Clinical trial NCT03018028
Conditions: Diabetes Diabetes Mellitus, Type 2
Sponsor: Novo Nordisk A/S
Start date: 2017-01-10; Completion date: 2018-08-15
Enrollment: 243 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This trial is conducted in Asia. The aim of this trial is to investigate the dose-response relationship of once-daily dosing of three dose levels (3, 7 and 14 mg) of oral semaglutide versus placebo as monotherapy on glycaemic control in Japanese subjects with type 2 diabetes mellitus

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None arm 4: None arm 5: None
Interventions: intervention 1: Semaglutide intervention 2: Placebo intervention 3: Liraglutide
Intervention descriptions: intervention 1: Oral administration once daily intervention 2: Oral administration once daily intervention 3: Subcutaneous (s.c., under the skin) injection once daily

Protocol documents:
Prot_000.pdf: 
Cover Page for Protocol 
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT03018028 
Sponsor trial ID: 
NN9924-4281 
Official title of study: 
PIONEER 9 – Japan Monotherapy. Dose-response, Safety and 
Efficacy of Oral Semaglutide versus Placebo and versus 
Liraglutide, All as Monotherapy in Japanese Subjects with 
Type 2 Diabetes 
Document date: 
28 February 2019 
 


Link
Link
Link
Link
Link
List of contents
Protocol ...............................................................................................................................................
Appendix A .........................................................................................................................................
Appendix B..........................................................................................................................................
Attachment I and II............................................................................................................................
Protocol amendment 1 .......................................................................................................................
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
Oral semaglutide
Trial ID: NN9924-4281
Clinical Trial Report
Appendix 16.1.1
2 February 2019
1.0
Final
16.1.1 Protocol and protocol amendments
CONFIDENTIAL
Redacted protocol 
Lncludes redaction of personal identifiable DQGFRPSDQ\
FRQILGHQWLDOinformation. 
. 


Protocol
CONFIDENTIAL
Date:
23 September 2016
Novo Nordisk
Trial ID: NN9924-4281
Version:
2.0
UTN: U1111-1181-4048
Status:
Final
Page:
1 of 119
Protocol
Trial ID: NN9924-4281
PIONEER 9 – Japan Monotherapy
Dose-response, Safety and Efficacy of Oral Semaglutide 
versus Placebo and versus Liraglutide, 
All as Monotherapy in Japanese Subjects with Type 2 Diabetes
A 52-week randomised, double-blind placebo-controlled and open-label active-controlled trial
Trial phase: 2/3a
Protocol originator
, Novo Nordisk Pharma Ltd.
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:
23 September 2016
Novo Nordisk
Trial ID: NN9924-4281
Version:
2.0
UTN: U1111-1181-4048
Status:
Final
     
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 ................................................................................................................................................14
3
Background information and rationale for the trial............................................................................19
3.1
Background information..............................................................................................................19
3.1.1
Type 2 diabetes mellitus ............................................................................................19
3.1.2
Glucagon-like peptide-1 ............................................................................................19
3.1.3
Oral semaglutide........................................................................................................19
3.1.4
Nonclinical data.........................................................................................................20
3.1.4.1
Semaglutide.........................................................................................20
3.1.4.2
SNAC ..................................................................................................21
3.1.5
Clinical data for oral semaglutide..............................................................................22
3.1.5.1
Pharmacokinetics ................................................................................22
3.1.5.2
Efficacy ...............................................................................................23
3.1.5.3
Safety...................................................................................................23
3.1.6
Liraglutide..................................................................................................................24
3.2
Rationale for the trial...................................................................................................................24
4
Objectives and endpoints........................................................................................................................25
4.1
Objectives ....................................................................................................................................25
4.1.1
Primary objective.......................................................................................................25
4.1.2
Secondary objectives .................................................................................................25
4.2
Endpoints .....................................................................................................................................25
4.2.1
Primary endpoint........................................................................................................25
4.2.2
Secondary endpoints..................................................................................................25
4.2.2.1
Confirmatory secondary endpoints .....................................................25
4.2.2.2
Supportive secondary endpoints..........................................................25
5
Trial design ..............................................................................................................................................28
5.1
Type of trial .................................................................................................................................28
5.2
Rationale for trial design..............................................................................................................29
5.3
Treatment of subjects...................................................................................................................30
5.3.1
Dosing instructions ....................................................................................................31
5.3.2
Background medication.............................................................................................32
5.4
Treatment after discontinuation of trial product ..........................................................................32
5.5
Rationale for treatment ................................................................................................................32
6
Trial population.......................................................................................................................................33
6.1
Number of subjects......................................................................................................................33
6.2
Inclusion criteria ..........................................................................................................................33
6.3
Exclusion criteria.........................................................................................................................33
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
23 September 2016
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Trial ID: NN9924-4281
Version:
2.0
UTN: U1111-1181-4048
Status:
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6.4
Rescue criteria..............................................................................................................................34
6.5
Criteria for premature discontinuation of trial product................................................................35
6.6
Withdrawal from trial ..................................................................................................................35
6.7
Subject replacement.....................................................................................................................36
6.8
Rationale for trial population.......................................................................................................36
7
Milestones.................................................................................................................................................37
8
Methods and assessments .......................................................................................................................38
8.1
Visit procedures...........................................................................................................................38
8.1.1
Screening, visit 1........................................................................................................38
8.1.2
Fasting visits ..............................................................................................................39
8.1.3
Randomisation and trial product administration (visit 2) ..........................................40
8.1.4
Phone contacts after randomisation (P3) ...................................................................40
8.1.5
End-of-treatment (visit 12) and Follow-up (visit 13).................................................41
8.1.6
Premature discontinuation of trial product and follow-up (visits 12A and 13A) ......41
8.1.7
Withdrawals...............................................................................................................42
8.1.8
Investigator assessments............................................................................................42
8.2
Subject related information/assessments .....................................................................................43
8.2.1
Demography...............................................................................................................43
8.2.2
Diabetes history and diabetes complications .............................................................43
8.2.3
Concomitant illness and medical history...................................................................43
8.2.4
Concomitant medication............................................................................................44
8.2.5
Childbearing potential................................................................................................44
8.2.6
Tobacco use ...............................................................................................................45
8.3
Efficacy assessments....................................................................................................................45
8.3.1
Laboratory assessments for efficacy..........................................................................45
8.3.1.1
Fasting plasma glucose........................................................................46
8.3.2
Self-measured plasma glucose (SMPG) ....................................................................46
8.3.3
Body weight and height .............................................................................................47
8.3.4
Waist circumference ..................................................................................................47
8.3.5
Patient reported outcomes questionnaires..................................................................47
8.4
Safety assessments.......................................................................................................................48
8.4.1
Adverse events...........................................................................................................48
8.4.1.1
Medication error..................................................................................48
8.4.1.2
Adverse events requiring additional data collection ...........................48
8.4.2
Physical examination.................................................................................................49
8.4.3
Vital signs ..................................................................................................................50
8.4.4
Eye examination ........................................................................................................50
8.4.5
Electrocardiogram (12-lead)......................................................................................50
8.4.6
Laboratory assessments for safety .............................................................................51
8.4.7
Pregnancy testing.......................................................................................................52
8.4.8
Anti-semaglutide antibodies ......................................................................................52
8.4.9
Hypoglycaemic episodes ...........................................................................................53
8.5
Laboratory assessments ...............................................................................................................55
8.6
Other assessments........................................................................................................................56
8.6.1
Pharmacokinetics.......................................................................................................56
8.6.2
Subject diary ..............................................................................................................56
8.6.3
Training in the pen-injector for liraglutide ................................................................57
8.7
Subject compliance......................................................................................................................57
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
23 September 2016
Novo Nordisk
Trial ID: NN9924-4281
Version:
2.0
UTN: U1111-1181-4048
Status:
Final
     
Page:
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9
Trial supplies ...........................................................................................................................................58
9.1
Trial products...............................................................................................................................58
9.2
Labelling......................................................................................................................................58
9.3
Storage .........................................................................................................................................59
9.4
Drug accountability and destruction............................................................................................60
9.5
Auxiliary supplies........................................................................................................................60
10 Interactive web response system............................................................................................................61
11 Randomisation procedure and breaking of blinded codes..................................................................62
11.1
Breaking of blinded codes ...........................................................................................................62
12 Adverse events, and technical complaints and pregnancies................................................................63
12.1
Definitions ...................................................................................................................................63
12.1.1
Adverse event ............................................................................................................63
12.1.2
Serious adverse event.................................................................................................64
12.1.3
Non-serious adverse event.........................................................................................65
12.1.4
Medication errors.......................................................................................................65
12.1.5
Adverse events requiring additional data collection..................................................66
12.1.6
Technical complaints.................................................................................................67
12.2
Reporting of adverse events.........................................................................................................68
12.3
Follow-up of adverse events........................................................................................................70
12.4
Technical complaints and technical complaint samples ..............................................................71
12.4.1
Reporting of technical complaints .............................................................................71
12.4.2
Collection, storage and shipment of technical complaint samples ............................72
12.5
Pregnancies..................................................................................................................................72
12.5.1
Pregnancies in female subjects ..................................................................................72
12.6
Precautions and/or overdose with oral semaglutide.....................................................................74
12.7
Committees related to safety........................................................................................................75
12.7.1
Novo Nordisk safety committee ................................................................................75
12.7.2
Event adjudication committee....................................................................................75
13 Case report forms....................................................................................................................................79
13.1
Corrections to case report forms..................................................................................................79
13.2
Case report form flow..................................................................................................................80
14 Monitoring procedures ...........................................................................................................................81
15 Data management....................................................................................................................................82
16 Computerised systems.............................................................................................................................83
17 Statistical considerations ........................................................................................................................84
17.1
Sample size calculation................................................................................................................86
17.2
Definition of analysis sets............................................................................................................87
17.3
Primary endpoint..........................................................................................................................89
17.3.1
Analysis for the primary estimand.............................................................................89
17.3.2
Analysis for the secondary estimand .........................................................................90
17.4
Secondary endpoints....................................................................................................................91
17.4.1
Supportive secondary endpoints ................................................................................91
17.4.1.1
Efficacy endpoints...............................................................................91
17.4.1.2
Safety endpoints..................................................................................93
17.4.1.3
Pharmacokinetic endpoints..................................................................97
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
23 September 2016
Novo Nordisk
Trial ID: NN9924-4281
Version:
2.0
UTN: U1111-1181-4048
Status:
Final
     
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17.5
Interim analysis............................................................................................................................97
17.6
Pharmacokinetic and/or pharmacodynamic modelling................................................................97
17.7
Health economics and/or patient reported outcomes...................................................................98
18 Ethics........................................................................................................................................................99
18.1
Benefit-risk assessment of the trial..............................................................................................99
18.1.1
Risks and precautions with oral semaglutide.............................................................99
18.1.2
Risks and precautions with liraglutide.....................................................................102
18.1.3
Risks and precautions with placebo.........................................................................102
18.1.4
Benefits....................................................................................................................102
18.1.5
Risk and benefit conclusion.....................................................................................102
18.2
Informed consent .......................................................................................................................103
18.3
Data handling.............................................................................................................................104
18.4
Information to subjects during trial............................................................................................104
18.5
Premature termination of the trial and/or trial site.....................................................................104
19 Protocol compliance..............................................................................................................................105
19.1
Protocol deviations ....................................................................................................................105
19.2
Prevention of missing data.........................................................................................................105
20 Audits and inspections ..........................................................................................................................106
21 Critical documents ................................................................................................................................107
22 Responsibilities......................................................................................................................................108
23 Reports and publications......................................................................................................................109
23.1
Communication of results..........................................................................................................109
23.1.1
Authorship ...............................................................................................................110
23.1.2
Site-specific publication(s) by investigator(s) .........................................................110
23.2
Investigator access to data and review of results.......................................................................110
24 Retention of clinical trial documentation and human biosamples....................................................111
24.1
Retention of clinical trial documentation...................................................................................111
24.2
Retention of human biosamples.................................................................................................111
25 Institutional Review Boards and regulatory authorities ...................................................................113
26 Indemnity statement .............................................................................................................................114
27 References..............................................................................................................................................115
Appendix A
Calcitonin monitoring
Appendix B 
Adverse events requiring additional data collection
Attachment I List of key staff and relevant departments and suppliers 
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
23 September 2016
Novo Nordisk
Trial ID: NN9924-4281
Version:
2.0
UTN: U1111-1181-4048
Status:
Final
     
Page:
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Table of Figures
Page
Figure 5–1
Trial design.............................................................................................................................29
Figure 12–1
Reporting of AEs....................................................................................................................69
Figure 17–1
ADA classification of hypoglycaemia....................................................................................96
Table of Tables
Page
Table 5–1
Overview of treatment of subjects..........................................................................................31
Table 9–1
Investigational medicinal products.........................................................................................58
Table 9–2
Storage conditions ..................................................................................................................59
Table 12–1
Adverse events requiring completion of specific event forms and/or are subject to event 
adjudication ............................................................................................................................67
Table 12–2
Adverse events for adjudication .............................................................................................76
Table 17–1
Treatment effects in HbA1c (%-point) ....................................................................................87
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
23 September 2016
Novo Nordisk
Trial ID: NN9924-4281
Version:
2.0
UTN: U1111-1181-4048
Status:
Final
     
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
CCDS
Company Core Data Sheet
CK
creatine kinase
CKD-EPI
Chronic Kidney Disease Epidemiology collaboration
CLAE
clinical laboratory adverse event
CRF
case report form
CRO
contract research organisation
CVD
cardiovascular disease
draft AD guideline
Draft Guideline for Clinical Evaluation of Hypoglycaemic 
Agents
DFU
direction for use
DTR-QOL
Diabetes Therapy-Related Quality of Life
DUN
dispensing unit number
EAC
event adjudication committee
ECG
electrocardiogram
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
EOT
end of treatment
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
23 September 2016
Novo Nordisk
Trial ID: NN9924-4281
Version:
2.0
UTN: U1111-1181-4048
Status:
Final
     
Page:
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FAS
full analysis set
FDA
U.S. Food and Drug Administration
FDAAA
U.S. Food and Drug Administration Amendment Act
FPG
fasting plasma glucose
FSFV
first subject first visit
GCP
Good Clinical Practice
GLP-1
glucagon-like peptide-1
GLP-1 RA
glucagon-like peptide-1 receptor agonist
HbA1c
glycosylated haemoglobin
HDL
high density lipoprotein
HOMA-B
homeostatic model assessment index of beta-cell function
HOMA-IR
homeostatic model assessment index of insulin resistance
IB
investigator’s brochure
ICH
International Conference on Harmonisation
ICMJE
International Committee of Medical Journal Editors
IMP
investigational medicinal product
IRB
institutional review board
IWRS
interactive web response system
LDL
low density lipoprotein
LLoQ
lower limit of quantification 
LSFV
last subject first visit
LSLV
last subject last visit
MAR
missing at random
MedDRA
Medical Dictionary for Regulatory Activities
MEN 2
multiple endocrine neoplasia type 2
MI
myocardial infarction
MMRM
mixed model for repeated measurements
MTC
medullary thyroid carcinoma
NIMP
non-investigational medicinal product
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
23 September 2016
Novo Nordisk
Trial ID: NN9924-4281
Version:
2.0
UTN: U1111-1181-4048
Status:
Final
     
Page:
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NYHA
New York Heart Association
OAD
oral antidiabetic drug
PG
plasma glucose
PK
pharmacokinetics
PRO
patient reported outcome
SAE
serious adverse event
SAP
statistical analysis plan
SAS
safety analysis set
s.c.
subcutaneous(ly)
SGLT-2
sodium-glucose co-transporter-2
SF-36
short form-36
SIF
safety information form
SMPG
self-measured plasma glucose
SNAC
sodium N-[8-(2-hydroxybenzoyl) amino] caprylate
STEMI
ST-elevation acute myocardial infarction
SUSAR
suspected unexpected serious adverse reaction
T2DM
type 2 diabetes mellitus
TEAE
treatment-emergent adverse events 
TIA
transient ischaemic attack
TMM
trial materials manual
UNL
upper normal limit
UTN
Universal Trial Number
VLDL
very low density lipoprotein
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
23 September 2016
Novo Nordisk
Trial ID: NN9924-4281
Version:
2.0
UTN: U1111-1181-4048
Status:
Final
     
Page:
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1
Summary
Objectives and endpoints:
Primary objective
To assess the dose-response relationship of once-daily dosing of three dose levels (3, 7 and 14 mg) 
of oral semaglutide versus placebo as monotherapy on glycaemic control in Japanese subjects with 
type 2 diabetes mellitus.
Secondary objectives
To compare the safety and tolerability of once-daily dosing of three dose levels (3, 7 and 14 mg) of 
oral semaglutide versus placebo and versus once-daily 0.9 mg liraglutide subcutaneously, all as 
monotherapy in Japanese subjects with type 2 diabetes mellitus.
To compare the effect of once-daily dosing of three dose levels (3, 7 and 14 mg) of oral semaglutide 
versus placebo and versus once-daily 0.9 mg liraglutide subcutaneously, all as monotherapy on 
glycaemic control and body weight in Japanese subjects with type 2 diabetes mellitus.
Primary endpoint
Change from baseline to week 26 in HbA1c
Key secondary endpoints
Number of treatment-emergent adverse events during exposure to trial product, assessed up to 
approximately 57 weeks
Number of treatment-emergent severe or blood glucose-confirmed symptomatic hypoglycaemic 
episodes during exposure to trial product, assessed up to approximately 57 weeks
Change from baseline to week 52 in:
!
HbA1c
Change from baseline to week 26 and week 52 in:
!
Fasting plasma glucose 
!
Body weight (kg)
If a subject after week 26 and week 52 achieves (yes/no):
!
HbA1c < 7.0% (53 mmol/mol) (American Diabetes Association target)
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
23 September 2016
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Trial ID: NN9924-4281
Version:
2.0
UTN: U1111-1181-4048
Status:
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Trial design:
This is a combined phase 2 dose response and phase 3 safety and efficacy trial. It is a 52-week, 
randomised, double-blind placebo-controlled and open-label active-controlled, parallel-group, 
multi-centre, single country trial with 5 treatment arms.
Japanese subjects with type 2 diabetes mellitus treated with diet and exercise therapy alone or oral 
anti-diabetic drug as monotherapy in addition to diet and exercise therapy will be included in this 
trial. Subjects will be randomised 1:1:1:1:1 manner to receive one of the following treatments:
!
Oral semaglutide 3 mg once-daily
!
Oral semaglutide 7 mg once-daily
!
Oral semaglutide 14 mg once-daily
!
Oral placebo once-daily
!
Liraglutide 0.9 mg subcutaneous (s.c.) injection once-daily
The total trial duration for the individual subject will be 59 to 65 weeks depending on pre-trial 
treatment. The trial includes a 2-week screening period, followed by a 52-week randomised 
treatment period and a follow-up period of 5 weeks. For subjects treated with oral anti-diabetic drug 
as monotherapy prior to the screening an 8-week wash-out period will replace the 2-week screening 
period.
Trial population:
Number of subjects planned to be randomised: 240
Inclusion criteria
!
Informed consent obtained before any trial-related activities. Trial-related activities are any 
procedures that are carried out as part of the trial, including activities to determine suitability for 
the trial.
!
Japanese male or female, age above or equal to 20 years at the time of signing informed consent.
!
Diagnosed with type 2 diabetes mellitus ≥ 30 days prior to day of screening.
!
HbA1c 6.5%−9.5% (48−80 mmol/mol) (both inclusive) for subjects treated with oral anti-
diabetic drug as monotherapy and 7.0%−10.0% (53−86 mmol/mol) (both inclusive) for subjects 
treated with diet and exercise therapy alone.
!
Treatment for ≥30 days prior to day of screening with;
–
stable daily dose of oral anti-diabetic drug as monotherapy (allowed oral anti-diabetic drugs 
are: metformin, sulphonylurea, glinide, α-glucosidase inhibitor, dipeptidyl peptidase-4 
inhibitor and sodium-glucose cotransporter-2 inhibitor) at a half-maximum approved dose 
or below according to Japanese labelling in addition to diet and exercise therapy. 
or
–
diet and exercise therapy alone.
CONFIDENTIAL


Protocol
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Date:
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Trial ID: NN9924-4281
Version:
2.0
UTN: U1111-1181-4048
Status:
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Key Exclusion criteria
!
Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing 
potential and not using an adequate contraceptive method. Adequate contraceptive measures are 
abstinence (not having sex), diaphragm, condom (by the partner), intrauterine device, sponge, 
spermicide or oral contraceptives.
!
Any disorder, which in the investigator’s opinion might jeopardise subject’s safety or 
compliance with the protocol.
!
Family or personal history of multiple endocrine neoplasia type 2 or medullary thyroid 
carcinoma.
!
History of pancreatitis (acute or chronic).
!
History of major surgical procedures involving the stomach and potentially affecting absorption 
of trial product (e.g. subtotal and total gastrectomy, sleeve gastrectomy, gastric bypass surgery).
!
Any of the following: myocardial infarction, stroke or hospitalisation for unstable angina or 
transient ischaemic attack within the past 180 days prior to the day of screening and 
randomisation.
!
Subject presently classified as being in New York Heart Association Class IV.
!
Planned coronary, carotid or peripheral artery revascularisation known on the day of screening.
!
Subjects with alanine aminotransferase > 2.5 x upper normal limit.
!
Renal impairment defined as estimated Glomerular Filtration Rate  <30 mL/min/1.73 m2 as per 
Chronic Kidney Disease Epidemiology Collaboration formula.
!
Treatment with once-weekly glucagon-like peptide-1 receptor agonist, once weekly dipeptidyl 
peptidase-4 inhibitor or thiazolidinedione in a period of 90 days before the day of screening.
!
Treatment with any medication for the indication of diabetes or obesity other than stated in the 
inclusion criteria in a period of 60 days before the day of screening. An exception is short-term 
insulin treatment for acute illness for a total of ≤ 14 days.
!
Proliferative retinopathy or maculopathy requiring acute treatment. Verified by fundus 
photography or dilated fundoscopy performed within 90 days prior to randomisation.
!
History or presence of malignant neoplasms within the last 5 years (except basal and squamous 
cell skin cancer and in-situ carcinomas).
!
Initiation of anti-diabetic medication between the day of screening and the day of randomisation.
Key assessments:
Safety
!
Adverse events
!
Hypoglycaemic episodes
Efficacy
!
HbA1c
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Protocol
CONFIDENTIAL
Date:
23 September 2016
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Trial ID: NN9924-4281
Version:
2.0
UTN: U1111-1181-4048
Status:
Final
     
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!
Fasting plasma glucose
!
Body weight
Trial products:
Investigational medicinal products:
Test products:
!
Semaglutide 3 mg, 7 mg and 14 mg, tablets
Reference therapies:
!
Placebo tablet
!
Liraglutide, solution for injection (strength: 6 mg/mL, 3 mL pre-filled pen-injector)
CONFIDENTIAL


Protocol
UTN: U1111-1181-4048
Date:
23 September 2016
Status:
Final
Novo Nordisk
Trial ID: NN9924-4281
     
Version:
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2
Flow chart
Trial Periods
Screenin
ga
Wash-
out 
Rand
omisa
tion
Treatment
End of 
treatme
nt 
(EOT)
Foll
ow-
upb
EOT 
premature 
discontinuati
onc
Follow-up 
premature 
discontinuationc
Visit (V), Phone contact (P)
V1
P1Wd
V2
P3
V4
V5
V6
V7
V8
V9
V
10
V
11
V12
V1
3
V12A
V13A
Timing of visit (Weeks)
Up to -2 
weeks
N/A
0
2
4
8
14
20
26
32
38
45
52
57
Day of 
discontinuati
on of trial 
product
5 weeks after
discontinuation
of trial product
(last dose)
-8 weeks
-4
Visit window (Days)
-7
N/A
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+3
+3
+3
±3
±7
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
Demography
x
Tobacco use
x
Concomitant illness and Medical 
history
x
Diagnosis of diabetes and 
Diabetes complications
x
History of cardiovascular disease
x
History of gallbladder disease
x
History of gastrointestinal disease
x
Randomisation
x
Criteria for premature 
discontinuation of trial product
x
x
x
x
x
x
x
x
x
x
x


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Trial Periods
Screenin
ga
Wash-
out 
Rand
omisa
tion
Treatment
End of 
treatme
nt 
(EOT)
Foll
ow-
upb
EOT 
premature 
discontinuati
onc
Follow-up 
premature 
discontinuationc
Visit (V), Phone contact (P)
V1
P1Wd
V2
P3
V4
V5
V6
V7
V8
V9
V
10
V
11
V12
V1
3
V12A
V13A
Timing of visit (Weeks)
Up to -2 
weeks
N/A
0
2
4
8
14
20
26
32
38
45
52
57
Day of 
discontinuati
on of trial 
product
5 weeks after
discontinuation
of trial product
(last dose)
-8 weeks
-4
Visit window (Days)
-7
N/A
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+3
+3
+3
±3
±7
EFFICACY
HbA1c
x
x
x
x
x
x
x
x
x
x
x
x
Fasting plasma glucose
x
x
x
x
x
x
x
x
x
Fasting insulin and pro-insulin
x
x
x
x
Fasting C-peptide
x
x
x
x
Fasting glucagon
x
x
x
x
7-point profile
x
x
x
x
Lipids
x
x
x
x
x
Height
x
Body weight
x
x
x
x
x
x
x
x
x
x
x
Waist circumference
x
x
x
x
x
x
PRO questionnaires
x
x
x
x
SAFETY
Eye examinatione
x
x
x
Physical examination
x
x
x
x
ECG
x
x
x
x
x
x
Vital signs
x
x
x
x
x
x
x
x
x
x
x
x
x
Pregnancy testf
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Calcitonin
x
x
x
x
x
x
x
x


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Trial Periods
Screenin
ga
Wash-
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Rand
omisa
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Treatment
End of 
treatme
nt 
(EOT)
Foll
ow-
upb
EOT 
premature 
discontinuati
onc
Follow-up 
premature 
discontinuationc
Visit (V), Phone contact (P)
V1
P1Wd
V2
P3
V4
V5
V6
V7
V8
V9
V
10
V
11
V12
V1
3
V12A
V13A
Timing of visit (Weeks)
Up to -2 
weeks
N/A
0
2
4
8
14
20
26
32
38
45
52
57
Day of 
discontinuati
on of trial 
product
5 weeks after
discontinuation
of trial product
(last dose)
-8 weeks
-4
Visit window (Days)
-7
N/A
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+3
+3
+3
±3
±7
Biochemistryg
x
x
x
x
x
x
x
x
x
x
x
Haematology
x
x
x
x
x
x
x
x
x
x
Antibodiesh
x
x
x
x
x
x
x
x
x
x
Adverse eventsi
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
Technical complaints
x
x
x
x
x
x
x
x
x
x
x
OTHER ASSESSMENTS
Semaglutide PK samplingj
x
x
x
x
x
x
x
x
TRIAL MATERIAL
IWRS call
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
Dispensing visit
x
x
x
x
x
x
x
x
x
REMINDERS
Training in trial product and pen 
handlingk
x
x
x
x
x
x
x
x
x
Attend visit fastingl
x
x
x
x
x
x
x
x
x
Handout and instruct in BG meter 
use
x
Handout ID card
x


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Trial Periods
Screenin
ga
Wash-
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Rand
omisa
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Treatment
End of 
treatme
nt 
(EOT)
Foll
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upb
EOT 
premature 
discontinuati
onc
Follow-up 
premature 
discontinuationc
Visit (V), Phone contact (P)
V1
P1Wd
V2
P3
V4
V5
V6
V7
V8
V9
V
10
V
11
V12
V1
3
V12A
V13A
Timing of visit (Weeks)
Up to -2 
weeks
N/A
0
2
4
8
14
20
26
32
38
45
52
57
Day of 
discontinuati
on of trial 
product
5 weeks after
discontinuation
of trial product
(last dose)
-8 weeks
-4
Visit window (Days)
-7
N/A
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+3
+3
+3
±3
±7
Dispense and/or collect
diary
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Footer
Description
a
Subjects treated with diet and exercise therapy alone prior to the day of screening can be randomised as soon as all inclusion and exclusion criteria are 
confirmed. Screening assessments should be performed up to 2 weeks prior to randomisation. The screening assessments must not exceed 3 weeks prior 
to randomisation (V2). 
Subjects treated with OAD as monotherapy prior to the day of screening can be randomised after 8-week wash-out period when all inclusion and 
exclusion criteria are confirmed. The visit window between V1 and V2 is 8 weeks ±3 days.
b
The follow-up visit (V13) should be scheduled 5 weeks after the last date on trial product (+3 days visit window). 
Subjects, who have discontinued trial product prematurely, are not required to attend V13.
c
V12A and V13A are only applicable for subjects who have discontinued trial product prematurely.
d
The phone contact (P1W) is applied only for subjects previously treated with OAD as monotherapy. Phone contact can be replaced with a visit if further 
examination is needed at the investigator´s discretion. 
e
Fundus photography/dilated fundoscopy performed within 90 days prior to randomisation is acceptable if results are available for evaluation at V2, unless 
worsening of visual function since last examination.
Fundus photography/dilated fundoscopy at V12 is allowed to be performed between V11 and V12 (preferably as close to V12 as possible).


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f
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.
g
At V1 only ALT, creatinine and eGFR will be assessed as part of Biochemistry.
h
For the subjects randomised to oral semaglutide/placebo treatment only.  At randomisation, the antibody sampling must be done after randomisation and 
before administration of first dose of trial product.
For subjects who have discontinued trial product prematurely, no antibodies sampling should be done for visits occurring after V13A.
i
Adverse events reporting includes adverse events from the first trial-related activity after the subject has signed the informed consent, however, pre-
existing conditions identified as a result of the screening procedures should be reported as medical history or concomitant illness.
j
For the subjects randomised to oral semaglutide/placebo treatment only. At V8 one PK sample should be taken pre-dose and one should be taken 60-90 
minutes post-dose. At the other visits sample will be taken at any time during the visit. 
For subjects who have discontinued trial product prematurely, no PK sampling should be done for visits occurring after V13A.
k
The investigator must document that direction for use is given to the subject verbally and in writing at the first dispensing visit (V2). Direction for use
should be given to the subject at subsequent visits when judged necessary by the investigator. 
The subjects allocated to liraglutide must be trained in how to handle the pen-injector when handed out the first time and at subsequent visits when judged 
necessary by the investigator. 
l
Fasting for blood sampling is defined as no food or liquid within the last 8 hours prior to blood sampling, however, water is allowed up until 2 hours prior 
to blood sampling. 


