 Assumptions for sample size calculation
Oral semaglutide vs. 
sitagliptin
HbA1c
Body weight
Treatment dose
14 mg
7 mg
3 mg
14 mg
7 mg
3 mg
Treatment effect (TE) . 
-0.5%
-0.3%
-0.1%
-3.0 kg
-2.0 kg
-1.0 kg
Adjusted TE, non-inferiority 
-0.395%
-0.255%
-0.055%
-2.52 kg
-1.67 kg
-0.82 kg
Adjusted TE, superiority 
-0.425%
-0.255%
-0.085%
-2.55 kg
-1.70%kg
-0.85%kg
Standard deviation 
1.1%
1.1%
1.1%
4.0 kg
4.0 kg
4.0 kg
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
10 November 2015
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Trial ID: NN9924-4222
Version:
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UTN:U1111-1168-4339
Status:
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EudraCT No.: 2015-001351-71
Page:
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2.12
Section 17.3.1 Primary analysis for the primary estimand
The primary estimand will be estimated based on the FAS using week 26 measurements from the
in-trial observation period. The primary statistical analysis will be a pattern mixture model using
multiple imputation to handle missing data assuming that the missing data mechanism is missing at
random (MAR). Imputation of missing data at week 26 will be done within 16 8 groups of subjects
defined by randomised treatment arm, stratification factor and whether subjects at week 26; (i) have
discontinued treatment or initiated rescue medication or (ii) 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 26 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 a categorical 
fixed effects and baseline HbA1c measurement as a covariate will be fitted to observed 
values of the change from baseline in HbA1c at week 26.
!
The estimated parameters for location and dispersion will be used to impute 100 values for 
each subject with missing week 26 data based on region, stratification factor and baseline 
HbA1c. Thus, 100 complete data sets will be generated including observed and imputed 
values.
Analysis used for confirming superiority versus sitagliptin at week 26:
For each of the 100 (now complete) imputed data sets the change from baseline to week 26 will be
analysed using an ANCOVA with treatment, region and stratification factor as categorical fixed 
effects and baseline HbA1c as covariate. The results obtained from analysing the datasets will be 
combined using Rubin’s rule to draw inference.
2.13
Section 17.4.2.1 Efficacy endpoints
[…]
For evaluation of the primary estimand the analysis will be performed separately for week 26, 52
and 78. For the analysis at week 52 and at week 78, the imputation of missing data will be further
differentiated by whether subjects have discontinued trial product or initiated rescue medication
prior to week 26 or at or after week 26. This will result in imputation of missing data within 16 32  
groups of subjects instead of the 16 8 groups as described for the week 26 evaluation in
Section 17.3.1. The frequency of missing data is expected to be slightly larger at week 52 and week
78 compared to week 26. The rate of missing data is expected to decline over time.
[…]
Time to event endpoint
!
Time to rescue medication
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
10 November 2015
Novo Nordisk
Trial ID: NN9924-4222
Version:
1.0
UTN:U1111-1168-4339
Status:
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EudraCT No.: 2015-001351-71
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Subjects completing the study without need for rescue medication will be censored at the time point
of actual date of last trial product. Start time is date of first trial product. Time to rescue medication
will be described and compared for each of the oral semaglutide dose level versus sitagliptin 100
mg using likelihood ratio tests obtained from a proportional Cox hazards model. From this analysis
the estimated Hazard ratios between each dose levels and sitagliptin will be presented together with
95 % confidence intervals and two-sided p-values for test of no difference. This endpoint will be
evaluated after week 26, after week 52 and after week 78. Furthermore, the endpoint will be 
presented by a Kaplan-Meier plot.
2.14
Section 17.4.2.2 Safety endpoints
Classification of Hypoglycaemia:
Hypoglycaemic episodes will be summarised for the SAS and the on-treatment observation period 
only.
Treatment emergent: hypoglycaemic episode 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).
A treatment emergent hypoglycaemic episode is defined as a hypoglycaemic episode with onset in 
the on-treatment observation period (see definition of observation periods in Section 17.2).
2.15
Appendix B: Section 1 Adverse Events requiring additional data collection
!
Hepatotoxicity events:
o
ALT or AST > 510x UNL and total bilirubin ≤ 2x UNL
o
ALT or AST > 3x UNL and total bilirubin > 2x UNL
o
Hepatic eventHepatotoxicity leading to trial product discontinuation 
2.16
Appendix B: Section 1.13 Hepatotoxicity events
o
ALT or AST > 510x UNL and total bilirubin ≤ 2x UNL
o
ALT or AST > 3x UNL and total bilirubin > 2x UNL
o
Hepatic eventHepatotoxicity leading to trial product discontinuation 
CONFIDENTIAL


Protocol Amendment no. 2
CONFIDENTIAL
Date:
14 November 2016
Novo Nordisk
Trial ID: NN9924-4222
Version:
1.0
UTN: U111-1168-4339
Status:
Final
EudraCT No.: 2015-001351-71
Page:
1 of 19
Protocol Amendment
no 2
to Protocol, final version 3
dated 12 November 2015
Trial ID: NN9924-4222
PIONEER 3 - vs. DPP-4 inhibitor
Efficacy and long-term safety of oral semaglutide versus sitagliptin
in subjects with type 2 diabetes
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 November 2016
Novo Nordisk
Trial ID: NN9924-4222
Version:
1.0
UTN: U111-1168-4339
Status:
Final
EudraCT No.: 2015-001351-71
Page:
2 of 19
Table of Contents   
Page
Table of Contents..............................................................................................................................................2
Table of Figures................................................................................................................................................3
Table of Tables..................................................................................................................................................3
1
Introduction including rationale for the protocol amendment.............................................................4
1.1
Additional eye examinations and additional data collection on diabetic retinopathy....................4
1.2
Investigator’s responsibility in ensuring evaluation and management of certain risk factors 
and complications ..........................................................................................................................4
1.3
Clarification of the criteria for completion, withdrawal and lost to follow-up..............................5
1.4
Other minor adjustments, clarifications and correction of typographical errors............................5
2
Changes......................................................................................................................................................7
2.1
Section 2 Flow chart ......................................................................................................................7
2.2
Section 4.2.2.2 Supportive secondary endpoints ...........................................................................7
2.3
Section 5.3.2 Background medication ...........................................................................................8
2.4
Section 6.4 Rescue criteria.............................................................................................................8
2.5
Section 6.6 Withdrawal criteria .....................................................................................................8
2.6
Section 8.1 Visit procedures ..........................................................................................................9
2.7
Section 8.1.4 End-of-treatment (visit 16) and Follow-up (visit 17)...............................................9
2.8
Section 8.1.5 Premature discontinuation of trial product and follow-up (visits 16A and 
17A) ...............................................................................................................................................9
2.9
Section 8.1.6.1 Lost to follow-up .................................................................................................10
2.10
Section 8.4.1 Physical examination .............................................................................................10
2.11
Section 8.4.3 Eye examination.....................................................................................................11
2.12
Section 8.4.7 Antibodies..............................................................................................................11
2.13
Section 8.5 Laboratory assessments ............................................................................................11
2.14
Section 8.7.1 Assessments in case of suspicion of acute pancreatitis..........................................11
2.15
Section 12.1 Definitions ..............................................................................................................12
2.16
Section 12.2 Reporting of adverse events....................................................................................12
2.17
Section 12.7.2 Event adjudication committee..............................................................................13
2.18
Section 17.2 Definition of analysis sets.......................................................................................14
2.19
Section 17.3.1 Primary analysis for the primary estimand ..........................................................14
2.20
Section 17.4.2.1 Efficacy endpoints ............................................................................................14
2.21
Section 17.4.2.2 Safety endpoints................................................................................................15
2.22
Section 18.1.1.1 Oral Semaglutide ..............................................................................................16
2.23
Section 27 References..................................................................................................................16
2.24
Reference numbers ......................................................................................................................17
2.25
Appendix B, Section 1 Adverse events requiring additional data collection...............................17
2.26
Appendix B, Section 1.14 Diabetic retinopathy and related complications................................18
3
References................................................................................................................................................19
CONFIDENTIAL


Protocol Amendment no. 2
CONFIDENTIAL
Date:
14 November 2016
Novo Nordisk
Trial ID: NN9924-4222
Version:
1.0
UTN: U111-1168-4339
Status:
Final
EudraCT No.: 2015-001351-71
Page:
3 of 19
Table of Figures   
Page
No table of figures entries found.
Table of Tables   
Page
No table of figures entries found.
CONFIDENTIAL


Protocol Amendment no. 2
CONFIDENTIAL
Date:
14 November 2016
Novo Nordisk
Trial ID: NN9924-4222
Version:
1.0
UTN: U111-1168-4339
Status:
Final
EudraCT No.: 2015-001351-71
Page:
4 of 19
1
Introduction including rationale for the protocol amendment
This protocol amendment introduces:
1. Additional eye examinations and additional data collection on diabetic retinopathy
2. Investigator’s responsibility in ensuring evaluation and management of certain risk factors 
and complications
3. Clarification of the criteria for completion, withdrawal and lost to follow-up
4. Other minor corrections and clarifications
1.1
Additional eye examinations and additional data collection on diabetic retinopathy 
Protocol sections updated: 2, 4.2.2.2, 8.4.3, 12.1, 12.2, 17.2, 17.4.2.2, 18.1.1.1, 27; Appendix B 
section 1 and 1.14 (new).
Transient worsening of diabetic retinopathy is a recognised complication in selected patients with 
diabetes after initiation of intensive antidiabetic treatment1-3. 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. As recruitment has been completed, the information will be collected for all 
subjects retrospectively as well as going forward, 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. 
1.2
Investigator’s responsibility in ensuring evaluation and management of certain risk 
factors and complications
Protocol sections updated: 8.4.1, 18.1.1.1, 27.
, text is added to highlight the investigators 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.
CONFIDENTIAL


Protocol Amendment no. 2
CONFIDENTIAL
Date:
14 November 2016
Novo Nordisk
Trial ID: NN9924-4222
Version:
1.0
UTN: U111-1168-4339
Status:
Final
EudraCT No.: 2015-001351-71
Page:
5 of 19
1.3
Clarification of the criteria for completion, withdrawal and lost to follow-up
Protocol sections updated: 6.6, 8.1, 8.1.4, 8.1.5, 8.1.6.1 (new).
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.
1.4
Other minor adjustments, clarifications and correction of typographical errors
Laboratory analysis
Protocol sections updated: 8.4.7, 8.5, 8.7.1.
The protocol is updated to reflect that on suspicion of acute pancreatitis the investigator has the 
option of performing measurement of lipase and amylase not only via local laboratory but also via 
central lab in accordance with the specific clinical situation.
The protocol currently specifies that the in vitro neutralising antibody assays will be performed by 
Novo Nordisk, however it may be decided by Novo Nordisk that the laboratory currently 
responsible for antibody binding analysis (Celerion) will perform the assay.
Statistical considerations
Protocol sections updated: 17.3.1, 17.4.2.1.
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. In addition, an 
error in the number of groups used for imputation is corrected. Furthermore, the description of the 
Cox hazard model used for the time to event endpoint has been clarified.
Adverse events for Adjudication
Protocol sections updated: 12.7.2.
Table 12-2 has been aligned with Table 12-1 reflecting that unstable angina pectoris (UAP) requires
hospitalisation to qualify for Event Adjudication.
CONFIDENTIAL


Protocol Amendment no. 2
CONFIDENTIAL
Date:
14 November 2016
Novo Nordisk
Trial ID: NN9924-4222
Version:
1.0
UTN: U111-1168-4339
Status:
Final
EudraCT No.: 2015-001351-71
Page:
6 of 19
Initial reporting of AEs
Protocol sections updated: 12.2.
Figure 12-1 has been aligned with PIONEER trials to reflect the legislation of “within” timelines 
which is now interpreted as “less than”.
Background medication
Protocol sections updated: 5.3.2.
Section has been updated to specify that dose changes of background medication is allowed in case 
of a safety concern.
Rescue criteria
Protocol sections updated: 6.4.
The section has been updated to specify that rescue medication should be offered until end of 
treatment and not end of trial as previously specified. After end of treatment, the protocol section 
5.4 applies.
CONFIDENTIAL