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3
Background information and rationale for the trial
The trial will be conducted in compliance with this protocol, International Conference on 
Harmonisation (ICH) Good Clinical Practice (GCP)1 and applicable regulatory requirements, and in 
accordance with the Declaration of Helsinki2.
In this document, the term investigator refers to the individual responsible for the overall conduct of 
the clinical trial at a trial site.
3.1
Background information
For an assessment of benefits and risks of the trial, see Section 18.1.
3.1.1
Type 2 diabetes mellitus 
Type 2 diabetes mellitus (T2DM) is a progressive metabolic disease primarily characterised by 
abnormal glucose metabolism. The pathogenesis is heterogeneous involving environmental, 
lifestyle and genetic factors leading to chronic hyperglycaemia caused by peripheral tissue insulin 
resistance, impaired insulin secretion due to abnormal beta-cell function and abnormal glucose 
metabolism in the liver3.
Optimal glycaemic control is the treatment goal in subjects with T2DM in order to prevent long-
term complications associated with chronic hyperglycaemia4. Despite the availability of several 
anti-diabetic drugs, a significant proportion of subjects with T2DM do not achieve the 
recommended targets for glycaemic control5,6.
3.1.2
Glucagon-like peptide-1
Glucagon-like peptide-1 (GLP-1) is an incretin hormone with a glucose-dependent stimulatory 
effect on insulin and inhibitory effect on glucagon secretion from the pancreatic islets7,8. Subjects 
with T2DM have a decreased incretin effect9,10,11,12. However, the insulinotropic action of GLP-1 
and thus, the ability to lower blood glucose (BG) levels, is preserved when GLP-1 is administered at 
supraphysiological levels13. In addition, supraphysiological levels of GLP-1 induce reduction in 
body weight14. GLP-1 is a physiological regulator of appetite and food intake and GLP-1 receptors 
are present in several areas of the brain involved in appetite regulation15,16. Physiologically, GLP-1 
also has a pronounced inhibitory effect on gastric emptying; however this effect seems to diminish 
upon chronic exposure14,15,16. These mechanisms of action make GLP-1 receptor agonists (GLP-1
RA) an attractive pharmacological treatment for T2DM17,18,19.
3.1.3
Oral semaglutide
Semaglutide is a long-acting GLP-1 RA structurally similar to liraglutide (Victoza®), a once-daily 
GLP-1 RA developed by Novo Nordisk and approved worldwide for the treatment of T2DM. 
Compared to human native GLP-1, which has a short half-life, the semaglutide molecule has three 
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minor but important modifications ensuring protraction of its action: amino acid substitutions at 
position 8 (alanine to alpha-aminoisobutyric acid, a synthetic amino acid) and position 34 (lysine to 
arginine) and acylation of the peptide backbone with a spacer and C-18 fatty di-acid chain to lysine 
in position 2620,21. The fatty di-acid side chain and the spacer mediate strong binding to albumin, 
thereby reducing renal clearance. The amino acid substitution at position 8 makes semaglutide less 
susceptible to degradation by dipeptidyl peptidase-4 (DPP-4). The change in position 34 from a 
lysine to an arginine is included to have only one lysine in the sequence where to a spacer can be 
attached.
Semaglutide is in development for oral once-daily treatment of T2DM. As the bioavailability of 
GLP-1 RAs is low when administered orally, semaglutide has been co-formulated with the 
absorption-enhancing excipient sodium N-[8-(2-hydroxybenzoyl) amino]caprylate (SNAC) to 
increase the bioavailability of semaglutide. The absorption-enhancing properties of SNAC co-
formulation are based on the 
concept developed by
SNAC facilitates the absorption of semaglutide in a strictly time and size dependent manner, 
primarily via the transcellular route. The available data for semaglutide co-formulated with SNAC 
support that the absorption takes place in the stomach in a localised, buffered environment in close 
proximity to the tablet erosion. The absorption process is hampered if dosed with food, liquid or in 
the presence of significant stomach content.
The absorption enhancement requires co-formulation between semaglutide and SNAC. Throughout 
this document “oral semaglutide” will refer to the drug product, that is, semaglutide co-formulated 
with 300 mg SNAC.
3.1.4
Nonclinical data
3.1.4.1
Semaglutide
The nonclinical programme for semaglutide was designed according to the ICH M3 guideline to 
support the clinical development22. The standard nonclinical data package required to support phase 
3 clinical trials has been completed. In addition, 2-year carcinogenicity studies and a pre- and 
postnatal development toxicity study have been completed. Semaglutide was generally well 
tolerated in animals (mice, rats and cynomolgus monkeys). Two potential safety issues have been 
identified and these are detailed below.
Thyroid C-cell tumours in rodents
Treatment-related non-genotoxic proliferative changes in the thyroid C-cells of mice and rats were 
observed in 2-year carcinogenicity studies with semaglutide; thyroid hyperplasia was preceded by 
an increase in serum calcitonin. C-cell changes have not been observed in long-term studies in non-
human primate. The observed pattern of effects in mice and rats and lack of these effects in the non-
human primate and in man suggest that the mechanism by which semaglutide acts on the thyroid C-
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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 low23.
Embryo−foetal development toxicity
Semaglutide caused embryo-foetal development toxicity in the rat through a GLP-1 receptor 
mediated effect on the inverted yolk sac placenta leading to impaired nutrient supply to the 
developing embryo. Primates do not have an inverted yolk sac placenta which makes this 
mechanism unlikely to be of relevance to humans and cynomolgus monkeys. In the developmental 
toxicity studies in cynomolgus monkey, a marked maternal body weight loss associated with the 
pharmacological effect of semaglutide coincided with increased early foetal loss; however, there 
was no indication of a teratogenic potential of semaglutide in this species.
A review of the results from the nonclinical studies can be found in the investigator’s brochure (IB) 
for semaglutide (subcutaneous administration), edition 1124 and the IB for oral administration of 
semaglutide (NN9924), edition 725, or any updates of these documents.
3.1.4.2
SNAC
SNAC was developed as an absorption-enhancing excipient for the oral route of administration. The 
nonclinical programme to support clinical phase 3 development and marketing authorisation 
application submission has been conducted including a 26-week carcinogenicity study in transgenic 
rasH2 mice and a 2-year carcinogenicity study in Sprague-Dawley rats.
 
 
 
 
 
 
 Measurements of lactate levels have 
been included at selected time points around peak concentrations of SNAC in two of the phase 3a 
trials in the PIONEER programme (PIONEER 1 and 2) with the intention to document that SNAC 
does not impair cellular respiration in humans. In addition, events of lactic acidosis must be 
reported as an AE requiring additional data collection, please refer to Section 8.4.1.2, Section 12.1.5
and appendix B.
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The carcinogenicity studies demonstrated that SNAC was not carcinogenic to the transgenic rasH2 
mouse or the Sprague-Dawley rat. The doses tested covered total exposures of SNAC in plasma (in 
terms of area under the curve [AUC]) of 2-fold in the mouse and up to 44-fold in the rat when 
compared to the mean total exposure of SNAC in humans following a clinical dose of 300 mg 
SNAC/day.
A review of the SNAC results from the nonclinical studies can be found in the IB for oral 
administration of semaglutide (NN9924), edition 725, or any updates hereof.
3.1.5
Clinical data for oral semaglutide
A comprehensive clinical pharmacology programme including 12 trials has been completed, as well 
as a 26-week phase 2 dose-finding trial involving more than 600 subjects with T2DM.
For details on the individual trials, please see the IB for oral administration of semaglutide 
(NN9924) edition 725, or any updates hereof.
3.1.5.1
Pharmacokinetics
In the multiple-dose trial (NN9924-3991), oral semaglutide has demonstrated a long mean terminal 
half-life (t½) ranging from 153 to 161 hours (~1 week) and a median time to reach maximum 
observed concentration (tmax) ranging from 1 to 2 hours in healthy subjects. 
In multiple-dose pharmacokinetics (PK) trials, the exposure to oral semaglutide increased with 
increasing dose. Overall, the pharmacokinetic properties of semaglutide appeared similar in healthy 
subjects and in subjects with T2DM.
Exposure to semaglutide exhibits a substantially greater dose-to-dose variation following oral 
administration compared to subcutaneous (s.c.) administration. However, when administered orally 
once-daily the PK properties of semaglutide, i.e. low clearance and long half-life, will limit the 
variation in exposure at steady state.
Data obtained following investigation of different dosing conditions for oral semaglutide have 
demonstrated that subjects should take the oral semaglutide tablet in the morning in a fasting state 
and at least 30 minutes before the first meal of the day. 
 
 
 
 
 
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In subjects with mild to severe hepatic impairment, the exposure to semaglutide appeared to be 
unaffected by the degree of hepatic impairment, whereas the exposure to SNAC (in terms of both 
AUC and Cmax) was increased for subjects with hepatic impairment as compared to subjects with 
normal hepatic function.
All tablets of oral semaglutide contain 300 mg of SNAC regardless of the semaglutide dose. SNAC 
is rapidly absorbed with a median tmax ranging from 0.35−0.5 hours in healthy subjects and from 
0.52−1.43 hours in subjects with T2DM. It is extensively metabolised and no accumulation of 
SNAC has been observed in clinical trials.
3.1.5.2
Efficacy
The efficacy of oral semaglutide in adult subjects with T2DM was investigated in a 26-week phase 
2 dose-finding trial (NN9924-3790). In this trial, placebo or one of the following doses of oral 
semaglutide were administered once daily: 2.5, 5, 10, 20 and 40 mg.
Results from the trial showed that oral semaglutide effectively lowered glycosylated haemoglobin 
(HbA1c) and body weight. Placebo-adjusted reductions in HbA1c were dose-dependent and 
statistically significant for all oral semaglutide treatment arms at week 26 (range: -0.40% to -1.59%). 
Placebo-adjusted reductions in body weight were dose-dependent and statistically significant for 
oral semaglutide treatment doses of 10 mg and above at week 26 (range: -3.61 kg to -6.98 kg). 
3.1.5.3
Safety
In the clinical trials completed so far, no unexpected safety findings have been identified for oral 
semaglutide administered up to 40 mg once daily. Consistent with other GLP-1 RAs, commonly 
reported adverse events (AEs) included nausea and vomiting, most of which were mild to moderate 
in severity. In line with findings for other GLP-1 RAs, an increase in heart rate and serum levels of 
lipase and amylase has also been observed in subjects exposed to oral semaglutide.
In addition to the 13 completed clinical trials with oral semaglutide, SNAC has been investigated in 
the programme of orally administrated heparin in combination with SNAC (heparin/SNAC). The 
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 trials covered formulation development, food effect, hepatic and renal 
impairment, age-effect and drug-drug interaction. The programme also included a total of three 
phase 2 and 3 trials in which the effects of orally delivered heparin solution (with >1.5 g SNAC 
three times a day) was investigated. The overall safety profile of oral semaglutide and 
heparin/SNAC indicates that SNAC is safe and well-tolerated.
For further details, please see the IB for oral administration of semaglutide (NN9924) edition 725, or 
any updates hereof.
3.1.6
Liraglutide
The selected active comparator in this trial is liraglutide, an injectable GLP-1 RA approved for 
once-daily administration. Liraglutide was developed by Novo Nordisk and approved in 2009 in the 
EU, in 2010 in Japan, and in 2010 in the US under the trade name Victoza® to improve glycaemic 
control in adults with T2DM.
For further details, please see the current approved label for liraglutide (Victoza®) in Japan26.
3.2
Rationale for the trial
Many patients with T2DM are not in glycaemic control with the currently marketed oral anti-
diabetic drugs (OADs). Nevertheless, treatment with more efficacious injectable therapies such as 
GLP-1 RAs and insulin are rarely added during the early stages of the disease. Oral semaglutide is 
the first GLP-1 RA in development in a tablet formulation and it has the potential of becoming a 
new attractive treatment option early in the treatment cascade due to its effects on both 
hyperglycaemia and body weight.
'The “Draft Guideline for Clinical Evaluation of Hypoglycaemic Agents”27 (hereafter, draft AD 
guideline) provided by the Ministry of Health, Labour and Welfare (MHLW), Japan, specifies that 
in order to obtain the indication “T2DM” the investigational drug must be evaluated in a phase 2
study in Japanese patients with T2DM evaluating the efficacy, safety and dosage regimen as well as 
the dose-response relationship of the glucose-lowering effect. In addition, the “long-term” safety 
and efficacy of an investigational drug should be confirmed in monotherapy in a sufficient number 
of Japanese patients.
The rationale for this trial is to assess the dose-response relationship of the glucose-lowering effect 
of oral semaglutide after 6 months and to evaluate the long-term safety and efficacy of oral 
semaglutide compared to placebo and liraglutide as monotherapy after 12 months of treatments.
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4
Objectives and endpoints
4.1
Objectives
4.1.1
Primary objective
To assess the dose-response relationship of once-daily dosing of three dose levels (3, 7 and 14 mg) 
of oral semaglutide versus placebo as monotherapy on glycaemic control in Japanese subjects with 
type 2 diabetes mellitus.
4.1.2
Secondary objectives
To compare the safety and tolerability of once-daily dosing of three dose levels (3, 7 and 14 mg) of 
oral semaglutide versus placebo and versus once-daily 0.9 mg liraglutide subcutaneously, all as 
monotherapy in Japanese subjects with type 2 diabetes mellitus.
To compare the effect of once-daily dosing of three dose levels (3, 7 and 14 mg) of oral semaglutide 
versus placebo and versus once-daily 0.9 mg liraglutide subcutaneously, all as monotherapy on 
glycaemic control and body weight in Japanese subjects with type 2 diabetes mellitus.
4.2
Endpoints
Baseline refers to randomisation, and week 26 and week 52 refer to 26 weeks after randomisation
and 52 weeks after randomisation respectively.
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
Not applicable.
4.2.2.2
Supportive secondary endpoints
Key supportive secondary endpoints prospectively selected for disclosure (e.g. Clinical Trials 
Information/JapicCTI site: clinicaltrials.jp and clinicaltrials.gov) are marked with an asterisk (*).
Supportive secondary safety endpoints
Number of treatment-emergent adverse events (TEAEs) during exposure to trial product, assessed 
up to approximately 57 weeks*
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Number of treatment-emergent severe or BG-confirmed symptomatic hypoglycaemic episodes 
during exposure to trial product, assessed up to approximately 57 weeks*
Treatment-emergent severe or BG-confirmed symptomatic hypoglycaemic episodes during 
exposure to trial product, assessed up to approximately 57 weeks (yes/no)
Change from baseline to week 26 and 52 in:
!
Haematology
!
Biochemistry
!
Calcitonin
!
Pulse
!
Systolic blood pressure
!
Diastolic blood pressure
!
Electrocardiogram (ECG) category
!
Physical examination 
Change from baseline to week 52 in:
!
Fundus photography/dilated fundoscopy
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 antibodies:
!
Anti-semaglutide binding antibody levels
Supportive secondary efficacy endpoints
Change from baseline to week 26 and 52 in:
!
HbA1c (only week 52)*
!
Fasting plasma glucose (FPG)*
!
7-point self-measured plasma glucose (SMPG) profile
–
Mean 7-point profile
–
Mean postprandial increment over all meals
!
Body weight (kg)*
!
Body weight (%)
!
Body mass index (BMI)  
!
Waist circumference
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!
Fasting lipid profile (total cholesterol, low-density lipoprotein [LDL] cholesterol, high-density 
lipoprotein [HDL] cholesterol and triglycerides, very low density lipoprotein [VLDL], free fatty 
acids)
!
Fasting insulin, C-peptide, glucagon, pro-insulin 
!
Pro-insulin/insulin ratio 
!
Insulin resistance (homeostatic model assessment index of insulin resistance [HOMA-IR])
!
Beta-cell function (homeostatic model assessment index of beta-cell function [HOMA-B])
!
Patient-reported outcomes (PROs)
–
Short Form (SF)-36v2TM (acute version) health survey
–
Diabetes Therapy-Related QOL (DTR-QOL) questionnaire
If a subject after week 26 and week 52 achieves (yes/no):
!
HbA1c <7.0% (53 mmol/mol) (American Diabetes Association [ADA] target)*
!
HbA1c ≤6.5% (48 mmol/mol) (American Association of Clinical Endocrinologists [AACE]
target)
!
HbA1c reduction ≥1%-point (10.9 mmol/mol)
!
Body weight loss ≥3%
!
Body weight loss ≥5% 
!
Body weight loss ≥10% 
!
HbA1c <7.0% (53 mmol/mol) without hypoglycaemia (treatment-emergent severe or BG-
confirmed symptomatic hypoglycaemic episodes) and no body weight gain
!
HbA1c reduction ≥1%-point (10.9 mmol/mol) and body weight loss ≥3%
Time to event:
!
Time to rescue medication 
Supportive secondary pharmacokinetic endpoints
!
Semaglutide plasma concentrations for population PK analysis
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5
Trial design
5.1
Type of trial
This is a combined phase 2 dose-response and phase 3 safety and efficacy trial. It is a 52-week, 
randomised double-blind placebo-controlled and open-label active-controlled, parallel-group, multi-
centre, single country trial with 5 treatment arms in Japanese subjects with T2DM to: 
!
assess dose-response relationship of once-daily dosing of 3 dose levels of oral semaglutide (3, 7 
and 14 mg) versus placebo on glycaemic control at week 26
!
compare the safety and efficacy of once-daily dosing of 3 dose levels of oral semaglutide (3, 7 
or 14 mg) versus placebo and versus once-daily 0.9 mg liraglutide subcutaneously at week 26 
and week 52 
Japanese subjects with T2DM treated with diet and exercise therapy alone or OAD as monotherapy 
(half maximum approved dose or below) in addition to diet and exercise therapy will be included in 
this trial. For subjects treated with OAD as monotherapy, pre-trial OAD will be discontinued at 
screening and washed-out before randomisation. Subjects treated with diet and exercise therapy 
alone will be randomised without a wash-out period after their eligibility has been confirmed. 
Subjects will be randomised in a 1:1:1:1:1 manner to receive one of the following treatments: 
!
Oral semaglutide 3 mg once-daily
!
Oral semaglutide 7 mg once-daily
!
Oral semaglutide 14 mg once-daily
!
Oral placebo once-daily
!
Liraglutide 0.9 mg subcutaneous (s.c.) injection once-daily 
Randomisation will be stratified based on:
!
pre-trial OAD treatment at screening (yes/no)
The trial is double-blinded with regard to dose levels of oral semaglutide and placebo. In order to 
maintain the blinding of the trial for oral semaglutide and placebo all tablets containing oral 
semaglutide or placebo are identical with regards to visual appearance. 
The treatment administration of liraglutide will be open-label.
The total trial duration for the individual subject will be 59 to 65 weeks depending on pre-trial 
treatment. The trial includes a 2-week screening period, followed by a 52-week randomised 
treatment period and a follow-up period of 5 weeks. For subjects treated with OAD as monotherapy 
prior to the screening an 8-week wash-out period including the screening period will replace the 2-
week screening period.
A schematic illustration of the trial design is shown in Figure 5–1.
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Figure 5–1
Trial design
5.2
Rationale for trial design
The trial was designed in accordance with the draft AD guideline27 and is in accordance with the 
advice of Pharmaceuticals and Medical Devices Agency (PMDA) obtained at the End of Phase 2 
meeting.
The number of subjects has been set based on the agreement with PMDA and is considered 
adequate to evaluate the dose-response relationship of once-daily dosing of three dose levels (3, 7 
and 14 mg) of oral semaglutide versus placebo as monotherapy on glycaemic control. 
The parallel treatment groups, a randomised (double-blind/open-label) design have been chosen to 
assess the dose-response relationship, long-term safety and efficacy of oral semaglutide compared 
to placebo and active comparator liraglutide. Randomisation will be stratified based on pre-trial 
OAD treatment at screening (yes/no) to ensure even distribution of the 5 treatment arms within each 
stratum.
There will be strict rescue criteria in place to ensure acceptable glycaemic control during the trial 
for all treatment arms, including the placebo arm.
The treatment duration will be 52 weeks for the assessment of long-term safety of oral semaglutide 
as monotherapy in accordance with the draft AD guideline. The dose-response relationship will be 
evaluated based on data at week 26. No interim analysis will be done and the blinding will remain 
throughout the trial.
The follow-up period is 5 weeks to allow for wash-out of semaglutide and to prevent interference in 
the antibody assay.
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5.3
Treatment of subjects
Treatment of subjects is summarised in Table 5–1.
Oral semaglutide treatment arms
Oral semaglutide is a long-acting GLP-1 RA to be administered orally once-daily. All subjects 
randomised to oral semaglutide will initiate treatment with 3 mg once-daily. Subjects randomised to 
a treatment dose of 7 and 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, followed by 4 weeks on 7 mg once daily (Table 5–1). All dose levels, including the dose-
escalation, will be blinded. To mitigate the risk of gastrointestinal AEs, it is important to follow the 
fixed 4-week dose escalation intervals. The dose must not be changed once the randomised dose of 
oral semaglutide has been reached. 
Placebo treatment
Treatment with placebo tablets will follow the same rules for oral semaglutide treatment outlined 
above.
Liraglutide treatment
Treatment with liraglutide injections will be initiated at 0.3 mg once-daily. The dose will be 
escalated weekly, first to 0.6 mg once-daily and then to the recommended maximum dose of 0.9 mg 
once-daily according to the approved label in T2DM in Japan26. To mitigate the risk of 
gastrointestinal AEs, it is important to follow the weekly dose escalation intervals. The dose must 
not be changed during the course of the trial once the 0.9 mg maintenance dose of liraglutide has 
been reached.
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Table 5–1
Overview of treatment of subjects
Trial periods
Screening
Treatment
Follow-up
First visits in each period
Visit 1
Visit 2
Visit 4
Visit 5
Visit 13
Duration of each period
Up to 2  
weeksa
4 weeks
4 weeks
44 weeks
5 weeks
8  weeksb
Treatment arm
N
Oral semaglutide 3 mg
48
Screening
3 mg
3 mg
3 mg
Follow-up
Oral semaglutide 7 mg
48
Screening
3 mg
7 mg
7 mg
Follow-up
Oral semaglutide 14 mg
48
Screening
3 mg
7 mg
14 mg
Follow-up
Placebo
48
Screening
placebo
placebo
placebo
Follow-up
Liraglutide 0.9 mg
48
Screening
0.3 mg (0.05 
mL) 
liraglutide  
injection with  
weekly dose 
escalation to 
0.6 mg (0.1 
mL) and 0.9 
mg (0.15 mL)
0.9 mg
0.9 mg
Follow-up
a Subject treated with diet and exercise therapy alone prior to the day of screening can be randomised as soon as all 
inclusion and exclusion criteria are confirmed.
b Subjects treated with OAD as monotherapy prior to the day of screening can be randomised after 8-week wash-out 
period when all inclusion and exclusion criteria are confirmed.
5.3.1
Dosing instructions
Oral semaglutide/placebo dosing
Absorption of oral semaglutide is significantly affected by food and fluid in the stomach, hence 
dosing should be once-daily in the morning in a fasting state and at least 30 minutes before the first 
meal of the day. The tablet can be taken with up to half a glass of water (approximately 120 mL). 
The tablet must be swallowed whole by the subject and must not be broken or chewed (see Table 9–
2). Furthermore, other oral medication can be taken 30 minutes after administration of the oral trial 
product.
Liraglutide dosing
Liraglutide should be administered once-daily in the morning or evening at a fixed time and 
irrespective of meals. Liraglutide is injected subcutaneously in the abdomen, the thigh or the upper 
arm. The injection site should be changed at every injection and about 2~3 cm apart from the 
previous one.
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5.3.2
Background medication
As this trial is a monotherapy trial, there are no background anti-diabetic medications after the 
screening.
Please see section 6.4 with regards to rescue medication.
5.4
Treatment after discontinuation of trial product
When discontinuing trial products, either at the scheduled end of treatment visit (see Section 8.1.5) 
or if trial product is discontinued prematurely (see Section 8.1.6), the subject should be switched to 
a suitable marketed product at the discretion of the investigator. For subjects randomised to oral 
semaglutide/placebo treatment only, after discontinuation of trial products, GLP-1 RAs are not 
allowed before completion of the follow-up visit 5 weeks after the last date on trial products (to 
avoid interference with the antibody assay for semaglutide). Throughout the protocol, last date on 
trial product is defined as date of the subject’s last dosage of trial product.
As this trial is a phase 2/3a trial, oral semaglutide will not be available for prescription until after 
marketing authorisation.
5.5
Rationale for treatment
For oral semaglutide, the three dose levels (3, 7 and 14 mg), treatment initiation with the lowest 
dose and the 4-week dose escalation steps have been chosen based on data from the global phase 2 
dose-finding trial. This regime is expected to have the optimal benefit-risk profile for further 
development for treatment of T2DM in the PIONEER programme. 
Liraglutide has been chosen as active comparator since it is a well-established injectable GLP-1 RA 
once-daily dosing. Treatment will be initiated at 0.3 mg once-daily in accordance with the current, 
approved label in Japan. Liraglutide will be dose escalated to the highest approved maintenance 
dose in Japan (0.9 mg) to compare all 3 dose levels of oral semaglutide with maximum dose of 
liraglutide as monotherapy in terms of efficacy and safety.
The duration of randomised treatments is considered adequate to collect sufficient data on efficacy 
and safety in accordance with the trial objectives.
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6
Trial population
6.1
Number of subjects 
Number of subjects planned to be screened: 300
Number of subjects planned to be randomised: 240
Number of subjects expected to complete the trial on or off randomised trial product: 216
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. Japanese male or female, age above or equal to 20 years at the time of signing informed 
consent. 
3. Diagnosed with type 2 diabetes mellitus ≥ 30 days prior to day of screening.
4. HbA1c 6.5%−9.5% (48−80 mmol/mol) (both inclusive) for subjects treated with OAD as 
monotherapy and 7.0%−10.0% (53−86 mmol/mol) (both inclusive) for subjects treated with diet 
and exercise therapy alone.
5. Treatment for ≥30 days prior to day of screening with;
–
stable daily dose of OAD as monotherapy (allowed OADs are: metformin, sulphonylurea
[SU], glinide, α-glucosidase inhibitor [α-GI], dipeptidyl peptidase-4 [DPP-4] inhibitor and 
sodium-glucose cotransporter-2 [SGLT-2] inhibitor) at a half-maximum approved dose or 
below according to Japanese labelling in addition to diet and exercise therapy. 
or
–
diet and exercise therapy alone.
6.3
Exclusion criteria
For an eligible subject, all exclusion criteria must be answered “no”. 
1. Known or suspected hypersensitivity to trial product(s) or related products. 
2. Previous participation in this trial. Participation is defined as signed informed consent.
3. Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing 
potential and not using an adequate contraceptive method. Adequate contraceptive 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. 
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5. Any disorder, which in the investigator’s opinion might jeopardise subject’s safety or 
compliance with the protocol.
6. Family or personal history of multiple endocrine neoplasia type 2 (MEN 2) or medullary thyroid 
carcinoma (MTC). 
7. History of pancreatitis (acute or chronic)
8. History of major surgical procedures involving the stomach potentially affecting absorption of 
trial product (e.g. subtotal and total gastrectomy, sleeve gastrectomy, gastric bypass surgery).
9. Any of the following: myocardial infarction, stroke or hospitalisation for unstable angina or 
transient ischaemic attack within the past 180 days prior to the day of screening and 
randomisation.
10. Subjects presently classified as being in New York Heart Association (NYHA) Class IV.
11. Planned coronary, carotid or peripheral artery revascularisation known on the day of screening.
12. Subjects with alanine aminotransferase (ALT) > 2.5 x upper normal limit (UNL). 
13. Renal impairment defined as estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2
as per Chronic Kidney Disease Epidemiology Collaboration formula (CKD-EPI). 
14. Treatment with once-weekly glucagon-like peptide-1 receptor agonist (GLP-1 RA), once 
weekly dipeptidyl peptidase-4 (DPP-4) inhibitor or thiazolidinedione in a period of 90 days 
before the day of screening
15. Treatment with any medication for the indication of diabetes or obesity other than stated in the 
inclusion criteria in a period of 60 days before the day of screening. An exception is short-term 
insulin treatment for acute illness for a total of ≤ 14 days.
16. Proliferative retinopathy or maculopathy requiring acute treatment. Verified by fundus 
photography or dilated fundoscopy performed within 90 days prior to randomisation.
17. History or presence of malignant neoplasms within the last 5 years (except basal and squamous 
cell skin cancer and in-situ carcinomas).
18. Initiation of anti-diabetic medication between the day of screening and the day of 
randomisation.
6.4
Rescue criteria
Subjects with persistent and unacceptable hyperglycaemia should be offered treatment 
intensification. To allow time for dose escalation to maximum dose 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. If the confirmatory FPG also 
exceeds the value described below, the subject should be offered rescue medication (initiation of 
new anti-diabetic medication): 
!
13.3 mmol/L (240 mg/dL) from week 8 to end of week 13
!
11.1 mmol/L (200 mg/dL) from week 14 to end of treatment
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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 treatment.
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 at investigator’s discretion as add-on to randomised treatment and according to clinical 
practice in Japan or ADA/European Association for the Study of Diabetes guidelines28,29 (excluding 
GLP-1 RAs, DPP-4 inhibitors and amylin analogues).
If a subject experience persistent decline in renal function after starting rescue medication, the 
treatment with the rescue medication should be adjusted/discontinued according to the current 
approved label or guideline.
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 non-investigational medicinal product (NIMP) and will not 
be provided by Novo Nordisk A/S.
6.5
Criteria for premature discontinuation of trial product 
All efforts should be made to keep the subject on trial product. However, the subject may be 
prematurely discontinued from trial product at the discretion of the investigator due to a safety 
concern. For additional guidance, refer to appendix B.
The subject must be prematurely discontinued from trial product if the following applies:
1. Safety concern related to trial product or unacceptable intolerability 
2. Included in the trial in violation of the inclusion and/or exclusion criteria
3. Pregnancy 
4. Intention of becoming pregnant
5. Simultaneous participation in another clinical trial of an approved or non-approved 
investigational medicinal product.
6. Calcitonin ≥ 100 ng/L
If a criterion for premature discontinuation of trial product is met, trial product should not be re-
initiated but subjects should continue with the scheduled site contacts.
See Section 8.1.6 for procedures to be performed for subjects discontinuing trial product 
prematurely.
6.6
Withdrawal from trial
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The subject may withdraw consent at will at any time. The subject’s request to withdraw from the 
trial must always be respected. Only subjects who withdraw consent should be considered as 
withdrawn from trial.
See Section 8.1.7 for procedures to be performed for subjects withdrawing consent.
6.7
Subject replacement
Subjects who withdraw consent or discontinue trial product prematurely will not be replaced. 
6.8
Rationale for trial population 
The trial population will include Japanese subjects with T2DM treated with diet and exercise 
therapy alone or a stable dose of one OAD as monotherapy in addition to diet and exercise for at 
least 30 days prior to screening. As the pre-trial OAD will be washed out before randomisation,
only subjects treated with a OAD at half-maximum approved dose or below can be included in the 
trial. The HbA1c limits are between 6.5% and 9.5% for subjects treated with OAD as monotherapy 
and 7.0% and 10.0% for subjects treated with diet and exercise therapy alone. The limits of HbA1c
have been chosen, in order to include subjects needing intensification of anti-diabetic treatment. As 
it is expected that HbA1c will increase after discontinuation of the pre-trial OAD a lower HbA1c
level will be applied for subjects treated with OAD as monotherapy. The upper limit will secure that 
subjects with severely dysregulated T2DM are not enrolled in this placebo controlled trial. In 
addition, FPG and HbA1c will be monitored throughout the trial and rescue medication should be 
initiated in subjects with persistent, unacceptable hyperglycaemia. No BMI or blood pressure 
restrictions will be applied. Subjects with liver test abnormalities (ALT>2.5 x UNL) will be 
excluded to avoid potential confounding of liver safety assessments. In addition, subjects with 
severe and end-stage renal impairment will be excluded due to restrictions in the label of the 
comparator, liraglutide. Overall, the eligibility criteria allow for enrolment of a relatively broad trial 
population resembling the target population in common practice. Finally, the trial population was 
selected on the basis of the draft AD guideline27 and the advice from PMDA.
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7
Milestones
Planned duration of recruitment period (first subject first visit [FSFV] – last subject first visit 
[LSFV]):
20 weeks
Planned FSFV:
  10-Jan-2017
Planned last subject last visit (LSLV):
  11-Sep-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. All subjects screened during the recruitment period and found eligible for randomisation 
can be randomised within the timelines specified in the flow chart (see Section 2).
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 Disclosure30, it will also be disclosed according to other applicable 
requirements such as those of the International Committee of Medical Journal Editors (ICMJE)31, 
the Food and Drug Administration Amendment Act (FDAAA)32, European Commission 
Requirements33,34 and other relevant recommendations or regulations. If a subject requests to be 
included in the trial via the Novo Nordisk e-mail contact at these web sites, Novo Nordisk may 
disclose the investigator’s contact details to the subject. As a result of increasing requirements for 
transparency, some countries require public disclosure of investigator names and their affiliations.
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8
Methods and assessments
8.1
Visit procedures
The following sections describe the assessments and procedures. These are also included in the flow 
chart (see Section 2).
Informed consent must be obtained before any trial related activity, see Section 18.2.
Refer to flowchart (Section 2) for number and timing of visits and specific assessments to be 
performed. 
Each subject will attend 12 site visits and 1 or 2 phone contacts. It is the responsibility of the 
investigator to ensure that all site visits and phone contacts occur according to the flow chart.
Planned visits can be conducted and re-scheduled within the allowed visit window. If a visit is 
missed and it is not possible to re-schedule, every effort should be made to ensure information is 
collected at a telephone contact (within the visit window) and entered into the eCRF. Subjects will 
be invited for the next scheduled visit according to the visit schedule.
The investigator must keep a subject screening log, a subject identification code list and a subject 
enrolment log. Only subjects who have signed the informed consent form should be included on the 
logs. The subject screening log and subject enrolment log may be combined in one log.
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.
8.1.1
Screening, visit 1
At screening, subjects will be provided with a card stating that they are participating in a trial and 
giving contact address(es) and telephone number(s) of relevant trial site staff. Subjects should be 
instructed to return the card to the investigator at the last trial visit or to destroy the card after the 
last visit.
A screening session must be made in the IWRS. Each subject will be assigned a unique 6-digit 
subject number which will remain the same throughout the trial.
Once all data relating to V1 have been obtained, these must be reviewed, dated and signed by the 
investigator and/or documented in medical records to assess that the subject is eligible to continue 
in the trial.
If any untoward medical occurrence that might have worsened the renal or hepatic function from 
screening to randomisation, the investigator should reconsider the subject´s eligibility.
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Wash-out period for subjects previously treated with OAD as monotherapy:
For subjects previously treated with OAD as monotherapy, their pre-trial OAD will be washed out 
for 8 weeks before Visit 2. 
During the wash-out period, the subjects should measure pre-breakfast SMPG (fasting for at least 6 
hours) at least twice a week and if they experience hyperglycaemic symptoms. The subjects should 
record the SMPG values measured in the diary.
If pre-breakfast SMPG (fasting state) is above 240 mg/dL (13.3 mmol/L) or postprandial SMPG, if 
measured, is above 270 mg/dL (15.0 mmol/L), the subjects should contact the investigator for 
advice. The investigator should instruct the subject to measure his/her pre-breakfast SMPG on 3 
consecutive days. If the subject has pre-breakfast SMPG (fasting state) above 240 mg/dL (13.3 
mmol/L) on 3 consecutive days, and/or if the investigator judges the subject's condition as unsafe 
regardless of the pre-breakfast SMPG, the subject will be excluded from the trial at the 
investigator's discretion, and regarded as screening failure.
Phone contact 1 during wash-out period (P1W) will be performed at 4 weeks (±7 days) before Visit 
2. The phone contact can be replaced with a “visit” if for instance further examination is needed at 
the investigator's discretion.
Screening failures:
For screening failures the screening failure form in the eCRF must be completed with the reason for 
not continuing in the trial. Serious adverse events (SAEs) from screening failures must be 
transcribed by the investigator into the eCRF. Follow-up on SAEs must be carried out according to 
Section 12.
A screening failure session must be made in the IWRS. The case book must be signed.
Re-screening is NOT allowed if the subject has failed one of the inclusion or exclusion criteria, this 
includes re-sampling if the subject has failed one of the inclusion or exclusion criteria related to 
laboratory parameters. However, in case laboratory samples are lost (e.g. haemolysed/displaced), 
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 no food or liquid within the last 8 hours prior to blood 
sampling, however water is allowed up until 2 hours prior to blood sampling.
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For the subjects allocated to oral semaglutide/placebo, trial product must be taken after blood 
sampling (see Section 5.3.1 for dosing instructions). Other oral medication can be taken 30 minutes 
after trial product. Injectable medications can be administered after blood sampling.
For the subjects allocated to liraglutide, the trial product and/or other oral and injectable 
medications must be taken after the blood sampling has been performed.
In case a subject attends a fasting visit in a non-fasting state, all non-fasting measurements should 
be performed. The subject should return to the site in a fasting state to have the fasting blood 
samples done within the visit window for the relevant visit.
For fasting samples, see Section 8.3.1.
8.1.3
Randomisation and trial product administration (visit 2)
Eligible subjects will be randomised into one of 5 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 must be performed before administration of first dose of trial product. Blood 
samples should be taken after randomisation session since semaglutide antibodies are not applicable 
for subjects randomised to liraglutide.
Trial products (see Section 9) will be dispensed to the subject by the site, hospital pharmacy or 
equivalent at each site visit during the trial from randomisation to last visit before the End-of-
treatment visit (see Section 2). The investigator must document that subjects are trained in the 
dosing instructions at every dispensing visit, please see Section 5.3.1.
For the subjects randomised to liraglutide, the investigator must instruct the subject to escalate the 
dose of liraglutide from 0.3 mg once-daily to 0.6 mg once-daily after the first week of treatment and 
to 0.9 mg once daily after the second week of treatment. 
Date of first administration of trial product will be captured in the eCRF.
8.1.4
Phone contacts after randomisation (P3)
The planned phone contact (P3) should be conducted 2 weeks (±3 days) after randomisation (see 
Section 2).
For the subjects randomised to liraglutide, at P3, the investigator should follow-up to ensure the 
dose escalation that should be done by subject.
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8.1.5
End-of-treatment (visit 12) and Follow-up (visit 13)
Subjects, who stay on trial product throughout the trial, must attend the End-of-treatment visit (visit 
12) 52 weeks after randomisation (±3 days visit window) and the Follow-up visit (visit 13) 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 12 (see Section 10).
In case the subject cannot be reached (by clinic visit or phone contact) at the scheduled visit 13, the 
site should consult the contacts provided by the subject (e.g. close relatives), relevant physicians
and medical records to collect health status. If no health status can be collected, the subject should 
be considered lost to follow-up and this should be specified in the end-of-trial form. 
8.1.6
Premature discontinuation of trial product and follow-up (visits 12A and 13A)
Subjects, who discontinue trial product prematurely, should attend visit 12A scheduled to take place 
on the day of discontinuation of trial product (+ 3 days visit window). Visit 13A should be 
scheduled 5 weeks (+3 days visit window) after the last date on trial product. The primary reason 
for premature discontinuation of trial product must be specified in the end-of-trial form in the eCRF, 
and final drug accountability must be performed. A treatment discontinuation session must be made 
in the IWRS at visit 12A (see Section 10).
If premature discontinuation of trial product is decided during a scheduled visit, the visit will be 
converted into a visit 12A and trial procedures must be performed accordingly.
Subjects should continue with the originally scheduled site contacts after visit 13A and up to and 
including visit 12. If necessary, in order to retain the subject in the trial, site visits can be replaced 
by phone contacts after visit 13A. However, as a minimum, these subjects should be asked to attend 
the scheduled visit 8 at week 26 and end-of-treatment (visit 12) at week 52 as these visits should be 
performed for all subjects, if at all possible (except subjects who withdraw informed consent, see 
Section 8.1.7).
Subjects, who only agree to attend or provide health status at the planned visit 12, should not be 
considered withdrawn from the trial. In case the subject cannot be reached (by clinic visit or phone 
contact) at the scheduled visit 12, the site should consult the contacts provided by the subject (e.g. 
close relatives), relevant physicians and medical records to collect health status. If no health status 
can be collected, the subject should be considered lost to follow-up and this should be specified in 
the end-of-trial form. 
In summary, subjects should stay in the trial irrespective of lack of adherence to randomised 
treatment, lack of adherence to visit schedule, missing assessments or trial product discontinuation 
for any reason. Only subjects who decline any further contact with the site in relation to the trial 
should be considered as withdrawn from the trial (for withdrawal procedures, see Section 8.1.7). 
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8.1.7
Withdrawals
If a subject considers withdrawing from the trial, the investigator must aim to undertake procedures 
for visit 12A as soon as possible and visit 13A 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. The case book must be signed. 
Although a subject is not obliged to give his/her reason(s) for withdrawing consent, the investigator 
must make a reasonable effort to ascertain the reason(s), while fully respecting the subject’s rights. 
Where the reasons are obtained, the primary reason for withdrawing consent must be specified in 
the end-of-trial form in the eCRF.
8.1.8
Investigator assessments
Review of diaries, PROs, laboratory reports, ECGs and fundus photography/dilated fundoscopy
must be documented either on the documents or in the subject’s medical record.
If clarification of entries or discrepancies in the diary or PROs is needed, the subject must be 
questioned and a conclusion made in the subject’s medical record. Care must be taken not to bias 
the subject.
The documents must be retained at the site as source documentation.
For ECGs, physical examinations and eye examinations, the evaluations must follow the categories:
!
Normal
!
Abnormal
–
Was the result clinically significant? (yes/no)
The evaluation should be based on investigator’s judgement.
For laboratory report values outside the reference range, the investigator must specify whether the 
value is clinically significant or not clinically significant. All laboratory printouts must be signed 
and dated by the investigator prior to the following visit. The signed laboratory report is retained at 
the site as source documentation.
In case of abnormal clinically significant findings found as a result of screening procedures 
conducted at V1 or assessments revealing baseline conditions at V2, the investigator must state a 
comment in the subject’s medical record and record this in the medical history/concomitant illness 
form in the eCRF. 
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The Investigator or his/her delegate must collect and review the PROs and diaries for completeness 
and to ensure that AEs are reported. 
8.2
Subject related information/assessments 
8.2.1
Demography
Demography will be recorded in the eCRF at screening and consists of:
!
Date of birth
!
Sex
!
Ethnicity
!
Race
8.2.2
Diabetes history and diabetes complications 
Diabetes history and diabetes complications will be recorded on a disease specific form at screening 
and consists of:
!
Date of diagnosis of T2DM
!
Information regarding diabetes complications including date of onset
–
Diabetic retinopathy
–
Diabetic neuropathy
–
Diabetic nephropathy
Please note that macroangiopathy (including peripheral arterial disease) should be reported on the 
disease specific form History of cardiovascular disease (CVD) (see Section 8.2.3).
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 or other trial procedures performed before exposure to trial product. 
Medical history is a medical event that the subject has experienced in the past. Only relevant 
medical history as judged by the investigator should be reported.
The information collected for concomitant illness and medical history should include diagnosis, 
date of onset and date of resolution or continuation, as applicable.
The following must be recorded in the eCRF on the disease specific forms only, i.e. not on the 
medical history/concomitant illness form:
!
History of CVD (e.g. ischaemic heart disease, myocardial infarction [MI], heart failure incl. 
NYHA class, hypertension, stroke, peripheral arterial disease)
!
History of gallbladder disease (e.g. gallstone, cholecystitis, cholecystectomy)
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!
History of gastrointestinal disease (e.g. gastroesophageal reflux disease, ulcer disease, chronic 
gastritis)
Any change to a concomitant illness should be recorded during the trial. A clinically significant
worsening of a concomitant illness must be reported as an AE (see Section 12).
It must be possible to verify the subject’s medical history in source documents such as subject’s 
medical record. If a subject is not from the investigators own practice; the investigator must make 
reasonable effort to obtain a copy of subject’s medical record from relevant party e.g. primary 
physician. The investigator must document any attempt to obtain external medical information by 
noting the date(s) when information was requested and who has been contacted.
8.2.4
Concomitant medication
A concomitant medication is any medication, other than the trial product(s), which is taken during 
the trial, including the screening and follow-up periods.
For subjects previously treated with OAD as monotherapy, this OAD information must be recorded 
in the concomitant medication form in eCRF.
Details of any concomitant medication must be recorded at the first visit. Changes in concomitant 
medication must be recorded at each visit as they occur. 
The information collected for each concomitant medication includes:
!
trade name or generic name
!
indication
!
start date and stop date or continuation
!
only applicable for anti-diabetic medication :start date of current dose and total daily dose
If a change is due to an AE, then this must be reported according to Section 12. If the change 
influences the subject’s eligibility to continue in the trial, the monitor must be informed.
8.2.5
Childbearing potential
It must be recorded in the eCRF whether female subjects are of childbearing potential. 
Pregnancy testing must be performed on female subjects of childbearing potential as described in 
Section 8.4.7. Female subjects of childbearing potential must be instructed to use adequate 
contraceptive method throughout the trial and until 5 weeks after end of treatment. Adequate 
contraceptive measures are abstinence (not having sex), diaphragm, condom (by the partner), 
intrauterine device, sponge, spermicide or oral contraceptives.
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Female of non-childbearing potential is defined as:
!
Female who has undergone a hysterectomy, bilateral oophorectomy or bilateral tubal ligation 
!
Postmenopausal defined as no menses for 12 months without an alternative medical cause
!
Other medical reasons preventing childbearing potential
8.2.6
Tobacco use
Details of tobacco use must be recorded at V1. Smoking is defined as smoking at least one cigarette 
or equivalent daily. 
Smoking status:
!
Never smoked
!
Previous smoker, smoking stop date
!
Current smoker
8.3
Efficacy assessments
8.3.1
Laboratory assessments for efficacy
For overall laboratory process see Section 8.5.
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 (for fasting 
see Section 8.1.2):
Glucose metabolism:
!
HbA1c
!
FPG
!
Fasting insulin
!
Fasting C-peptide
!
Fasting glucagon
!
Fasting pro-insulin
Fasting lipid profile:
!
Total cholesterol
!
LDL-cholesterol
!
HDL-cholesterol
!
VLDL-cholesterol
!
Free fatty acids
!
Triglycerides
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8.3.1.1
Fasting plasma glucose
FPG is measured at the central laboratory in order to evaluate glycaemic control. The subject must 
attend these visits fasting (see Section 8.1.2).
A central FPG result ≤ 3.9 mmol/L (70 mg/dL) in relation to planned fasting visits should not be 
reported as a hypoglycaemic episode but as a clinical laboratory adverse event (CLAE) at the 
discretion of the investigator (see Section 12.1.1).
8.3.2
Self-measured plasma glucose (SMPG)
At visit 1, subjects will be provided with a blood glucose meter (BG meter) including auxiliaries as 
well as instructions for use. The subjects will be instructed in how to use the device and the 
instruction will be repeated as necessary during the trial. The provided BG meter should be used for 
SMPG measurement.
The BG meters use test strips calibrated to plasma values. Therefore, all measurements performed 
with capillary blood are automatically calibrated to plasma equivalent glucose values, which will be 
shown on the display. 
Only the BG meter provided by Novo Nordisk or the same model purchased by the trial site should 
be used for the measurements required in the protocol. 
Subjects should be instructed in how to record the results of the SMPG values in the diaries. The 
record of each SMPG value should include date, time and value. All data from the diary must be 
transcribed into the eCRF during or following the contact. If obtained via phone and a discrepancy 
is later detected, between the diary and the SMPG data obtained at the phone contact, the values in 
the eCRF must be corrected.
Occasional review by the investigator of the values stored in the memory of the BG meter and 
correct reporting of these in the diary is advised in order to ensure adequacy of the data reported in 
the trial database. 
7-point self-measured plasma glucose profile
The subject will be instructed to perform a 7-point SMPG profile 3 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 
SMPG profile should preferably be taken within a week prior to the visit.
The record of each SMPG measurement should include the following seven time points:
!
before breakfast
!
90 minutes after start of breakfast
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!
before lunch
!
90 minutes after start of lunch
!
before dinner
!
90 minutes after start of dinner
!
at bedtime
8.3.3
Body weight and height
Body weight must be measured and recorded in the eCRF in kilogram (kg), 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 and recorded in the eCRF to nearest ½ cm.
8.3.4
Waist circumference
The waist circumference is defined as the minimal abdominal circumference located midway 
between the lower rib margin and the iliac crest.
The measurement of waist circumference must be performed and recorded in the eCRF. Waist 
circumference is measured in the horizontal plane and rounded up or down to the nearest ½ cm 
using a non-stretchable measuring tape. The same measuring tape should be used throughout the 
trial.
The circumference should be measured when the subject is in a standing position, with an empty 
bladder and wearing light clothing. The subject should be standing, feet together with arms down 
their side and waist accessible. The tape should touch the skin but not compress soft tissue and 
twists in the tape should be avoided. The subject should be asked to breathe normally and the 
measurement should be taken when the subject is breathing out gently.
8.3.5
Patient reported outcomes questionnaires
PRO will be assessed using the questionnaires:
!
SF-36v2™ (acute version) health survey35,36,37
!
Diabetes Therapy-Related QOL (DTR-QOL) questionnaire38
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 15 minutes to 
complete the two questionnaires. Subjects should be given the opportunity to complete the 
questionnaires by themselves without interruption. The completed questionnaires must be reviewed 
for potential AEs and missing data while the subject is still at the site. All results from the  
questionnaires must be transferred into the eCRF.
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SF-36 acute version
SF-36v2™ is a commonly used instrument to evaluate PROs, also in the T2DM area.
SF-36v2™ acute version measures the individual overall health related quality of life on 8 domains; 
Physical functioning, Role physical, Bodily pain, General health, Vitality, Social functioning, Role 
emotional and Mental health. The acute version’s questions are based on a recall period of one 
week. SF-36v2™ contains 36 items.
SF-36v2™ will be translated to Japanese, and also be linguistically validated before being handed 
out to the subjects participating in the trial.
Diabetes Therapy-Related QOL (DTR-QOL) questionnaire
DTR-QOL is a Japanese questionnaire.
DTR-QOL assesses the influence of diabetes treatment on the individual health related quality of 
life on 4 domains: “burden on social activities and daily activities”, “anxiety and dissatisfaction 
with treatment”, “hypoglycemia” and “satisfaction with treatment”. DTR-QOL contains 29 items.
8.4
Safety assessments  
8.4.1
Adverse events
Adverse events (AEs) must be reported at each visit in accordance with the procedures outlined in 
Section 12 and appendix B.
8.4.1.1
Medication error
If a medication error is observed during the trial, the following information is required and a 
specific event form must be completed in the eCRF in addition to the AE form (see Sections
8.4.1.2, 12.1.5 and appendix B): 
!
Trial product(s) involved 
!
Classification of medication error
!
Whether the subject experienced any hypoglycaemic episode and/or AE(s) as a result of the 
medication error 
!
Suspected primary reason for the medication error 
For definition of medication errors, see Section 12.1.4 and appendix B.
8.4.1.2
Adverse events requiring additional data collection
For the following AEs additional data collection is required and specific event forms must be 
completed in the eCRF in addition to the AE form:
!
Acute coronary syndrome (MI or unstable angina pectoris requiring hospitalisation)
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!
Cerebrovascular event (stroke or transient ischaemic attack[TIA])
!
Heart failure 
!
Pancreatitis
!
Neoplasm (excluding thyroid neoplasm)
!
Thyroid disease (including thyroid neoplasm)
!
Renal event
!
Hypersensitivity reaction
!
Acute gallstone disease
!
Medication error
!
Lactic acidosis
!
Creatine kinase (CK) > 10x UNL
!
Hepatic event defined as:
–
ALT or aspartate aminotransferase (AST) > 5x UNL and total bilirubin ≤ 2x UNL
–
ALT or AST > 3x UNL and total bilirubin > 2x UNL*
–
Hepatic event leading to trial product discontinuation.
*Please note that in case of a hepatic event defined as ALT or AST >3 x UNL and total bilirubin >2 
x UNL, where no alternative aetiology exists (Hy's law), this must be reported as an SAE using the 
important medical event criterion if no other seriousness criteria are applicable.
See Section 12 and appendix B for details about the additional information to report. 
Note that additional assessments will be required according to appendix B in case of: 
!
suspicion of acute pancreatitis
!
suspicion of hypersensitivity reaction
!
increased levels of CK
!
increased levels of aminotransferases
In case any of these events fulfil the criteria for a SAE, please report accordingly, see Section 12.
8.4.2
Physical examination
A physical examination will be performed by the investigator according to local procedure (see 
Sections 2 and 8.1.8). A physical examination must include:
!
General appearance
!
Head, ears, eyes, nose, throat, neck
!
Thyroid gland
!
Respiratory system
!
Cardiovascular system
!
Gastrointestinal system including mouth
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!
Musculoskeletal system
!
Central and peripheral nervous system
!
Skin
!
Lymph node palpation
8.4.3
Vital signs
Systolic and diastolic blood pressure
Systolic and diastolic blood pressure should be measured in a sitting position after the subject has 
been resting for at least 5 minutes and by using the standard clinical practice at the site. The data 
must be recorded in the eCRF. The actual value of the blood pressure measurement should be 
recorded in the eCRF (without rounding). The same equipment should be used throughout the trial.
Pulse
Pulse (beats per minute) must be recorded in the eCRF at site visits after resting for 5 minutes in a 
sitting position.
8.4.4
Eye examination 
Fundus photography or dilated fundoscopy will be performed as per flow chart (see Section 2) by 
the investigator or according to local practise. Results of the fundus photography or dilated 
fundoscopy will be interpreted by the investigator (see Section 8.1.8).
If fundus photography or dilated fundoscopy has been performed within 90 days prior to 
randomisation, the procedure does not need to be repeated at visit 1, unless worsening of visual 
function since the last examination. The results must be available prior to randomisation.
If the fundus photography or dilated fundoscopy is performed before the subject has signed the 
informed consent form, it must be documented in the medical records that the reason for performing 
the procedure was not related to this trial.
8.4.5
Electrocardiogram (12-lead)
12-lead ECG will be performed as per flowchart (see Section 2) and the assessment must be 
reviewed as described in Section 8.1.8 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 MI, the investigator will be 
notified. The investigator should consider if an update of the History of CVD form is required.
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If the central ECG evaluation of a post-baseline ECG is suggestive of new MI, the investigator will 
be notified and a confirmatory ECG should be performed. Unless already done, the investigator 
should report this as an AE or a SAE at investigator’s discretion and according to Section 12. 
Additional ECG recordings can be performed at the investigator’s site at investigator’s discretion at 
other visits than the planned ECG visits. All these ECGs will undergo central assessment. The 
reason for additional ECG assessments should be documented and an AE should be reported if 
applicable.
All findings suggestive of new MI detected by the central ECG reading will be adjudicated by the 
event adjudication committee (EAC) (see Section 12.7.2).
8.4.6
Laboratory assessments for safety
For overall laboratory process see Section 8.5.
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:
Haematology:
!
Haemoglobin
!
Haematocrit
!
Leucocytes
!
Thrombocytes
!
Differential count (eosinophils, neutrophils, basophils, lymphocytes and monocytes)
Biochemistry: 
!
ALT
!
Albumin
!
Alkaline phosphatase (ALP)
!
Amylase
!
AST
!
Bilirubin, total
!
Calcium, total
!
Creatinine 
!
eGFR per CKD-EPI39
!
CK
!
Lipase
!
Potassium
!
Sodium
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!
Urea
Hormones:
!
Calcitonin
In case any calcitonin value at any time during the trial is ≥ 10 ng/L, the algorithm in appendix A 
must be followed.
8.4.7
Pregnancy testing
Females of childbearing potential will have a urine dip-stick pregnancy test performed at site as 
specified in Section 2. For definition of female of non-childbearing potential and contraceptive 
methods, see Section 8.2.5.
In case a menstrual period is missed or if pregnancy is suspected between the scheduled visits, a 
urine pregnancy test should be performed. Investigator should instruct the subject to contact the site 
in case the pregnancy test is positive. Females of childbearing potential will be provided with urine 
dip-sticks for pregnancy test at home.
8.4.8
Anti-semaglutide antibodies
Samples of anti-semaglutide antibodies are taken only for subjects randomised to oral 
semaglutide/placebo treatment.
Blood samples will be drawn for measurement of antibodies against 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 binding 
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.
At randomisation, the antibody sampling must be done pre-dose. 
The special laboratory responsible for anti-semaglutide antibodies will be provided with the 
randomization list and only samples from subjects treated with oral semaglutide will be analysed for 
anti-semaglutide antibodies.
Antibody samples will be stored as described in Section 24.2.
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8.4.9
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) and/or symptoms have been resolved in 
accordance to current guidelines40.
A SMPG value ≤3.9 mmol/L (70 mg/dL) or hypoglycaemic symptoms must trigger a 
hypoglycaemic episode form to be completed by the subject. Repeated SMPG measurements and/or 
symptoms will per default be considered as one hypoglycaemic episode until a succeeding SMPG 
value is >3.9 mmol/L (70 mg/dL) and/or symptoms have been resolved. One hypoglycaemic 
episode form is to cover these measurements and/or symptoms.
In case of several low SMPG values within the hypoglycaemic episode, the lowest value is the one 
that will be reported as the SMPG value for the hypoglycaemic episode but the start time of the 
episode will remain as the time for the first SMPG value and/or symptom.
The record should include the following information:
!
Start date and time of the hypoglycaemic episode 
!
Stop date and time of the hypoglycaemic episode (stop time is the first time the PG value is >3.9 
mmol/L [70 mg/dL] and/or symptoms have been resolved).
If a stop date and time is not reported, a hypoglycaemic episode will cover a period of 60 
minutes.
!
The PG level before treating the episode (if available) and any follow-up measurements. 
The lowest value measured during the hypoglycaemic episode will be reported as the PG value 
for the episode, the remaining values will be kept as source data in the diary.
!
Whether the episode was symptomatic (Yes/No)
A hypoglycaemic episode starting without symptoms should be updated to symptomatic if the 
subject experiences symptoms later during the episode. 
!
Whether the subject was able to treat him/herself
If the severity of a hypoglycaemic episode aggravates, only one hypoglycaemic episode should 
be reported, reflecting the most severe degree of hypoglycaemia. 
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!
For oral semaglutide and placebo: Date and time of last trial product administration prior to the 
episode
!
For liraglutide or selected anti-diabetes medication: Date, time and dose of last medication
administered prior to the episode 
!
Date and time of last main meal (not including snacks) prior to the episode
!
Whether the episode occurred in relation to physical activity
!
Change in any concomitant illness
!
Any sign of fever and/or other acute disease 
!
Whether the subject was asleep when the episode occurred
–
If yes, whether the symptoms of the episode woke up the subject
The answer to the question: "Was the subject able to treat him/herself?" must be answered "No" for 
an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or 
take other corrective actions. PG concentrations may not be available during an event, but 
neurological recovery following the return of PG to normal is considered sufficient evidence that 
the event was induced by a low PG concentration40. 
Oral carbohydrates must not be given if the subject is unconscious.
If the question "Was the subject able to treat him/herself?" is answered "No", the following 
information should be recorded by the subject:
!
Who assisted in the treatment of the hypoglycaemic episode (i.e. medical person or non-medical 
person)?
!
Where the treatment was administered (in clinic/emergency room/hospital or other. If the 
subject was treated in clinic/emergency room/hospital, whether they were transported in an 
ambulance or not)
!
Type of treatment provided by another person (i.e. oral carbohydrates, glucagon, IV glucose or 
other)
!
Were symptoms alleviated after administration of treatment?
!
Factors contributing to the episode (i.e. physical activity, missed meal, diet change, medication 
error (i.e. overdose, mix-up between products, incorrect use of device), other factors not listed 
or unknown)
!
Did the subject experience seizure?
!
Was the subject unconscious/comatose?
!
Did the subject experience any of the following symptoms?41
–
Autonomic: sweating, trembling, hunger or palpitations (rapid or irregular heart beat)
–
Neuroglycopenic: confusion, drowsiness, speech difficulty, visual disturbances, odd 
behaviour, impaired balance or incoordination (reduced ability to coordinate movement)
–
General malaise: headache or malaise (feeling discomfort/unease)
!
Other symptoms
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The investigator must review the diary 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 start date, SMPG value and whether the subject was able to self-
treat due to decreased validity of such data42,43.
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.
8.5
Laboratory assessments
The laboratory analyses will mainly be performed by a central laboratory. Anti-semaglutide 
antibodies, in vitro neutralising effect to semaglutide and GLP-1, IgE anti-semaglutide antibodies
and semaglutide plasma concentration will be analysed by a special laboratory and Novo Nordisk 
A/S (see Sections 8.4.8 and 8.6.1). For some of the analyses related to suspicion of acute 
pancreatitis and hypersensitivity, a local laboratory must be used (see appendix B).
The handling, transportation and storage of biological samples are described in the laboratory 
manual (for central 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 ongoing basis. 
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).
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The laboratory provides results to the trial sites in the units preferred by the trial sites while the 
results that are transferred to the trial database will always be in SI units.
The laboratory equipment may provide analyses not requested in the protocol but produced 
automatically in connection with the requested analyses according to specifications in the laboratory 
standard operating procedures. Such data will not be transferred to the trial database, but abnormal 
values will be reported to the investigator. The investigator must review all laboratory results for 
concomitant illnesses and AEs and report these according to Section 8.2.3 and Section 12.
Laboratory samples will be destroyed at the latest at the completion of the CTR except samples 
obtained for antibody analysis. Antibody samples will be stored as described in Section 24.2.
8.6
Other assessments
8.6.1
Pharmacokinetics
Samples for PK of semaglutide are taken only for subjects randomised to oral semaglutide/placebo 
treatment. 
Blood samples will be drawn for assessment of plasma concentration of semaglutide at selected
visits (see Section 2). The semaglutide concentrations will be used for population PK analysis. 
Samples for PK analysis will be drawn at any time during the visit except for V8. At V8, samples 
should be taken pre-dose and 60−90 minutes post dosing.
The date and time of the latest trial product administration prior to the sampling for PK analysis
must be recorded and transcribed into the eCRF. The exact date and time for sampling the blood for 
PK analysis must be recorded on the lab requisition form.
Blood samples for PK analysis must be collected, handled and shipped according to the description 
in the laboratory manual supplied by the central laboratory (see attachment I).
The special laboratory responsible for PK will be provided with the randomisation list and only 
samples from subjects treated with oral semaglutide will be analysed for semaglutide plasma 
concentrations. Semaglutide PK samples will be stored at the special laboratory responsible for PK 
until final CTR in case Novo Nordisk requests further analysis of the PK samples.
8.6.2
Subject diary
The diaries should be handed out at the visits described in the flow chart Section 2. The recordings 
must be reviewed as described in Section 8.1.8 and transcribed to the eCRF at the following visit.
Entries in the diaries are only to be made by the subject, unless otherwise specified.
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The investigator should instruct the subject in recording the following data in the diary:
!
SMPG taken at pre-breakfast (fasting state) and at any points (if necessary) during wash-out 
period (for subjects treated with OAD as monotherapy prior to screening only)
!
date of first trial product administration
!
hypoglycaemic episodes
!
changes in concomitant medication
!
AEs
!
7-point SMPG profile
!
date and time of last trial product administration prior to visits with PK sampling (for subjects 
randomised to oral semaglutide/placebo treatment only)
8.6.3
Training in the pen-injector for liraglutide
An prefilled pen-injector is used for s.c. administration of liraglutide. The subjects must be trained 
in how to handle the pen-injector when handed out the first time. Training should be repeated 
during the trial at regular intervals in order to ensure correct use of the pen-injector. The following 
should be emphasised:
!
Always use a new needle for each injection as this will prevent contamination and blocked 
needles
!
Priming the pen to ensure product flow 
!
The needle should be kept in the skin while counting slowly to 6 (or as described in the 
direction for use [DFU]) after the dose counter has returned to zero after injection. If the needle 
is removed too early then the full dose may not have been delivered. Always remove the needle 
after each injection and store the pen-injector with no needle attached.
The investigator must document that direction for use is given to the subject verbally and in writing 
at the first dispensing visit (visit 2) (see Section 9.2) and at subsequent visits when judged necessary 
by the investigator.
8.7
Subject compliance
Throughout the trial, the investigator will remind the subjects to follow the trial procedures and 
requirements to ensure subject compliance. 
Treatment compliance: Will be assessed by monitoring of drug accountability. Prior to visits 
where drug accountability is performed, the subject will be asked to return all used, partly used and 
unused trial products. The investigator must assess the amount of trial products returned compared 
to what was dispensed at the last dispensing visit and, in case of discrepancies, question the subject.
If a subject is found to be non-compliant, the investigator will remind the subject of the importance 
of following the instructions given including taking the trial products as prescribed and should 
document this discussion in the subject’s medical 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.
Liraglutide must only be used, if it appears clear and colourless or almost colourless. 
9.1
Trial products
The following trial products are considered as investigational medicinal products (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
Dosepacka
Semaglutide 7 mg tablet
7 mg
Semaglutide 14 mg tablet
14 mg
Placebo tablet
N/A
Liraglutide
6 mg/mL
Solution for 
injection
s.c.
Pen-injector
a One dosepack contains one blister card with 7 tablets
Rescue medication is considered NIMPs and will not be supplied by Novo Nordisk. However, 
during the treatment period, all anti-diabetic medication including rescue medication will be 
reimbursed by Novo Nordisk Japan according to the local requirement.
For semaglutide tablets the active drug and the corresponding placebo are identical with regard to 
visual appearance. Furthermore, all semaglutide tablets are visually identical to each other, 
irrespective of the dose levels
9.2
Labelling
The trial products will be labelled in accordance with Annex 1344, local regulations and trial 
requirements.
Each trial site will be supplied with sufficient trial products for the trial on an on-going basis 
controlled by the IWRS. Trial product will be distributed to the trial sites according to enrolment 
and randomisation. 
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The investigator must document that direction for use is given to the subject verbally and in writing 
at the first dispensing visit (visit 2). Direction for use should be given to the subject at subsequent 
visits when judged necessary by the investigator. 
The subjects allocated to liraglutide must be trained in how to handle the pen-injector when handed 
out the first time. Training should be repeated during the trial at regular intervals in order to ensure 
correct use of the pen-injector.
9.3
Storage 
Storage conditions of the trial products are outlined in Table 9–2.
Table 9–2
Storage conditions
Trial product
Storage conditions
(not-in-use)
In-use conditions
In-use time
Semaglutide 3 mg tablet
Do not store above 
30ºC 
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
N/A
Semaglutide 7 mg tablet
Semaglutide 14 mg tablet
Placebo tablet
Liraglutide 6 mg/mL
Store in a refrigerator
2°C to 8°C
Protect from light
Do not freeze
At temperatures below 
30°C or in a 
refrigerator 2°C to 8°C
Protect from light
Do not freeze
Use within one 
montha
a In-use time starts when first dose is taken out of the refrigerator at subjects’ home.
The head of the study site and/or the trial product storage manager (if assigned by the head of the 
study site) must ensure that trial product is kept under proper storage conditions and record and 
evaluate the temperature. The head of the study site and/or the trial product storage manager must 
inform Novo Nordisk immediately if any trial product has been stored outside specified conditions 
(e.g. outside temperature range). Additional details regarding handling of temperature deviations 
can be found in the TMM.
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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 head of the study site and/or the 
trial product storage manager must take appropriate action to ensure correct storage.
9.4
Drug accountability and destruction
Drug accountability of all trial products received at site is the responsibility of the head of the study 
site and/or the trial product storage manager.
Subjects must be instructed to return all used, partly used and unused trial products including empty 
packaging material at each dispensing visit.
Returned trial product (used/partly used and/or unused), expired or damaged trial product can be 
stored at room temperature and must be stored separately from non-allocated trial product.
Non-allocated trial products including expired or damaged products must be accounted as unused at 
the latest at closure of the trial site.
Drug accountability is performed by using the IWRS. Drug accountability must be done on tablet 
level for semaglutide and placebo and pen level for liraglutide.
Destruction of trial products can be performed on an on-going basis and will be done according to 
local procedures after accountability is finalised and reconciled by the monitor. Destruction of 
products must be documented in the IWRS.
9.5
Auxiliary supplies
The following will be provided by Novo Nordisk in accordance with the TMM.
!
DFU for liraglutide pen-injector
The following will also be provided by Novo Nordisk Pharma Ltd. The trial sites are allowed to 
purchase and supply themselves with auxiliary supplies except for needles, if possible. BG meters 
and test strips must be the same model as supplied by Novo Nordisk.
!
Needles for pen-injector
!
BG meter and BG meter auxiliaries
Only needles provided by Novo Nordisk must be used for administration of liraglutide.
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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-blind trial with regard to three dose levels of oral semaglutide (3, 7 and 14 mg) 
and placebo, and open-label trial (between oral semaglutide/placebo arms and a liraglutide arm). A 
randomisation session will be carried out for all subjects using the IWRS.
At the randomisation visit (visit 2), subjects meeting all eligibility criteria will be randomised to one 
of five parallel treatment arms as described in Section 5.1.
Randomisation will be stratified based on pre-trial treatment (with or without OAD) at screening to 
ensure an even distribution of the 5 treatment arms within strata.
11.1
Breaking of blinded codes
Since the trial is double-blinded with regard to semaglutide and placebo, the blinded codes may 
possibly be broken for the subjects allocated to semaglutide/placebo treatment arms. The IWRS will 
notify Novo Nordisk (monitor and the Global Safety department) immediately after the code is 
broken.
The code for a particular subject allocated to oral semaglutide/placebo may be broken in a medical 
emergency if knowing the actual treatment would influence the treatment of the subject. Whenever 
a code is broken the person breaking the code must print the Code Break Confirmation Notification 
generated by the IWRS, record the reason, and sign and date the document.
When the code is broken, the treatment allocation will be accessible to the investigator and the 
Novo Nordisk Global Safety department. If IWRS is not accessible at the time of code break the 
IWRS helpdesk should be contacted. Contact details are listed in Attachment I. If the code has been 
broken, the subject must discontinue treatment with trial product but be asked to continue in the 
trial (see Section 8.1.6). A treatment discontinuation session must be completed in IWRS.
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12 Adverse events, and technical complaints and pregnancies
12.1
Definitions
12.1.1
Adverse event
An adverse event (AE) is any untoward medical occurrence in a subject administered a medicinal 
product, and which does not necessarily have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom or disease temporally associated with the use of a product, whether or not 
considered related to the product.
An AE includes:
!
A clinically significant worsening of a concomitant illness.
!
A 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 or other trial procedures 
performed before exposure to trial product (pre-existing conditions should be reported as 
medical history or concomitant illness).
!
Pre-planned procedures unless the condition for which the procedure was planned has worsened 
from the first trial related activity after the subject has signed the informed consent.
!
Non-serious hypoglycaemia is an AE, but is reported on a hypoglycaemic episode form instead 
of on an AE form, see Section 8.4.9.
The following three definitions are used when assessing an AE:
!
Severity
–
Mild – no or transient symptoms, no interference with the subject’s daily activities.
–
Moderate – marked symptoms, moderate interference with the subject’s daily activities.
–
Severe – considerable interference with the subject’s daily activities; unacceptable.
!
Causality
Relationship between an AE and the relevant trial product(s): 
–
Probable – Good reason and sufficient documentation to assume a causal relationship.
–
Possible – A causal relationship is conceivable and cannot be dismissed.
–
Unlikely – The event is most likely related to aetiology other than the trial product.
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!
Final outcome
–
Recovered/resolved – The subject has fully recovered, or by medical or surgical treatment 
the condition has returned to the level observed at the first trial-related activity after the 
subject signed the informed consent.
–
Recovering/resolving – The condition is improving and the subject is expected to recover 
from the event. This term is only applicable if the subject has completed the trial or has died 
from another AE.
–
Recovered/resolved with sequelae – The subject has recovered from the condition, but 
with lasting effect due to a disease, injury, treatment or procedure. If a sequela meets an 
SAE criterion, the AE must be reported as an SAE.
–
Not recovered/not resolved – The condition of the subject has not improved and the 
symptoms are unchanged, or the outcome is not known.
–
Fatal – This term is only applicable if the subject died from a condition related to the 
reported AE. Outcomes of other reported AEs in a subject before he/she died should be 
assessed as “recovered/resolved”, “recovering/resolving”, “recovered/resolved with 
sequelae” or “not recovered/not resolved”. An AE with fatal outcome must be reported as 
an SAE.
–
Unknown – This term is only applicable if the subject is lost to follow-up.
12.1.2
Serious adverse event
A serious adverse event (SAE) is an experience that at any dose results in any of the following:
!
Death.
!
A life-threateninga experience.
!
In-patient hospitalisationb or prolongation of existing hospitalisation.
!
A persistent or significant disability or incapacityc.
!
A congenital anomaly or birth defect.
!
Important medical events that may not result in death, be life threateninga or require 
hospitalisationb may be considered an SAE when - based on appropriate medical judgement -
they may jeopardise the subject and may require medical or surgical intervention to prevent one 
of the outcomes listed in the definition of SAEd. 
a. The term “life threatening” in the definition of SAE refers to an event in which the subject 
was at risk of death at the time of the event. It does not refer to an event which hypothetically 
might have caused death if it was more severe.
b. The term “hospitalisation” is used when a subject:
–
Is admitted to a hospital or in-patient, irrespective of the duration of physical stay, or 
–
Stays at the hospital for treatment or observation for more than 24 hours
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Medical judgement must always be exercised, and when in doubt, the hospital contact should be 
regarded as a hospitalisation. Hospitalisations for administrative, trial related and social 
purposes do not constitute AEs and should therefore not be reported as AEs or SAEs. Hospital 
admissions for surgical procedures, planned before trial inclusion, are not considered AEs or 
SAEs.
c. A substantial disruption of a subject’s ability to conduct normal life functions (e.g. following 
the event or clinical investigation the subject has significant, persistent or permanent change, 
impairment, damage or disruption in his/her body function or structure, physical activity and/or 
quality of life).
d. For example intensive treatment in an emergency room or at home of allergic bronchospasm, 
blood dyscrasia or convulsions that do not result in hospitalisation, or development of drug 
dependency or drug abuse.
The following AEs must always be reported as an SAE using the important medical event criterion 
if no other seriousness criteria are applicable:
!
suspicion of transmission of infectious agents via the trial product 
!
risk of liver injury defined as ALT or AST >3 x UNL and total bilirubin >2 x UNL, where no 
alternative aetiology exists (Hy's law).
Additional assessments should be made for events meeting the criterion of Hy’s law as stated above 
(see appendix B).
12.1.3
Non-serious adverse event
A non-serious AE is any AE which does not fulfil the definition of an SAE.
12.1.4
Medication errors
A medication error concerning trial products is defined as:
!
Administration of wrong drug or use of wrong device. 
Note: Use of wrong DUN is not considered a medication error unless it results in administration 
of wrong drug.  
!
Wrong route of administration, such as intramuscular instead of s.c..
!
Administration of an overdose with the intention to cause harm (e.g. suicide attempt), misuse or 
abuse of trial product.
!
Accidental administration of a higher dose than intended. A higher dose is a dose of at least one 
tablet more than the intended dose and for pen injection a higher dose than 0.9 mg/day; however, 
the administered dose must deviate from the intended dose to an extent where clinical 
consequences for the trial subject were likely to happen as judged by the investigator, although 
they did not necessarily occur.
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Medication errors must be reported on an AE form and a specific event form, see Sections 8.4.1.1, 
12.1.5 and appendix B.
12.1.5
Adverse events requiring additional data collection
AEs requiring additional data collection are AEs where the additional data will benefit the 
evaluation of the product safety. A number of AEs that always require additional data collection 
have been pre-specified. See appendix B for details about these events and the additional 
information to report.
Some events in this trial will be adjudicated by an independent external committee as described in 
Section 12.7.2.
Table 12–1 lists AEs that require completion of specific event forms in the eCRFs and/or are 
subject to event adjudication.
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Table 12–1
Adverse events requiring completion of specific event forms and/or are subject 
to event adjudication
Event
Specific event form
Event adjudication
Death
No
Yes
Acute coronary syndrome (MI or unstable angina
pectoris requiring hospitalisation)
Yes
Yes
Cerebrovascular event (stroke or TIA)
Yes
Yes
Heart failure 
Yes
Yes (only if requiring 
hospitalisation)
Pancreatitis
Yes
Yes (only if acute pancreatitis)
Neoplasm (excluding thyroid neoplasm)
Yes
Yes (only if malignant)
Thyroid disease (including thyroid neoplasm)
Yes
Yes (only if malignant thyroid 
neoplasm or C-cell hyperplasia)
Renal event
Yes
Yes (only if acute kidney injury)
Hypersensitivity reaction
Yes
No
Acute gallstone disease
Yes
No
Medication error
Yes
No
Lactic acidosis
Yes
Yes
CK > 10x UNL
Yes
No
Hepatic event defined as:
ALT or AST > 5x UNL and total bilirubin ≤ 2x UNL
ALT or AST > 3x UNL and total bilirubin > 2x UNL*
Hepatic event leading to trial product discontinuation.
Yes
No
* Please note that in case of a hepatic event defined as ALT orAST > 3 x UNL and total bilirubin > 2 x UNL, where no 
alternative aetiology exists (Hy's law), this must be reported as an SAE using the important medical event criterion if no 
other seriousness criteria are applicable.
For details about specific event forms, see Sections 8.4.1.2, 12.2 and appendix B.
12.1.6
Technical complaints
A technical complaint is any written, electronic, or oral communication that alleges product 
(medicine or device) defects. The technical complaint may be associated with an AE, but does not 
concern the AE itself.
Examples of technical complaints:
!
The physical or chemical appearance of trial products (e.g. discoloration, particles or 
contamination)
!
All packaging material including labelling
!
Problems related to devices (e.g. to the injection mechanism, dose setting mechanism, push 
button or interface between the pen and the needle) 
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12.2
Reporting of adverse events
All events meeting the definition of an AE must be collected and reported. This includes events 
occurring from the first trial-related activity after the subject has signed the informed consent until 
the end of the post-treatment follow-up period (V13) for subjects on trial product OR until the end 
of trial (V12 or V13A, whichever comes last) for the subjects who have discontinued trial product 
prematurely. Events for withdrawn subjects will be collected and reported until last trial related 
contact with the subject. The events must be recorded in the applicable eCRF forms in a timely 
manner, see timelines below and Figure 12–1. 
During each contact with the trial site staff, the subject must be asked about AEs and technical 
complaints, for example by asking: “Have you experienced any problems since the last contact?”
All AEs, either observed by the investigator or subject, must be reported by the investigator and 
evaluated. 
All AEs must be recorded by the investigator in the eCRF 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 in the eCRF.
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 events and the additional information to 
report. In case any of these events fulfil the criteria for seriousness in Section 12.1.2, then the event 
should be reported as serious.
Some events will undergo event adjudication by the EAC, please refer to Section 12.7.2. For AEs 
qualifying for event adjudication, the adjudication form will also have to be completed in the eCRF. 
The adjudication form is a checklist of clinical data to be provided from the site.
For an overview of AEs requiring additional data collection and AEs that will undergo event 
adjudication, please see Table 12–1.
For all non-serious AEs, the applicable forms should be signed when the event is resolved or at the 
end of the trial at the latest.
Timelines for initial reporting of AEs:
The investigator must complete the following forms in the eCRF within the specified timelines:
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!
SAEs: The AE form within 24 hours and the SIF within 5 calendar days of the investigator’s 
first knowledge of the SAE.
Both forms must be signed within 7 calendar days from the date the information was entered in 
the eCRF.
For SAEs requiring reporting on a specific event form: In addition to the above the specific 
event form within 14 calendar days from the investigator’s first knowledge of the AE.
!
Events for adjudication: The adjudication form should be completed within 14 calendar days
of the investigator’s first knowledge of the AE, see Section 12.7.2. The investigator should 
preferably provide the medical documentation within 4 weeks of event identification according 
to instructions in the event adjudication site manual.
If the eCRF is unavailable, the concerned AE information must be reported on a paper AE form and 
sent to Novo Nordisk by fax, e-mail or courier within the same timelines as stated above. When the 
eCRF becomes available again, the investigator must enter the information on the form into the 
eCRF.
Contact details (fax, telephone, e-mail and address) are provided in the investigator trial master file. 
AE identified
Does the AE require 
a specific event 
form?
Is the AE subject to 
adjudication and/or 
is the outcome 
fatal?
AE form < 24 hours
SIF < 5 calendar days
Specific event form 
For SAEs:
< 14 calendar days
Is the AE serious or 
non-serious?
AE form
Adjudication form
< 14 calendar days
Source data < 4 weeks
Non-serious
Serious
No
Yes
Yes
Queries and follow-up 
requests to be resolved 
< 14 calendar days
Timelines are for the completion of forms from the time of investigator’s awareness.
AE: Adverse event  SAE: Serious adverse event  SIF: Safety Information form 
No additional action
No additional action
No
Figure 12–1
Reporting of AEs 
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Novo Nordisk assessment of AE expectedness:
Novo Nordisk assessment of expectedness is performed according to the following reference 
documents: 
!
IB for oral semaglutide (NN9924)25; Current version and any updates thereto.
!
Company Core Data Sheet (CCDS) for liraglutide; current version and any updates thereto.
Reporting of trial product-related SUSARs by Novo Nordisk:
Novo Nordisk will notify the investigator of trial product-related suspected unexpected serious 
adverse reactions (SUSARs) in accordance with local requirements and ICH GCP1. In addition, the 
investigator will be informed of any trial-related SAEs that may warrant a change in any trial 
procedure.
In accordance with regulatory requirements, Novo Nordisk will inform the regulatory authorities, 
including European Medicines Agency (EMA), of trial product-related SUSARs. In addition, Novo 
Nordisk will inform the institutional review boards (IRBs) of trial product-related SUSARs in 
accordance with local requirement and ICH GCP1, unless locally this is an obligation of the 
investigator.
Novo Nordisk products used as concomitant medication or non-investigational medicinal 
product:
If an AE is considered to have a causal relationship with a Novo Nordisk marketed product used as 
NIMP product or concomitant medication in the trial, it is important that the suspected relationship 
is reported to Novo Nordisk, e.g. in the alternative aetiology section on the 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 
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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.
!
Events for adjudication: if new information becomes available for events in scope of 
adjudication, this must be uploaded to the adjudication database in order for the EAC to 
evaluate if re-adjudication is needed. 
The investigator must ensure that the recording of the worst case severity and seriousness of an 
event is kept throughout the trial. A worsening of an unresolved AE must be reported as follow-up 
with re-assessment of severity and/or seriousness of the event.
Queries or follow-up requests from Novo Nordisk must be responded to within 14 calendar days
from the date of receipt of the request, unless otherwise specified in the follow-up request.
SAEs after end of trial: If the investigator becomes aware of an SAE with a suspected causal 
relationship to the IMP occurring to a subject after the subject has ended the trial, the investigator 
should report this SAE within the same timelines as for SAEs during the trial. 
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 tablets
!
liraglutide 6 mg/mL, 3 mL pre-filled pen-injector
!
needles for pen-injector
which occur from the time of first usage of the product until the time of the last usage of the product, 
must be collected and reported to Customer Complaint Center, Novo Nordisk.
Contact details (fax, e-mail and address) are provided in Attachment I to the protocol.
The investigator must assess whether the technical complaint is related to any AEs and/or SAEs.
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Technical complaints must be reported on a separate technical complaint form: 
!
One technical complaint form must be completed for each affected DUN 
!
If DUN is not available, a technical complaint form for each batch, code or lot number must be 
completed 
The investigator must complete the technical complaint form in the eCRF within the following 
timelines of the trial site obtaining knowledge of the technical complaint:
!
Technical complaint assessed as related to an SAE within 24 hours
!
All other technical complaints within 5 calendar days
If the eCRF is unavailable or when reporting a technical complaint that is not subject related, the 
information must be provided on a paper form by fax, e-mail or courier to Customer Complaint 
Center, Novo Nordisk, within the same timelines as stated above. When the eCRF becomes 
available again, the investigator must enter the information on the technical complaint form in the 
eCRF.
12.4.2
Collection, storage and shipment of technical complaint samples
The investigator must collect the technical complaint sample and notify the monitor within 5 
calendar days of obtaining the sample at trial site. The monitor must coordinate the shipment to 
Customer Complaint Center, Novo Nordisk (the address is provided in Attachment I) and ensure 
that the sample is sent as soon as possible. A copy of the technical complaint form must be included 
in the shipment of the sample. If several samples are returned in one shipment, the individual 
sample and the corresponding technical complaint form must be clearly separated.
The investigator must ensure that the technical complaint sample contains the batch, code or lot 
number and, if available, the DUN. All parts of the DUN should be returned.
If the technical complaint sample is unobtainable, the investigator must specify on the technical 
complaint form why it is unobtainable. 
Storage of the technical complaint sample must be done in accordance with the conditions 
prescribed for the product.
12.5
Pregnancies
12.5.1
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).
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The investigator must follow the pregnancy until the pregnancy outcome and the newborn infant is 
one month of age.
The investigator must report information about the pregnancy, pregnancy outcome, and health of 
the newborn infant(s), as well as AEs in connection with the pregnancy, and AEs in the foetus and 
newborn infant.
The following must be collected and reported by the investigator to Novo Nordisk - electronically 
(e.g. in PDF format), or by fax or courier:
1. Reporting of pregnancy information
Information about the pregnancy and pregnancy outcome/health of the newborn infant(s) has to 
be reported on Maternal Form 1A and 1B, respectively.
When the pregnancy outcome is abnormal (i.e. congenital anomalies, foetal death including 
spontaneous abortion and/or any anomalies of the foetus observed at gross examination or 
during autopsy), and/or when a congenital anomaly is diagnosed within the first month, further 
information has to be reported for the female subject on Maternal Form 2. In addition, 
information from the male partner has to be reported on the Paternal Form, after an informed 
consent has been obtained from the male partner.
Initial reporting and follow-up information must be reported within 14 calendar days of the 
investigator’s first knowledge of initial or follow-up information.
2. Reporting of AE information
The investigator has to report AEs in connection with the pregnancy as well as in the foetus and 
newborn infant(s). The SAEs that must be reported include abnormal outcome, such as foetal 
death (including spontaneous abortion), and congenital anomalies (including those observed at 
gross examination or during autopsy of the foetus), as well as other pregnancy complications 
fulfilling the criteria of an SAE.
Forms and timelines for reporting AEs:
Non-serious AEs:
!
AE forma within 14 calendar days of the investigator’s first knowledge of the initial or 
follow-up information to the non-serious AE.
SAEs: 
!
AE forma within 24 hours of the investigator’s first knowledge of the SAE.
!
SIF within 5 calendar days of the investigator’s first knowledge of the SAE.
!
SAE follow-up information to the AE form and/or SIF within 24 hours of the investigator’s 
first knowledge of the follow-up information.
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a
It must be clearly stated in the AE diagnosis field on the AE form if the event occurred in 
the subject, foetus or newborn infant. If the AE occurred in the foetus or newborn infant, the AE 
can only be reported on paper AE form and SIF.
Any queries or follow-up requests from Novo Nordisk to non-serious AEs, SAEs and pregnancy 
forms must be responded to by the investigator within 14 calendar days from the date of receipt of 
the request, unless otherwise specified in the follow-up request.
12.6
Precautions and/or overdose with oral semaglutide
There are no specific antidotes to semaglutide. Treatment of an overdose should be symptomatic.
There is a potential risk of hypoglycaemia during dosing with semaglutide. The typical signs and 
symptoms of a non-severe hypoglycaemia include: hunger, slight headache, nausea, light-
headedness, palpitations and sweating. Symptoms of non-severe hypoglycaemia should be treated 
by ingestion of carbohydrates. 
Severe hypoglycaemia resulting in loss of consciousness should be treated according to best 
available medical practise. 
One case of accidental overdose of oral semaglutide was reported in the NN9924-3692 trial. The 
subject accidentally took the trial product 
 day and was thus treated with 20 mg of 
oral semaglutide.  The subject did not report any symptoms and treatment was continued without 
any change. 
One case of accidental overdose has been reported in subjects treated with s.c. semaglutide once 
weekly. The subject inadvertently injected  mg of semaglutide instead of 0.4 mg, which 
corresponds to a 
-fold higher dose than the maximum dose included in that trial. After 
 hours 
the subject felt nauseated, vomited and had a headache. The subject was instructed to drink 
sufficient amounts of fluids. 
 and the subject 
wished to continue in the trial. No symptoms of hypoglycaemia or any other symptoms or signs 
were noted.  
For further details please see the current edition of the IB for oral administration of semaglutide 
(NN9924), edition 7, and any updates hereof.
For liraglutide and placebo, see Sections 18.1.2 and 18.1.3, respectively.
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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 EAC is established to perform validation of selected AEs according to pre-
defined diagnostic criteria. The validation is based on review of pre-defined clinical data related to 
the specific AE. Pre-defined clinical data consist of copies of source documents collected and 
delivered by the investigational sites.
The EAC is composed of permanent members covering required medical specialities. EAC 
members must disclose any potential conflicts of interest and must be independent of Novo Nordisk. 
The events are reviewed by the EAC in a blinded manner. The EAC will have no authorisations to 
impact on trial conduct, trial protocol or amendments.
The EAC works in accordance with written guidelines included in the EAC Charter describing in 
details the composition, tasks, responsibilities and work processes of the committee.
The events outlined in Table 12–2 have been selected for adjudication in order to obtain an external 
independent validation of the diagnosis. In addition, cardiovascular events are being adjudicated 
according to U.S. Food and Drug Administration (FDA) requirements45.
The EAC will review copies in English (translated if necessary) of medical documentation received 
in the adjudication packages (e.g. x-rays, ECGs, ultrasound images, discharge summaries, 
pathology reports and death certificates). The investigator must provide medical documentation as 
soon as possible, when they receive the request from Novo Nordisk or the event adjudication 
vendor.
The AEs for adjudication are listed in Table 12–2.
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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 requiring 
hospitalisation
! Acute MI (STEMI or 
NSTEMI), silent MI
! Unstable angina pectoris 
requiring hospitalisation
Cerebrovascular event
! Episode of focal or global neurological 
dysfunction caused by brain, spinal cord, or 
retinal vascular injury as a result of 
haemorrhage or infarction
! TIA is defined as a transient episode (< 24 
hours) of focal neurological dysfunction caused 
by brain, spinal cord, or retinal ischaemia, 
without acute infarction
! Ischaemic stroke
! Haemorrhagic stroke
! Undetermined stroke
! TIA
Heart failure requiring 
hospitalisation
Hospitalisation with a primary diagnosis of heart 
failure (new episode or worsening of existing heart 
failure)
! Heart failure requiring 
hospitalisation
Acute pancreatitis
The diagnosis of acute pancreatitis requires two of 
the following three features:
! Abdominal pain consistent with acute 
pancreatitis (acute onset of a persistent, severe, 
epigastric pain often radiating to the back)
! Serum lipase activity (and/or amylase activity) 
at least three times greater than the UNL
! Characteristic findings of acute pancreatitis on 
imaging
Acute pancreatitis
! Mild
! Moderately severe
! Severe
Malignant neoplasm
Malignant neoplasms are defined as
! neoplasms in which abnormal cells divide 
without control and can invade nearby tissues 
and/or spread to other parts of the body through 
the blood and lymph systems
Thyroid neoplasms are excluded in this event 
category
! Malignant neoplasm
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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 injury46 is defined as any of the 
following (not graded):
! Increase in serum creatinine by ≥ 0.3 mg/dL 
(≥26.5 μmol/L) within 48 hours, or
! Increase in serum creatinine to ≥ 1.5 times 
baseline, which is known or presumed to have 
occurred within the prior 7 days, or
! Urine volume < 0.5 mL/kg/h for 6 hours
! Acute kidney injury
Lactic acidosis
! Lactic acidosis is characterized by increased 
blood lactate level in association with metabolic 
acidosis
! Lactic acidosis
*Death is not a separate event, but an outcome
There are different processes for capturing events for adjudication:
!
Direct reporting by investigator:
–
All AEs need to be assessed by the investigator if any AE category is applicable. If the AE 
category selected is in scope for adjudication, the event specific adjudication form in the 
eCRF will be populated for sites to complete
–
AEs with fatal outcome
!
Screening: 
–
All AEs will be screened by NN for potential missed events for adjudication and if needed, 
the investigator will be asked to provide additional information such as an alternative 
aetiology, underlying cause(s) and/or clinical details.
–
All ECGs will be centrally read. If the central reading conclusion is suggestive of new MI, 
the ECG adjudication form will be populated for sites to complete for all post-baseline 
ECGs.
!
EAC identified events:
–
The EAC can decide to have an AE adjudicated even if not initially reported as an event for 
adjudication by the investigator.
Event adjudication will be performed for AEs in randomised subjects including AEs with an onset 
date during the screening period. Event adjudication will not be performed for AEs in screening 
failures. 
AEs for adjudication must be reported according to Section 12.2. In addition the specific 
adjudication form should be completed within 14 calendar days of the investigator’s first 
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knowledge of the AE, and all relevant predefined documents provided within 4 weeks according to 
instructions in the event adjudication site manual.
The assessment made by the EAC will be included in the clinical trial report as well as the 
assessments made by the investigator. However, the adjudication made by the EAC, given its 
independent analysis of each event, will be attributed with greater importance of the two. 
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13 Case report forms 
Novo Nordisk will provide a system for the eCRFs. This system and support services to the system 
will be provided by an external supplier.
Ensure that all relevant questions are answered, and that no empty data field exists. If a test or an 
assessment has not been done and will not be available, or if the question is irrelevant (e.g. is not 
applicable), indicate this according to the data entry instructions.
The following will be provided as paper case report forms (CRFs):
!
Pregnancy forms
The following will be provided as paper CRFs to be used when access to the eCRF is revoked or if 
the eCRF is unavailable:
!
AE forms 
!
SIFs
!
Technical complaint forms (also to be used to report complaints that are not subject related [e.g. 
discovered at trial site before allocation])
On the paper CRF forms print legibly, using a ballpoint pen. Ensure that all questions are answered, 
and that no empty data blocks exist. Ensure that no information is recorded outside the data blocks. 
If a test/assessment has not been done and will not be available, indicate this by writing “ND” (not 
done) in the appropriate answer field in the CRF. If the question is irrelevant (e.g. is not applicable) 
indicate this by writing “NA” (not applicable) in the appropriate answer field. Further guidance can 
be obtained from the instructions in the CRF.
The investigator must ensure that all information is consistent with the source documentation. By 
electronically signing the case book in the eCRF, the investigator confirms that the information in 
the eCRF and related forms is complete and correct.
13.1
Corrections to case report forms 
Corrections to the eCRF data may be made by the investigator or the investigator’s delegated staff. 
An audit trail will be maintained in the eCRF application containing as a minimum: the old and the 
new data, identification of the person entering the data, date and time of the entry and reason for the 
correction.
If corrections are made by the investigator’s delegated staff after the date the investigator has signed 
the case book, the case book must be signed and dated again by the investigator.
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13.2
Case report form flow
The investigator must ensure that data is recorded in the eCRF as soon as possible, preferably 
within 5 days after the visit. Once data has been entered, it will be available to Novo Nordisk for 
data verification and validation purposes.
At the end of the trial, the investigator must ensure that all remaining data have been entered into 
the eCRF no later than 3 days after LSLV at the site in order to ensure the planned lock of the 
database.
Site specific eCRF data (in an electronic readable format) will be provided to the trial site before 
access to the eCRF is revoked. This data must be retained at the trial site. When the final CTR is 
available, the data will be archived by Novo Nordisk A/S.
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14 Monitoring procedures
During the course of the trial, the monitor will visit the trial site to ensure that the protocol is 
adhered to, that all issues have been recorded, to perform source data verification and to monitor 
drug accountability. The first monitoring visit will be performed as soon as possible after FSFV at 
the trial site and no later than 4 weeks after. The monitoring visit intervals will depend on the 
outcome of the remote monitoring of the eCRFs, the trial site's recruitment rate and the compliance
of the trial site to the protocol and GCP, but will not exceed 12 weeks until LSLV at the trial site
(for trial sites with active subjects [defined as subjects in screening, treatment or follow-up]).
The monitor must be given direct access to all source documents (original documents, data and 
records). Direct access includes permission to examine, analyse, verify and reproduce any record(s) 
and report(s) that are important to the evaluation of the trial. If the electronic medical record does 
not have a visible audit trail, the investigator must provide the monitor with signed and dated 
printouts. In addition the relevant trial site staff should be available for discussions at monitoring 
visits and between monitoring visits (e.g. by telephone).
All data must be verifiable in source documentation other than the eCRF.
For all data recorded the source document must be defined in a source document agreement at each 
trial site. There must only be one source defined at any time for any data element.
Source data generated by the trial site can be corrected by another person than the person entering 
the source data; any correction must be explained, signed and dated by the person making the 
correction.
The original of the completed diaries and/or PROs must not be removed from the trial site, unless 
they form part of the CRF/eCRF and a copy is kept at the site.
The monitor will ensure that the eCRFs are completed and that paper CRFs are collected.
The following data will be source data verified for screening failures: 
!
Date for obtaining informed consent
!
Reason for screening failure
Monitors will review the subject’s medical records and other source data (e.g. the diaries and PROs) 
to ensure consistency and/or identify omissions compared to the eCRF. If discrepancies are found, 
the investigator must be questioned about these.
A follow-up letter (paper or electronic) will be sent to the investigator following each monitoring 
visit. This should address any action to be taken.
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15 Data management
Data management is the responsibility of Novo Nordisk. Data management may be delegated under 
an agreement of transfer of responsibilities to a contract research organisation (CRO). 
Appropriate measures, including encryption of data files containing person identifiable data, will be 
used to ensure confidentiality of subject data, when they are transmitted over open networks. 
Data from central laboratories will be transferred electronically. In cases where data is transferred 
via non-secure electronic networks, data will be encrypted during transfer.
The subject and any biological material obtained from the subject will be identified by subject 
number and trial ID. Appropriate measures such as encryption or leaving out certain identifiers will 
be enforced to protect the identity of subjects in all presentations and publications as required by 
local, regional and national requirements.
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16 Computerised systems
Novo Nordisk will capture and process clinical data using computerised systems that are described 
in Novo Nordisk Standard Operating Procedures and IT architecture documentation. The use and 
control of these systems are documented.
Investigators working on the trial may use their own electronic systems to capture source data.
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17 Statistical considerations
General considerations
If necessary, a statistical analysis plan (SAP) may be written in addition to the protocol, including a 
more technical and detailed elaboration of the statistical analyses. The SAP will be finalised before 
database lock.
The blinding of the randomised treatments will be maintained until the database has been released 
for statistical analysis. No interim analyses will be performed before the database is locked.
Data from all sites will be analysed and reported together.
In statistical analyses where stratification is included, the pre-trial OAD treatment at screening 
(yes/no) will be included based on the actual information collected through the eCRF. In case of 
missing eCRF information the information collected from the IWRS system will be used. In the 
statistical analyses the stratification factor will refer to pre-trial OAD treatment at screening.
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 efficacy endpoints will be evaluated at week 26. This approach will result in a lower 
proportion of missing data, use of rescue medication and premature treatment discontinuation, 
compared to the expected proportion of missing data at week 52 and therefore considered a 
meaningful representation and confirmation of the dose-response relationship of oral semaglutide. 
Results from a statistical analysis will as a minimum be presented by the estimated treatment 
contrasts for the below six comparisons with associated two-sided 95% confidence intervals and p-
values corresponding to two-sided tests of no difference:
!
oral semaglutide 14 mg vs. placebo 
!
oral semaglutide 14 mg vs. liraglutide 0.9 mg
!
oral semaglutide 7 mg vs. placebo
!
oral semaglutide 7 mg vs. liraglutide 0.9 mg 
!
oral semaglutide 3 mg vs. placebo
!
oral semaglutide 3 mg vs. liraglutide 0.9 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-jure 
(efficacy) estimand and a secondary de-facto (effectiveness) estimand:
!
Primary estimand 
–
de-jure treatment difference (oral semaglutide versus placebo and oral semaglutide versus 
liraglutide) at week 26 in all randomised subjects if all subjects adhered to treatment and did 
not initiate rescue medication
The primary de-jure estimand assesses the expected glycaemic benefit under adherence to trial 
product and is considered the primary interest for evaluating the dose-response relationship of oral 
semaglutide. Generalisation of this estimand depends among other things on the extent to which the 
adherence to trial product administration in this trial reflects the behaviour of the target population. 
Accordingly, only data collected prior to discontinuation of trial product or initiation of rescue 
medication will be used to draw inference. This will avoid confounding from rescue medication.
!
Secondary estimand
–
de-facto treatment difference (oral semaglutide versus placebo and oral semaglutide versus 
liraglutide) at week 26 in all randomised subjects regardless of discontinuation of trial 
product or initiation of rescue medication(s)
The secondary de-facto estimand assesses the expected glycaemic benefit in a future population that 
results from subjects initiating treatment with oral semaglutide including potential rescue 
medication(s). Generalisation of this estimand depends among other things on the extent to which 
the use of rescue medication in this trial reflects clinical practice and the adherence to trial product 
administration in this trial reflects the behaviour of the target population. Accordingly, data 
collected regardless of discontinuation of trial product or initiation of rescue medication(s) will be 
used to draw inference. 
Missing data considerations
Based on the results from similar Japanese phase 3 trials investigating liraglutide and s.c. 
semaglutide as monotherapy (NN2211-1700, NN9535-4091 and NN9535-4092) and the oral 
semaglutide phase 2 trial (NN9924-3790), it is expected that maximum 30% of the subjects will 
discontinue trial product or withdrawal from the trial at week 52. 
When estimating the secondary estimand, the proportion of subject with 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 is expected to be maximum 10% based on the oral semaglutide 
phase 2 trial (NN9924-3790). Thus, missing data will mainly be due to withdrawal from trial or lost 
to follow-up.
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When estimating the primary estimand, the proportion of subject with missing data is expected to be 
higher (20%) than for the secondary estimand because data collected after discontinuation of trial 
product or initiation of rescue medication(s) will be set to missing. The proportion of subject with
missing data at week 26 is expected to be maximum 20% based on the liraglutide phase 3 trial 
(NN2211-1700), s.c. semaglutide phase 3 trials (NN9535-4091 and NN9535-4092) and the oral 
semaglutide phase 2 trial (NN9924-3790). 
Across treatment arms the main reasons for missing data are expected to be early treatment 
discontinuation due to AEs (gastrointestinal AEs for oral semaglutide and liraglutide) and initiation 
of rescue medication. Initiation of rescue medication is expected to be more frequent in the placebo 
arm than for the oral semaglutide and liraglutide arms. A higher proportion of subjects are expected 
to discontinue treatment due to AEs in the oral semaglutide and liraglutide arms, compared to the 
placebo arm. 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 total sample size of 240 subjects and duration of this trial have been determined to allow for 
adequate (i) evaluation of the dose-response relationship and (ii) safety evaluation in a monotherapy 
setting in line with the Japanese draft AD guideline27. With a maximum expected premature 
treatment discontinuation rate of 30% after week 52, this trial ensures that at least 100 subjects are 
exposed to oral semaglutide for one year.
Based on 48 subjects per treatment arm and a standard deviation of 1.1% in change from baseline to 
week 26 in HbA1c, the width of the 95% confidence interval (precision) for the mean difference in 
HbA1c will at most be +/- 0.5 %-point with 90% probability.
Furthermore, with 48 subjects per treatment arm the trial will be able to show a significant HbA1c
treatment difference of 0.74 %-point with 90% power and a treatment difference of 0.64 %-point 
with 80% power. As a reference, the assumed treatment effects (TE) and adjusted treatment effects 
are presented in Table 17–1. These are based on the oral semaglutide phase 2 results (NN9924-
3790) and supported by results from the s.c. semaglutide phase 2 trial (NN9535-1821).
The adjustment of the treatment effects are done differently when estimating the primary and the 
secondary estimand, due to the different analyses and the inclusion of data collected after treatment 
discontinuation and initiation of rescue medication for the secondary estimand. The treatment 
effects will be adjusted according to a 50% smaller effect in subjects with missing data when 
estimating the primary estimand. Whereas a 75% smaller effect will be used for the 10% of the 
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subjects who are expected to discontinue trial product or initiate rescue medication and for the 10% 
of subjects who are expected to have missing data when estimating the secondary estimand.
!
Primary estimand
–
Adjusted TE = 0.8×TE + 0.2×TE×0.50
!
Secondary estimand
–
Adjusted TE = 0.8×TE + 0.1×TE×0.25 + 0.1×TE×0.25
Table 17–1
Treatment effects in HbA1c (%-point)
Oral semaglutide 
3 mg
7 mg
14 mg
Treatment effects (TE)
0.45
0.75
1.0
Primary estimand: Adjusted TE
0.405
0.675
0.9
Secondary estimand: Adjusted TE
0.3825
0.6375
0.85
17.2
Definition of analysis sets
The following analysis sets will be defined:
Full analysis set (FAS): Includes all randomised subjects. Subjects in the FAS will contribute to 
the evaluation “as randomised”.
Safety analysis set (SAS): Includes all subjects exposed to at least one dose of trial product. 
Subjects in the SAS will contribute to the evaluation based on the trial product received for the 
majority of the period where treated. This will be referred to as contributing to the evaluation “as 
treated”.
Data selections and observation periods
Unless subjects withdraw their informed consent, data collection will continue for the full duration 
of the trial. The full duration of the trial is defined as up to and including:
!
The follow-up visit (V13) for subjects on trial product
!
The latest occurring visit of the end-of-treatment visit (V12) or the follow-up premature 
discontinuation visit (V13A), for subjects who have discontinued trial product prematurely
Subjects and data to be used in an analysis will be selected in a two-step manner:
!
Firstly, subjects will be selected based on the specified analysis set
!
Secondly, data points on the selected subjects from first step will be selected based on the 
specified observation period
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Definition of the observation periods
In-trial: This observation period represents the time period where subjects are considered to be in 
the trial, regardless of discontinuation of trial product or initiation of rescue medication. The in-trial 
observation period starts at randomisation (as registered in IWRS) and ends at the date of:
!
The last direct subject-site contact, which is scheduled to take place 5 weeks after planned last 
dose of trial product at a follow-up visit
!
Withdrawal for subjects who withdraw their informed consent
!
The last subject-investigator contact as defined by the investigator for subjects who are lost to 
follow-up
!
Death for subjects who dies before any of the above
On-treatment: This observation period represents the time period where subjects are considered 
treated with trial product. The observation period is a subset of the in-trial observation period. It 
starts at the date of first dose of trial product. Two slightly different end dates will be needed to 
cover all assessments appropriately. For adjudicated events, ECGs, anti-semaglutide antibodies and 
AEs including hypoglycaemic episodes, the observation period ends at the first date of any of the 
following:
!
The follow-up visit (V13)
!
The follow-up prematurely discontinuation visit (V13A)
!
The last date on trial product + 38 days
!
The end-date for the in-trial observation period
The follow-up visit is scheduled to take place 5 weeks after the last date on trial product 
corresponding to approximately five half-lives of oral semaglutide. The visit window for the follow-
up visit is +3 days.
For efficacy and other safety assessments (laboratory assessments, physical examination and vital 
signs) the observation period ends at the last date on trial product +3 days. This will be used in 
order to ensure specificity to reversible effects of treatment.
On-treatment without rescue medication: This observation period is a subset of the on-treatment 
observation period, where subjects are considered treated with trial product, but have not initiated 
any rescue medications. Specifically it starts at date of first dose of trial product and the observation 
period ends at the first date of:
!
The last dose of trial product +3 days
!
Initiation of rescue medication
The in-trial observation period will be the primary observation period when estimating the 
secondary estimand. The on-treatment without rescue medication observation period will be the 
primary observation period when estimating the primary estimand. The on-treatment observation 
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period will be considered supportive for evaluating efficacy. Safety will be evaluated based on the 
in-trial and the on-treatment observation periods.
Data points collected outside an observation period will be treated as missing in the analysis. 
Baseline data will always be included in an observation period. For adjudicated events, the onset 
date will be the EAC adjudicated onset date.
Before data are locked for statistical analysis and the randomisation code is broken, a review of all 
data will take place. Any decision to exclude either a subject or single observations from the 
statistical analysis is the joint responsibility of the members of the Novo Nordisk study group. 
Exclusion of data from analyses should be used restrictively, and normally no data should be 
excluded from the FAS. The subjects or observations to be excluded, and the reasons for their 
exclusion must be documented and signed by those responsible before database lock. The subjects 
and observations excluded from analysis sets, and the reason for this, will be described in the 
clinical trial report.
17.3
Primary endpoint
The primary endpoint is change from baseline to week 26 in HbA1c.
17.3.1
Analysis for the primary estimand
The primary estimand will be estimated based on the FAS using post-baseline measurements up to 
and including week 26 from the on-treatment without rescue medication observation period.
The dose-response will be evaluated by a mixed model for repeated measurements (MMRM). A 
restricted maximum likelihood 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 and stratification factor as categorical 
fixed effects and baseline HbA1c as a covariate, all nested within visit. An unstructured covariance 
matrix for HbA1c measurements within the same subject will be employed, assuming measurements 
from different subjects are independent. From this analysis estimated differences with 
corresponding two sided p-values and 95% confidence intervals after 26 weeks of treatment will be 
presented for all pairwise comparison of oral semaglutide versus placebo. In addition to the dose-
response evaluation, oral semaglutide will be compared to liraglutide 0.9 mg and estimated 
differences with corresponding two sided p-values and 95% confidence intervals after 26 weeks of 
treatment will be presented for all pairwise comparison of oral semaglutide versus liraglutide 0.9 
mg.
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 
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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.
The dose-response relationship of oral semaglutide will be supported by an exploratory analysis. In 
this model data from all oral semaglutide treatment arms will be included and data from the placebo 
arm (corresponding to a dose of zero mg) could be included if appropriate. The model will be 
developed ad hoc after unblinding of the trial to aim for a suitable fit of the dose-response 
relationship using e.g. a linear or a four-parameter logistic relation of HbA1c vs. the logarithm of the 
dose.
17.3.2
Analysis for the secondary estimand
The secondary estimand will be estimated based on the FAS using week 26 measurements from the 
in-trial observation period. The statistical analysis for the secondary estimand will be a pattern 
mixture model using multiple imputation to handle missing data assuming that the missing data 
mechanism is missing at random (MAR) within the groups used for imputation. Imputation of 
missing data at week 26 will be done within 10 groups of subjects defined by randomised treatment 
arm, and whether subjects at week 26; (i) have discontinued treatment or initiated rescue medication 
or (ii) are still on treatment and have not initiated rescue medication. It is hereby assumed that the 
likely values of what the missing data would have been if available are best described by 
information from subjects who at week 26 are similar in terms of randomised treatment arm and 
treatment adherence/rescue medication status. 
Missing values for each group will be imputed as follows:
!
An analysis of covariance (ANCOVA) with stratification factor 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 stratification factor and baseline HbA1c. Thus, 100 
complete data sets will be generated including observed and imputed values.
Analysis used for testing superiority versus placebo at week 26:
For each of the 100 (now complete) imputed data sets the change from baseline to week 26 in 
HbA1c will be analysed using an analysis of covariance (ANCOVA) with treatment 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 rule47 to draw inference.
From this analysis the estimated treatment differences between each of the oral semaglutide dose 
levels and placebo together with associated two-sided 95% CIs and unadjusted two-sided p-values 
will be presented for all pairwise comparison of oral semaglutide versus placebo. In addition to this 
analysis, oral semaglutide will be compared to liraglutide 0.9 mg and estimated differences with 
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corresponding two sided p-values and 95% confidence intervals after 26 weeks of treatment will be 
presented for all pairwise comparison of oral semaglutide versus liraglutide 0.9 mg.
17.4
Secondary endpoints
17.4.1
Supportive secondary endpoints
17.4.1.1
Efficacy endpoints
The below supportive secondary efficacy endpoints will be evaluated for:
!
The primary estimand based on FAS using the on-treatment without rescue medication 
observation period
!
The secondary estimand based on FAS using the in-trial observation period
Continuous efficacy endpoints
Change from baseline to week 52 in:
!
HbA1c
Change from baseline to week 26 and week 52 in:
!
FPG
!
Body weight (kg)
!
Body weight (%)
!
BMI 
!
Waist circumference
!
Fasting lipid profile (total cholesterol, LDL cholesterol, HDL cholesterol and triglycerides, 
VLDL, free fatty acids)
!
Fasting insulin, C-peptide, glucagon, pro-insulin 
!
Pro-insulin/insulin ratio 
!
Insulin resistance (HOMA-IR)
!
Beta-cell function (HOMA-B)
BMI will be calculated based on body weight and height based on the formulae:
BMI kg/m2 = body weight (kg)/(height (m) × height (m)) or (kg/m2 = [lb/in2 × 703])
Change from baseline to week 26 and 52 in the below derived endpoints from the 7-point SMPG 
profile:
!
Mean 7-point profile, defined as the area under the profile, calculated using the trapezoidal 
method, divided by the measurement time
!
Mean postprandial increment over all meals
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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. No model development of dose-response relationship is planned for these.
For evaluation of the primary estimand the MMRM based primary analysis will include all 
scheduled post-baseline measurement up to and including week 52. From this analysis the estimated 
treatment differences (ratios) between each of the oral semaglutide dose levels and placebo at week 
26 and 52 and between each of the oral semaglutide dose levels and liraglutide 0.9 mg at week 26 
and week 52 together with associated two-sided 95% CIs and unadjusted two-sided p-values will be 
presented for all pairwise comparison of oral semaglutide versus placebo and versus liraglutide 0.9 
mg.
For evaluation of the secondary estimand the analysis will be performed separately for week 26 and 
52. For the analysis at week 52, 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 20 groups of subjects 
instead of the 10 groups as described for the week 26 evaluation in Section 17.3.2. If less than 5 
subjects have available data in one of the 20 groups, the imputation will be made within the 10
groups specified for the primary evaluation. The frequency of missing data is expected to be slightly 
larger at week 52 compared to week 26. The rate of missing data is expected to decline over time.
Binary efficacy endpoints
If a subject after week 26 achieves (yes/no):
!
HbA1c <7.0% (53 mmol/mol) (ADA target)
!
HbA1c ≤6.5% (48 mmol/mol) (AACE target)
!
HbA1c reduction ≥1%-point (10.9 mmol/mol)
!
Body weight loss ≥3%
!
Body weight loss ≥5% 
!
Body weight loss ≥10% 
!
HbA1c <7.0% (53 mmol/mol) without hypoglycaemia (treatment-emergent severe or BG-
confirmed symptomatic hypoglycaemic episodes) and no body weight gain
!
HbA1c reduction ≥1%-point (10.9 mmol/mol) and body weight loss ≥3%
The above eight endpoints will also be evaluated after week 52.
The above eight binary endpoints will be analysed separately using a logistic regression model with 
treatment and stratification factor as fixed effects and baseline response as covariate (i.e. baseline 
HbA1c for binary HbA1c endpoints, baseline body weight for body weight endpoints and both 
baseline HbA1c and baseline body weight for the binary endpoints that combines both parameters). 
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To account for missing data, the analysis will be made using a sequential multiple imputation 
approach as described below:
!
Multiple imputed data sets (100) will be created in which missing values for the underlying 
continuous assessments are imputed by treatment group and treatment adherence/rescue status 
assuming MAR and as described in section 17.3.2 for the secondary estimand and by treatment 
group assuming MAR and as described in section 17.3.1 for the primary estimand.
!
The binary endpoint will be created for each of the 100 complete data sets
!
Each of the created complete data set will be analysed with the logistic model and inference will 
be drawn using Rubin’s rule47.
Time to event endpoint
!
Time to rescue medication
The endpoint will be analysed based on FAS using both the on-treatment observation period and the 
in-trial observation period. For the analysis based on the on-treatment observation period, subject 
without need for rescue medication during the on-treatment observation period will be censored at 
the time point of the date of last trial product. For the in-trial period subject without need for 
addition of glucose-lowering medication during the in-trial observation period, will be censored at 
the time point of the date of end of the in-trial observation period. For this analysis, the follow-up 
period will be excluded from the in-trial observation period, since subjects will have to stop 
treatment at the end-of-treatment visit and therefore might need addition of glucose-lowering 
medication during the follow-up period.
The endpoint will be described and compared for oral semaglutide versus placebo and versus 
liraglutide 0.9 mg using likelihood ratio tests obtained from a Cox proportional hazards model with 
treatment and stratification factor as categorical fixed effects and baseline HbA1c as a covariate. 
From this analysis the estimated Hazard ratios between each of the oral semaglutide dose levels and 
placebo and between each of the oral semaglutide dose levels and liraglutide 0.9 mg together with 
associated two-sided 95% CIs and unadjusted two-sided p-values will be presented for all pairwise 
comparison of oral semaglutide versus placebo and versus liraglutide 0.9 mg.
17.4.1.2
Safety endpoints
The safety endpoints will be evaluated based on SAS using the on-treatment observation period and 
based on SAS using the in-trial observation period unless otherwise stated. The following endpoints 
are used to support the safety objectives.
Adverse events
!
Number of TEAEs during exposure to trial product, assessed up to approximately 57 weeks
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All AEs will be coded using the most recent version of the Medical Dictionary for Regulatory 
Activities (MedDRA) coding. 
A treatment-emergent AE is defined as an AE with onset in the on-treatment observation period 
(see definition of observation periods in Section 17.2).
TEAEs will be summarised in terms of the number of subjects with at least one event (N), the 
percentage of subjects with at least one event (%), the number of events (E) and the event rate per 
100 patient years of observation time (R) for the on-treatment observation period. Supportive 
summaries of AEs will be made for the in-trial observation period. The development over time in 
gastrointestinal AEs will be presented graphically.
Other safety endpoints
Change from baseline to week 26 and 52 in:
!
Amylase
!
Lipase
!
Pulse
!
Systolic blood pressure
!
Diastolic blood pressure
The above safety endpoints will be evaluated using the primary analysis for the secondary estimand 
based on SAS using the in-trial observation period and using the primary analysis for the primary 
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 and 52. 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 and 52 in:
!
Haematology 
!
Biochemistry (except for amylase and lipase)
!
Calcitonin
!
ECG category
!
Physical examination
Change from baseline to week 52 in:
!
Fundus photography/dilated fundoscopy
Occurrence of anti-semaglutide antibodies (yes/no):
!
Anti-semaglutide binding antibodies
!
Anti-semaglutide neutralising antibodies 
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!
Anti-semaglutide binding antibodies cross reacting with native GLP-1
!
Anti-semaglutide neutralising antibodies cross reacting with native GLP-1
Anti-semaglutide antibodies:
!
Anti-semaglutide binding antibody levels
The above safety endpoints will be summarised descriptively by treatment arm and visit. 
Categorical safety endpoints will be summarised as counts and relative frequencies. Calcitonin will 
also be presented by gender.
Hypoglycaemia
!
Number of treatment-emergent severe or BG-confirmed symptomatic hypoglycaemic episodes 
during exposure to trial product, assessed up to approximately 57 weeks
!
Treatment-emergent severe or BG-confirmed symptomatic hypoglycaemic episodes during 
exposure to trial product, assessed up to approximately 57 weeks (yes/no)
Classification of hypoglycaemia
Hypoglycaemic episodes will be summarised for the SAS and the on-treatment observation period 
only.
Treatment emergent: hypoglycaemic episodes will be defined as treatment-emergent if the onset of 
the episode occurs within the on-treatment observation period (see definition of observation periods 
in Section 17.2).
Nocturnal hypoglycaemic episodes: episodes occurring between 00:01 and 05.59 both inclusive.
Hypoglycaemic episodes are classified according to the Novo Nordisk classification of 
hypoglycaemia and the ADA classification of hypoglycaemia (see Figure 17.1).
Novo Nordisk classification of hypoglycaemia
In normal physiology, symptoms of hypoglycaemia occur below a PG level of 3.1 mmol/L 
(56 mg/dL)48. 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 classification40 or BG confirmed by a PG value < 3.1 mmol/L (56 mg/dL) with
symptoms consistent with hypoglycaemia.
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ADA classification40 of hypoglycaemia
!
Severe hypoglycaemia: An episode requiring assistance of another person to actively administer 
carbohydrate, glucagon, or take other corrective actions. PG concentrations may not be 
available during an event, but neurological recovery following the return of PG to normal is 
considered sufficient evidence that the event was induced by a low PG concentration.
!
Asymptomatic hypoglycaemia: An episode not accompanied by typical symptoms of 
hypoglycaemia, but with a measured PG concentration ≤ 3.9 mmol/L (70 mg/dL).
!
Documented symptomatic hypoglycaemia: An episode during which typical symptoms of 
hypoglycaemia are accompanied by a measured PG concentration ≤ 3.9 mmol/L (70 mg/dL).
!
Pseudo-hypoglycaemia: An episode during which the person with diabetes reports any of the 
typical symptoms of hypoglycaemia with a measured PG concentration > 3.9 mmol/L (70 
mg/dL) but approaching that level.
!
Probable symptomatic hypoglycaemia: An episode during which symptoms of hypoglycaemia 
are not accompanied by a PG determination but that was presumably caused by a PG 
concentration ≤ 3.9 mmol/L (70 mg/dL).
Hypoglycaemic 
episode 
PG ≤ 3.9 mmol/L 
(70 mg/dL) 
or 
Alleviation of 
symptoms 
or
Seizure, coma or 
fatal 
SMPG
measurement
Asymptomatic 
hypoglycaemia
Documented 
symptomatic 
hypoglycaemia
Pseudo-
hypoglycaemia
Probable 
symptomatic 
hypoglycaemia
No
Yes
No measurement 
with symptoms
PG > 3.9 mmol/L 
(70 mg/dL)
with symptoms
PG ≤3.9 mmol/L 
(70 mg/dL)
with symptoms
PG ≤3.9 mmol/L 
(70 mg/dL)
without symptoms
No
Yes
Note: Glucose measurements are performed with capillary blood calibrated to plasma equivalent glucose values
PG: plasma glucose  SMPG: Self-measured plasma glucose  
Subject 
able to 
treat him/
herself
Severe 
hypoglycaemia
(ADA 2013)
Figure 17–1
ADA classification of hypoglycaemia
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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 evaluated for the on-treatment period using a negative binomial regression model with a log-
link function and the logarithm of the duration of the subject’s on-treatment observation period as 
offset. The model will include treatment and stratification factor 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 and stratification factor as fixed factors and baseline HbA1c as covariate.
17.4.1.3
Pharmacokinetic endpoints
!
Semaglutide plasma concentrations for population PK analysis
The semaglutide plasma concentrations collected in this trial will be evaluated using relevant 
summary statistics. In addition, the semaglutide plasma concentration will be part of a meta-
analysis across the oral semaglutide phase 3a trials, see more details in Section 17.6.
17.5
Interim analysis
No interim analyses or other analyses of unblinded data will be performed before the database is 
locked.
17.6
Pharmacokinetic and/or pharmacodynamic modelling
Data from this trial will be evaluated using population pharmacokinetic analysis and exposure-
response for semaglutide. The purpose of the population pharmacokinetic analysis will be: 
!
To describe the covariate factors (such as body weight, age, gender, race and ethnicity) that 
influence semaglutide exposure
!
To estimate a steady-state exposure level for each subject with pharmacokinetic data, in order to 
facilitate subsequent exposure-response analyses
The purpose of the exposure-response analyses will be to support the recommended dose, by 
investigating response and potentially side effects across the exposure range. 
The population pharmacokinetic and exposure-response analyses will be conducted as a meta-
analysis, including all relevant oral semaglutide phase 3a trials with PK assessments. A separate 
modelling analysis plan will be prepared before first database lock in the oral semaglutide phase 3a 
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programme, outlining details of the analyses. The modelling will be performed by Quantitative 
Clinical Pharmacology at Novo Nordisk A/S and will be reported separately from the clinical trial 
report.
17.7
Health economics and/or patient reported outcomes
PRO endpoints
Change from baseline to week 26 and week 52 in:
!
SF-36v2TM (acute version) health survey: Total score and scores from the 8 domains
!
DTR-QOL questionnaire: Total score and scores from the 4 factors
The PRO endpoints will be analysed separately as the other continuous efficacy endpoints using a 
similar model approach as for the primary endpoint with the associated baseline response as a 
covariate.
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18 Ethics
18.1
Benefit-risk assessment of the trial
18.1.1
Risks and precautions with oral semaglutide
The nonclinical safety programme of oral semaglutide has not revealed any safety issues precluding 
use in humans. 
The sections below describe the important identified and potential risks and precautions associated 
with oral semaglutide treatment. These are based on findings in nonclinical studies and clinical 
trials with oral semaglutide as well as other GLP-1 RAs. For each of these risks and precautions, 
mitigating actions have been implemented to minimise the risks for subjects enrolled in this trial.
Identified risks
Gastrointestinal adverse events
Consistent with findings with other GLP-1 RAs, the most frequently reported AEs in clinical trials 
with oral semaglutide have been gastrointestinal disorders (nausea, vomiting, diarrhoea, dyspepsia 
and constipation). Clinical trials have indicated that a low starting dose and gradual dose escalation 
mitigates the risk of gastrointestinal AEs. Consequently, a low starting dose and dose escalation 
with 4 week dose-escalation steps have been implemented in the trial. 
Potential risks
Medullary thyroid cancer
The human relevance of the proliferative C-cell changes found in rodents treated with GLP-1 RAs 
is unknown, but data suggest that rodents are more sensitive to the mode of action of GLP-1 RAs 
for induction of C-cell tumours. However, as a precaution, subjects with a family or personal 
history of MEN 2 or MTC will not be enrolled in the trial. During the trial, calcitonin will be 
measured on a regular basis, and the guidance for investigators on further evaluation and action on 
elevated calcitonin concentrations is included in appendix A. 
Acute pancreatitis
Acute pancreatitis has been reported in subjects treated with GLP-1 RAs including oral semaglutide. 
As a precaution, subjects with a history of acute or chronic pancreatitis will not be enrolled in the 
trial. Also, subjects will be informed about the symptoms of acute pancreatitis and serum levels of 
lipase and amylase will be monitored throughout the trial.
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Pancreatic cancer
Patients with T2DM have an increased risk of certain types of cancer such as pancreatic cancer. 
There is currently no support from nonclinical studies or clinical trials or post-marketing data that 
GLP-1-based therapies increase the risk of pancreatic cancer. However, pancreatic cancer has been 
included as a separate potential risk due to the scientific debate surrounding a potential association 
to GLP-1-based therapies and the unknown long-term effects of stimulation of β-cells and 
suppression of α-cells. Pancreatic cancer has been classified as a potential class risk of GLP-1 RAs 
by EMA.
Allergic reactions
As in the case with all protein-based pharmaceuticals, treatment with oral semaglutide may evoke 
allergic reactions. These may include urticaria, rash, pruritus as well as anaphylactic reactions. As a 
precaution, subjects with known or suspected hypersensitivity to trial product(s) or related products 
will not be enrolled in the trial. In addition, subjects will be instructed to contact the site staff as 
soon as possible for further guidance if suspicion of a hypersensitivity reaction to the trial product 
occurs.
Hypoglycaemia
Based on current knowledge about the GLP-1 RA drug class, there is a risk of hypoglycaemic 
episodes. Hypoglycaemic episodes have mainly been observed when a GLP-1 RA is combined with 
sulphonylurea or insulin. The risk for development of hypoglycaemia with oral semaglutide in 
combination with sulphonylurea and insulin is currently unknown. 
Acute renal impairment
In subjects treated with GLP-1 RAs, including oral semaglutide, gastrointestinal AEs such as 
nausea, vomiting and diarrhoea may lead to significant dehydration and secondary acute renal 
impairment. Subjects with gastrointestinal AEs are recommended to drink plenty of fluids to avoid 
volume depletion. Also, serum creatinine and other markers of kidney function will be monitored 
throughout the trial.
If rescue medication is indicated it should be in accordance with the current, approved labels.
SGLT-2 inhibitors, an allowed rescue medication, have also been associated with volume depletion. 
It is recommended to monitor renal function and for signs and symptoms of fluid loss during 
therapy. Severe dehydration may be a risk factor for ketoacidosis.
Impaired renal function may increase the risk of metformin-associated lactic acidosis when GLP-1 
RAs are co-administered with metformin. In case subject is treated with metformin as a rescue 
medication and experiences prolonged or severe nausea and vomiting, the investigator should 
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monitor serum creatinine, and if clinically indicated, withhold metformin until resolution of renal 
dysfunction. 
Other safety considerations
Diabetic retinopathy
A transient worsening of diabetic retinopathy is a recognised complication in selected patients with 
diabetes after initiation of intensive antidiabetic treatment49,50,51. Risk factors for these events 
include long-standing poor glycaemic control and presence of proliferative retinopathy, and initial 
large improvements in blood glucose may be an additional aggravating factor. Several studies have, 
however, documented long-term beneficial effects of intensive glycaemic treatment in reducing 
retinopathy progression4,52 even in intensively treated patients who experienced early worsening50. 
In a cardiovascular outcomes trial with s.c. semaglutide, results indicate an increased risk of events 
related to diabetic retinopathy in subjects treated with semaglutide compared to placebo. As a 
precaution in this trial, all subjects are required to have a fundus photography or dilated fundoscopy 
performed before enrolment into the trial; moreover, subjects with proliferative retinopathy or 
maculopathy requiring acute treatment will be excluded.
Teratogenicity (embryo-foetal development toxicity)
Semaglutide caused embryo-foetal malformations in the rat through a GLP-1 receptor mediated 
effect on the inverted yolk sac placenta leading to impaired nutrient supply to the developing 
embryo. Primates do not have an inverted yolk sac placenta which makes this mechanism unlikely 
to be of relevance to humans. However, as a precaution, females who are pregnant, breast-feeding 
or intend to become pregnant or are of childbearing potential and not using an adequate 
contraceptive method will not be enrolled in the trial. In addition, pregnancy tests will be performed 
at all visits, including screening and follow-up and at any time during the trial if a menstrual period 
is missed.
General precautions
All subjects will be included after a thorough evaluation with regards to in- and exclusion criteria 
defined in order to ensure that subjects are eligible for trial treatment. There are also strict 
glyacemic rescue criteria in place to ensure acceptable glycaemic control during the trial. If rescue 
medication is required, it should be in accordance with ADA/European Association for the Study of 
Diabetes28,29 (excluding GLP-1 RAs, DPP-4 inhibitors and amylin analogues).
It is the responsibility of the investigator to ensure the best possible care according to clinical 
practice in Japan and/or the principles outlined in Diabetes Care 2016 Standards of Medical Care in 
Diabetes53.
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Further details with regards to safety of trial product are described in the current edition of the IB 
for oral semaglutide (NN9924)25, or any updates thereto.
18.1.2
Risks and precautions with liraglutide
The most commonly reported side effects associated with liraglutide are nausea, diarrhoea, 
vomiting, other GI symptoms, nasopharyngitis, hypoglycaemia (when combined with SU or insulin), 
anorexia, headache, increased heart rate, dizziness, rash and injection site reactions. Also, 
dehydration, renal impairment and pancreatitis have been reported26.
From clinical trials and marketed use, overdoses have been reported of up to 72 mg. Generally, the 
patients reported severe nausea, vomiting and diarrhoea. None of the patients reported severe 
hypoglycaemia. All patients recovered without complications.
In the event of overdose, appropriate supportive treatment should be initiated according to the 
patient's clinical signs and symptoms
18.1.3
Risks and precautions with placebo
There will be strict glycaemic rescue criteria in place to ensure acceptable glycaemic control for all 
treatment arms at all times during the trial. Subjects will in case of unacceptable, persistent 
hyperglycaemia be offered treatment intensification (rescue medication) at the discretion of the 
investigator.
18.1.4
Benefits
In this trial, subjects will be randomised 1:1:1:1:1 to either one of the 3 dose levels of semaglutide, 
liraglutide or placebo. The majority of the patients will be treated with a treatment regimen 
anticipated to be equally or more efficacious than the treatment they received at the time of trial 
entry. Based on the results of the phase 2 dose finding trial, oral semaglutide is expected to provide 
clinically relevant improvements in glycaemic control and body weight in subjects with T2DM. 
Similarly, treatment with liraglutide is expected to provide clinically relevant improvements in 
glycaemic control26. 
In addition, it is expected that all subjects, including subjects randomised to placebo, will benefit 
from participation through close contact with the trial 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.
18.1.5
Risk and benefit conclusion 
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The safety profile for oral semaglutide generated from the clinical and nonclinical development 
programme has not revealed any safety issues that would prohibit administration of oral 
semaglutide in accordance with the planned clinical trial.
The phase 2 results indicate that oral semaglutide will provide clinically relevant improvements in 
glycaemic control and body weight.
Liraglutide is already a marketed drug approved for the use in subjects with T2DM. 
Safety and efficacy will be monitored regularly and acceptable glycaemic control will be reinforced 
at all times during the trial.
In conclusion, the potential risk to the subjects in this trial is considered low and acceptable in view 
of the anticipated benefits oral semaglutide/liraglutide would provide to subjects with T2DM.
18.2
Informed consent 
In seeking and documenting informed consent, the investigator must comply with applicable 
regulatory requirement(s) and adhere to ICH GCP1 and the requirements in the Declaration of 
Helsinki2.
Before any trial-related activity, the investigator must give the subject verbal and written 
information about the trial and the procedures involved in a form that the subject can read and 
understand.
The subjects must be fully informed of their rights and responsibilities while participating in the 
trial as well as possible disadvantages of being treated with the trial products.
The investigator must ensure the subject ample time to come to a decision whether or not to 
participate in the trial. 
A voluntary, signed and personally dated informed consent must be obtained from the subject 
before any trial-related activity.
The responsibility for seeking informed consent must remain with the investigator, but the 
investigator may delegate the task to a medically qualified person, in accordance with local 
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.
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In order to avoid missing data, the subjects will be informed about the importance of completing the 
trial also if the subjects discontinue from trial product.
18.3
Data handling
If the subject withdraws from the trial or is lost to follow-up, then the subject’s data will be handled 
as follows:
!
Data already collected and any data collected at the end-of-trial visit including follow-up visits 
will be retained by Novo Nordisk, entered into the database and used for the clinical trial report. 
!
Safety events will be reported to Novo Nordisk and regulatory authorities according to 
local/national requirements.
If data is used, it will always be in accordance with local regulations and IRBs.
18.4
Information to subjects during trial
All written information to subjects must be sent to IRB for approval/favourable opinion and to 
regulatory authorities for approval or notification according to local regulations.
18.5
Premature termination of the trial and/or trial site
Novo Nordisk, the IRBs or a regulatory authority may decide to stop the trial, part of the trial or a 
trial site at any time, but agreement on procedures to be followed must be obtained.
If the trial is suspended or prematurely terminated, the investigator must inform the subjects 
promptly and ensure appropriate therapy and follow-up. The investigator and/or Novo Nordisk must 
also promptly inform the regulatory authorities and IRBs and provide a detailed written explanation. 
If, after the termination of the trial, the benefit-risk analysis changes, the new evaluation must be 
provided to the IRBs in case it has an impact on the planned follow-up of subjects who have 
participated in the trial. If it has an impact, the actions needed to inform and protect the subjects 
should be described.
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19 Protocol compliance
19.1
Protocol deviations
Deviations from the protocol should be avoided.
If deviations do occur, the investigator must inform the monitor and the implications of the 
deviation must be reviewed and discussed.
Deviations must be documented and explained in a protocol deviation by stating the reason, date
and the action(s) taken. Some deviations, for which corrections are not possible, can be 
acknowledged and confirmed via edit checks in the eCRF or via listings from the trial database. 
Documentation on protocol deviations must be kept in the investigator trial master file and sponsor 
trial master file.
19.2
Prevention of missing data
The importance of subject retention will be addressed by Novo Nordisk in the training and 
communication with the trial sites. 
The subjects will be carefully informed about the trial procedures before signing informed consent, 
so that they know the implications of participating in the trial. 
Close surveillance of subject retention will be performed throughout the trial by Novo Nordisk with 
focus on reasons for premature discontinuation of trial product or withdrawal of consent to secure 
early mitigations in collaboration with the trial sites. 
The investigator will make every effort to ensure that all assessments are performed and data is 
collected. If missing data does occur the reason will be collected via the protocol deviation process, 
see Section 19.1. Novo Nordisk will monitor protocol deviations on an on-going basis throughout 
the trial followed by appropriate actions (e.g. re-training of site staff).
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20 Audits and inspections
Any aspect of the clinical trial may be subject to audits conducted by Novo Nordisk or inspections 
from domestic or foreign regulatory authorities or from IRBs. Audits and inspections may take 
place during or after the trial. The investigator and the site staff as well as Novo Nordisk staff have 
an obligation to cooperate and assist in audits and inspections. This includes giving auditors and 
inspectors direct access to all source documents and other documents at the trial site relevant to the 
clinical trial. This includes permission to examine, analyse, verify and reproduce any record(s) and 
report(s) that are relevant to the evaluation of the trial.
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21 Critical documents
Before a trial site is allowed to start screening subjects, written notification from Novo Nordisk 
must be received and the following documents must be available to Novo Nordisk:
!
Regulatory approval and/or acknowledgement of notification as required 
!
Approval/favourable opinion from IRBs clearly identifying the documents reviewed as follows: 
protocol, any protocol amendments, subject information/informed consent form, any other 
written information to be provided to the subject and subject recruitment materials
!
List of IRB members and/or constitution (or a general assurance number/statement of 
compliance)
!
Curricula vitae of investigator and sub-investigator(s) (current, dated and signed - must include 
documented GCP training or a certificate)
!
Signed receipt of IB for oral semaglutide and s.c. semaglutide and package insert for liraglutide 
(Victoza®)
!
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)
Novo Nordisk will analyse and report data from all sites together if more than one site is involved in 
the trial.
By signing the protocol agreement, each investigator agrees to comply fully with ICH GCP1,
applicable regulatory requirements and the Declaration of Helsinki2. 
By signing the protocol agreement, each investigator also agrees to allow Novo Nordisk to make 
investigator’s name and information about site name and address publically available if this is 
required by national or international regulations.
It should be noted that a seal is accepted as signature in Japan.
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22 Responsibilities
The investigator is accountable for the conduct of the trial at his/her site and must ensure adequate 
supervision of the conduct of the trial at the trial site. If any tasks are delegated, the investigator 
must maintain a log of appropriately qualified persons to whom he/she has delegated specified trial-
related duties. The investigator must ensure that there is adequate and documented training for all 
staff participating in the conduct of the trial. It is the investigator’s responsibility to supervise the 
conduct of the trial and to protect the rights, safety, and well-being of the subjects.
A qualified physician, who is an investigator or a sub-investigator for the trial, must be responsible 
for all trial-related medical decisions.
The investigator will follow instructions from Novo Nordisk when processing data.
The investigator is responsible for filing essential documents (i.e. those documents which 
individually and collectively permit evaluation of the conduct of a trial and the quality of the data 
produced) in the investigator trial master file. The documents including the subject identification 
code list must be kept in a secure locked facility, so no unauthorized persons can get access to the 
data. 
The investigator will take all necessary technical and organisational safety measures to prevent 
accidental or wrongful destruction, loss or deterioration of data. The investigator will prevent any 
unauthorised access to data or any other processing of data against applicable law. The investigator 
must be able to provide the necessary information or otherwise demonstrate to Novo Nordisk that 
such technical and organisational safety measures have been taken.
During any period of unavailability, the investigator must delegate responsibility for medical care of 
subjects to a specific qualified physician who will be readily available to subjects during that time.
If the investigator is no longer able to fulfil the role as investigator (e.g. if he/she moves or retires), 
a new investigator will be appointed in consultation with Novo Nordisk. 
The investigator and other site personnel must have sufficient English skills according to their 
assigned task(s).
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23 Reports and publications
The information obtained during the conduct of this trial is considered confidential, and may be 
used by or on behalf of Novo Nordisk for regulatory purposes as well as for the general 
development of the trial product. All information supplied by Novo Nordisk in connection with this 
trial shall remain the sole property of Novo Nordisk and is to be considered confidential 
information. 
No confidential information shall be disclosed to others without prior written consent from Novo 
Nordisk. Such information shall not be used except in the performance of this trial. The information 
obtained during this trial may be made available to other physicians who are conducting other 
clinical trials with the trial product, if deemed necessary by Novo Nordisk. Provided that certain 
conditions are fulfilled, Novo Nordisk may grant access to information obtained during this trial to 
researchers who require access for research projects studying the same disease and/or trial product 
studied in this trial.
Novo Nordisk may publish on its clinical trials website a redacted clinical trial report for this trial.
One or two investigators will be appointed by Novo Nordisk to review and sign the clinical trial 
report (signatory investigator) on behalf of all participating investigators. The signatory 
investigator(s) will be appointed based upon the criteria defined by the International Committee of 
Medical Journal Editors for research publications54. 
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 Disclosure30.
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 Editors54 (sometimes referred to as the Vancouver 
Criteria). Novo Nordisk will appoint investigator(s) to prepare publications in collaboration with 
Novo Nordisk.
23.1.2
Site-specific publication(s) by investigator(s)
For a multi-centre clinical trial, analyses based on single-site data usually have significant statistical 
limitations and frequently do not provide meaningful information for healthcare professionals or 
subjects, and therefore may not be supported by Novo Nordisk. It is a Novo Nordisk policy that 
such individual reports do not precede the primary manuscript and should always reference the 
primary manuscript of the trial.
Novo Nordisk reserves the right to prior review of such publications. Further to allow for the 
primary manuscript to be published as the first, Novo Nordisk asks for deferment of publication of 
individual site results until the primary manuscript is accepted for publication. As Novo Nordisk 
wants to live up to the industry publication policy, submission of a primary publication will take 
place no later than 18 months after trial completion. 
23.2
Investigator access to data and review of results
As owner of the trial database, Novo Nordisk has the discretion to determine who will have access 
to the database. 
Individual investigators will have their own research subjects' data, and will be provided with the 
randomisation code after results are available.
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24 Retention of clinical trial documentation and human biosamples
24.1
Retention of clinical trial documentation
Subject’s medical records must be kept for the maximum period permitted by the hospital, 
institution or private practice.
The investigator must agree to archive the documentation (this includes both electronic and paper-
based records) pertaining to the trial in an archive after completion or discontinuation of the trial if 
not otherwise notified. The investigator should not destroy any documents without prior permission 
from Novo Nordisk. If the investigator cannot archive the documents at the trial site, Novo Nordisk 
can refer the investigator to an independent archive provider that has a system in place to allow only 
the investigator to access the files.
The investigator must be able to access his/her trial documents without involving Novo Nordisk in 
any way. Site-specific CRFs and other subject data (in an electronic readable format or as paper 
copies or prints) will be provided to the investigator before access is revoked to the systems and/or 
electronic devices supplied by Novo Nordisk. These data must be retained by the trial site. If the 
provided data (e.g. the CD-ROM) is not readable during the entire storage period, the investigator 
can request a new copy. A copy of all data will be stored by Novo Nordisk.
Novo Nordisk will maintain Novo Nordisk documentation pertaining to the trial for at least 20 years 
after discontinuation of the marketing authorisation, termination of the trial or cancellation of the 
research project whichever is longest.
The files from the trial site/institution must be retained for 15 years after end of trial as defined in 
Section 7, or longer if required by local regulations or Novo Nordisk. In any case trial files cannot 
be destroyed until the trial site/institution is notified by Novo Nordisk. The deletion process must 
ensure confidentiality of data and must be done in accordance with local regulatory requirements. 
24.2
Retention of human biosamples
Antibody samples may be retained for later analysis for further characterisation of antibody 
responses towards drug if required by health authorities or for safety reasons.
The samples will be stored at a central bio-repository after end of trial and until marketing 
authorisation approval or until the research project terminates, but no longer than 15 years from end 
of trial after which they will be destroyed. 
The subject’s identity will remain confidential and the antibody samples will be identified only by 
subject number, visit number and trial identification number. No direct identification of the subject 
will be stored together with the samples.
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Only Novo Nordisk staff and bio-repository personnel will have access to the stored antibody 
samples. 
Subjects can contact the investigator if they wish to be informed about results derived from stored 
antibody samples obtained from their own body. 
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25 Institutional Review Boards and regulatory authorities
IRB:
Written approval or favourable opinion must be obtained from IRB prior to commencement of the 
trial.
During the trial, the investigator or Novo Nordisk, as applicable, must promptly report the 
following to the IRB, in accordance with local requirements: updates to IB, unexpected SAEs where 
a causal relationship cannot be ruled out, protocol amendments according to local requirements, 
deviations to the protocol implemented to eliminate immediate hazards to the subjects, new 
information that may affect adversely the safety of the subjects or the conduct of the trial (including 
new benefit-risk analysis in case it will have an impact on the planned follow-up of the subjects), 
annually written summaries of the trial status, and other documents as required by the local IRB.
Protocol amendments must not be implemented before approval or favourable opinion according to 
local regulations, unless necessary to eliminate immediate hazards to the subjects.
The investigator must maintain an accurate and complete record of all submissions made to the 
IRB. The records must be filed in the investigator trial master file and copies must be sent to Novo 
Nordisk.
Regulatory Authorities:
Regulatory authorities will receive the clinical trial application, protocol amendments, reports on 
SAEs, and the clinical trial report according to national requirements.
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26 Indemnity statement
Novo Nordisk carries product liability for its products, and liability as assumed under the special 
laws, acts and/or guidelines for conducting clinical trials in any country, unless others have shown 
negligence.
Novo Nordisk assumes no liability in the event of negligence, or any other liability of the sites or 
investigators conducting the trial, or by persons for whom the said site or investigator are 
responsible.
Novo Nordisk accepts liability in accordance with the compensation scheme specified in ‘The 
guideline on compensation for harmful effects resulting from participation in clinical trials’ issued 
by Japanese Pharmaceutical Industry Legal Affairs Association55.
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27 References
1 International Conference on Harmonisation. ICH Harmonised Tripartite Guideline. Guideline for 
Good Clinical Practice E6(R1), Step 4, including Post Step 4 errata. 10 June 1996.
2 World Medical Association. WMA Declaration of Helsinki - Ethical Principles for Medical 
Research Involving Human Subjects. Last amended by the 64th WMA General Assembly, 
Fortaleza, Brazil. October 2013.
3 DeFronzo RA. Pathogenesis of type 2 diabetes mellitus. Med Clin North Am. 2004;88(4):787-
835, ix.
4 UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with 
sulphonylureas or insulin compared with conventional treatment and risk of complications in 
patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352(9131):837-53.
5 Chuang LM, Tsai ST, Huang BY, Tai TY, Diabcare-Asia Study Group. The status of diabetes 
control in Asia--a cross-sectional survey of 24 317 patients with diabetes mellitus in 1998. 
Diabet Med. 2002;19(12):978-85.
6 Ford ES, Li C, Little RR, Mokdad AH. Trends in A1C concentrations among U.S. adults with 
diagnosed diabetes from 1999 to 2004. Diabetes Care. 2008;31(1):102-4.
7 Holst JJ, Vilsboll T, Deacon CF. The incretin system and its role in type 2 diabetes mellitus. Mol 
Cell Endocrinol. 2009;297(1-2):127-36.
8 Kieffer TJ, Habener JF. 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 
incretin effect in patients with type 2 diabetes. J Clin Endocrinol Metab. 2011;96(3):737-45.
10 Perley MJ, Kipnis DM. Plasma insulin responses to oral and intravenous glucose: studies in 
normal and diabetic sujbjects. J Clin Invest. 1967;46(12):1954-62.
11 Nauck M, Stockmann F, Ebert R, Creutzfeldt W. Reduced incretin effect in type 2 (non-insulin-
dependent) diabetes. Diabetologia. 1986;29(1):46-52.
12 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;54:10-8.
13 Hojberg PV, Vilsboll T, Rabol R, Knop FK, Bache M, Krarup T, et al. Four weeks of near-
normalisation of blood glucose improves the insulin response to glucagon-like peptide-1 and 
glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes. Diabetologia. 
2009;52(2):199-207.
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14 Meier JJ. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nat 
Rev Endocrinol. 2012;8(12):728-42.
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):515-20.
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 Pt 1):E981-8.
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):741-4.
18 Toft-Nielsen MB, Damholt MB, Madsbad S, Hilsted LM, Hughes TE, Michelsen BK, et al. 
Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients. J 
Clin Endocrinol Metab. 2001;86(8):3717-23.
19 Toft-Nielsen MB, Madsbad S, Holst JJ. Determinants of the effectiveness of glucagon-like 
peptide-1 in type 2 diabetes. J Clin Endocrinol Metab. 2001;86(8):3853-60.
20Lau J, Bloch P, Schäffer L, Pettersson I, Spetzler J, Kofoed J, et al. Discovery of the Once-
Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide. J Med Chem. 
2015;58(18):7370-80.
21 Kapitza C, Nosek L, Jensen L, Hartvig H, Jensen CB, Flint A. Semaglutide, a once-weekly 
human GLP-1 analog, does not reduce the bioavailability of the combined oral contraceptive, 
ethinylestradiol/levonorgestrel. J Clin Pharmacol. 2015;55(5):497-504.
22 European Medicines Agency. ICH guideline M3(R2) on non-clinical safety studies for the 
conduct of human clinical trials and marketing authorisation for pharmaceuticals 
(EMA/CPMP/ICH/286/1995). December 2009.
23 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. 2015;28(3):391-
402.
24 Investigator's Brochure for s.c. Semaglutide (NN9535), Edition 11 or any updates hereof. 2016.
25 Investigator's brochure for oral semaglutide (NN9924), edition 7 or any updates hereof. 2016.
26 Victoza Japanese Package Insert. August 2014 or any updates hereof.
27 Ministry of Health, Labour and Welfare. Draft Guideline for Clinical Evaluation of 
Hypoglycaemic Agents. 19 May 2015.
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28 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):1364-79.
29 Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. Management 
of hyperglycaemia in type 2 diabetes, 2015: a patient-centred approach. Update to a position 
statement of the American Diabetes Association and the European Association for the Study of 
Diabetes. Diabetologia. 2015;58(3):429-42.
30 Novo Nordisk Code of Conduct for Clinical Trial Disclosure. Avaliable from: 
http://novonordisk-trials.com/website/content/how-we-disclose-trial-information.aspx. 11 Jan 
2015.
31 De Angelis C, Drazen JM, Frizelle FA, Haug C, Hoey J, Horton R, et al. Clinical trial 
registration: a statement from the International Committee of Medical Journal Editors. N Engl J 
Med. 2004;351(12):1250-1.
32 U.S. Department of Health and Human Services, Food and Drug Administration. Food and 
Drug Administration Amendments Act of 2007. 27 September 2007.
33 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. 1 May 2001.
34 The European Parliament and the Council of the European Council. Regulation (EC) No 
726/2004 of the European Parliament and of the Council of 31 March 2004 laying down 
Community procedures for the authorisation and supervision of medicinal products for human 
and veterinary use and establishing a European Medicines Agency, article 57. Official Journal 
of the European Communities. 2004.
35 Ware JE, Jr., Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. 
Conceptual framework and item selection. Med Care. 1992;30(6):473-83.
36 Ware JE, Kosinski M, Dewey JE. How to Score Version Two of the SF-36 Health Survey. 3rd 
ed: Lincoln RI: QualityMetric, Incorporated. 2000.
37 Turner-Bowker DM, Bartley PJ, Ware JE. SF-36® Health Survey and "SF" Bibliography. 
Lincoln, Rhode Island: QualityMetric Incorporated; 2002.
38 Ishii H. Development and psychometric validation of the Diabetes Therapy-Related QOL 
(DTR-QOL) questionnaire. J Med Econ. 2012;15(3):556-63.
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39 National Kidney F. KDOQI Clinical Practice Guideline for Diabetes and CKD: 2012 Update. 
Am J Kidney Dis. 2012;60(5):850-86.
40 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.
41 McAulay V, Deary IJ, Frier BM. Symptoms of hypoglycaemia in people with diabetes. Diabet 
Med. 2001;18(9):690-705.
42 U.S. Department of Health and Human Services, Food and Drug Administration. Guidance for 
Industry. Patient-Reported Outcome Measures: Use in Medical Product Development to 
Support Labeling Claims. December 2009.
43 Stull DE, Leidy NK, Parasuraman B, Chassany O. Optimal recall periods for patient-reported 
outcomes: challenges and potential solutions. Curr Med Res Opin. 2009;25(4):929-42.
44 European Commission. The Rules Governing Medicinal Products in the European Union, 
Volume 4, Annex 13, Investigational Medicinal Products (ENTR/F/2/AM/an D(2010) 3374). 3 
February 2010.
45 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.
46 KDIGO. KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney international 
supplements. 2012;2(1):1-138.
47 Little RJA, Rubin DB. Statistical analysis with missing data: New York: John Wiley & Sons. 
1987.
48 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.
49 Dahl-Jørgensen K, Brinchmann-Hansen O, Hanssen KF, Sandvik L, Aagenaes O. Rapid 
tightening of blood glucose control leads to transient deterioration of retinopathy in insulin 
dependent diabetes mellitus: the Oslo study. Br Med J (Clin Res Ed). 1985;290(6471):811-5.
50 The Diabetes Control and Complications Trial Research Group. Early worsening of diabetic 
retinopathy in the Diabetes Control and Complications Trial. Arch Ophthalmol. 
1998;116(7):874-86.
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51 Varadhan L, Humphreys T, Walker AB, Varughese GI. The impact of improved glycaemic 
control with GLP-1 receptor agonist therapy on diabetic retinopathy. Diabetes Res Clin Pract. 
2014;103(3):e37-9.
52 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.
53 American Diabetes Association. Standards of medical care in diabetes -2016. Diabetes Care. 
2016;39 Suppl. 1:S13-S22.
54 International Committee of Medical Journal Editors. Recommendations for the Conduct, 
Reporting, Editing, and Publication of Scholarly Work in Medical Journals. 12/16/2014 2014.
55 Guideline on Compensation for harmful effect resulting from participation in clinical trials. 
Japanese Pharmaceutical Industry Legal Affaires Association; Last amended 18 Aug 2015.
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Protocol - Appendix A
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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
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Date:
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Version:
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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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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 Criteria for premature 
discontinuation of trial 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.
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Protocol - Appendix A
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Version:
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Background: These values were found in 9 (0.15%) of a population of 5817 patients with thyroid 
nodular disease.1 All of these patients were diagnosed with medullary thyroid carcinoma (MTC) 
resulting in a positive predictive value of 100%.
Diagnostic evaluation should include:
!
thyroid ultrasound examination
!
fine needle aspiration of any nodules > 1 cm 
!
potentially surgery with neck dissection
In case a subject is diagnosed with MTC, it is common clinical practice to explore the family 
history of MTC or multiple endocrine neoplasia type 2 (MEN 2) and perform a genetic test for RET 
proto-oncogene mutation.
2.2
Calcitonin ≥ 50 and < 100 ng/L
Action: The subject should be referred to a thyroid specialist for further evaluation. The subject 
should remain in the trial and continuation on trial product should be based on the evaluation done 
by the thyroid specialist. 
Background: These values were found in 8 (0.14%) of the population of 5817 patients with thyroid 
nodular disease1. Two of these subjects were diagnosed with MTC and two were diagnosed with 
C-cell hyperplasia, resulting in a positive predictive value of a C-cell anomaly of 50%.
Diagnostic evaluation should include: 
!
thyroid ultrasound examination 
!
if available and there are no contraindication, a pentagastrin stimulation test should be done. For 
subjects with positive pentagastrin stimulation test, surgery should be considered. 
!
if pentagastrin stimulation test is not available, thyroid ultrasound and fine needle aspiration 
biopsy may add important clinical information about the need for surgery.
2.3
Calcitonin ≥ 10 and < 50 ng/L
Action: The subject can continue in the trial on trial product. Continue sampling of calcitonin 
according to the protocol.
If the value is from the last sample taken in the trial, the subject should be referred to a thyroid 
specialist for further evaluation.
Background: Calcitonin values from 20-50 ng/L were found in up to 1% of subjects of the 
population of 5817 patients with thyroid nodular disease1. The predictive value of a C-cell anomaly 
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Protocol - Appendix A
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for this calcitonin level was 8.3%. However, the likelihood of having a medullary carcinoma >1 cm 
with calcitonin in this range is extremely low.
For calcitonin values between 10-20 ng/L Costante et al1 identified 216 (3.7%) patients. One patient 
out of the 216 had a subsequent basal (unstimulated) calcitonin of 33 ng/L and had C-cell 
hyperplasia at surgery. Two other studies used a cut-off of calcitonin > 10 ng/L to screen for C-cell 
disease, but they do not provide sufficient information on patients with basal calcitonin > 10 and < 
20 ng/L to allow conclusions.2, 3
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Protocol - Appendix A
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Date:
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Trial ID: NN9924-4281
Version:
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3
References
1.
Costante G, Meringolo D, Durante C, Bianchi D, Nocera M, Tumino S, et al. Predictive 
value of serum calcitonin levels for preoperative diagnosis of medullary thyroid carcinoma 
in a cohort of 5817 consecutive patients with thyroid nodules. J Clin Endocrinol Metab. 
2007;92(2):450-5.
2.
Scheuba C, Kaserer K, Moritz A, Drosten R, Vierhapper H, Bieglmayer C, et al. Sporadic 
hypercalcitoninemia: clinical and therapeutic consequences. Endocr Relat Cancer. 
2009;16(1):243-53.
3.
Verga U, Ferrero S, Vicentini L, Brambilla T, Cirello V, Muzza M, et al. Histopathological 
and molecular studies in patients with goiter and hypercalcitoninemia: reactive or neoplastic 
C-cell hyperplasia? Endocr Relat Cancer. 2007;14(2):393-403.
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Protocol - Appendix B
CONFIDENTIAL
Date:
23 September 2016
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Trial ID: NN9924-4281
Version:
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Appendix B
Adverse events requiring additional data collection
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disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties
CONFIDENTIAL
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disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol - Appendix B
CONFIDENTIAL
Date:
23 September 2016
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Trial ID: NN9924-4281
Version:
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Status:
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1
Adverse events requiring additional data collection
For the following adverse events (AEs) additional data collection is required and specific event 
forms must be completed in the electronic case report form (eCRF) in addition to the AE form:
!
Acute coronary syndrome (myocardial infarction or unstable angina pectoris requiring 
hospitalisation)
!
Cerebrovascular event (stroke or transient ischaemic attack)
!
Heart failure
!
Pancreatitis
!
Neoplasm (excluding thyroid neoplasm)
!
Thyroid disease (including thyroid neoplasm)
!
Renal event
!
Hypersensitivity reaction
!
Acute gallstone disease
!
Medication error (concerning trial products):
!
Administration of wrong drug or use of wrong device. 
Note: Use of wrong dispensing unit number (DUN) is not considered a medication error
unless it results in administration of wrong drug.
!
Wrong route of administration, such as intramuscular instead of s.c..
!
Administration of an overdose with the intention to cause harm (e.g. suicide attempt), 
misuse or abuse of trial product.
!
Accidental administration of a higher dose than intended. A higher dose is a dose of at least 
one tablet more than the intended dose and for pen injection a higher dose than 0.9 mg/day; 
however the administered dose must deviate from the intended dose to an extent where 
clinical consequences for the trial subject were likely to happen as judged by the 
investigator, although they did not necessarily occur.
!
Lactic acidosis
!
Creatine kinase (CK) > 10 x upper normal limit (UNL)
!
Hepatic event defined as:
!
alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 5 x UNL and total 
bilirubin ≤ 2 x UNL
!
ALT or AST >3 x UNL and total bilirubin > 2 x UNL*
!
Hepatic event leading to trial product discontinuation
*Please note that in case of a hepatic event defined as ALT or AST > 3 x UNL and total bilirubin > 
2 x UNL, where no alternative aetiology exists (Hy's law), this must be reported as an SAE using 
the important medical event criterion if no other seriousness criteria are applicable.
In case any of these events fulfil the criteria for a serious adverse event (SAE), please report 
accordingly, see protocol Section 12.1.2.
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Protocol - Appendix B
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Date:
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Version:
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Some of these events will undergo event adjudication by the event adjudication committee (EAC), 
see protocol Section 12.7.2 and protocol Table 12-1.
1.1
Acute coronary syndrome
If an event of acute coronary syndrome (ranging from unstable angina pectoris requiring 
hospitalisation to myocardial infarction) is observed during the trial, the following additional 
information must be reported if available:
!
Duration of symptoms
!
Changes in electrocardiogram (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. transient ischaemic attack, stroke) is observed during the trial, the 
following additional information must be reported if available:
!
Type of event (e.g. transient ischaemic attack, stroke)
!
Contributing condition
!
Neurologic signs and symptoms
!
History of neurologic disease
!
Imaging supporting the condition
!
Treatment given for the condition
1.3
Heart failure
If an event of heart failure is observed during the trial, the following additional information must be 
reported if available:
!
Signs and symptoms of heart failure
!
New York Heart Association (NYHA) Class
!
Supportive imaging
!
Supportive laboratory measurements
!
Initiation or intensification of treatment for this condition
1.4
Pancreatitis
For all confirmed events of pancreatitis the following additional information must be reported if 
available:
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
23 September 2016
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Trial ID: NN9924-4281
Version:
2.0
UTN: U1111-1181-4048
Status:
Final
     