Protocol Amendment no. 2
CONFIDENTIAL
Date:
14 November 2016
Novo Nordisk
Trial ID: NN9924-4222
Version:
1.0
UTN: U111-1168-4339
Status:
Final
EudraCT No.: 2015-001351-71
Page:
7 of 19
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
For V12, V16 and V16A: ‘x’ in ‘Eye examination’
Footer
Description
X5
Dilated fundoscopy/fundus photography performed within 90 days prior to 
randomisation is acceptable if results are available for evaluation at V2, unless 
worsening of visual function since last examination.
Dilated fundoscopy/fundus photography must be performed again:
!
at V12 or within 5 weeks prior to or after V12 (applicable for all subjects)
!
at V16 or within 5 weeks thereafter (for subjects completing treatment)
!
at V16A or within 5 weeks thereafter, and again within 5 weeks prior to V16 
(for subjects who have prematurely discontinued trial product)
2.2
Section 4.2.2.2
Supportive secondary endpoints
Supportive secondary safety endpoints
!
Number of TEAEs during exposure to trial product, assessed up to approximately 83 weeks*
!
Number of treatment emergent severe or BG confirmed symptomatic hypoglycaemic episodes
during exposure to trial product, assessed up to approximately 83 weeks*
!
Treatment emergent severe or BG confirmed symptomatic hypoglycaemic episodes during
exposure to trial product, assessed up to approximately 83 weeks (yes/no)
Change from baseline to week 26, 52 and 78 in:
!
Haematology
!
Biochemistry
!
Calcitonin
!
Pulse
!
Systolic blood pressure
!
Diastolic blood pressure
!
Electrocardiogram (ECG) category
!
Physical examination (week 52 and 78 only)
!
Eye examination category (week 52 and 78 only)
CONFIDENTIAL


Protocol Amendment no. 2
CONFIDENTIAL
Date:
14 November 2016
Novo Nordisk
Trial ID: NN9924-4222
Version:
1.0
UTN: U111-1168-4339
Status:
Final
EudraCT No.: 2015-001351-71
Page:
8 of 19
2.3
Section 5.3.2
Background medication
After inclusion (V1), subjects must continue anti-diabetic pre-trial background medication (i.e. 
metformin alone or in combination with SU) throughout the entire trial. The background medication 
must be maintained at the stable, pre-trial dose and at the same frequency during the whole 
treatment period unless rescue medication is needed (see Section 6.4),or if the subject has 
unacceptable hypoglycaemia on a background of SU in which case the dose of SU can be reduced 
or if another safety concern related to the background medication arises.
2.4
Section 6.4
Rescue criteria
Subjects with persistent and unacceptable hyperglycaemia should be offered treatment 
intensification. To allow time for dose escalation and to observe the expected effect of treatment on 
glycaemic parameters, rescue criteria will be applied from week 8 and onwards. If any of the FPG 
values (including fasting SMPG) exceed the limits outlined below and no intercurrent cause of the 
hyperglycaemia can be identified, a confirmatory FPG (at central laboratory) should be obtained by 
calling the subject for a re-test:
!
14.4 mmol/L (260 mg/dL) from week 8 to end of week 13
!
13.3 mmol/L (240 mg/dL) from week 14 to end of week 25
!
11.1 mmol/L (200 mg/dL) from week 26 to end of trialtreatment 
If the confirmatory FPG also exceeds the values described above, the subject should be offered 
rescue medication (i.e. intensification of existing anti-diabetic background medication and/or 
initiation of new anti-diabetic medication). 
In addition, subject should be offered rescue medication if:
!
HbA1c (at central laboratory) > 8.5% (69.4 mmol/mol) from week 26 to end of trialtreatment
2.5
Section 6.6
Withdrawal criteria
The subject may withdraw consent at will at any time. The subject’s request to withdraw from the 
trial must always be respected.
A subject who does not complete the trial is also considered withdrawn from the trial. Hence, a 
subject is considered withdrawn from trial 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 - 8.1.6.1)
!
Other (subject deceased or closure of trial site)
CONFIDENTIAL


Protocol Amendment no. 2
CONFIDENTIAL
Date:
14 November 2016
Novo Nordisk
Trial ID: NN9924-4222
Version:
1.0
UTN: U111-1168-4339
Status:
Final
EudraCT No.: 2015-001351-71
Page:
9 of 19
2.6
Section 8.1
Visit procedures
[…]
If a subject is unable or unwilling to attend all subsequent visit(s) the investigator should at least 
aim to have the subject attend the V8, V12 and the End-of-treatment visit (V16) as these visits 
should be performed for all subjects (except subjects who withdraw informed consent, see 
Section 8.1.6).
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.
2.7
Section 8.1.4
End-of-treatment (visit 16) and Follow-up (visit 17)
At V16 the subject should be reminded about the importance of attending the follow-up visit (V17). 
If the subject, nonetheless, does not attend V17, 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 are in contact with the site, at the subject’s 
last scheduled visit. For subjects who complete treatment, the last scheduled visit is V17. (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 17 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) to collect health status. If no health status can be collected, the subject should be 
considered lost to follow.
2.8
Section 8.1.5
Premature discontinuation of trial product and follow-up (visits 16A 
and 17A)
Subjects who discontinue trial product prematurely should attend visit 16A, scheduled to take place 
after discontinuation of trial product (+3 days visit window). Visit 17A should be scheduled 5 
weeks (+3 days visit window) after the last date on trial product. A treatment discontinuation 
session must be performed in the IWRS at visit 16A (see Section 10).
Subjects should continue with the originally scheduled site contacts after visit 17A and up to and 
including visit 16. If necessary, in order to retain the subject in the trial, site visits can be replaced 
by phone contacts after V17A. However, as a minimum, these subjects should be asked to attend 
the scheduled V8 at week 26, V12 at week 52 and End-of-treatment (V16) at week 78. if a subject 
is unable or unwilling to attend all subsequent visit(s), the investigator should at least aim to have 
the subject attend V8 (week 26), V12 (week 52) and End-of-treatment (V16) (week 78) as these 
CONFIDENTIAL


Protocol Amendment no. 2
CONFIDENTIAL
Date:
14 November 2016
Novo Nordisk
Trial ID: NN9924-4222
Version:
1.0
UTN: U111-1168-4339
Status:
Final
EudraCT No.: 2015-001351-71
Page:
10 of 19
visits should be performed for all subjects, if at all possible (except subjects who withdraw consent, 
see Section 8.1.6). 
In case the subject cannot be reached (by clinic visit or phone contact) at the scheduled visit 17 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) to collect health status. If no health status can be collected, the subject should be 
considered lost to follow up. 
A subject who prematurely discontinues 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 V16 (or V17A if it 
is scheduled after V16). (For subjects completing treatment, see Section 8.1.4). The site should in 
due time prepare for establishing contact with the subject within the visit window of the scheduled 
V8, V12 and V16 respectively, if the subject has agreed to attend these visits.
2.9
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: V17 for subjects who have completed treatment, whereas for subjects who have discontinued 
trial product prematurely the last scheduled visit is V16 (or V17A if it is scheduled after V16). Only 
if contact with the subject is not regained by the end of the visit window of the subject’s last 
scheduled visit, can the subject be considered lost to follow up (see Section 6.6).
2.10
Section 8.4.1
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
CONFIDENTIAL


Protocol Amendment no. 2
CONFIDENTIAL
Date:
14 November 2016
Novo Nordisk
Trial ID: NN9924-4222
Version:
1.0
UTN: U111-1168-4339
Status:
Final
EudraCT No.: 2015-001351-71
Page:
11 of 19
!
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 hereof62, and adapted to 
local treatment guidelines if applicable.
2.11
Section 8.4.3
Eye examination
Dilated fundoscopy/fundus photography will be performed as per flow chart (see Section 2) by the 
investigator or according to local practice. Fundoscopy requires pharmacological dilation of both 
pupils. Results of the dilated fundoscopy/fundus photography will be interpreted by the investigator 
(see Section 8.1.7).
2.12
Section 8.4.7
Antibodies
Furthermore, samples drawn at randomisation may be used for calculations of the neutralising effect 
in the in vitro neutralising antibody assays. The in vitro neutralising assays will be performed by 
Novo Nordisk or the special laboratory responsible for antibody binding analysis.
At randomisation, the antibody sampling must be done pre-dose. 
2.13
Section 8.5
Laboratory assessments
The laboratory analyses will mainly be performed by a central laboratory. Anti-semaglutide 
antibodies, in vitro neutralising effect, IgE anti-semaglutide antibodies and PK samples will be 
analysed by a special laboratory andor Novo Nordisk A/S (see Sections 8.4.7, 8.6.1 and 8.7.2. For 
some of the analyses described in Section 8.7.1 and 8.7.2 a local or central laboratory must be used.
2.14
Section 8.7.1
Assessments in case of suspicion 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 or central
measurement of amylase and lipase.
CONFIDENTIAL


Protocol Amendment no. 2
CONFIDENTIAL
Date:
14 November 2016
Novo Nordisk
Trial ID: NN9924-4222
Version:
1.0
UTN: U111-1168-4339
Status:
Final
EudraCT No.: 2015-001351-71
Page:
12 of 19
2.15
Section 12.1
Definitions
Adverse events requiring additional data collection
Adverse events requiring additional data collection are events which, in the evaluation of safety, 
have a special focus (e.g. required by the health authorities). The AEs requiring additional data 
collection are:
!
Acute coronary syndrome (myocardial infarction or hospitalisation for unstable angina)
!
Cerebrovascular event (stroke or transient ischaemic attack (TIA))
!
Heart failure requiring hospitalisation
!
Pancreatitis 
!
Neoplasm (excluding thyroid neoplasm)
!
Thyroid disease (including thyroid neoplasm)
!
Renal event 
!
Hypersensitivity reactions
!
Acute gallstone disease
!
Medication error (concerning trial products):
o
Administration of wrong drug. 
Note: Use of wrong DUN is not considered a medication error.
o
Wrong route of administration.
o
Administration of an overdose with the intention to cause harm (e.g. suicide attempt).
o
Accidental administration of a higher dose than intended. 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) > 10x UNL
!
Hepatotoxicity events:
o
ALT or AST > 5x UNL and total bilirubin ≤ 2x UNL
o
ALT or AST > 3x UNL and total bilirubin > 2 UNL
o
Hepatic event leading to trial product discontinuation 
!
Diabetic retinopathy and related complications
2.16
Section 12.2
Reporting of adverse events
Table 12-1
Overview of AEs requiring additional data collection and AEs subject to event
adjudication[Note: In this document only the additional event is shown, all other events are 
unchanged]
CONFIDENTIAL


Protocol Amendment no. 2
CONFIDENTIAL
Date:
14 November 2016
Novo Nordisk
Trial ID: NN9924-4222
Version:
1.0
UTN: U111-1168-4339
Status:
Final
EudraCT No.: 2015-001351-71
Page:
13 of 19
Event
Specific event form
Event adjudication
Diabetic retinopathy and related complications
Yes
No
[Note: In the below figure all “≤” are substituted with “<”. The text in boxes will align once the 
update is done]:
AE identified
Is additional data 
collection required?
Is the AE to be 
adjudicated and/or 
is the outcome fatal?
AE form ≤<  24 hours
SIF ≤< 5 calendar days
Specific event form (AEs 
and SAEs)
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
AE: adverse event
SAE: serious adverse event
SIF: safety information form 
AEs for adjudication are described in the protocol section 12.7.2
All timelines are from investigators first knowledge of the event
No additional action
No additional action
No
Figure 12-1 Initial reporting of AEs
2.17
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 (UAP) requiring 
hospitalisation
! Acute myocardial 
infarction (STEMI or 
NSTEMI), silent MI
! Unstable angina pectoris 
requiring hospitalisation
CONFIDENTIAL