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!
Signs and symptoms of pancreatitis
!
Specific laboratory test supporting a diagnosis of pancreatitis
!
Imaging performed and consistency with pancreatic disease
!
Treatment for and complications of the event
!
Relevant risk factors for pancreatic disease
!
Family history of pancreatic disease
1.4.1
Assessments in case of suspicion of acute pancreatitis
Most patients with acute pancreatitis experience severe abdominal pain that is located generally in 
the epigastrium and radiates to the back. The onset of the pain may be swift reaching maximum 
intensity within 30 min, it is frequently unbearable and characteristically persists for more than 
24 hours without relief1. The pain is often associated with nausea and vomiting. Physical 
examination usually reveals severe upper abdominal tenderness at times associated with guarding.
In general, both amylase and lipase are elevated during the course of acute pancreatitis. The serum 
lipase may remain elevated slightly longer than amylase. The level of the serum amylase and/or 
lipase does not correlate with the severity of acute pancreatitis1. In general, serum lipase is thought 
to be more sensitive and specific than serum amylase in the diagnosis of acute pancreatitis.
In case of suspicion of acute pancreatitis, the trial product should promptly be interrupted (no 
treatment discontinuation call should be made in the interactive web response system (IWRS)
before diagnosis of acute pancreatitis is confirmed). Appropriate additional examinations must be 
performed, including local measurement of amylase and lipase.
The diagnosis of acute pancreatitis requires two of the following three features2:
!
abdominal pain consistent with acute pancreatitis (acute onset of a persistent, severe, epigastric 
pain often radiating to the back)
!
serum lipase activity (and/or amylase activity) at least three times greater than the upper limit of 
normal
!
characteristic findings of acute pancreatitis on imaging.
If acute pancreatitis is ruled out, trial product should be re-initiated.
If acute pancreatitis is confirmed, appropriate treatment and careful monitoring of the subject 
should be initiated. The subject must be discontinued from trial product (treatment discontinuation 
call), but should remain in the trial (see protocol Section 6.5 and 8.1.6).
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
23 September 2016
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Trial ID: NN9924-4281
Version:
2.0
UTN: U1111-1181-4048
Status:
Final
     
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1.5
Neoplasm
All events of neoplasms (excluding thyroid neoplasm, which will be reported under thyroid disease) 
must be reported during the trial and the following additional information must be reported if 
available:
!
Type of neoplasm
!
Symptoms leading to identification of event
!
Diagnostic imaging
!
Pathological examination results
!
Treatment for the event
!
Participation in screening programs
!
Risk factors associated to the event
1.6
Thyroid disease
If an event of thyroid disease, including any thyroid neoplasms, is observed during the trial, the 
following additional information must be reported if available:
!
History of thyroid disease
!
Signs and symptoms leading to investigations of thyroid disease
!
Specific laboratory tests describing thyroid function
!
Diagnostic imaging performed and any prior imaging supporting the disease history 
!
Pathologic examinations
!
Treatment given for the condition
!
Risk factors identified
!
Family history of thyroid disease
1.7
Renal event 
If a renal event is observed during the trial, the following additional information must be reported if 
available:
!
Signs and symptoms of renal failure
!
Specific laboratory tests supporting the diagnosis
!
Imaging performed supporting the diagnosis
!
Kidney biopsy results
!
Risk or confounding factors identified including exposure to nephrotoxic agents
1.8
Hypersensitivity reaction
All events of hypersensitivity reactions must be reported and the following additional information
must be reported if available:
!
Signs and symptoms associated to the event
!
Time of appearance after administration of trial drug
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
23 September 2016
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Trial ID: NN9924-4281
Version:
2.0
UTN: U1111-1181-4048
Status:
Final
     