Protocol Amendment no. 2
CONFIDENTIAL
Date:
14 November 2016
Novo Nordisk
Trial ID: NN9924-4222
Version:
1.0
UTN: U111-1168-4339
Status:
Final
EudraCT No.: 2015-001351-71
Page:
14 of 19
2.18
Section 17.2
Definition of analysis sets
On-treatment: This observation period is a subset of the in-trial observation period and represents 
the time period in which a subject is considered exposed to trial product. For adjudicated events, 
ECGs, eye examination category, anti-semaglutide antibodies and AEs including hypoglycaemic 
episodes information collected on or after the first date of trial product up to and including the first 
date of (i) the follow-up visit V17, (ii) the follow-up prematurely discontinuation visit V17A, (iii) 
the last date on trial product +38 days or (iv) the end-date for the in-trial observation period will be 
used.
2.19
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, stratification factor as categorical fixed 
effects and baseline HbA1c measurement as a covariate will be fitted to observed values of 
the change from baseline in HbA1c at week 26.
!
The estimated parameters for location and dispersion will be used to impute 100 1000 values 
for each subject with missing week 26 data based on region, stratification factor and 
baseline HbA1c. Thus, 100 1000 complete data sets will be generated including observed and 
imputed values.
Analysis used for confirming superiority versus placebo at week 26:
For each of the 100 1000 (now complete) imputed data sets the change from baseline to week 26 in 
HbA1c will be analysed using an ANCOVA with treatment, stratification factor and region as 
categorical fixed effects and baseline HbA1c as covariate. The results obtained from analysing the 
datasets will be combined using Rubin’s rule55 to draw inference.
2.20
Section 17.4.2.1
Efficacy endpoints
Continuous efficacy endpoints 
[…]
For evaluation of the primary estimand the analysis will be performed separately for week 26, 52 
and week 78. For the analysis at week 52 and at week 78, the imputation of missing data will be 
further differentiated by whether subjects have discontinued trial product or initiated rescue 
medication prior to week 26 or at/or after week 26. This will result in imputation of missing data 
within 1612 groups of subjects instead of the 8 groups as described for the week 26 evaluation in 
Section 17.3.1. If less than five subjects have available data in one of the 12 groups, the imputation 
will be made within the 8 groups specified for the primary evaluation. The frequency of missing 
data is expected to be slightly larger at week 52 and week 78 compared to week 26. The rate of 
missing data is expected to decline over time.
[…]
CONFIDENTIAL


Protocol Amendment no. 2
CONFIDENTIAL
Date:
14 November 2016
Novo Nordisk
Trial ID: NN9924-4222
Version:
1.0
UTN: U111-1168-4339
Status:
Final
EudraCT No.: 2015-001351-71
Page:
15 of 19
Handling of missing data for the response status of the above categorical endpoints will be 
determined from the imputed continuous responses. A total of 1001000 imputed data sets will be 
created based on the same models as used to analyse HbA1c and body weight. For the secondary 
estimand the MMRM based analysis will be implemented in a MI setting. The imputed complete 
data sets will be analysed using a logistic regression model with treatment, stratification factor and 
region as categorical fixed effects and baseline response as covariate (i.e. baseline HbA1c for binary 
HbA1c endpoints, baseline weight for binary weight endpoints and both baseline HbA1c and body 
weight for the binary endpoint that combines both parameters). Inference comparing treatments will 
be drawn using Rubin’s rule55.
Time to event endpoint
!
Time to rescue medication
Subjects completing the study without need for rescue medication will be censored at the time point 
of actual date of last trial product. Start time is date of first trial product. Time to rescue medication 
will be described and compared for each of the oral semaglutide dose level versus sitagliptin 100 
mg using likelihood ratio tests obtained from a proportional Cox hazards model with treatment, 
stratification factor and region as categorical fixed effects and baseline HbA1c as a covariate. From 
this analysis the estimated Hazard ratios between each dose levels and sitagliptin will be presented 
together with 95 % confidence intervals and two-sided p-values for test of no difference. 
Furthermore, the endpoint will be presented by a Kaplan-Meier plot. 
2.21
Section 17.4.2.2
Safety endpoints
Other safety endpoints
[…]
Other safety endpoints
Change from baseline to week 26, 52 and 78 in:
!
Amylase
!
Lipase
!
Pulse
!
Systolic blood pressure
!
Diastolic blood pressure
[…]
Change from baseline to week 26, 52 and 78 in:
!
Haematology 
!
Biochemistry (except for amylase and lipase)
!
Calcitonin
!
ECG evaluation
CONFIDENTIAL


Protocol Amendment no. 2
CONFIDENTIAL
Date:
14 November 2016
Novo Nordisk
Trial ID: NN9924-4222
Version:
1.0
UTN: U111-1168-4339
Status:
Final
EudraCT No.: 2015-001351-71
Page:
16 of 19
!
Physical examination (week 52 and 78 only)
!
Eye examination category (week 52 and 78 only)
2.22
Section 18.1.1.1
Oral Semaglutide
Diabetic retinopathy complications
A transient worsening of diabetic retinopathy is a recognised complication in selected patients with 
diabetes after initiation of intensive antidiabetic treatment63-65. 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 progression66,67even in intensively treated patients who experienced early worsening64. 
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 placebo68. As a 
precaution in this trial, all subjects are required to have a fundus photography or dilated 
fundoscopy performed before enrolment into the trial; moreover, subjects with proliferative 
retinopathy or maculopathy requiring acute treatment will be excluded. As part of good diabetes 
management the investigator is encouraged to ensure adequate monitoring and treatment of 
diabetic retinopathy in subjects enrolled into the trial69.
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 
glycaemic 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, amylin analogues and SGLT-2 inhibitors). 
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 retinopathy69.
2.23
Section 27
References
62.
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.
63.
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 
CONFIDENTIAL


Protocol Amendment no. 2
CONFIDENTIAL
Date:
14 November 2016
Novo Nordisk
Trial ID: NN9924-4222
Version:
1.0
UTN: U111-1168-4339
Status:
Final
EudraCT No.: 2015-001351-71
Page:
17 of 19
dependent diabetes mellitus: the Oslo study. Br Med J (Clin Res Ed). 1985;290(6471):811-
5.
64.
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.
65.
Varadhan L, Humphreys T, Walker AB, Varughese GI. The impact of improved glycaemic 
control with GLP-1 receptor agonist therapy on diabetic retinopathy. Diabetes Res Clin 
Pract. 2014;103(3):e37-9.
66.
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.
67.
The Action to Control Cardiovascular Risk in Diabetes Follow-On (ACCORDION) Eye 
Study Group and the Action to Control Cardiovascular Risk in Diabetes Follow-On 
(ACCORDION) Study Group. Persistent Effects of Intensive Glycemic Control on 
Retinopathy in Type 2 Diabetes in the Action to Control Cardiovascular Risk in Diabetes 
(ACCORD) Follow-On Study. Diabetes Care. 2016;39(7):1089-100.
68.
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.
69.
American Diabetes Association. Standards of medical care in diabetes - 2016. Diabetes 
Care. 2016;39 (Suppl. 1).
2.24
Reference numbers
Numbers will change throughout the updated protocol when the above new references are
introduced.
2.25
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 or hospitalisation for unstable angina)
!
Cerebrovascular event (stroke or TIA)
!
Heart failure requiring hospitalisation
!
Pancreatitis
!
Neoplasm (excluding thyroid neoplasm)
!
Thyroid disease (including thyroid neoplasm)
!
Renal event
!
Hypersensitivity reactions
!
Acute gallstone disease
!
Medication error (concerning trial products):
CONFIDENTIAL


Protocol Amendment no. 2
CONFIDENTIAL
Date:
14 November 2016
Novo Nordisk
Trial ID: NN9924-4222
Version:
1.0
UTN: U111-1168-4339
Status:
Final
EudraCT No.: 2015-001351-71
Page:
18 of 19
o
Administration of wrong drug. 
Note: Use of wrong DUN is not considered a medication error.
o
Wrong route of administration.
o
Administration of an overdose with the intention to cause harm (e.g. suicide 
attempt).
o
Accidental administration of a higher dose than intended. 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) > 10x UNL
!
Hepatotoxicity events:
o
ALT or AST > 5x UNL and total bilirubin ≤ 2x UNL
o
ALT or AST > 3x UNL and total bilirubin > 2x UNL
o
Hepatic event leading to trial product discontinuation
!
Diabetic retinopathy and related complications
2.26
Appendix B, 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 November 2016
Novo Nordisk
Trial ID: NN9924-4222
Version:
1.0
UTN: U111-1168-4339
Status:
Final
EudraCT No.: 2015-001351-71
Page:
19 of 19
3
References
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):e37-9.
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.
CONFIDENTIAL


Local Amendment FR n°1
CONFIDENTIAL
Date:
22 January 2016
Novo Nordisk
Trial ID: NN9924-4222
Version:
1.0
UTN: U1111-1168-4339
Status:
Final
EudraCT No.: 2015-001351-71
Page:
1 of 6
Local Amendment
no 1-FR
Trial ID: NN9924-4222
PIONEER 3 - vs. DPP-4 inhibitor
Efficacy and long-term safety of oral semaglutide versus sitagliptin
in subjects with type 2 diabetes
Applicable to FRANCE
Amendment originator:
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Local Amendment FR n°1
CONFIDENTIAL
Date:
22 January 2016
Novo Nordisk
Trial ID: NN9924-4222
Version:
1.0
UTN: U1111-1168-4339
Status:
Final
EudraCT No.: 2015-001351-71
Page:
2 of 6
Table of contents   "Double click to update Table of Content" 
Page 
1 
Introduction including rationale for the local amendment ................................................................... 3 
2 
Changes ...................................................................................................................................................... 4 
CONFIDENTIAL


Local Amendment FR n°1
CONFIDENTIAL
Date:
22 January 2016
Novo Nordisk
Trial ID: NN9924-4222
Version:
1.0
UTN: U1111-1168-4339
Status:
Final
EudraCT No.: 2015-001351-71
Page:
3 of 6
1
Introduction including rationale for the local amendment
The rationale for issuing this substantial amendment is to add 2 new sites  and to delete one site that 
withdrawn its participation. 
New sites : 
Deletion of site form Nantes: 
Attachment II and List of investigators are updated accordingly. 
In this protocol amendment: 
x
Any new text is written in italics.
x
Any text deleted from the protocol is written using strike through.
CONFIDENTIAL


Local Amendment FR n°1
CONFIDENTIAL
Date:
22 January 2016
Novo Nordisk
Trial ID: NN9924-4222
Version:
1.0
UTN: U1111-1168-4339
Status:
Final
EudraCT No.: 2015-001351-71
Page:
4 of 6
2
Changes
The following changes to List of investigators to NN9924-4222: 
Attachment II – Addition of new sites 
Investigator:
Name:
Title:
Address:
Tel:
Fax:
E-mail:
Investigator:
Name:
Title:
Address:
Tel:
Fax:
E-mail:
CONFIDENTIAL


Local Amendment FR n°1
CONFIDENTIAL
Date:
22 January 2016
Novo Nordisk
Trial ID: NN9924-4222
Version:
1.0
UTN: U1111-1168-4339
Status:
Final
EudraCT No.: 2015-001351-71
Page:
5 of 6
Deletion of site: 
Investigator:
Name:
Title:
Address:
Tel:
Fax:
E-mail
1. List of Investigators – Addition of a new sub-investigator at site
 2 new sites (
and 
and deletion of site 
 
CONFIDENTIAL


Local Amendment FR n°1
CONFIDENTIAL
Date:
22 January 2016
Novo Nordisk
Trial ID: NN9924-4222
Version:
1.0
UTN: U1111-1168-4339
Status:
Final
EudraCT No.: 2015-001351-71
Page:
6 of 6
CONFIDENTIAL


Local Amendment FR n°2
CONFIDENTIAL
Date:
03 March 2016
Novo Nordisk
Trial ID: NN9924-4222
Version:
2.0
UTN: U1111-1168-4339
Status:
Final
EudraCT No.: 2015-001351-71
Page:
1 of 6
Local Amendment
no 2-FR
Trial ID: NN9924-4222
PIONEER 3 - vs. DPP-4 inhibitor
Efficacy and long-term safety of oral semaglutide versus sitagliptin
in subjects with type 2 diabetes
Applicable to FRANCE
Amendment originator:
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Local Amendment FR n°2
CONFIDENTIAL
Date:
03 March 2016
Novo Nordisk
Trial ID: NN9924-4222
Version:
2.0
UTN: U1111-1168-4339
Status:
Final
EudraCT No.: 2015-001351-71
Page:
2 of 6
Table of contents   "Double click to update Table of Content" 
Page
1
Introduction including rationale for the local amendment ...................................................................3
2
Changes......................................................................................................................................................4
CONFIDENTIAL


Local Amendment FR n°2
CONFIDENTIAL
Date:
03 March 2016
Novo Nordisk
Trial ID: NN9924-4222
Version:
2.0
UTN: U1111-1168-4339
Status:
Final
EudraCT No.: 2015-001351-71
Page:
3 of 6
1
Introduction including rationale for the local amendment
The rationale for issuing this substantial amendment is to add 1 new site, to modify the Investigator
of one site and to add sub-investigators at one site.
-
New site :
-
Modification of the Investigator for the site from 
 (site 
 due to change in local
organisation and the existing Investigator become an investigator from satellite’s site:
and addition of a satellite site :
 