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!
Relevant immunological tests performed
!
Treatment given for the reaction
!
Previous history of similar reaction
!
Risk or confounding factors identified
1.8.1
Assessments in case of suspicion of hypersensitivity reaction
In case of suspicion of a severe immediate systemic hypersensitivity reaction3 to the trial product, 
the subject must be discontinued from trial product but should remain in the trial (see protocol 
Section 6.5 and 8.1.6).
If suspicion of a hypersensitivity reaction occurs, the subjects should be instructed to contact the 
site staff as soon as possible for further guidance.
To assist in the diagnostic evaluation it is recommended to draw a blood sample for measurement of 
tryptase (total and/or mature tryptase, local assessment) within 3 hours of onset of the 
hypersensitivity reaction, and if this is achieved, a tryptase sample should also be drawn at V13A. 
Furthermore, a blood sample for assessment of anti-semaglutide IgE antibodies should be drawn as 
soon as possible after the event and at V13A and sent to central laboratory. Tryptase concentrations, 
if available, should be included in the specific event form when reporting the AE.
In case of suspicion of immune complex disease3, the subject must be discontinued from trial 
product but should remain in the trial (see protocol Section 6.5 and 8.1.6). It is recommended to 
draw a blood sample for local assessment of complement levels (C3 and C4) to assist in the 
diagnostic evaluation. Complement level results should be included in the specific event form when 
reporting the AE.
1.9
Acute gallstone disease
If an event of acute gallstone disease or clinical suspicion of this is observed during the trial, the 
following additional information must be reported if available:
!
Signs and symptoms of acute gallstone disease
!
Specific laboratory tests supporting a diagnosis of gallstone
!
Imaging performed and consistency with gallstone disease
!
Treatment given for the condition
!
Relevant risk factors for acute gallstone disease
!
Family history of gallstones
1.10
Medication error
If a medication error is observed during the trial, the following additional information is required 
and must be reported:
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
23 September 2016
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Trial ID: NN9924-4281
Version:
2.0
UTN: U1111-1181-4048
Status:
Final
     
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!
Trial product(s) involved
!
Classification of medication error
!
Wrong drug(s) administered
!
Administration of an overdose
!
Whether the subject experienced any hypoglycaemic episode and/or AE(s) as a result of the 
medication error
!
Suspected primary reason for the medication error
For definition of medication error, see protocol Section 12.1.4.
1.11
Lactic acidosis
If an event of lactic acidosis is observed during the trial, the following additional information must 
be reported if available:
!
Signs and symptoms of lactic acidosis
!
Specific laboratory tests describing the event
!
Possible cause(s) of the event
1.12
Creatine kinase > 10 x UNL
If an event of CK > 10 x UNL is observed during the trial, the following additional information 
must be reported if available:
!
Signs and symptoms associated to the event 
!
Recent physical activity
!
Possible cause(s) of the event
1.12.1
Assessments in case of increased levels of creatine kinase
In case of CK > 10 x UNL, prompt repeat testing (at central laboratory) of CK should be done. 
Repeat testing (at central laboratory) should be done regularly until CK levels return to normal or 
baseline state. Additional clinical information should be gathered to seek the possible cause of the 
observed CK elevation.
1.13
Hepatic event
!
ALT or AST > 5 x UNL and total bilirubin ≤ 2 x UNL
!
ALT or AST >3 x UNL and total bilirubin > 2 x UNL*
!
Hepatic event leading to trial product discontinuation
*Please note that risk of liver injury defined as ALT or AST > 3 x UNL and total 
bilirubin>2 x UNL, where no alternative aetiology exits (Hy’s law), should also be reported as a 
SAE (important medical event, according to protocol Section 12.1.2).
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
23 September 2016
Novo Nordisk
Trial ID: NN9924-4281
Version:
2.0
UTN: U1111-1181-4048
Status:
Final
     
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If one of the above events is observed during the trial, the following additional information must be 
reported if available:
!
Signs and symptoms associated to the event
!
Risk factors
!
Relevant laboratory test results
!
Diagnostic imaging performed
!
Possible cause(s) of the event
1.13.1
Assessments in case of increased levels of aminotransferases
Both events should prompt repeat testing (at central laboratory) including ALT, AST, alkaline 
phosphatase (ALP) and total bilirubin and discontinuation of trial product should be considered. 
Thereafter, repeat testing (at central laboratory) of ALT, AST, ALP and total bilirubin should be 
done regularly until the abnormalities return to normal or baseline state. Additional clinical 
information such as related symptoms, risk factors and contributing conditions (e.g. viral hepatitis, 
autoimmune hepatitis, alcoholic hepatitis, hepatobiliary or pancreatic disorders) should be gathered 
to seek a possible cause of the observed laboratory test abnormalities.
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
23 September 2016
Novo Nordisk
Trial ID: NN9924-4281
Version:
2.0
UTN: U1111-1181-4048
Status:
Final
     
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2
References
1.
Banks PA, Freeman ML, Practice Parameters Committee of the American College of G. 
Practice guidelines in acute pancreatitis. Am J Gastroenterol. 2006;101(10):2379-400.
2.
Banks PA, Bollen TL, Dervenis C, Gooszen HG, Johnson CD, Sarr MG, et al. Classification 
of acute pancreatitis-2012: revision of the Atlanta classification and definitions by 
international consensus. Gut. 2013;62(1):102-11.
3.
U.S. Department of Health and Human Services, Food and Drug Administration. Guidance 
for Industry: Immunogenicity Assessment for Therapeutic Protein Products. August 2015.
CONFIDENTIAL


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: NN9924-4281
Clinical Trial Report
Appendix 16.1.1
20 December 2018
0.1
Review
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Protocol Amendment
CONFIDENTIAL
Date:
17 November 2016
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Trial ID: NN9924-4281
Version:
1.0
UTN: U1111-1181-4048
Status:
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Protocol Amendment
no 1
to Protocol, final version 2.0
dated 23 September 2016
Trial ID:NN9924-4281
PIONEER 9- Japan Monotherapy
Dose-response, Safety and Efficacy of Oral Semaglutide
versus Placebo and versus Liraglutide,
All as Monotherapy in Japanese Subjects with Type 2 Diabetes
Trial phase: 2/3a
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:
17 November 2016
Novo Nordisk
Trial ID: NN9924-4281
Version:
1.0
UTN: U1111-1181-4048
Status:
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Table of Contents   
Page
Table of Contents..............................................................................................................................................2
1
Introduction including rationale for the protocol amendment.............................................................3
1.1
Additional eye examinations and additional data collection on diabetic retinopathy....................3
1.2
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..............................4
1.4
Other minor adjustments, clarifications and correction of typographical errors............................4
2
Changes......................................................................................................................................................5
2.1
Section 2  Flow chart .....................................................................................................................5
2.2
Section 4.2.2.2 Supportive secondary endpoints ...........................................................................5
2.3
Section 6.6 Withdrawal from trial .................................................................................................5
2.4
Section 8.1.5 End-of-treatment (visit 12) and Follow-up (visit 13)...............................................6
2.5
Section 8.1.6 Premature discontinuation of trial product and follow-up (visits 12A and 
13A) ...............................................................................................................................................6
2.6
Section 8.1.7.1  Lost to follow-up ..................................................................................................7
2.7
Section 8.4.1.2 Adverse events requiring additional data collection.............................................7
2.8
Section 8.4.2 Physical examination ...............................................................................................8
2.9
Section 8.4.4 Eye examination.......................................................................................................9
2.10
Section 8.4.8 Anti-semaglutide antibodies ....................................................................................9
2.11
Section 12.1.5 Adverse events requiring additional data collection..............................................9
2.12
Section 17.2 Definition of analysis sets........................................................................................9
2.13
Section 17.3.2 Analysis for the secondary estimand ...................................................................10
2.14
Section 17.4.1.1 Efficacy endpoints ............................................................................................10
2.15
Section 17.4.1.2 Safety endpoints................................................................................................11
2.16
Section 18.1.1 Risks and precautions with oral semaglutide.......................................................11
2.17
Section 27 References..................................................................................................................12
2.18
Reference numbers ......................................................................................................................12
2.19
Appendix B, section 1 Adverse events requiring additional data collection ...............................12
2.20
Appendix B, Section 1.14 Diabetic retinopathy and related complications................................13
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
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Trial ID: NN9924-4281
Version:
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UTN: U1111-1181-4048
Status:
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1
Introduction including rationale for the protocol amendment
This protocol amendment introduces:
1. Change in allowance of 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, 8.4.1.2, 8.4.4, 12.1.5, 17.2, 17.4.1.2, 18.1.1, 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 treatment1,2,3. Risk factors for these events include 
long-standing poor glycaemic control and presence of proliferative retinopathy, and initial large 
improvements in blood glucose may be an additional aggravating factor. In a recently completed 
cardiovascular outcomes trial with s.c. semaglutide, results indicate an increased risk of events 
related to diabetic retinopathy in subjects treated with semaglutide compared to placebo4. The 
majority of the related adverse events were moderate in severity and did not lead to premature 
discontinuation of trial product. Also, to further understand this safety signal, additional information 
will be collected for all diabetic retinopathy events reported during the trial. Furthermore, 
information to the investigators and subjects related to diabetic retinopathy has been added to the 
protocol (see Section 18).
The timepoint of the eye examination taken at end of treatment (EoT; visit 12 or visit 12A) has been 
moved to ensure the treatment is completed or finished as for other assessments performed at EoT. 
                                                
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


Protocol Amendment
CONFIDENTIAL
Date:
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Trial ID: NN9924-4281
Version:
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Status:
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The Eye examination at the EoT must be performed at visit 12 or within 5 weeks thereafter for 
subjects completing treatment, and at visit 12A or within 5 weeks thereafter and again within 5 
weeks prior to visit 12 for subjects who have prematurely discontinued trial product. 
1.2
Investigator’s responsibility in ensuring evaluation and management of certain risk 
factors and complications
Updated sections in the protocol: 8.4.2, 18.1.1
, 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.
1.3
Clarification of the criteria for completion, withdrawal and lost to follow-up
Updated sections in the protocol: 6.6, 8.1.5, 8.1.6, 8.1.7.1
The criteria for subject completion, -withdrawal and -lost to follow-up respectively are clarified and 
have been made consistent across sections. Lost to follow-up is considered a subcategory to 
withdrawal from trial. In addition, it is emphasised that as soon as contact to a subject is lost, efforts 
must be made to regain contact and the efforts must continue until the subjects last planned visit. 
Only if contact is not regained at that time point can the subject be considered lost to follow up. 
Because this trial is not an outcome trial the terminology ‘health status’ is replaced with “relevant 
safety information” - the purpose of which is to follow up on any adverse events or pregnancy, and 
not to determine if a subject completes the trial or not.
1.4
Other minor adjustments, clarifications and correction of typographical errors
Laboratory analysis
Updated sections in the protocol: 8.4.8
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
Updated sections in the protocol: 17.3.2, 17.4.1.1
CONFIDENTIAL


Protocol Amendment
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Date:
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Trial ID: NN9924-4281
Version:
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Status:
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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.
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
Footer
Description
e
Fundus photography/dilated fundoscopy performed within 90 days prior to 
randomisation is acceptable if results are available for evaluation at V2, unless 
worsening of visual function since last examination.
Fundus photography/dilated fundoscopy at V12 is allowed to be performed between 
V11 and V12 (preferably as close to V12 as possible).
Fundus photography or dilated fundoscopy must be performed again:
!
at V12 or within 5 weeks thereafter for subjects completing treatment
!
at V12A or within 5 weeks thereafter, and again within 5 weeks prior to V12, 
for subjects who have prematurely discontinued trial product 
2.2
Section 4.2.2.2
Supportive secondary endpoints
Supportive secondary safety endpoints
…
Change from baseline to week 52 in:
!
Fundus photography/dilated fundoscopy Eye examination category
2.3
Section 6.6
Withdrawal from trial
The subject may withdraw consent at will at any time. The subject’s request to withdraw from the 
trial must always be respected. Only subjects who withdraw consent should be considered as 
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Protocol Amendment
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Trial ID: NN9924-4281
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withdrawn from trial. A subject who does not complete the trial is also considered withdrawn from 
the trial. Hence a subject is considered withdrawn if the following applies:
!
Subject withdrew consent 
!
Subject is lost to follow up (only to be used if there is no contact with the subject by the time 
of the subject’s last scheduled visit, see sections 8.1.5 – 8.1.7.1)
!
Other (subject deceased or closure of trial site)
2.4
Section 8.1.5
End-of-treatment (visit 12) and Follow-up (visit 13)
Subjects, who stay on trial product throughout the trial, must attend the End-of-treatment visit (visit 
12) 52 weeks after randomisation (±3 days visit window) and the Follow-up visit (visit 13) 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 12 (see Section 10).
At visit 12 the subject should be reminded about the importance of attending the follow-up visit 
(visit 13). If the subject, nonetheless, does not attend visit 13, the site should make efforts to obtain 
contact with the subject within the visit window. 
A trial completer is defined as a subject who attends, or is in contact with the site, at the subject’s 
last scheduled visit. For subjects who complete treatment, the last scheduled visit is visit 13. (For 
subjects who discontinue trial product, see Section 8.1.6) 
In case the subject cannot be reached (by clinic visit or phone contact) at the scheduled visit 13, the 
site should consult the contacts provided by the subject (e.g. close relatives), relevant physicians
and medical records to collect health status. If no health status can be collected, the subject should 
be considered lost to follow-up and this should be specified in the end-of-trial form. 
2.5
Section 8.1.6
Premature discontinuation of trial product and follow-up (visits 12A 
and 13A)
...
Subjects should continue with the originally scheduled site contacts after visit 13A and up to and 
including visit 12. If necessary, in order to retain the subject in the trial, site visits can be replaced 
by phone contacts after visit 13A. However, as a minimum, these subjects should be asked to attend 
the scheduled visit 8 at week 26 and end-of-treatment (visit 12) at week 52 as these visits should be 
performed for all subjects, if at all possible (except subjects who withdraw informed consent, see 
Section 8.1.7).
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Protocol Amendment
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Date:
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Trial ID: NN9924-4281
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Subjects, who only agree to attend or provide health status at the planned visit 12, should not be 
considered withdrawn from the trial. In case the subject cannot be reached (by clinic visit or phone 
contact) at the scheduled visit 12, the site should consult the contacts provided by the subject (e.g. 
close relatives), relevant physicians and medical records to collect health status. If no health status 
can be collected, the subject should be considered lost to follow-up and this should be specified in 
the end-of-trial form. 
A subject who prematurely discontinued trial product is still considered a trial completer if the 
subject attends or is in contact with the site, at the subject’s last scheduled visit. For subjects who 
prematurely discontinue trial product, the last scheduled visit is visit 12 (or visit 13A if it is 
scheduled after visit 12). The site should in due time prepare for establishing contact with the 
subject within the visit window of the scheduled visit 8 and visit 12, respectively if the subject has 
agreed to attend these visits.
In summary, subjects should stay in the trial irrespective of lack of adherence to randomised 
treatment, lack of adherence to visit schedule, missing assessments or trial product discontinuation 
for any reason. Only subjects who decline any further contact with the site in relation to the trial 
should be considered as having withdrawn consent from the trial (for withdrawal procedures, see 
Section 8.1.7).
2.6
Section 8.1.7.1
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 and medical records 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: visit 13 for subjects who have completed 
treatment, whereas for subjects who have discontinued trial product prematurely the last visit is 
visit 12 (or visit 13A if it is scheduled after visit 12). Only if contact with the subject is not regained 
by the end of the visit window of the last scheduled visit can the subject be considered lost to follow 
up (see Section 6.6).
2.7
Section 8.4.1.2
Adverse events requiring additional data collection 
For the following AEs additional data collection is required and specific event forms must be 
completed in the eCRF in addition to the AE form:
!
Acute coronary syndrome (MI or unstable angina pectoris requiring hospitalisation)
!
Cerebrovascular event (stroke or transient ischaemic attack[TIA])
CONFIDENTIAL


Protocol Amendment
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Date:
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Trial ID: NN9924-4281
Version:
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Status:
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!
Heart failure 
!
Pancreatitis
!
Neoplasm (excluding thyroid neoplasm)
!
Thyroid disease (including thyroid neoplasm)
!
Renal event
!
Hypersensitivity reaction
!
Acute gallstone disease
!
Medication error
!
Lactic acidosis
!
Creatine kinase (CK) > 10x UNL
!
Hepatic event defined as:
–
ALT or aspartate aminotransferase (AST) > 5x UNL and total bilirubin ≤ 2x UNL
–
ALT or AST > 3x UNL and total bilirubin > 2x UNL*
–
Hepatic event leading to trial product discontinuation.
!
Diabetic retinopathy and related complications
*Please note that in case of a hepatic event defined as ALT or AST >3 x UNL and total bilirubin >2 
x UNL, where no alternative aetiology exists (Hy's law), this must be reported as an SAE using the 
important medical event criterion if no other seriousness criteria are applicable.
2.8
Section 8.4.2
Physical examination
A physical examination will be performed by the investigator according to local procedure (see 
Sections 2 and 8.1.8). A physical examination must include:

General appearance

Head, ears, eyes, nose, throat, neck

Thyroid gland*

Respiratory system

Cardiovascular system

Gastrointestinal system including mouth

Musculoskeletal system

Central and peripheral nervous system

Skin

Lymph node palpation
*Please note that the diagnostic evaluation of thyroid nodules should be in accordance with the 
American Thyroid Association Management Guidelines or any updates hereof 39, and adapted to 
local treatment guidelines if applicable.
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Trial ID: NN9924-4281
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2.9
Section 8.4.4
Eye examination 
Fundus photography or dilated fundoscopy will be performed as per flow chart (see Section 2) by 
the investigator or according to local practise. Fundoscopy requires pharmacological dilation of 
both pupils. Results of the fundus photography or dilated fundoscopy will be interpreted by the 
investigator (see Section 8.1.8).
2.10
Section 8.4.8
Anti-semaglutide 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 binding antibody analysis.
2.11
Section 12.1.5
Adverse events requiring additional data collection
Table 12-1
Adverse events requiring completion of specific event forms and/or are subject to 
event adjudication
[Note: In this document only the additional event is shown, all other events are unchanged]
Event
Specific event form
Event adjudication
Diabetic retinopathy and related complications
Yes
No
2.12
Section 17.2 
Definition of analysis sets
Definition of the observation periods
...
On-treatment: This observation period represents the time period where subjects are considered
treated with trial product. The observation period is a subset of the in-trial observation period. It
starts at the date of first dose of trial product. Two slightly different end dates will be needed to
cover all assessments appropriately. For adjudicated events, ECGs, eye examination category, anti-
semaglutide antibodies and AEs including hypoglycaemic episodes, the observation period ends at 
the first date of any of the following:
!
the follow-up visit (V13)
!
the follow-up prematurely discontinuation visit (V13A)
!
the last date on trial product + 38 days
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Version:
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!
the end-date for the in-trial observation period
2.13
Section 17.3.2
Analysis for the secondary estimand
...
Missing values for each group will be imputed as follows:
!
An analysis of covariance (ANCOVA) with stratification factor 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 1000 values 
for each subject with missing week 26 data based on stratification factor and baseline 
HbA1c. Thus, 100 1000 complete data sets will be generated including observed and imputed 
values.
Analysis used for testing 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 analysis of covariance (ANCOVA) with treatment 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 rule4748 to draw inference.
2.14
Section 17.4.1.1
Efficacy endpoints 
For evaluation of the secondary estimand the analysis will be performed separately for week 26 
and 52. For the analysis at week 52, 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 20 15 groups of 
subjects instead of the 10 groups as described for the week 26 evaluation in Section 17.3.2. If 
less than 5 subjects have available data in one of the 20 15 groups, the imputation will be made 
within the 10 groups specified for the primary evaluation. The frequency of missing data is 
expected to be slightly larger at week 52 compared to week 26. The rate of missing data is 
expected to decline over time.
Binary efficacy endpoints
…
To account for missing data, the analysis will be made using a sequential multiple imputation 
approach as described below:
!
Multiple imputed data sets (100 1000) will be created in which missing values for the 
underlying continuous assessments are imputed by treatment group and treatment 
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Protocol Amendment
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adherence/rescue status assuming MAR and as described in section 17.3.2 for the secondary
estimand and by treatment group assuming MAR and as described in section 17.3.1 for the 
primary estimand.
!
The binary endpoint will be created for each of the 100 1000 complete data sets
!
Each of the created complete data set will be analysed with the logistic model and inference 
will be drawn using Rubin’s rule4748.
2.15
Section 17.4.1.2
Safety endpoints
Other safety endpoints
…
Change from baseline to week 52 in:
!
Fundus photography/dilated fundoscopy Eye examination category
2.16
Section 18.1.1
Risks and precautions with oral semaglutide
Other safety considerations
Diabetic retinopathy complications
A transient worsening of diabetic retinopathy is a recognised complication in selected patients with 
diabetes after initiation of intensive antidiabetic treatment49, 50, 51, 52. 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 progression4, 5253 even in intensively treated patients who experienced early 
worsening5051. In a cardiovascular outcomes trial with s.c. semaglutide, results indicate an increased 
risk of events related to diabetic retinopathy in subjects treated with semaglutide compared to 
placebo54. As a precaution in this trial, all subjects are required to have a fundus photography or 
dilated fundoscopy performed before enrolment into the trial; moreover, subjects with proliferative 
retinopathy or maculopathy requiring acute treatment will be excluded. As part of good diabetes 
management the investigator is encouraged to ensure adequate monitoring and treatment of 
diabetic retinopathy in subjects enrolled into the trial55
...
General precautions 
…
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Protocol Amendment
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It is the responsibility of the investigator to ensure the best possible care of the subject. This 
includes adequate glycaemic control, appropriate risk factor modification such as optimal 
treatment of hypertension, dyslipidaemia and other cardiovascular risk factors, as well as regular 
monitoring and treatment of diabetic kidney disease and diabetic retinopathy (Diabetes Care 2016
Standards of Medical Care in Diabetes)5355.
2.17
Section 27
References 
39 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.
54 Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, et al. Semaglutide and 
Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2016.
5355.American Diabetes Association. Standards of medical care in diabetes -2016. Diabetes Care. 
2016;39 (Suppl. 1):S13-S22.
2.18
Reference numbers
Will change throughout the protocol when new reference numbers are introduced.
2.19
Appendix B, section 1
Adverse events requiring additional data collection
For the following adverse events (AEs) additional data collection is required and specific event 
forms must be completed in the electronic case report form (eCRF) in addition to the AE form:
!
Acute coronary syndrome (myocardial infarction or unstable angina pectoris requiring 
hospitalisation)
!
Cerebrovascular event (stroke or transient ischaemic attack)
!
Heart failure
!
Pancreatitis
!
Neoplasm (excluding thyroid neoplasm)
!
Thyroid disease (including thyroid neoplasm)
!
Renal event
!
Hypersensitivity reaction
!
Acute gallstone disease
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Protocol Amendment
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!
Medication error (concerning trial products):
!
Administration of wrong drug or use of wrong device. 
Note: Use of wrong dispensing unit number (DUN) is not considered a medication error
unless it results in administration of wrong drug.
!
Wrong route of administration, such as intramuscular instead of s.c..
!
Administration of an overdose with the intention to cause harm (e.g. suicide attempt), 
misuse or abuse of trial product.
!
Accidental administration of a higher dose than intended. A higher dose is a dose of at 
least one tablet more than the intended dose and for pen injection a higher dose than 0.9 
mg/day; however the administered dose must deviate from the intended dose to an 
extent where clinical consequences for the trial subject were likely to happen as judged 
by the investigator, although they did not necessarily occur.
!
Lactic acidosis
!
Creatine kinase (CK) > 10 x upper normal limit (UNL)
!
Hepatic event defined as:
!
alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 5 x UNL and 
total bilirubin ≤ 2 x UNL
!
ALT or AST >3 x UNL and total bilirubin > 2 x UNL*
!
Hepatic event leading to trial product discontinuation
!
Diabetic retinopathy and related complications
2.20
Appendix B, 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

SAP_001.pdf: 
Cover Page for Statistical Analysis Plan  
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT03018028 
Sponsor trial ID: 
NN9924-4281 
Official title of study: 
PIONEER 9 – Japan Monotherapy. Dose-response, Safety and 
Efficacy of Oral Semaglutide versus Placebo and versus 
Liraglutide, All as Monotherapy in Japanese Subjects with 
Type 2 Diabetes 
Document date: 
28 February 2019 
 


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: NN9924-4281
Clinical Trial Report
Appendix 16.1.9
2 February 2019
1.0
Final
16.1.9 Documentation of statistical methods
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Redacted VWDWLVWLFDODQDO\VLVSODQ
Lncludes redaction of personal identifiable DQGFRPSDQ\
FRQILGHQWLDOinformation. 
. 


Statistical Analysis Plan
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Date:
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Trial ID: NN9924-4281
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Statistical Analysis Plan
Trial ID: NN9924-4281
PIONEER 9 – Japan Monotherapy
Dose-response, Safety and Efficacy of Oral Semaglutide
versus Placebo and versus Liraglutide,
All as Monotherapy in Japanese 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.
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This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Statistical Analysis Plan
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Date:
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Trial ID: NN9924-4281
Version:
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Table of contents   
Page
Table of contents.........................................................................................................................................2
List of abbreviations ...................................................................................................................................3
1
Introduction .........................................................................................................................................5
1.1
Trial information.......................................................................................................................5
1.2
Scope of the statistical analysis plan..........................................................................................6
2
Statistical considerations .....................................................................................................................6
2.1
General considerations ..............................................................................................................6
2.1.1
Primary and secondary estimands.............................................................................7
2.1.1.1
Primary estimand - ‘Hypothetical’......................................................7
2.1.1.2
Secondary estimand - ‘Treatment policy’............................................7
2.1.2
Missing data considerations .....................................................................................8
2.2
Sample size calculation .............................................................................................................8
2.3
Definition of analysis sets..........................................................................................................9
2.4
Primary endpoint.....................................................................................................................11
2.4.1
Analysis for the primary estimand..........................................................................11
2.4.2
Analysis for the secondary estimand ......................................................................12
2.5
Secondary endpoint.................................................................................................................13
2.5.1
Supportive secondary endpoint...............................................................................13
2.5.1.1
Efficacy endpoints............................................................................13
2.5.1.2
Safety endpoints...............................................................................18
2.5.1.3
Pharmacokinetic endpoints...............................................................21
2.6
Interim analysis.......................................................................................................................21
2.7
Pharmacokinetic and/or pharmacodynamic modelling .............................................................22
2.8
Health economics and/or patient reported outcomes.................................................................22
2.8.1
SF-36v2® Health Survey (acute version) ................................................................22
2.8.2
Diabetes Therapy-Related Quality of Life (DTR-QoL)...........................................24
2.8.3
Responder analyses................................................................................................25
3
Changes to the statistical analyses planned in the protocol..............................................................26
4
References ..........................................................................................................................................28
CONFIDENTIAL


Statistical Analysis Plan
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List of abbreviations
ADA
American Diabetes Association
AE
adverse event
AACE 
American Association of Clinical Endocrinologists
ANOVA
analysis of variance
ATC 
Anatomical Therapeutic Chemical
BG 
blood glucose
BMI
body mass index
CI
confidence interval
CTR
clinical trial report
DTR-QOL 
Diabetes Therapy-Related Quality of Life
EAC 
event adjudication committee
ECG 
electrocardiogram
eCRF
electronic case report form
FAS
full analysis set
HbA1c
glycosylated haemoglobin
HDL
high density lipoprotein
HRQoL
health-related quality of life
HOMA-B
homeostatic model assessment index of beta-cell function
HOMA-IR
homeostatic model assessment index of insulin resistance
IWRS
interactive web response system
LDL
low density lipoprotein
LLoQ
lower limit of quantification
MAR
missing at random
MCS 
mental component score
MCMC
Markov Chain Monte Carlo
MedDRA
Medical Dictionary for Regulatory Activities
MH 
mental Health
MI 
multiple imputation
MMRM
mixed model for repeated measurements
NBS 
norm-based score
OAD
oral antidiabetic drug
PCS 
physical component score
PF 
physical Functioning
PG 
plasma glucose
PK
pharmacokinetics
PRO 
patient reported outcome
RE
role Limitations Due to Emotional Problems
REML 
restricted maximum likelihood
CONFIDENTIAL


Statistical Analysis Plan
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Date:
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Trial ID: NN9924-4281
Version:
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Status:
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RP 
role Limitations Due to Physical Health
SAP
statistical analysis plan
SAS
safety analysis set
s.c.
subcutaneous
SD
standard deviation
SF
social Functioning
SF-36v2 (acute version)
SF-36v2® Health Survey (acute version)
SMPG 
self-measured plasma glucose
T2DM
type 2 diabetes mellitus
TEAE
treatment-emergent adverse events
VLDL
very low density lipoprotein
VT 
vitality
CONFIDENTIAL


Statistical Analysis Plan
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Date:
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Trial ID: NN9924-4281
Version:
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1
Introduction
1.1
Trial information
This is a combined phase 2 dose-response and phase 3 safety and efficacy trial. It is a 52-week, 
randomised double-blind placebo-controlled and open-label active-controlled, parallel-group, 
multicentre, single country trial with 5 treatment arms in Japanese subjects with T2DM to:
!
assess dose-response relationship of once-daily dosing of 3 dose levels of oral semaglutide 
(3, 7 and 14 mg) versus placebo on glycaemic control at week 26
!
compare the safety and efficacy of once-daily dosing of 3 dose levels of oral semaglutide (3, 
7 or 14 mg) versus placebo and versus once-daily 0.9 mg liraglutide subcutaneously at week 
26 and week 52
Primary objective
To assess the dose-response relationship of once-daily dosing of three dose levels (3, 7 and 14 mg) 
of oral semaglutide versus placebo as monotherapy on glycaemic control in Japanese subjects with 
type 2 diabetes mellitus.
Secondary objective
To compare the safety and tolerability of once-daily dosing of three dose levels (3, 7 and 14 mg) of 
oral semaglutide versus placebo and versus once-daily 0.9 mg liraglutide subcutaneously, all as 
monotherapy in Japanese subjects with type 2 diabetes mellitus.
To compare the effect of once-daily dosing of three dose levels (3, 7 and 14 mg) of oral semaglutide 
versus placebo and versus once-daily 0.9 mg liraglutide subcutaneously, all as monotherapy on 
glycaemic control and body weight in Japanese subjects with type 2 diabetes mellitus.
Trial design
Japanese subjects with T2DM treated with diet and exercise therapy alone or OAD as monotherapy 
(half maximum approved dose or below) in addition to diet and exercise therapy will be included in 
this trial. For subjects treated with OAD as monotherapy, pre-trial OAD will be discontinued at 
screening and washed-out before randomisation. Subjects treated with diet and exercise therapy 
alone will be randomised without a wash-out period after their eligibility has been confirmed.
Subjects will be randomised in a 1:1:1:1:1 manner to receive either a oral semaglutide 3, 7 or 14 mg 
once-daily, oral placebo once-daily or liraglutide 0.9 mg subcutaneous (s.c.) injection once-daily. 
Randomisation will be stratified based on pre-trial OAD treatment at screening (yes/no).
The trial is double-blinded with regard to dose levels of oral semaglutide and placebo. In order to 
maintain the blinding of the trial for oral semaglutide and placebo all tablets containing oral 
CONFIDENTIAL


Statistical Analysis Plan
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Date:
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Trial ID: NN9924-4281
Version:
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semaglutide or placebo are identical with regards to visual appearance. The treatment 
administration of liraglutide will be open-label.
The total trial duration for the individual subject will be 59 to 65 weeks depending on pre-trial 
treatment. The trial includes a 2-week screening period, followed by a 52-week randomised 
treatment period and a follow-up period of 5 weeks. For subjects treated with OAD as monotherapy 
prior to the screening an 8-week wash-out period including the screening period will replace the 2-
week screening period.
1.2
Scope of the statistical analysis plan
This statistical analysis plan (SAP) is based on the protocol for trial NN9924-4281 “Dose-response, 
Safety and Efficacy of Oral Semaglutide versus Placebo and versus Liraglutide, all as Monotherapy 
in Japanese Subjects with Type 2 Diabetes”, version 3.0 (17 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.
Novo Nordisk will be responsible for the statistical analyses and reporting. 
2
Statistical considerations
2.1
General considerations
The blinding of the randomised treatments will be maintained until the database has been released 
for statistical analysis. No interim analyses will be performed before the database is locked.
Data from all sites will be analysed and reported together.
In statistical analyses where stratification is included, the pre-trial OAD treatment at screening 
(yes/no) will be included based on the actual information collected through the eCRF. In case of 
missing eCRF information the information collected from the IWRS system will be used. In the 
statistical analyses the stratification factor will refer to pre-trial OAD treatment at screening.
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.
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Statistical Analysis Plan
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Date:
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Trial ID: NN9924-4281
Version:
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The primary efficacy endpoints will be evaluated at week 26. This approach will result in a lower 
proportion of missing data, use of rescue medication and premature treatment discontinuation, 
compared to the expected proportion of missing data at week 52 and therefore considered a 
meaningful representation and confirmation of the dose-response relationship of oral semaglutide.
Results from a statistical analysis will as a minimum be presented by the estimated treatment 
contrasts for the below six comparisons with associated two-sided 95% confidence intervals (CIs)
and p-values corresponding to two-sided tests of no difference:
!
oral semaglutide 14 mg vs. placebo 
!
oral semaglutide 14 mg vs. liraglutide 0.9 mg
!
oral semaglutide 7 mg vs. placebo
!
oral semaglutide 7 mg vs. liraglutide 0.9 mg 
!
oral semaglutide 3 mg vs. placebo
!
oral semaglutide 3 mg vs. liraglutide 0.9 mg 
If no statistical analysis is specified, data will be presented using relevant summary statistics.
2.1.1
Primary and secondary estimands
Two estimands addressing different aspect of the trial objective will be defined; a primary 
“Hypothetical” estimand and a secondary “Treatment policy” estimand.
2.1.1.1
Primary estimand - ‘Hypothetical’
!
Treatment difference (oral semaglutide versus placebo and oral semaglutide versus 
liraglutide) at week 26 in all randomised subjects if all subjects adhered to treatment and did 
not initiate rescue medication
The hypothetical estimand assesses the expected glycaemic benefit under adherence to trial product 
and is considered the primary interest for evaluating the dose-response relationship of oral 
semaglutide. Generalisation of this estimand depends among other things on the extent to which the 
adherence to trial product administration in this trial reflects the behaviour of the target population. 
Accordingly, only data collected prior to discontinuation of trial product or initiation of rescue 
medication will be used to draw inference. This will avoid confounding from rescue medication.
2.1.1.2
Secondary estimand - ‘Treatment policy’
!
Treatment difference (oral semaglutide versus placebo and oral semaglutide versus 
liraglutide) at week 26 in all randomised subjects regardless of discontinuation of trial 
product or initiation of rescue medication(s)
The treatment policy estimand assesses the expected glycaemic benefit in a future population that 
results from subjects initiating treatment with oral semaglutide including potential rescue 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
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Trial ID: NN9924-4281
Version:
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Status:
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medication(s). Generalisation of this estimand depends among other things on the extent to which 
the use of rescue medication in this trial reflects clinical practice and the adherence to trial product 
administration in this trial reflects the behaviour of the target population. Accordingly, data 
collected regardless of discontinuation of trial product or initiation of rescue medication(s) will be 
used to draw inference.
2.1.2
Missing data considerations
Based on the results from similar Japanese phase 3 trials investigating liraglutide and s.c. 
semaglutide as monotherapy (NN2211-1700, NN9535-4091 and NN9535-4092) and the oral 
semaglutide phase 2 trial (NN9924-3790), it is expected that maximum 30% of the subjects will 
discontinue trial product or withdrawal from the trial at week 52. 
When estimating the secondary estimand, the proportion of subject with 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 is expected to be maximum 10% based on the oral semaglutide 
phase 2 trial (NN9924-3790). Thus, missing data will mainly be due to withdrawal from trial or lost 
to follow-up.
When estimating the primary estimand, the proportion of subject with missing data is expected to be 
higher (20%) than for the secondary estimand because data collected after discontinuation of trial 
product or initiation of rescue medication(s) will be set to missing. The proportion of subject with
missing data at week 26 is expected to be maximum 20% based on the liraglutide phase 3 trial 
(NN2211-1700), s.c. semaglutide phase 3 trials (NN9535-4091 and NN9535-4092) and the oral 
semaglutide phase 2 trial (NN9924-3790). 
Across treatment arms, the main reasons for missing data are expected to be early treatment 
discontinuation due to AEs (gastrointestinal AEs for oral semaglutide and liraglutide) and initiation 
of rescue medication. Initiation of rescue medication is expected to be more frequent in the placebo 
arm than for the oral semaglutide and liraglutide arms. A higher proportion of subjects are expected 
to discontinue treatment due to AEs in the oral semaglutide and liraglutide arms, compared to the 
placebo arm. 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.
2.2
Sample size calculation
The total sample size of 240 subjects and duration of this trial have been determined to allow for 
adequate (i) evaluation of the dose-response relationship and (ii) safety evaluation in a monotherapy 
setting in line with the Japanese draft AD guideline1. With a maximum expected premature 
CONFIDENTIAL