-
Addition of a new sub-investigator :
Attachment II and List of investigators are updated accordingly.
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
CONFIDENTIAL


Local Amendment FR n°2
CONFIDENTIAL
Date:
03 March 2016
Novo Nordisk
Trial ID: NN9924-4222
Version:
2.0
UTN: U1111-1168-4339
Status:
Final
EudraCT No.: 2015-001351-71
Page:
4 of 6
2
Changes
The following changes to Attachment II to NN9924-4222:
1. Attachment II – Addition of a new site and change of Investigator to another site with new
satellite site associated
Investigator:
Name:
Title/
qualification:
Address:
Tel:
Fax:
E-mail:
Modification of the PI for one 
site:
Investigator:
Name:
Title/
qualification:
Address:
Tel:
Fax:
E-mail:
CONFIDENTIAL


Local Amendment FR n°2
CONFIDENTIAL
Date:
03 March 2016
Novo Nordisk
Trial ID: NN9924-4222
Version:
2.0
UTN: U1111-1168-4339
Status:
Final
EudraCT No.: 2015-001351-71
Page:
5 of 6
Investigator:
Name:
Title/
qualification:
Address:
Tel:
Fax:
E-mail:
Satellite site:
Name:
Title/
qualification:
Address:
Tel:
Fax:
E-mail:
CONFIDENTIAL


Local Amendment FR n°2
CONFIDENTIAL
Date:
03 March 2016
Novo Nordisk
Trial ID: NN9924-4222
Version:
2.0
UTN: U1111-1168-4339
Status:
Final
EudraCT No.: 2015-001351-71
Page:
6 of 6
2. List of Investigators – Addition of 1 new sub-investigator at site
, modification of the 
Investigator at site 
 addition of 2 new sub-investigators at site 
and addition of a new 
site
CONFIDENTIAL


Local Amendment FR n°3
CONFIDENTIAL
Date:
02 May 2016
Novo Nordisk
Trial ID: NN9924-4222
Version:
1.0
UTN: U1111-1168-4339
Status:
Final
EudraCT No.: 2015-001351-71
Page:
1 of 4
Local Amendment
no 3-FR
Trial ID: NN9924-4222
PIONEER 3 - vs. DPP-4 inhibitor
Efficacy and long-term safety of oral semaglutide versus sitagliptin
in subjects with type 2 diabetes
Applicable to FRANCE
Amendment originator:
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Local Amendment FR n°3
CONFIDENTIAL
Date:
02 May 2016
Novo Nordisk
Trial ID: NN9924-4222
Version:
1.0
UTN: U1111-1168-4339
Status:
Final
EudraCT No.: 2015-001351-71
Page:
2 of 4
Table of contents   "Double click to update Table of Content" 
Page
1
Introduction including rationale for the local amendment ...................................................................3
2
Changes......................................................................................................................................................4
CONFIDENTIAL


Local Amendment FR n°3
CONFIDENTIAL
Date:
02 May 2016
Novo Nordisk
Trial ID: NN9924-4222
Version:
1.0
UTN: U1111-1168-4339
Status:
Final
EudraCT No.: 2015-001351-71
Page:
3 of 4
1
Introduction including rationale for the local amendment
The rationale for issuing this substantial amendment is to add sub-investigators at 4 sites.
-
Addition of a new sub-investigators : 
o
 
o
 
 
o
 
o
  
 
List of investigators is updated accordingly.
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
CONFIDENTIAL


Local Amendment FR n°3
CONFIDENTIAL
Date:
02 May 2016
Novo Nordisk
Trial ID: NN9924-4222
Version:
1.0
UTN: U1111-1168-4339
Status:
Final
EudraCT No.: 2015-001351-71
Page:
4 of 4
2
Changes
1. List of Investigators – Addition of 1 new sub-investigator at sites
 
 
and 
.
CONFIDENTIAL

SAP_001.pdf: 
Cover Page for Statistical Analysis Plan  
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT02607865 
Sponsor trial ID: 
NN9924-4222 
Official title of study: 
Efficacy and long-term safety of oral semaglutide versus 
sitagliptin in subjects with type 2 diabetes 
Document date: 
21-November-2018 
 


Link
Link
List of contents
Statistical analysis plan......................................................................................................................
Pre-defined MedDRA search – list of preferred terms...................................................................
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
Oral semaglutide
Trial ID: NN9924-4222
Clinical Trial Report
Appendix 16.1.9
21 November 2018
1.0
Final
16.1.9 Documentation of statistical methods
CONFIDENTIAL
Redacted VWDWLVWLFDODQDO\VLVSODQ 
Includes redaction of personal identifiable information only. 
. 


Statistical Analysis Plan
CONFIDENTIAL
Date:
22 May 2018
Novo Nordisk
Trial ID: NN9924-4222
Version:
1.0
UTN: U1111-1168-4339
Status:
Final
EudraCT No.: 2015-001351-71
Page:
1 of 37
Statistical Analysis Plan
Trial ID: NN9924-4222
PIONEER 3 - vs. DPP-4 inhibitor
Efficacy and long-term safety of oral semaglutide versus 
sitagliptin
in subjects with type 2 diabetes
Author:
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Statistical Analysis Plan
CONFIDENTIAL
Date:
22 May 2018
Novo Nordisk
Trial ID: NN9924-4222
Version:
1.0
UTN: U1111-1168-4339
Status:
Final
EudraCT No.: 2015-001351-71
Page:
2 of 37
Table of Contents
Page
Table of Contents........................................................................................................................................2
List of abbreviations ...................................................................................................................................3
1
Introduction .........................................................................................................................................6
1.1
Trial information.......................................................................................................................6
1.1.1
Objective(s) .............................................................................................................6
1.1.1.1
Primary objective...............................................................................6
1.1.1.2
Secondary objectives..........................................................................6
1.1.2
Type of trial.............................................................................................................6
1.2
Scope of the statistical analysis plan..........................................................................................7
2
Statistical considerations .....................................................................................................................8
2.1
Sample size calculation ...........................................................................................................10
2.2
Definition of analysis sets........................................................................................................13
2.3
Primary endpoint.....................................................................................................................15
2.3.1
Primary analysis for the primary estimand..............................................................15
2.3.2
Primary analysis for the secondary estimand ..........................................................16
2.3.3
Sensitivity analyses................................................................................................17
2.3.3.1
Pattern mixture models.....................................................................18
2.3.3.2
Other sensitivity analysis..................................................................19
2.3.3.3
Assessment of sensitivity analyses....................................................19
2.4
Secondary endpoints ...............................................................................................................19
2.4.1
Confirmatory secondary endpoints.........................................................................19
2.4.2
Supportive secondary endpoints .............................................................................20
2.4.2.1
Efficacy endpoints............................................................................20
2.4.2.2
Safety endpoints...............................................................................25
2.5
Pharmacokinetic modelling .....................................................................................................28
2.6
Health economics and/or patient reported outcomes.................................................................29
2.6.1
SF-36v2® (acute version) health survey..................................................................29
2.6.2
Impact of Weight on Quality of Life Clinical Trials Version (IWQOL-Lite-CT).....31
2.6.3
Control of Eating Questionnaire (CoEQ)................................................................32
2.6.4
Responder analyses................................................................................................33
3
Changes to the statistical analyses planned in the protocol..............................................................35
4
References ..........................................................................................................................................37
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
22 May 2018
Novo Nordisk
Trial ID: NN9924-4222
Version:
1.0
UTN: U1111-1168-4339
Status:
Final
EudraCT No.: 2015-001351-71
Page:
3 of 37
List of abbreviations
ADA
American Diabetes Association
AE
adverse event
AACE
American Association of Clinical Endocrinologists
ANOVA
analysis of variance
ANCOVA
analysis of covariance
ATC
Anatomical Therapeutic Chemical
BG
blood glucose
BMI
body mass index
CI
confidence interval
CoEQ
control of eating questionnaire
CTR
clinical trial report
EAC
event adjudication committee
ECG
electrocardiogram
eCRF
electronic case report form
EMA
European Medicines Agency
FAS
full analysis set
FPG
fasting plasma glucose
GLP-1
glucagon-like peptide-1
GI
gastrointestinal
HbA1c
glycosylated haemoglobin
HDL
high-density lipoprotein
HRQoL
health-related quality of life
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
22 May 2018
Novo Nordisk
Trial ID: NN9924-4222
Version:
1.0
UTN: U1111-1168-4339
Status:
Final
EudraCT No.: 2015-001351-71
Page:
4 of 37
IWRS
interactive web response system
LDL
low-density lipoprotein
LLoQ
lower limit of quantification
LOCF
last observation carried forward
MAR
missing at random
MCAR 
missing completely at random
MCS
mental component score
MCMC
Markov Chain Monte Carlo
MedDRA
Medical Dictionary for Regulatory Activities
MI
multiple imputation
MMRM
mixed model for repeated measurements
MNAR
missing not at random
NBS 
norm-based score
PCS
physical component score
PG
plasma glucose
PK
pharmacokinetic
PP
per protocol analysis set
PRO
patient reported outcome
REML
restricted maximum likelihood
SAP
statistical analysis plan
SAS
safety analysis set
s.c.
subcutaneous
SD
standard deviation
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
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Trial ID: NN9924-4222
Version:
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UTN: U1111-1168-4339
Status:
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EudraCT No.: 2015-001351-71
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SF-36v2 (acute version) 
SF-36v2® Health Survey (acute version)
SNAC 
sodium N-[8-(2-hydroxybenzoyl)amino]caprylate
SU
sulfonylurea
SMPG
self-measured plasme glucose
T2DM
type 2 diabetes mellitus
TE
treatment effect
TEAE
treatment emergent adverse event
VLDL
very low-density lipoprotein
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
22 May 2018
Novo Nordisk
Trial ID: NN9924-4222
Version:
1.0
UTN: U1111-1168-4339
Status:
Final
EudraCT No.: 2015-001351-71
Page:
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1
Introduction
1.1
Trial information
1.1.1
Objective(s)
1.1.1.1
Primary objective
To compare the effect of once-daily dosing of three dose levels (3 mg, 7 mg and 14 mg) of oral 
semaglutide versus sitagliptin 100 mg once-daily, both in combination with metformin with or 
without SU, on glycaemic control in subjects with T2DM.
1.1.1.2
Secondary objectives
To compare the effect of once-daily dosing of three dose levels (3 mg, 7 mg and 14 mg) of oral 
semaglutide versus sitagliptin 100 mg once-daily, both in combination with metformin with or 
without SU, on body weight in subjects with T2DM.
To compare the long-term safety and tolerability of once-daily dosing of three dose levels (3 mg, 
7 mg and 14 mg) of oral semaglutide versus sitagliptin 100 mg once-daily, both in combination 
with metformin with or without SU, in subjects with T2DM.
1.1.2
Type of trial
The trial is a 78-week, randomised, double-blind, double-dummy, active-controlled, parallel-group, 
multi-centre, multi-national trial with four arms comparing efficacy and safety of oral semaglutide 
3 mg, 7 mg and 14 mg once-daily with sitagliptin 100 mg once-daily. Subjects with T2DM 
inadequately controlled on metformin alone or in combination with SU will be randomised in a 
1:1:1:1-manner to receive either:
!
oral semaglutide 3 mg and sitagliptin placebo
!
oral semaglutide 7 mg and sitagliptin placebo
!
oral semaglutide 14 mg and sitagliptin placebo
!
sitagliptin 100 mg and oral semaglutide placebo
Randomisation will be stratified according to descent (Japanese subjects/non-Japanese subjects) and 
anti-diabetic pre-trial background medication (metformin or metformin + SU) to ensure even 
distribution of the four treatment arms within strata.
To maintain the blinding of the trial, the treatment will consist of two tablets daily as the sitagliptin 
tablet is not visually identical to the oral semaglutide tablets.
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Statistical Analysis Plan
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Date:
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Trial ID: NN9924-4222
Version:
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Total trial duration for the individual subject will be approximately 85 weeks. The trial includes a 
2-week screening period, followed by a 78 week randomised treatment period and a follow-up 
period of 5 weeks.
A schematic diagram of the trial design is shown in Figure 1–1.
Figure 1–1
Trial design
1.2
Scope of the statistical analysis plan
This statistical analysis plan (SAP) is based on the protocol for trial NN9924-4222 “Efficacy and 
long-term safety of oral semaglutide versus sitagliptin”, version 4.0 (23 November 2016) as well as 
the Protocol amendment no. 1, version 1.0 (10 November 2015) and the Protocol amendment no. 1, 
version 2.0 (14 November 2016, and includes more detailed procedures for executing the statistical 
analyses of the primary and secondary endpoints. Statistical analyses and a number of clarifications 
additional to those specified in the trial protocol are pre-specified with this SAP. All changes to the 
statistical analyses planned in the trial protocol are documented in section 3.
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Statistical Analysis Plan
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Date:
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Trial ID: NN9924-4222
Version:
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UTN: U1111-1168-4339
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2
Statistical considerations
Novo Nordisk will be responsible for the statistical analyses and reporting. 
General considerations
The blinding of the randomised treatments will be maintained until the database has been released 
for statistical analysis. No interim analyses or other analyses of unblinded data will be performed 
before the database is locked.
Data from all sites will be analysed and reported together. 
The randomisation is stratified based on pre-trial therapy at screening (metformin or 
metformin+SU) and descent (Japanese subjects/non-Japanese subjects). In the statistical analyses 
descent is a part of region and pre-trial therapy at screening is referred to as stratification factor. The 
two combinations (metformin; metformin+SU) in the stratification factor will be included based on 
the actual information collected through the eCRF. In case of missing eCRF information the 
information collected from 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 ½LLoQ. Number of 
values below LLoQ by treatment and visit will be summarised if deemed relevant.
The primary and confirmatory efficacy endpoints will be confirmed at week 26. This approach will 
result in a lower proportion of missing data compared to the expected proportion of missing data at 
week 52 and week 78 and therefore a more reliable estimate of efficacy. 
Results from a statistical analysis will as a minimum be presented by the estimated treatment 
contrasts for the below three comparisons at week 26, week 52 and week 78 with associated two-
sided 95% confidence intervals and p-values corresponding to two-sided tests of no difference:
!
oral semaglutide 14 mg vs. sitagliptin 100 mg
!
oral semaglutide 7 mg vs. sitagliptin 100 mg
!
oral semaglutide 3 mg vs. sitagliptin 100 mg
If no statistical analysis is specified, data will be presented using relevant summary statistics.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
22 May 2018
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Trial ID: NN9924-4222
Version:
1.0
UTN: U1111-1168-4339
Status:
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EudraCT No.: 2015-001351-71
Page:
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Primary and secondary estimands
Two estimands adressing different aspect of the primary trial objective will be defined as follows: 
!
Primary estimand – ‘Treatment policy’
!
treatment difference at week 26 for all randomised subjects
!
Secondary estimand – ‘Hypothetical’
!
treatment difference at week 26 for all randomised subjects if all subjects adhered to 
treatment and did not initiate rescue medication
The treatment policy estimand assesses the average effect in a future population that results from 
initiating treatment with oral semaglutide including potential rescue medication(s) as compared to 
initiating treatment with sitagliptin 100 mg including potential rescue medication(s). Generalisation 
of this estimand depends among other things on the extent to which the use of rescue medication 
and treatment adherence in this trial reflects clinical practice. All post-baseline scheduled visit data 
will be included in the analysis, including data collected after discontinuation of trial product or 
initiation of rescue medication(s).
The hypothetical estimand assesses the glycaemic benefit a future subject is expected to achieve if 
initiating and continuing treatment with oral semaglutide as compared to sitagliptin 100 mg. 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 100 mg for purposes of 
treating individual subjects. Generalisation of this estimand depends among other things on the 
extent to which the compliance to trial product administration in this trial reflects clinical practice. 
Only post-baseline scheduled visit data collected prior to discontinuation of trial product or 
initiation of rescue medication will be included in the analysis. This will avoid confounding from 
rescue medication. 
Missing data considerations at week 26
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), when estimating the 
primary estimand, is expected to be maximum 10% based on the oral semaglutide phase 2 trial 
(NN9924-3790). Thus, missing data will be due to withdrawal from trial or lost to follow-up.
The proportion of missing data when estimating the secondary estimand is expected to be higher 
(20%) since data collected after discontinuation of trial product or initiation of rescue medication(s) 
will be set to missing. The 20% of missing data is based on the sitagliptin phase 3 trials1 the oral 
semaglutide phase 2 trial (NN9924-3790) and the indication that a low starting dose with gradual 
dose escalation diminishes GI AEs compared with more aggressive dosing regimens. Across 
treatment arms the main reasons for missing data are expected to be early treatment discontinuation 
due to GI AEs and eventually initiation of rescue medication. Initiation of rescue medication is 
expected to be more frequent in the sitagliptin 100 mg arm and in the oral semaglutide 3 mg arm 
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Statistical Analysis Plan
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Date:
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Trial ID: NN9924-4222
Version:
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than for the two highest dose levels of oral semaglutide. A higher proportion of subjects are 
expected to discontinue treatment due to AEs in the oral semaglutide 14 mg arm, compared to the 
other treatment arms. So overall the frequency of missing data is expected to be similar across 
treatment arms.
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 primary endpoint is change from baseline to week 26 in HbA1c. For HbA1c both non-inferiority 
and superiority versus sitagliptin 100 mg are planned to be tested at each dose level. The 
confirmatory secondary endpoint is change from baseline to week 26 in body weight (kg). For body 
weight, superiority versus sitagliptin 100 mg is planned to be tested at each dose level. The sample 
size calculation is based on jointly meeting the below three out of the nine pre-specified 
confirmatory hypotheses shown in Table 2–1. The closed testing procedure described in Bretz et al 
20112 is used to control the overall type-1 error at a nominal two-sided 5% level. The three 
hypotheses are
!
HbA1c superiority of oral semaglutide 14 mg vs. sitagliptin 100 mg
!
HbA1c superiority of oral semaglutide 7 mg vs. sitagliptin 100 mg
!
HbA1c non-inferiority of oral semaglutide 3 mg vs. sitagliptin 100 mg (margin 0.3%) 
The statistical testing strategy is based on the following two principles:
!
Within a dose level, glycaemic efficacy must be established by HbA1c non-inferiority before 
testing for added benefits in terms of superiority for HbA1c and/or superiority of body weight. 
!
Glycaemic efficacy by HbA1c non-inferiority must be established on all higher dose levels 
before continuing testing hypotheses on lower dose levels.
The sample size is calculated using the calcPower function in the R package, gMCP3 using 10000 
simulations. All of the nine pre-specified confirmatory tests are assumed to be independent. Since 
positive correlations among the tests are expected, the assumption of independence is viewed as 
conservative.
The sample size assumptions for treatment effects (TE), adjusted treatment effects and the common 
standard deviation (SD) used across dose levels are given in Table 2–1. These are based on the oral 
semaglutide phase 2 results (NN9924-3790), sitagliptin phase 3a trial results and supported by 
results from the s.c. semaglutide phase 2 trial (NN9535-1821).
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Statistical Analysis Plan
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Date:
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Trial ID: NN9924-4222
Version:
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Since the equalising effect of rescue medication will be included in the primary analysis as well as a 
conservative approach for handling of missing data will be performed, an adjustment in treatment 
effect will be implemented for the 10% of subjects who discontinue trial product or initiate rescue 
medication and for the 10% of subjects with missing data. The treatment effects used in the sample 
size calculation will be adjusted according to a 75% smaller effect in these subjects. In addition, the 
non-inferiority margin of 0.3 % for HbA1c is used, when testing for non-inferiority. The adjusted 
treatment effects for testing non-inferiority (HbA1c only) and superiority are as described below:
!
Non-inferiority 
!
0.8*TE + 0.2*TE*0.25 + non-inferiority margin*0.1
!
Superiority
!
0.8*TE + 0.2*TE*0.25 
Table 2–1
Assumptions for sample size calculation
Semaglutide vs. sitagliptin 
HbA1c
Body weight
Treatment dose
14 mg
7 mg
3 mg
14 mg
7 mg
3 mg
Treatment effect (TE)
-0.5%
-0.3%
-0.1%
-3.0 kg
-2.0 kg
-1.0 kg
Adjusted TE, non-
inferiority
-0.395%
-0.225%
-0.055%
Adjusted TE, superiority
-0.425%
-0.255%
-0.085%
-2.55 kg
-1.70 kg
-0.85 kg
Standard deviation 
1.1%
1.1%
1.1%
4.0 kg
4.0 kg
4.0 kg
With the above assumptions, allocating 465 subjects to each of the semaglutide treatment arms and 
sitagliptin 100 mg provides 90 % power to jointly confirm HbA1c superiority of semaglutide 14 mg 
vs. sitagliptin 100 mg, HbA1c superiority of semaglutide 7 mg vs. sitagliptin 100 mg and HbA1c
non-inferiority of semaglutide 3 mg vs. sitagliptin 100 mg. Calculated powers for selected 
individual hypotheses are presented in Table 2–2. In total 4×465 = 1860 subjects are planned to be 
randomised.
Table 2–2
Powers for individual hypotheses
Statistical test
HbA1c superiority
Body weight superiority
HbA1c non-
inferiority (margin 
= 0.3 %)
Treatment dose
14 mg
7 mg
3 mg
14 mg
7 mg
3 mg
3 mg
Power (%)
> 99
90
19
> 99
> 99
89
> 99
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Statistical Analysis Plan
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Page:
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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 non-
inferiority test of semaglutide 14 mg vs. sitagliptin 100 mg. The local significance level (α-local) 
will be reallocated if a hypothesis is confirmed according to the weight given by the directed edges 
between nodes (hypotheses).
 = 0.05
HbA1c (%)
Non-inferiority
 = 0
HbA1c (%)
Superiority
 = 0
HbA1c (%)
Non-inferiority
 = 0
Body weight (kg)
Superiority
1 3
⁄
1 2
⁄
1 3
⁄
1 3
⁄
1 2
⁄
1 2
⁄
1 2
⁄
 = 0
HbA1c (%)
Superiority
 = 0
HbA1c (%)
Non-inferiority
 = 0
Body weight (kg)
Superiority
1 3
⁄
1 2
⁄
1 3
⁄
1 3
⁄
1 2
⁄
1 2
⁄
1 2
⁄
 = 0
Body weight (kg)
Superiority
 = 0
HbA1c (%)
Superiority
1
1
semaglutide 7 mg
vs. sitagliptin 100 mg
semaglutide 3 mg
vs. sitagliptin 100 mg
semaglutide 14 mg
vs. sitagliptin 100 mg
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
22 May 2018
Novo Nordisk
Trial ID: NN9924-4222
Version:
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UTN: U1111-1168-4339
Status:
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2.2
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 
evaluation “as randomised”.
Safety analysis set (SAS): includes all subjects exposed to at least one dose of trial product. 
Subjects in the SAS will contribute to the evaluation based on the trial product received for the 
majority of the period where they were on treatment. This will be referred to as contributing to the 
evaluation “as treated”.
Per protocol (PP) analysis set: includes all subjects in the full analysis set who fulfils the 
following criteria
!
have not violated any inclusion criteria
!
have not fulfilled any exclusion criteria
!
have a valid baseline HbA1c measurement
!
is exposed to trial product and have at least one valid HbA1c measurement while on treatment 
without rescue medication at or after week 14
Subjects in the PP analysis set will contribute to the analysis “as treated”.
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 will be used restrictively and normally no subjects will be excluded 
from the FAS. If any subjects or observations are to be excluded from the analysis sets or the 
observation periods defined below, this, together with the reasons for their exclusion, will be 
documented and signed by those responsible before database lock. A description of these exclusions 
will be included in the clinical trial report.
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 (V17) for subjects on trial product
!
the End-of-treatment visit (V16) or the follow-up premature discontinuation visit (V17A), 
whichever comes last, 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.
!
First, subjects will be selected based on the specified analysis set
!
Next, data points on the selected subjects from first step will be selected based on the specified 
observation period
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Statistical Analysis Plan
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Trial ID: NN9924-4222
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In this trial, three observation periods will be defined, as described below. 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, onset date will be the EAC adjudicated 
onset date. 
Definition of the observation periods:
!
In-trial: This observation period will include information assessed at or after date of 
randomisation (as registered in the IWRS system) and up to and including the last direct 
subject-site contact, which is scheduled to take place 5 weeks (+3 days visit window) after the  
planned last dose on trial product at a follow-up visit. For subjects who withdraw their informed 
consent, the in-trial observation period ends at their date of withdrawal. If a subject is lost to 
follow-up, the end of the in-trial period is defined as the date of the last subject-investigator 
contact (site or phone visit). In the case a subject dies during the trial the date of death will be 
the end-date of the in-trial observation period regardless of the above defined end-dates. This 
observation period will be the primary observation period for estimating the primary estimand 
and used for evaluating safety.
!
On-treatment: This observation period is a subset of the in-trial observation period and 
represents the time period in which a subject is considered exposed to trial product. For 
adjudicated events, ECGs, eye examination category, anti-semaglutide antibodies and AEs 
including hypoglycaemic episodes information collected on or after the first date of trial product 
up to and including the first date of (i) the follow-up visit V17, (ii) the follow-up prematurely 
discontinuation visit V17A, (iii) the last date on trial product +38 days or (iv) the end-date for 
the in-trial observation period will be used. The follow-up visit is scheduled to take place 5 
weeks after the last date on trial product corresponding to approximately five half-lives of oral 
semaglutide. In addition, the ascertainment window includes the follow-up visit window of +3 
days after last date on trial product. For efficacy and other safety assessments (laboratory 
assessments, physical examination and vital signs) information collected on or after the first 
date of trial product up to and including the last date on trial product +3 days will be used in 
order to ensure specificity to reversible effects of treatment. The end-date for all assessments in 
the on-treatment observation period will be before or the same date as the end-date for the in-
trial observation period. This observation period will be used for evaluating safety. 
!
On-treatment without rescue medication: This observation period is a subset of the on-
treatment observation period. To avoid potential confounding from rescue medications, 
information that is collected after initiation of rescue medication will be excluded from this 
observation period. Specifically, it includes information collected at or after date of first dose on 
trial product up to and including the first date of; (i) last date on trial product +3 days or 
(ii) initiation of rescue medication. Thus, an ascertainment window of 3 days for subjects not 
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Statistical Analysis Plan
CONFIDENTIAL
Date:
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Trial ID: NN9924-4222
Version:
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initiating rescue medication. This observation period will be the primary observation period for 
estimating the secondary estimand.
2.3
Primary endpoint 
The primary endpoint is change from baseline to week 26 in HbA1c.
2.3.1
Primary analysis for the primary estimand 
The primary estimand will be estimated based on the FAS using week 26 measurements from the 
in-trial observation period. The primary statistical analysis will be a pattern mixture model using 
multiple imputation to handle missing data assuming that the missing data mechanism is missing at 
random (MAR). Imputation of missing data at week 26 will be done within 8 groups of subjects 
defined by randomised treatment arm and whether subjects at week 26; (i) have discontinued 
treatment or initiated rescue medication or (ii) 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 26 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 in HbA1c at week 26.
!
The estimated parameters for location and dispersion will be used to impute 1000 values for 
each subject with missing week 26 data based on region, stratification factor and baseline 
HbA1c. Thus, 1000 complete data sets will be generated including observed and imputed values.
In the statistical analysis models the variable region is included as a categorical fixed effect. The 
regions to be used in the statistical analyses are defined as Europe, North America, South America, 
Africa and Asia. When addressing the treatment policy estimand, the imputation is to be done 
within groups defined by randomised treatment and treatment adherence at time of evaluation. The 
number of subjects in the groups who at time of evaluation have discontinued trial product or 
initiated rescue medication are expected to be relatively low. Therefore the region variable included 
in the imputation model will be reduced in levels avoiding estimation problems due to sparse data. 
The regions to be used in these imputations are defined as North America and Other regions.
Analysis used for confirming superiority versus sitagliptin at week 26:
For each of the 1000 (now complete) imputed data sets the change from baseline to week 26 will be 
analysed using an ANCOVA with treatment, region and stratification factor as categorical fixed 
effects and baseline HbA1c as covariate. The results obtained from analysing the datasets will be 
combined using Rubin’s rule4 to draw inference.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
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Trial ID: NN9924-4222
Version:
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From this analysis the estimated treatment differences between each of the oral semaglutide dose 
levels and sitagliptin 100 mg together with associated two-sided 95 % CIs and unadjusted two-sided 
p-values for testing no difference from zero will be presented.
Analysis used for confirming non-inferiority versus sitagliptin at week 26:
Prior to analysing the data using the same model and approach as used for confirming superiority 
(see above) a value of 0.3 % (the non-inferiority margin) will be added to imputed values at 
week 26 for the oral semaglutide treatment arms only (Koch 2008)5. For evaluating non-inferiority 
versus sitagliptin 100 mg unadjusted two sided p-values for testing no difference from the non-
inferiority margin will be presented.
2.3.2
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 26 from the on-treatment without rescue observation period. The primary 
analysis for the secondary estimand will be a Mixed Model for Repeated Measurements (MMRM). 
A restricted maximum likelihood (REML) will be used. The model will include all post baseline 
HbA1c measurements collected at scheduled visits up to and including week 26 as dependent 
variables. The independent effects included in the model will be treatment, stratification factor and 
region 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. For subjects who have no post-
baseline scheduled assessments available, the baseline value will be carried forward to the first 
scheduled visit to ensure that all randomised subjects will contribute to the statistical analysis.
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. Even if the assumption of MAR is not 
satisfied, this analysis is not expected to bias the estimated HbA1c treatment effect for the secondary 
estimand in favour of oral semaglutide to any important degree. This is supported by the oral 
semaglutide phase 2 results (NN9924-3790) that showed that subjects who discontinue oral 
semaglutide do not have better outcome on average than those who remain on treatment.
Primary hypotheses 
For the primary HbA1c endpoint the following two confirmatory one-sided hypotheses are planned 
to be tested at each dose level of oral semaglutide versus sitagliptin 100 mg. Let the mean treatment 
difference be defined as μ = (oral semaglutide minus sitagliptin 100 mg):
!
Non-inferiority, using a non-inferiority margin of 0.3 %
!
H0: μ ≥ 0.3 % against Ha: μ < 0.3 %
CONFIDENTIAL


Statistical Analysis Plan
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Date:
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Trial ID: NN9924-4222
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EudraCT No.: 2015-001351-71
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!
Superiority
!
H0: μ ≥ 0.0 % against Ha: μ < 0.0 %
Operationally the hypotheses will be evaluated by two-sided tests.
Multiplicity and criteria for confirming hypotheses
The Type-I error for testing the nine confirmatory hypotheses related to the HbA1c and body weight 
endpoints (see Section 2.1) will be preserved in the strong sense at 5 % (two-sided) using the 
weighted Bonferroni-based closed testing procedure described in Bretz et al 20112 and outlined in . 
The first hypothesis to be tested is non-inferiority of HbA1c at the highest dose level. It will be 
tested at the overall significance level (5 %) while allocating 0 % local significance level to the 
remaining of the hypotheses. For this hypothesis, and in general, if a hypothesis is confirmed the 
significance level will be reallocated according to the weight and the direction of the edges going 
from the confirmed hypothesis to the next hypotheses as specified in . Each of the following 
hypotheses will be tested at their local significance level (α-local). This process will be repeated 
until no further hypotheses can be confirmed.
Non-inferiority and/or superiority will be considered confirmed if the mean 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 its local two -sided significance level as defined by 
the closed testing procedure in . This is equivalent to using a one-sided p-value (nominal alpha = 
0.025) and a one-sided 2.5 % overall significance level in the closed testing procedure.
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 EMA recommendations6
and with a report from the US National Research Council7, these analysis will primary evaluate the 
sensitivity of the results due to the impact of missing data. Since conservatism, i.e. avoiding bias in 
favour of semaglutide, depends on the context, separate sensitivity analyses will be made for non-
inferiority and superiority testing.
The evaluation of the robustness of the primary analysis results will primarily be based on a pattern 
mixture model approach using multiple imputation. An overview of the sensitivity analyses for each 
of the estimands are specified below followed by a more detailed description of the three different 
pattern mixture models used. Finally, one additional sensitivity analyses for the primary analysis 
will be described that are 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: 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
22 May 2018
Novo Nordisk
Trial ID: NN9924-4222
Version:
1.0
UTN: U1111-1168-4339
Status:
Final
EudraCT No.: 2015-001351-71
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!
A comparator multiple imputation analysis based on FAS using the in-trial observation period 
(superiority).
!
A comparator multiple imputation analysis differentiating between reasons for discontinuing 
treatment prematurely based on FAS using the in-trial observation period (superiority).
!
A tipping-point multiple imputation analysis based on FAS using the in-trial observation period 
(non-inferiority and superiority).
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 (non-inferiority and superiority).
2.3.3.1
Pattern mixture models
Common for the three pattern mixture model sensitivity analyses is that they all aim to stress-test 
the primary HbA1c results by changing the assumptions for part or all missing data in the oral 
semaglutide treatment arms, while maintaining the missing data assumption for the sitagliptin 
100 mg arm. The analyses will all be implemented using multiple imputation as described for the 
primary analysis of the primary estimand:
!
Comparator multiple imputation analysis: In this sensitivity analysis missing data at week 26 
for all subjects will be imputed to resemble in distribution the week 26 values observed in the 
sitagliptin 100 mg treatment arm. In effect this imputation approach removes the treatment 
difference between oral semaglutide and sitagliptin 100 mg for all subjects randomised to oral 
semaglutide, given that oral semaglutide is better than sitagliptin 100 mg. Due to the potential 
lack of sensitivity for testing non-inferiority this sensitivity analysis will only be used to 
evaluate the robustness of HbA1c superiority conclusions.
!
Comparator multiple imputation analysis differentiating between reasons for discontinuing 
treatment prematurely: In this sensitivity analysis missing data at week 26 for subjects who 
discontinue oral semaglutide treatment due to treatment related AE(s) will be imputed to 
resemble in distribution the week 26 values observed in the sitagliptin 100 mg treatment arm. 
Treatment related AEs are defined as AEs classified as possible or probable related to trial 
product as reported by the investigator. In effect this imputation approach removes the treatment 
difference between oral semaglutide and sitagliptin 100 mg for this selected group of subjects 
randomised to oral semaglutide. This sensitivity analysis is less conservative as compared to the 
first sensitivity analysis. Due to the potential lack of sensitivity for testing non -inferiority this 
sensitivity analysis will only be used to evaluate the robustness of HbA1c superiority 
conclusions.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
22 May 2018
Novo Nordisk
Trial ID: NN9924-4222
Version:
1.0
UTN: U1111-1168-4339
Status:
Final
EudraCT No.: 2015-001351-71
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!
Tipping-point multiple imputation analysis: In this sensitivity analysis, missing data will first be 
imputed according to the primary analysis. Second, for all oral semaglutide treatment arms a 
penalty will be added to the imputed values at week 26. The approach is to gradually increase 
this penalty until all confirmed HbA1c conclusions from the primary analysis are reversed. For 
each hypothesis tested the specific value of the penalty that reverses the conclusion will be used 
to evaluate the robustness of the primary analysis results. This sensitivity analysis will be used 
for evaluating the robustness of the HbA1c non-inferiority and superiority conclusions.
2.3.3.2
Other sensitivity analysis
The following additional sensitivity analysis will be specified
!
Per-protocol analysis: This sensitivity will be based on the per-protocol analysis set. Data from 
the on-treatment without rescue observation period will be analysed using the primary analysis 
approach for the secondary estimand. This sensitivity analysis will be used to evaluate the 
robustness of the HbA1c non-inferiority conclusions.
2.3.3.3
Assessment of sensitivity analyses
The results from the sensitivity analyses will be collectively used to interpret the robustness of the 
trial results for HbA1c and body weight. Due to the number of sensitivity analyses and their 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
Change from baseline to week 26 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. Body weight will only be tested for superiority. Baseline body weight 
will be used as a covariate instead of baseline HbA1c in both the imputation and analysis model.
From the analyses the three estimated treatment differences between each of the oral semaglutide 
dose levels and sitagliptin 100 mg will be presented together with associated two-sided 95 % CIs 
and unadjusted two-sided p-values for testing no difference from zero.
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.
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Statistical Analysis Plan
CONFIDENTIAL
Date:
22 May 2018
Novo Nordisk
Trial ID: NN9924-4222
Version:
1.0
UTN: U1111-1168-4339
Status:
Final
EudraCT No.: 2015-001351-71
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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.
2.4.2
Supportive secondary endpoints
2.4.2.1
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 and 78 in:
!
HbA1c
!
Body weight (kg)
Change from baseline to week 26, 52 and 78 in:
!
Body weight (%)
!
FPG
!
BMI
!
Waist circumference
!
Fasting lipid profiles (total cholesterol, LDL cholesterol, VLDL cholesterol, HDL cholesterol, 
triglycerides, free fatty acids)
Change from baseline to week 26, 52 and 78 in the below derived endpoints from the 7-point 
profile:
!
Mean of the 7-point profile, defined as the area under the profile, calculated using the 
trapezoidal method, divided by the measurement time
!
Mean increment over all meals
The above continuous endpoints will be analysed separately using similar model approaches as for 
the primary 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.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
22 May 2018
Novo Nordisk
Trial ID: NN9924-4222
Version:
1.0
UTN: U1111-1168-4339
Status:
Final
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For evaluation of the primary estimand the analysis will be performed separately for week 26, 
52 and 78. For the analysis at week 52 and at week 78, the imputation of missing data will be 
further differentiated by whether subjects have discontinued trial product or initiated rescue 
medication prior to week 26 or at/after week 26. This will result in imputation of missing data 
within12 groups of subjects instead of the 8 groups as described for the week 26 evaluation in 
Section 2.3.1. If less than five subjects have available data in one of the 12 groups, the imputation 
will be made within the 8 groups without differentiating by time of discontinuation of trial product 
or initiation of rescue medication in the same way as specified for the primary evaluation. . The 
frequency of missing data is expected to be slightly larger at week 52 and week 78 compared to 
week 26. The rate of missing data is expected to decline over time. 
For evaluation of the secondary estimand the MMRM based primary analysis will include all 
scheduled post-baseline measurement up to and including week 78. From this model the estimated 
treatment differences (ratios) will be presented at week 26 (except for HbA1c and body weight), 
52 and 78 with 95 % confidence intervals and two-sided p-values for test of no difference. The 
baseline will not be carried forward to first planned visit if the first planned visit falls later than 
8 weeks after randomisation.
Binary efficacy endpoints
Subjects who after 26 weeks of treatment achieve (yes/no):
!
HbA1c < 7.0 % (53 mmol/mol) (ADA) target*
!
HbA1c ≤ 6.5 % (48 mmol/mol) (AACE) target
!
Weight loss ≥ 5 %
!
Weight loss ≥ 10 %
!
HbA1c < 7.0 % (53 mmol/mol) without hypoglycaemia (severe or BG confirmed symptomatic 
hypoglycaemic episodes) and no weight gain
!
HbA1c reduction ≥ 1 % and weight loss ≥ 3 %
When addressing the treatment policy estimand the ‘without hypoglycaemia’ component of the 
composite endpoint will also 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 above six endpoints will be evaluated after week 52 
and after week 78 as well.
Handling of missing data for binary endpoints
HbA1c and body weight
Missing data for the above six binary endpoints will be accounted for using multiple imputation 
techniques. For the treatment policy estimand the binary endpoints will be calculated as 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
22 May 2018
Novo Nordisk
Trial ID: NN9924-4222
Version:
1.0
UTN: U1111-1168-4339
Status:
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dichotomisations of the 1000 multiple imputations underlying the primary MI analysis. For the 
hypothetical estimand the model will be implemented using a sequential imputation approach 
assuming MAR. The imputation will be done as described below:
!
Intermittent missing values in the on-treatment without rescue observation period will be 
imputed using a Markov Chain Monte Carlo (MCMC) method, in order to obtain a monotone 
missing data pattern. This imputation is done for each treatment group separately and a 
1000 copies of the data set will be generated.
!
A sequential regression approach for imputing monotone missing values at planned visits will 
be implemented starting with the first visit after baseline and sequentially continuing to the 
planned end of treatment visit. 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 as 
categorical effect and baseline and post-baseline values prior to the visit in question as 
covariates.
The binary endpoints will be derived as dichotomisations of the 1000 multiple imputations from the 
sequential imputation.
For both estimands, each of the 1000 data sets will be analysed using a logistic regression model 
with treatment and region as fixed effects and baseline value as covariate (i.e. baseline HbA1c for 
binary HbA1c endpoints, baseline body weight for body weight endpoints and both HbA1c and 
baseline body weight for the composite endpoints that comprises both parameters). The results will 
be combined using Rubin’s rule4 to draw inference.
For the composite endpoints involving both HbA1c and body weight the imputed data sets will be 
combined by imputation number.
Without hypoglycaemia
For both estimands missing data in the ‘without hypoglycaemia’ component will be accounted for 
using a multiple imputation approach8 in which the number of events of severe or BG-confirmed 
hypoglycaemia in the missing data period will be imputed. The ‘without hypoglycaemia’ 
component will be calculated as a dichotomization of the sum of the observed and the imputed 
number of episodes covering the observed and missing data periods. 
Treatment policy estimand
Analogously to the primary imputation model for the continuous endpoints the imputation of 
hypoglycaemic episodes will assume that the missing data is best described by information from 
subjects who are similar in terms of randomised treatment arm and whether subjects at time of 
evaluation; (i) have discontinued treatment or initiated rescue medication or (ii) are still on 
treatment and have not initiated rescue medication (treatment status). I.e. withdrawn subjects or 
subjects who are lost to follow-up are assumed to have the same conditional event rate after 
withdrawal conditional on the observed event rate before withdrawal and on randomised treatment 
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Statistical Analysis Plan
CONFIDENTIAL
Date:
22 May 2018
Novo Nordisk
Trial ID: NN9924-4222
Version:
1.0
UTN: U1111-1168-4339
Status:
Final
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and treatment  status and the other covariates. For evaluation at week 52 and 78 treatment status 
will be differentiated by whether subjects have discontinued trial product or initiated rescue 
medication prior to week 26 or at/after week 26. The imputation will be done as described below:
!
A Bayesian log-linear negative binomial model is fitted to the observed data from the in-trial 
observation period to obtain the posterior distribution of the model parameters. The model will 
include randomised treatment, treatment status and stratification factor as fixed factors and 
baseline HbA1c as a covariate. The logarithm of the duration of the subject’s observed data 
period will be included as offset.
!
Based on the estimated parameters in this model the number of events in the missing data period 
will be imputed conditional on the event rate in the observed data period. 1000 imputations will 
be done sampling from the posterior distribution of the model parameters.
Hypothetical estimand
Imputation of events when addressing the hypothetical estimand will be done in a similar way. 
Subjects who discontinue trial product or initiate recue medication are assumed to have the same 
conditional event rate after discontinuation/rescue initiation conditional on the observed event rate 
before discontinuation/rescue initiation and on randomised treatment and the other covariates. The 
imputation will be done as described below:
!
A Bayesian log-linear negative binomial model is fitted to the observed data from the on-
treatment without rescue observation period to obtain the posterior distribution of the model 
parameters. The model will include randomised treatment and stratification factors as fixed 
factors and baseline HbA1c as a covariate. The logarithm of the duration of the subject’s 
observed data period will be included as offset.
!
Based on the estimated parameters in this model the number of events in the missing data period 
will be imputed conditional on the event rate in the observed data period. 1000 imputations will 
be done sampling from the posterior distribution of the model parameters.
For the composite endpoint the imputed datasets of the three components will be combined by 
imputation number and analysed in the same way as described above for the other binary 
endpoints.4
Time to event endpoint
!
Time to additional anti-diabetic medication (to support the treatment policy estimand)
!
Time to rescue medication
Definition of 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.
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Statistical Analysis Plan
CONFIDENTIAL
Date:
22 May 2018
Novo Nordisk
Trial ID: NN9924-4222
Version:
1.0
UTN: U1111-1168-4339
Status:
Final
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Definition of 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 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 (see above) 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.
More than 21 days is chosen as a minimum duration for the medication to be considered as ‘anti-
diabetic medication’. This threshold is set to ensure that the short -term durations (i.e. ≤ 21 days) of 
anti-diabetic medication (e.g. in connection with concurrent illne sses) are not included because such 
intensifications are not likely to affect the effect endpoints.
Treatment policy estimand: Time to additional anti-diabetic medication
The treatment policy estimand is addressed for the FAS using the in-trial observation period and 
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 and region as categorical fixed effects and baseline 
HbA1c as a covariate. From this analysis the estimated Hazard ratios between oral semaglutide and 
sitagliptin 100 mg 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 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 subject 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. 
Hypothetical estimand: Time to rescue medication
The hypothetical estimand is addressed for the 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 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 date of last trial product. Potential events 
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Statistical Analysis Plan
CONFIDENTIAL
Date:
22 May 2018
Novo Nordisk
Trial ID: NN9924-4222
Version:
1.0
UTN: U1111-1168-4339
Status:
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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. 
2.4.2.2
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 83 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. 
Other safety endpoints
Change from baseline to week 26, 52 and 78 in:
!
Amylase
!
Lipase
!
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 
separately as described above for continuous efficacy endpoints. Results will be presented at week 
26, 52 and 78. Amylase and lipase endpoints will be log-transformed prior to analysis with the 
associated log-transformed baseline value as a covariate.
Change from baseline to week 26, 52 and 78 in:
!
Electrocardiogram (ECG) evaluation
!
Physical examination (week 52 and 78 only)
!
Eye examination category (week 52 and 78 only)
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Statistical Analysis Plan
CONFIDENTIAL
Date:
22 May 2018
Novo Nordisk
Trial ID: NN9924-4222
Version:
1.0
UTN: U1111-1168-4339
Status:
Final
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Occurrence of anti-semaglutide antibodies (positive/negative):
!
Anti-semaglutide binding antibodies
!
Anti-semaglutide neutralising antibodies 
!
Anti-semaglutide binding antibodies cross reacting with native GLP-1
!
Anti-semaglutide neutralising antibodies cross reacting with native GLP-1
Anti-semaglutide binding antibody levels
Safety assessments
Change from baseline to week 26, 52 and 78 in:
!
Haematology 
!
Biochemistry (except for amylase and lipase)
!
Calcitonin
The above safety endpoints and 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. 
Pharmacokinetics 
Please refer to Section 2.5.
Hypoglycaemia
!
Number of treatment emergent severe or BG confirmed symptomatic hypoglycaemic episodes
during exposure to trial product, assessed up to approximately 83 weeks
!
Treatment emergent severe or BG confirmed symptomatic hypoglycaemic episodes during 
exposure to trial product, assessed up to approximately 83 weeks (yes/no) 
Classification of Hypoglycaemia:
Hypoglycaemic episodes will be summarised for the SAS and the on-treatment observation period 
only.
Treatment emergent: hypoglycaemic episode 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: are 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
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Statistical Analysis Plan
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Date:
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Trial ID: NN9924-4222
Version:
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In normal physiology, symptoms of hypoglycaemia occur below a PG level of 3.1 mmol/L 
(56 mg/dL)9. 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:
!
Severe or BG confirmed symptomatic hypoglycaemia: An episode that is severe according to 
the ADA classification10 or BG confirmed by a PG value < 3.1 mmol/L (56 mg/dL) with
symptoms consistent with hypoglycaemia. 
ADA classification10 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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Statistical Analysis Plan
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Date:
22 May 2018
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Trial ID: NN9924-4222
Version:
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Hypoglycaemic 
episode 
PG ≤ 3.9 mmol/L 
(70 mg/dL) 
or 
Alleviation of 
symptoms 
or
Seizure, coma or 
fatal 
SMPG
measurement
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
Subject 
able to 
treat him/
herself
Severe 
hypoglycaemia
(ADA 2013)
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 endpoints
The number of treatment emergent severe or BG confirmed symptomatic hypoglycaemic episodes 
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 factors for 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 HbA 1c as covariate.
2.5
Pharmacokinetic modelling
Exploratory population PK modelling will be used to evaluate semaglutide exposure and the effects 
of pre-specified covariates on the exposure. As a minimum, the covariates sex, body weight at 
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Statistical Analysis Plan
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Date:
22 May 2018
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Trial ID: NN9924-4222
Version:
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UTN: U1111-1168-4339
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baseline and age at baseline will be explored. The modelling will include data from approximately 
50 % of randomised subjects that were exposed to semaglutide in this trial and will be performed as 
a meta-analysis across phase 3a trials. Actual time points for dose administration and PK sampling 
will be used. Results will be presented using criteria which will be pre-specified in a modelling 
analysis plan that is to be finalised before DBL. The modelling will be performed by Quantitative 
Clinical Pharmacology at Novo Nordisk A/S and will be reported separately from the CTR.
Covariate analysis 
Covariates will be tested on CL/F. Covariates for inclusion:
!
Body weight
!
Age group (< 65, 65-75 and ≥ 75 years)
!
Sex (Male/Female)
!
Race (White/ Black or African American/ Asian/ Hawaiian or Pacific Islander/ Other)
!
Ethnicity (Hispanic or Latino/ not Hispanic or Latino)
!
Upper GI comorbidity (Yes/No)
2.6
Health economics and/or patient reported outcomes
PROs
Change from baseline to week 26, 52 and 78 in:
!
SF-36v2™ (acute version) health survey: Physical component score, mental component score 
and scores from the 8 domains
!
IWQoL-Lite Clinical Trial Version: Total score and scores from the 4 domains
!
CoEQ: Scores from the 4 domains and scores from 19 individual items
The PRO endpoints will be analysed separately as the other continuous efficacy endpoints using a 
similar model approaches as for the primary endpoint with the associated baseline response as a 
covariate.
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 diabetes10. 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 
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Statistical Analysis Plan
CONFIDENTIAL
Date:
22 May 2018
Novo Nordisk
Trial ID: NN9924-4222
Version:
1.0
UTN: U1111-1168-4339
Status:
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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.
Domain scores
Norm-based scores (NBS) will be derived using the QualityMetric Health Outcomes™ Scoring 
Software1 including the 2009 US general population norm. The most recent version of the 
QualityMetric Health Outcomes™ Scoring Software available at time of licensing was used for the 
specific trial (version 4.5 for PIONEER 3). Table 2–3 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 do mains 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 2–3
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.
Responder threshold values
The responder threshold values, in terms of T-score points for change from baseline are defined in 
Table 2–4.11
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Table 2–4
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 
2.6.4.
2.6.2
Impact of Weight on Quality of Life Clinical Trials Version (IWQOL-Lite-CT)  
The IWQOL-Lite-CT is designed to assess the impact of changes in weight on patients' quality of 
life within the context of clinical trials. The items of the IWQOL-Lite-CT pertain to physical 
functioning and psychosocial domains and all items employ a 5-point graded response scale (never, 
rarely, sometimes, usually, always; or not at all true, a little true, moderately true, mostly true, 
completely true). The  23-item version of the IWQOL-Lite-CT was completed by patients. 
Composite scores
All IWQOL-Lite-CT composite scores range from 0 to 100, with higher scores reflecting better 
levels of functioning. Table 2–5 provides an overview of domains. 
Table 2–5
Overview of domains for IWQOL-Lite-CT   
Domain
Items numbers of items included in domain
23 items version
Psychosocial
6-8, 10, 12-17, 20, 22, 23
Physical
1-5, 18, 19
Physical Function
1-3, 18, 19
Pain/Discomfort
4, 5
IWQOL-Lite-CT Total
1-8, 10, 12-20, 22, 23
Missing data at instrument level will be handled in the following way. Raw scores for each subscale 
are computed if a minimum of 50% of the items for that subscale are nonmissing, and for the 
IWQOL-Lite-CT total score if a minimum of 75% of all items are nonmissing.
The scoring is done in three steps12.
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1. If the minimum number of items are answered for a composite, compute the average of the valid 
item responses for that composite where 1 = ”never” or “not at all true” and 5 = ”always” or 
“completely true.” This average must be a number between 1 and 5, inclusive.
2. Multiply that average by the total number of items in that composite. The total number of items 
in each IWQOL-Lite-CT composite is as follows: Psychosocial = 13, Physical = 7, Physical 
Function = 5, Pain/Discomfort = 2, IWQOL-Lite-CT Total = 20. Round to the nearest integer.
3. To convert the IWQOL-Lite-CT raw score (as calculated above) to the 0 (worst) to 100 (best) 
metric:
(a) Subtract the raw score from the maximum raw score for each composite. The maximum raw 
scores are as follows: Psychosocial = 13x5 = 65, Physical = 7x5 = 35, Physical Function = 5x5 = 
25, Pain/Discomfort = 2x5 = 10, IWQOL-Lite-CT Total = 20x5 = 100.
(b) Divide the difference in (a) by the raw score range for each composite. The ranges of the raw 
scores are as follows: Psychosocial = 65-13 = 52, Physical = 35-7 = 28, Physical Function = 25-5 = 
20, Pain/Discomfort = 10-2 = 8, IWQOL-Lite-CT Total = 100-20 = 80.
(c) Multiply the total in (b) by 100.
Responder threshold values
Data from the oral semaglutide phase 3a monotherapy trial (PIONEER 1; NN9924-4233) data were 
used as part of the confirmation of the psychometric properties of IWQOL-Lite-CT in patients with 
T2DM . To estimate potential responder threshold values for the composite scores in IWQOL-Lite-
CT anchor-based and distribution-based methods were applied to PIONEER 1 data . 
The resulting responder threshold values, in terms of score points for change from baseline are 
defined in Table 2–6.11
Table 2–6
Responder thresholds for IWQOL-Lite-CT
Domain
Responder threshold
Psychosocial
10
Physical
8
Physical Function
10
Pain/Discomfort
5
IWQOL-Lite-CT Total
8
Responder analyses will be based on the responder threshold values and are described in 
Section 2.6.4.
2.6.3
Control of Eating Questionnaire (CoEQ)
The CoEQ comprises 21-items designed to assess the intensity and type of food cravings, as well as 
subjective sensations of appetite and mood 11. In the oral semaglutide phase 3a programme trials a 
version with 19 items has been used. One of the two excluded items is open-ended and addresses 
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specific foods, and the other excluded item concerns how difficult it has been to resist this specific 
food; and the items are therefore not part of any of the four domains.
Item scores
The CoEQ items are scored on an 11-point graded response scale ranging from 10 to 0. If data are 
missing for an item, the item score is treated as missing. No reversal of item scores will be done.
Domain scores
The sum of the items in each domain is calculated, and divided by the number of items in the 
domain in order to obtain a domain score. Items 1 and 2 are not included in any domain score. 
Details are given in Table 2–7.
Table 2–7
Overview of domains for CoEQ
Domain
Items numbers of items 
included in domain
Comment
Craving Control 
9-12, 19
The domain score is reversed so that a greater score represents a greater level of 
Craving Control (i.e. 10 to 0, 9 to 1, …, 0 to 10)
Positive Mood
5-8
Scores from item 6 (“How anxious have you felt?’’) are reversed (i.e. 10 to 0, 9 to1, 
…, 0 to 10)
Craving for 
Savoury
4, 16-18
Craving for Sweet
3, 13-15
Missing data at instrument level will be handled in the following way. To score a domain it is 
required that at least 50% of the items need to be answered. Then, the domain is scored based on the 
average of the items answered. If less than 50% of the items of a domain are answered no score will 
be derived. 
Responder threshold values
Half of a standard deviation (SD) of the baseline CoEQ item and domain scores per trial are used as 
distribution-based approach defining the responder thresholds. The thresholds are derived from 
baseline CoEQ data across Oral semaglutide arms (3 mg, 7 mg, 14 mg) and Sitagliptin 100 mg arm. 
Responder analyses will be based on the responder threshold .
2.6.4
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:
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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. 
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3
Changes to the statistical analyses planned in the protocol
The main analyses were described in the protocol for the trial NN9924-4222. However, 
clarifications, more detailed descriptions of endpoints and analyses are provided in this SAP. The 
changes from the protocol of NN9924-4222 are summarised below:
!
It has been specified which regions will be used in the statistical analysisThe primary and 
secondary estimands have changed names from de-facto and de-jure to treatment policy and 
hypothetical, respectively.
!
The MMRM sensitivity analysis and the comparator multiple imputation analysis based on FAS 
using the on-treatment observation period of the primary estimand have been omitted in section 
2.3.3. It is considered sufficient to keep the two current sensitivity analyses to stress test the 
primary results.
!
For the MMRM analyses, it is specified that, the baseline value will only be carried forward to 
the first planned visit, if the first planned visit do not fall later than 8 weeks after randomisation. 
The 8 weeks are chosen as a balance to keep as many subjects as possible in the analysis and not 
carrying  baseline assessments too long forward in time.
!
The two MI sensitivity analyses of the secondary estimand have been omitted in Section 2.3.3. 
It is considered sufficient to keep the tipping point sensitivity analysis for the secondary 
hypothetical estimand as it can be considered as a progressive stress-testing to assess how 
severe departures from MAR must be in order to reverse the conclusions from the primary 
MMRM analysis used to address the hypothetical estimand.
!
The LOCF sensitivity analysis specified in the trial protocol (section 2.3.3.2) has been omitted, 
as it is not realistic that subjects with missing data would have had stable results from the point 
of drop out to trial completion.
!
The complete case analysis is based on the assumption that missing data are MCAR, this 
assumption seem questionable and since a per-protocol analysis is performed, this extra 
sensitivity analysis is excluded.
!
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.
!
For the binary efficacy endpoints, it has been specified how missing data in the analyses for the 
hypothetical estimand will be imputed using a sequential imputation approach assuming MAR.
!
A clarification of the ‘without hypoglycaemia’ component in composite binary endpoints has 
been added. The specification on how to analyse the binary component ‘without
hypoglycaemia’ in the composite endpoint ‘HbA1c <7% (53 mmol/mol) without hypoglycaemia 
(severe or BG-confirmed symptomatic hypoglycaemia) and no weight gain’ has not been 
described in the statistical section in the protocol. The specification is therefore included below. 
!
The definitions of initiation of rescue medication and additional anti-diabetic medication used 
for the time-to-event endpoints as well as the accompanying statistical analyses have been 
further clarified.
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!
Standard laboratory parameters have been downgraded from ‘endpoints’ to ‘assessments’ 
because these parameters are included to ensure that the investigator can monitor the individual 
subject and to allow for detection of potential safety signal on a trial-level that is not reflected in 
adverse event reporting.
!
All PROs, SF-36v2 (acute version), IWQOL-Lite, and CoEQ, will be analysed statistically. All
using the primary analysis of the primary estimand and in addtion, IWQOL-Lite will be 
analysed using secondary estimand.
!
The responder analyses and the primary analysis for the secondary estimand of all PROs, 
SF-36v2 (acute version), IWQOL-Lite, and CoEQ, will be presented in a report separate from 
and after finalisation of the CTR. 
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4
References
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Merck Sharp & Dohme Limited. JANUVIA - European Summary of Product Characteristics 
Annex 1. 26 May 2015.
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Bretz F, Posch M, Glimm E, Klinglmueller F, Maurer W, Rohmeyer K. Graphical 
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Rohmeyer K, Klinglmueller F. gMCP: Graph Based Multiple Test Procedures. R package 
version 0.8-8. 3 Oct 2014.
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Little RJA, Rubin DB. Statistical analysis with missing data: New York: John Wiley & 
Sons. 1987.
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Koch GG. Comments on 'Current issues in non-inferiority trials' by Thomas R. Fleming, 
Statistics in Medicine, DOI: 10.1002/sim.2855. Stat Med. 2008;27(3):333-42.
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(CHMP) EMACfMPfHU. Guideline on Missing Data in Confirmatory Clinical Trials 
(EMA/CPMP/EWP/1776/99 Rev. 1). 7/2/2010 2010.
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National Academy of Sciences (NAS). The Prevention and Treatment of Missing Data in 
Clinical Trials. Washington D.C.: The National Academies Press. 2010.
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Keene ON, Roger JH, Hartley BF, Kenward MG. Missing data sensitivity analysis for 
recurrent event data using controlled imputation. Pharmaceutical Statistics. 2014;13(4):258-
64.
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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.
10.
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.
11.
Fehnel S, Qin S, Williams V, RTI Health Solutions. Psychometric Evaluation of the 
IWQOL-Lite-CT in Overweight and Obese Patients With Type 2 Diabetes (RTI-HS Project 
No. 0303824.003). IWQOL-Lite-CT Scoring and Responder definitions (v. 1.0 Final). In: 
Meincke H, Novo Nordisk A/S, editors. 17 May 2018.
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Oral Semaglutide
PIONEER 1-10
Clinical Trial Report
Appendix 16.1.9
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