Statistical Analysis Plan
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Date:
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Trial ID: NN9924-4281
Version:
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treatment discontinuation rate of 30% after week 52, this trial ensures that at least 100 subjects are 
exposed to oral semaglutide for one year.
Based on 48 subjects per treatment arm and a standard deviation of 1.1% in change from baseline to 
week 26 in HbA1c, the width of the 95% confidence interval (precision) for the mean difference in 
HbA1c will at most be +/- 0.5 %-point with 90% probability.
Furthermore, with 48 subjects per treatment arm the trial will be able to show a significant HbA1c
treatment difference of 0.74 %-point with 90% power and a treatment difference of 0.64 %-point 
with 80% power. As a reference, the assumed treatment effects (TE) and adjusted treatment effects 
are presented in Table 2–1. These are based on the oral semaglutide phase 2 results (NN9924-3790) 
and supported by results from the s.c. semaglutide phase 2 trial (NN9535-1821).
The adjustment of the treatment effects are done differently when estimating the primary and the 
secondary estimand, due to the different analyses and the inclusion of data collected after treatment 
discontinuation and initiation of rescue medication for the secondary estimand. The treatment 
effects will be adjusted according to a 50% smaller effect in subjects with missing data when 
estimating the primary estimand. Whereas a 75% smaller effect will be used for the 10% of the 
subjects who are expected to discontinue trial product or initiate rescue medication and for the 10% 
of subjects who are expected to have missing data when estimating the secondary estimand.
Primary estimand
- Adjusted TE = 0.8×TE + 0.2×TE×0.50
Secondary estimand
- Adjusted TE = 0.8×TE + 0.1×TE×0.25 + 0.1×TE×0.25
Table 2–1
Treatment effects in HbA1c (%-point)
Oral semaglutide 
3 mg
7 mg
14 mg
Treatment effects (TE)
0.45
0.75
1.0
Primary estimand: Adjusted TE
0.405
0.675
0.9
Secondary estimand: Adjusted TE
0.3825
0.6375
0.85
2.3
Definition of analysis sets
The following analysis sets will be defined:
Full analysis set (FAS): Includes all randomised subjects. Subjects in the FAS will contribute to 
the evaluation “as randomised”.
Safety analysis set (SAS): Includes all subjects exposed to at least one dose of trial product. 
Subjects in the SAS will contribute to the evaluation based on the trial product received for the 
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Statistical Analysis Plan
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majority of the period where treated. This will be referred to as contributing to the evaluation “as 
treated”.
Data selections and observation periods
Unless subjects withdraw their informed consent, data collection will continue for the full duration 
of the trial. The full duration of the trial is defined as up to and including:
!
The follow-up visit (V13) for subjects on trial product
!
The latest occurring visit of the end-of-treatment visit (V12) or the follow-up premature 
discontinuation visit (V13A), for subjects who have discontinued trial product prematurely
Subjects and data to be used in an analysis will be selected in a two-step manner:
!
Firstly, subjects will be selected based on the specified analysis set
!
Secondly, data points on the selected subjects from first step will be selected based on the 
specified observation period
Definition of the observation periods
In-trial: This observation period represents the time period where subjects are considered to be in 
the trial, regardless of discontinuation of trial product or initiation of rescue medication. The in-trial 
observation period starts at randomisation (as registered in IWRS) and ends at the date of:
!
The last direct subject-site contact, which is scheduled to take place 5 weeks after planned 
last dose of trial product at a follow-up visit
!
Withdrawal for subjects who withdraw their informed consent
!
The last subject-investigator contact as defined by the investigator for subjects who are lost 
to follow-up
!
Death for subjects who dies before any of the above
On-treatment: This observation period represents the time period where subjects are considered 
treated with trial product. The observation period is a subset of the in-trial observation period. It 
starts at the date of first dose of trial product. Two slightly different end dates will be needed to 
cover all assessments appropriately. For adjudicated events, ECGs, eye examination category, anti-
semaglutide antibodies and AEs including hypoglycaemic episodes, the observation period ends at 
the first date of any of the following:
!
The follow-up visit (V13)
!
The follow-up prematurely discontinuation visit (V13A)
!
The last date on trial product + 38 days
!
The end-date for the in-trial observation period
The follow-up visit is scheduled to take place 5 weeks after the last date on trial product 
corresponding to approximately five half-lives of oral semaglutide. The visit window for the follow-
up visit is +3 days.
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Statistical Analysis Plan
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Date:
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Trial ID: NN9924-4281
Version:
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Status:
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For efficacy and other safety assessments (laboratory assessments, physical examination and vital 
signs) the observation period ends at the last date on trial product +3 days. This will be used in 
order to ensure specificity to reversible effects of treatment.
On-treatment without rescue medication: This observation period is a subset of the on-treatment 
observation period, where subjects are considered treated with trial product, but have not initiated 
any rescue medications. Specifically it starts at date of first dose of trial product and the observation 
period ends at the first date of:
!
The last dose of trial product +3 days
!
Initiation of rescue medication
The in-trial observation period will be the primary observation period when estimating the 
secondary estimand. The on-treatment without rescue medication observation period will be the 
primary observation period when estimating the primary estimand. Safety will be evaluated based 
on the in-trial and the on-treatment observation periods.
Data points collected outside an observation period will be treated as missing in the analysis. 
Baseline data will always be included in an observation period. For adjudicated events, the onset 
date will be the EAC adjudicated onset date.
Before data are locked for statistical analysis and the randomisation code is broken, a review of all 
data will take place. Any decision to exclude either a subject or single observations from the 
statistical analysis is the joint responsibility of the members of the Novo Nordisk study group. 
Exclusion of data from analyses should be used restrictively, and normally no data should be 
excluded from the FAS. The subjects or observations to be excluded, and the reasons for their 
exclusion must be documented and signed by those responsible before database lock. The subjects 
and observations excluded from analysis sets, and the reason for this, will be described in the 
clinical trial report.
2.4
Primary endpoint
The primary endpoint is change from baseline to week 26 in HbA1c.
2.4.1
Analysis for the primary estimand 
The primary estimand will be estimated based on the FAS using post-baseline measurements up to 
and including week 26 from the on-treatment without rescue medication observation period.
The dose-response will be evaluated by a mixed model for repeated measurements (MMRM). A 
restricted maximum likelihood 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 and stratification factor as categorical
fixed effects and baseline HbA1c as a covariate, all nested within visit. An unstructured covariance 
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Statistical Analysis Plan
CONFIDENTIAL
Date:
05 October 2018
Novo Nordisk
Trial ID: NN9924-4281
Version:
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UTN: U1111-1181-4048
Status:
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matrix for HbA1c measurements within the same subject will be employed, assuming measurements 
from different subjects are independent. From this analysis estimated differences with 
corresponding two sided p-values and 95% confidence intervals after 26 weeks of treatment will be 
presented for all pairwise comparison of oral semaglutide versus placebo. In addition to the dose-
response evaluation, oral semaglutide will be compared to liraglutide 0.9 mg and estimated 
differences with corresponding two sided p-values and 95% confidence intervals after 26 weeks of 
treatment will be presented for all pairwise comparison of oral semaglutide versus liraglutide 0.9 
mg.
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 missing at random (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.
For subjects who do not have post-baseline assessments for planned visits available in the on-
treatment without rescue medication period, the baseline value will be carried forward to the first 
planned visit to ensure that all randomised subjects will contribute to the statistical analysis.
The dose-response relationship of oral semaglutide will be supported by an exploratory analysis. In 
this model data from all oral semaglutide treatment arms will be included and data from the placebo 
arm (corresponding to a dose of zero mg) could be included if appropriate. The model will be 
developed ad hoc after unblinding of the trial to aim for a suitable fit of the dose-response 
relationship using e.g. a linear or a four-parameter logistic relation of HbA1c vs. the logarithm of the 
dose.
2.4.2
Analysis for the secondary estimand 
The secondary estimand will be estimated based on the FAS using week 26 measurements from the 
in-trial observation period. The statistical analysis for the secondary estimand will be a pattern 
mixture model using multiple imputation (MI) to handle missing data assuming that the missing 
data mechanism is MAR within the groups used for imputation. Imputation of missing data at week 
26 will be done within 6 groups of subjects: one group of subjects regardless of randomised 
treatment arm who at week 26 will have discontinued treatment or have initiated rescue medication, 
and 5 groups of subjects defined by randomised treatment arm for subjects who will still be on 
treatment and not have 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 
medication status. 
Missing values for each group will be imputed as follows:
!
An analysis of covariance (ANCOVA) with stratification factor as a categorical fixed effect 
and baseline HbA1c measurement as a covariate will be fitted to observed values of the 
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Statistical Analysis Plan
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Date:
05 October 2018
Novo Nordisk
Trial ID: NN9924-4281
Version:
1.0
UTN: U1111-1181-4048
Status:
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change from baseline in HbA1c at week 26. Furthermore, when fitting the ANCOVA model 
for the one group of subjects who at week 26 will have discontinued treatment or initiated 
rescue medication, also randomised treatment arm will be included in the model as a 
categorical fixed effect.
If the model does not fit due to sparse data the following factors will be removed from the 
imputation model in a step-wise manner, meaning that only baseline HbA1c will be included 
in the model if using the last approach:
o
randomised treatment factor (for the group of subjects who at week 26 will have 
discontinued treatment or initiated rescue medication)
o
stratification factor 
!
The estimated parameters for location and dispersion will be used to impute 1000 values for 
each subject with missing week 26 data based on factors included in the imputation model 
and baseline HbA1c. Thus, 1000 complete data sets will be generated including observed and 
imputed values.
Analysis used for testing superiority versus placebo at week 26:
For each of the 1000 (now complete) imputed data sets the change from baseline to week 26 in 
HbA1c will be analysed using an analysis of covariance (ANCOVA) with treatment 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 rule2 to draw inference.
From this analysis the estimated treatment differences between each of the oral semaglutide dose 
levels and placebo together with associated two-sided 95% CIs and unadjusted two-sided p-values 
will be presented for all pairwise comparison of oral semaglutide versus placebo. In addition to this 
analysis, oral semaglutide will be compared to liraglutide 0.9 mg and estimated differences with 
corresponding two sided p-values and 95% CIs after 26 weeks of treatment will be presented for all 
pairwise comparison of oral semaglutide versus liraglutide 0.9 mg.
2.5
Secondary endpoint
2.5.1
Supportive secondary endpoint
2.5.1.1
Efficacy endpoints
The below supportive secondary efficacy endpoints will be evaluated for:
!
The primary estimand based on FAS using the on-treatment without rescue medication 
observation period
!
The secondary estimand based on FAS using the in-trial observation period
Continuous efficacy endpoints
Change from baseline to week 52 in:
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Statistical Analysis Plan
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Date:
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Trial ID: NN9924-4281
Version:
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!
HbA1c
Change from baseline to week 26 and week 52 in:
!
FPG
!
Body weight (kg)
!
Body weight (%)
!
BMI 
!
Waist circumference
!
Fasting lipid profile (total cholesterol, LDL cholesterol, HDL cholesterol and triglycerides, 
VLDL)
!
Fasting insulin, C-peptide, glucagon, pro-insulin 
!
Pro-insulin/insulin ratio 
!
Insulin resistance (HOMA-IR)
!
Beta-cell function (HOMA-B)
BMI will be calculated based on body weight and height based on the formulae:
BMI kg/m2 = body weight (kg)/(height (m) × height (m)) or (kg/m2 = [lb/in2 × 703])
Change from baseline to week 26 and 52 in the below derived endpoints from the 7-point SMPG 
profile:
!
Mean 7-point profile, defined as the area under the profile, calculated using the trapezoidal 
method, divided by the measurement time
!
Mean postprandial 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. The following endpoints 
will be log-transformed prior to analysis with the associated log-transformed baseline value as a 
covariate: fasting insulin, C-peptide, glucagon, pro-insulin, pro-insulin/insulin ratio, HOMA-IR, 
HOMA-B and fasting lipid profile. No model development of dose-response relationship is planned 
for these.
For evaluation of the primary estimand the MMRM based primary analysis will include all 
scheduled post-baseline measurement up to and including week 52. From this analysis the estimated 
treatment differences (ratios) between each of the oral semaglutide dose levels and placebo at week 
26 and 52 and between each of the oral semaglutide dose levels and liraglutide 0.9 mg at week 26 
and week 52 together with associated two-sided 95% CIs and unadjusted two-sided p-values will be 
presented for all pairwise comparison of oral semaglutide versus placebo and versus liraglutide 0.9 
mg. The baseline will not be carried forward to first planned visit if the first planned visit falls later 
than 8 weeks after randomisation.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
05 October 2018
Novo Nordisk
Trial ID: NN9924-4281
Version:
1.0
UTN: U1111-1181-4048
Status:
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For evaluation of the secondary estimand the analysis will be performed separately for week 26 and 
52. For the analysis at week 52, the imputation of missing data will be performed similarly to the 
week 26 evaluation, only using week 52 instead of week 26 as treatment adherence/rescue status. 
This will lead to 6 groups of subjects: one group of subjects regardless of randomised treatment arm
who at week 52 will have discontinued treatment or have initiated rescue medication, and 5 groups 
of subjects defined by randomised treatment arm for subjects who will still be on treatment and not 
have initiated rescue medication. Furthermore treatment adherence/rescue status at week 26 will be 
included as a factor in the imputation model. If the model does not fit due to sparse data the same 
approach as for the week 26 evaluation will be used with the only exception that the treatment 
adherence/rescue status at week 26 will be removed from the model before removing the 
randomised treatment factor.
The frequency of missing data is expected to be slightly larger at week 52 compared to week 26. 
The rate of missing data is expected to decline over time.
Binary efficacy endpoints
If a subject after week 26 achieves (yes/no):
!
HbA1c < 7.0% (53 mmol/mol) (ADA target)
!
HbA1c ≤6.5% (48 mmol/mol) (AACE target)
!
Body weight loss ≥5% 
!
HbA1c < 7 .0% (53 mmol/mol) without hypoglycaemia (treatment-emergent severe or BG-
confirmed symptomatic hypoglycaemic episodes) and no body weight gain
!
HbA1c reduction ≥1 %-point (10.9 mmol/mol) and body weight loss ≥3%
The above five (5) endpoints will also be evaluated after week 52.
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.
Handling of missing data for binary endpoints
HbA1c and body weight
Missing data for the above five (5) binary endpoints will be accounted for using multiple imputation 
techniques. For the treatment policy estimand the binary endpoints will be calculated as 
dichotomisations of the 1000 multiple imputations underlying the 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:
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Statistical Analysis Plan
CONFIDENTIAL
Date:
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Novo Nordisk
Trial ID: NN9924-4281
Version:
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UTN: U1111-1181-4048
Status:
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!
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 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 ANCOVA model will be 
used to impute missing values at each planned visit. The model will include stratification 
factor 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 stratification factor 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 rule2 to draw inference.
For the composite endpoints involving both HbA1c and body weight the imputed data sets will be 
combined by imputation number.
Only observed data within the corresponding observation period will be included for the ‘without 
hypoglycaemia’ component of composite endpoint. Because the number of hypoglycaemic episodes 
is expected to be very low in this trial, the observed data is considered sufficient when addressing 
both estimands.
Time to event endpoint
!
Time to additional anti-diabetic medication (to support the treatment policy estimand)
!
Time to rescue medication (to support the hypothetical estimand)
Definition of additional anti-diabetic medication:
New anti-diabetic medication initiated at or after randomisation and before (planned) end-of-
treatment.
Definition of rescue medication:
New 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. 
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Statistical Analysis Plan
CONFIDENTIAL
Date:
05 October 2018
Novo Nordisk
Trial ID: NN9924-4281
Version:
1.0
UTN: U1111-1181-4048
Status:
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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 can be considered a 
new anti-diabetic medication:
- Anti-diabetic medication (4th-level ATC code) that is initiated at or after randomisation and with a 
dosing duration of more than 21 days 
More than 21 days are 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 illnesses) 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 whether or not subjects
prematurely discontinued treatment. Time from randomisation to additional anti-diabetic 
medication will be analysed using likelihood ratio tests obtained from a Cox proportional hazards 
model with treatment and stratification factor as categorical fixed effects and baseline HbA1c as a 
covariate. 
From this analysis the estimated Hazard ratios between each of the oral semaglutide dose levels and 
placebo and between each of the oral semaglutide dose levels and liraglutide 0.9 mg together with 
associated two-sided 95% CIs and unadjusted two-sided p-values will be presented for all pairwise 
comparison of oral semaglutide versus placebo and versus liraglutide 0.9 mg.
The analysis aims to address the need of additional anti-diabetic medication regardless of whether 
this is due to lack of effect or tolerability of the trial product. Switch to another 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 (that is, initiated additional anti-diabetic medication) 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 of the treatment with trial product. Only initiation of rescue medication as add-on to 
randomised treatment is considered an event. Switch to another anti-diabetic treatment is not 
considered an event (that is, initiation of rescue medication) and as a consequence subjects will be 
censored on the day before date of last trial product. Potential events occurring between 
randomisation and first date on trial product will be included in the analysis as events at day 0, in
order to count all events of rescue medication.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
05 October 2018
Novo Nordisk
Trial ID: NN9924-4281
Version:
1.0
UTN: U1111-1181-4048
Status:
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2.5.1.2
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 treatment emergent adverse events (TEAEs) during exposure to trial product, 
assessed up to approximately 57 weeks
All AEs will be coded using version 20.1 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 2.3).
TEAEs will be summarised in terms of the number of subjects with at least one event (N), the 
percentage of subjects with at least one event (%), the number of events (E) and the event rate per 
100 patient years of observation time (R) for the on-treatment observation period. Supportive 
summaries of AEs will be made for the in-trial observation period. The development over time in 
gastrointestinal AEs will be presented graphically.
Other safety endpoints
Change from baseline to week 26 and 52 in:
!
Amylase
!
Lipase
!
Pulse
!
Systolic blood pressure
!
Diastolic blood pressure
The above safety endpoints will be evaluated using the primary analysis for the secondary estimand 
based on SAS using the in-trial observation period and using the analysis for the primary 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 and 52. 
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 and 52 in:
!
ECG category
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
05 October 2018
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Trial ID: NN9924-4281
Version:
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UTN: U1111-1181-4048
Status:
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!
Physical examination
Change from baseline to week 52 in:
!
Eye examination category
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 antibodies:
!
Anti-semaglutide binding antibody levels
Other safety assessments
Change from baseline to week 26 and week 52 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.
Hypoglycaemia
!
Number of treatment-emergent severe or BG-confirmed symptomatic hypoglycaemic 
episodes during exposure to trial product, assessed up to approximately 57 weeks
!
Treatment-emergent severe or BG-confirmed symptomatic hypoglycaemic episodes during 
exposure to trial product, assessed up to approximately 57 weeks (yes/no)
Classification of hypoglycaemia
Hypoglycaemic episodes will be summarised for the SAS and the on-treatment observation period 
only.
Treatment emergent: hypoglycaemic episodes will be defined as treatment-emergent if the onset of 
the episode occurs within the on-treatment observation period (see definition of observation periods 
in Section 2.3).
Nocturnal hypoglycaemic episodes: episodes occurring between 00:01 and 05.59 both inclusive.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
05 October 2018
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Trial ID: NN9924-4281
Version:
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UTN: U1111-1181-4048
Status:
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Hypoglycaemic episodes are classified according to the Novo Nordisk classification of 
hypoglycaemia and the ADA classification of hypoglycaemia (see Figure 2–1).
Novo Nordisk classification of hypoglycaemia
In normal physiology, symptoms of hypoglycaemia occur below a PG level of 3.1 mmol/L 
(56 mg/dL)3. 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 classification4 or BG confirmed by a PG value < 3.1 mmol/L (56 mg/dL) with
symptoms consistent with hypoglycaemia.
ADA classification4 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
CONFIDENTIAL
Date:
05 October 2018
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Trial ID: NN9924-4281
Version:
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UTN: U1111-1181-4048
Status:
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Hypoglycaemic 
episode 
PG ≤ 3.9 mmol/L 
(70 mg/dL) 
or 
Alleviation of 
symptoms 
or
Seizure, coma or 
fatal 
SMPG
measurement
Asymptomatic 
hypoglycaemia
Documented 
symptomatic 
hypoglycaemia
Pseudo-
hypoglycaemia
Probable 
symptomatic 
hypoglycaemia
No
Yes
No measurement 
with symptoms
PG > 3.9 mmol/L 
(70 mg/dL)
with symptoms
PG ≤3.9 mmol/L 
(70 mg/dL)
with symptoms
PG ≤3.9 mmol/L 
(70 mg/dL)
without symptoms
No
Yes
Note: Glucose measurements are performed with capillary blood calibrated to plasma equivalent glucose values
PG: plasma glucose  SMPG: Self-measured plasma glucose  
Subject 
able to 
treat him/
herself
Severe 
hypoglycaemia
(ADA 2013)
Figure 2–1
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
Due to sparse data the protocol pre-specified analyses of severe or BG-confirmed symptomatic
hypoglycaemia will not be performed.
2.5.1.3
Pharmacokinetic endpoints
!
Semaglutide plasma concentrations for population PK analysis
The semaglutide plasma concentrations collected in this trial will be evaluated using relevant 
summary statistics. In addition, the semaglutide plasma concentration will be part of a meta-
analysis across the oral semaglutide phase 3a trials, see more details in Section 2.7.
2.6
Interim analysis
No interim analyses or other analyses of unblinded data will be performed before the database is 
locked.
CONFIDENTIAL


Statistical Analysis Plan
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Date:
05 October 2018
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Trial ID: NN9924-4281
Version:
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Status:
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2.7
Pharmacokinetic and/or pharmacodynamic modelling
Data from this trial will be evaluated using population pharmacokinetic analysis and exposure-
response for semaglutide. The purpose of the population pharmacokinetic analysis will be: 
!
To describe the covariate factors (such as body weight, age, gender, race and ethnicity) that 
influence semaglutide exposure
!
To estimate a steady-state exposure level for each subject with pharmacokinetic data, in 
order to facilitate subsequent exposure-response analyses
The purpose of the exposure-response analyses will be to support the recommended dose, by 
investigating response and potentially side effects across the exposure range. 
The population pharmacokinetic and exposure-response analyses will be conducted as a meta-
analysis, including all relevant oral semaglutide phase 3a trials with PK assessments. A separate 
modelling analysis plan will be prepared before first database lock in the oral semaglutide phase 3a 
programme, outlining details of the analyses. The modelling will be performed by Quantitative 
Clinical Pharmacology at Novo Nordisk A/S and will be reported separately from the clinical trial 
report.
2.8
Health economics and/or patient reported outcomes
Change from baseline to week 26 and week 52 in:
!
SF-36v2® Health Survey (SF-36v2) (acute version): Physical component score, mental 
component score and scores from the 8 domains
!
DTR-QOL questionnaire: Total score and scores from 4 domains
The PRO endpoints will be analysed separately as the other continuous efficacy endpoints using a 
similar model approach as for the primary endpoint with the associated baseline response as a 
covariate.
SF-36v2 (acute version) for the treatment policy estimand will be reported in the CTR. SF-36v2 
(acute version) for the hypothetical estimand will not be included in CTR but will be included in a 
separate PRO report. DTR-QOL questionnaire for both estimand will be reported in the CTR.
2.8.1
SF-36v2® Health Survey (acute version) 
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 diabetes5. The SF-36v2 (acute version) for adults with a 1-week recall period
contains 36 items.
A total of 35 items are used to 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
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Statistical Analysis Plan
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Trial ID: NN9924-4281
Version:
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health problems (4 items), bodily pain (2 items), general health perceptions (5 items), vitality (4 
items), social functioning (2 items), role limitations due to emotional problems (3 items) and
general mental health (5 items), mental component summary (MCS) score, physical component
summary (PCS) score. There is an additional single item giving information on health change over
the past week.
Domain scores:
Norm-based scores (NBS) will be derived using the QualityMetric Health Outcomes™ Scoring
Software including the 2009 US general population norm. Version 5.0 of the QualityMetric Health
Outcomes™ Scoring Software available at time of licensing will be used (version 5.0). Table 2–2
provides an overview of the domains. NBS standardises domain and component scores into T-
scores using the means and standard deviations from the US general population. Higher scores on
all domains and component summary measures (PCS and MCS) indicate better HRQoL/general
health status. Item 2 (i.e. Question 2 in CRF) is not included in any score.
Table 2–2
Overview of domains for SF-36v2 (acute version)
Domain
Items numbers of items 
included in domain
Comment
Physical Functioning (PF)
Items 3a-j
Role Limitations Due to Physical Health (Role-Physical; 
RP)
Items 4a-d
Bodily Pain (BP)
Items 7, 8
Both item scores reversed 
General Health Perceptions (General Health; GH)
Items 1, 11a-d
Item scores 1, 11b and 11d reversed
Vitality (VT)
Items 9a, 9e, 9g, 9i
Item scores 9a and 9e reversed 
Social Functioning (SF)
Items 6, 10
Item score 6 reversed 
Role Limitations Due To Emotional Problems (Role-
Emotional; RE)
Items 5a-c
Mental Health (MH)
Items 9b, 9c, 9d, 9f, 9h
Item scores 9d and 9h reversed 
Physical component summary (PCS)
NA
The PCS score is a weighted average of 
the 8 domain scores. 
Mental component summary (MCS)
NA
The MCS score is also a weighted average 
of the 8 domain scores. Weights differ 
from PCS to MCS. 
Missing data at instrument level will be handled using the Maximum Data Recovery method: The 
method applies a value to a domain item rendered missing if at least one of the items in that domain 
has valid data. A domain score is considered missing if all item values in the domain are missing. 
PCS and MCS are calculated when at least seven of the eight domains have valid data, either actual 
or estimated. However, to calculate PCS, the PF domain must be one of the seven domains having 
valid data. Also, to calculate MCS, the MH domain must be one of the seven domains having valid 
data.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
05 October 2018
Novo Nordisk
Trial ID: NN9924-4281
Version:
1.0
UTN: U1111-1181-4048
Status:
Final
     
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Responder threshold values
The responder threshold values, in terms of T-score points for change from baseline are defined in 
Table 2–3.
Table 2–3
Responder thresholds for SF-36v2 (acute version)
Domain
Responder threshold
Physical Functioning (PF)
4.3
Role Limitations Due to Physical Health (Role-Physical; RP)
4.0
Bodily Pain (BP)
5.5
General Health Perceptions (General Health; GH)
7.0
Vitality (VT)
6.7
Social Functioning (SF)
6.2
Role Limitations Due To Emotional Problems (Role-Emotional; RE)
4.6
Mental Health (MH)
6.7
Physical component summary (PCS)
3.8
Mental component summary (MCS)
4.6
Responder analyses will be based on the responder threshold values and are described in 2.8.3.
2.8.2
Diabetes Therapy-Related Quality of Life (DTR-QoL)
DTR-QoL is a diabetes specific HRQoL measure that assesses the influence of diabetes treatment 
on HRQoL on 4 domains: “Burden on social activities and daily activities”, “Anxiety and 
dissatisfaction with treatment”, “Hypoglycemia” and “Satisfaction with tr eatment”. DTR-QoL 
contains 29 items evaluated on a 7-point graded response scale (see Table 2–4). Higher item scores 
indicate a higher level of HRQoL for items 1-25. For items 26-29 a higher score indicates a lower 
level of HRQoL.
Domain scores
The response scale used was a 7-point Likert scale (1: completely true - 7: not true at all). The score 
of each item is reversed so that “7” represents the highest QoL. The domain score is calculated from 
the mean score of the attribute items, and the scoring range is converted to 0 - 100. The total score, 
after simple addition of the item scores, is converted to 0 - 100 (best-case response = 100; worst-
case response = 0).
Table 2–4
Overview of domains for DTR-QoL
Domain
Items numbers of 
items included in 
domain
Comment
Burden on social activities and daily activities
1-13
Formula for domain score derivation1: 
(Sum of item scores -13) * (100/(13*6))
Anxiety and dissatisfaction with treatment
14, 19-25
Formula for domain score derivation1: 
(Sum of item scores -8) * (100/(8*6))
Hypoglycemia
15-18
Formula for domain score derivation1: 
(Sum of item scores -4) * (100/(4*6))
Satisfaction with treatment
26-29
Step 1: Item scores 26-29 to be reversed2
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Statistical Analysis Plan
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Date:
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Trial ID: NN9924-4281
Version:
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UTN: U1111-1181-4048
Status:
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Step 2: Formula for domain score derivation1: 
(Sum of item scores -4) * (100/(4*6))
Total score
1-29
Step 1: Item scores 26-29 to be reversed2
Step 2: Formula for domain score derivation1: 
(Sum of item scores -29) * (100/(29*6))
1 General formula: (Sum of item scores - Number of items included in domain) * (100/ (Number of items included in 
domain * Scaling point range))
2 Item scores are reversed in the following way: 7 to 1, 6 to 2, …, 1 to 7
Missing data at instrument level will be handled in the following way. If the number of items with a 
missing value in a domain is less than 50% of the total items in the domain, the mean value 
excluding the missing value(s) is calculated and substituted for the missing value(s). If the number 
of items with a missing value in the domain is 50% or more of the total items in the domain, the 
domain score is not calculated. The total score is not calculated, if none of the domain scores can be 
calculated. 
Responder threshold values
Half of a standard deviation (SD) of the baseline DTR-QoL total and domain scores per trial were 
used as distribution-based approach defining the responder thresholds. The thresholds are derived 
from baseline DTR-QoL data across trial arms per trial. Responder analyses will be based on the 
responder threshold values and are described in Section 2.8.3.
2.8.3
Responder analyses
Responder analyses will be conducted for both estimands, for the same time points that are defined 
for the analyses of PRO endpoints (see protocols) and separately for each score.
For descriptive statistics the following subject responder categorisation is applied for all relevant 
time points and domain:
!
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 (see section 2.5.1.1). Estimated proportions and differences in proportions will be 
reported in addition to odds and odds ratios.
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Statistical Analysis Plan
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Date:
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Trial ID: NN9924-4281
Version:
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UTN: U1111-1181-4048
Status:
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The responder analyses will not be included in the CTR, but in a separate PRO report.
3
Changes to the statistical analyses planned in the protocol
The main analyses were described in the protocol for the trial NN9924-4281. However, 
clarifications, more detailed descriptions of endpoints and analyses are provided in this SAP. The 
changes from the protocol of NN9924-4281 are summarised below:
!
The primary and secondary estimands have changed names from de-jure and de-facto to 
hypothetical and treatment policy, respectively.
!
Adjustments to the imputation method for the analyses for the secondary estimand have 
been made due to sparse missing data. Instead of using the 10 imputation groups as specified 
in the protocol only 6 imputation groups will be used: one group of subjects regardless of 
randomised treatment arm who at week 26 will have discontinued treatment or have initiated 
rescue medication, and 5 groups of subjects defined by randomised treatment arm for 
subjects who will still be on treatment and have not initiated rescue medication. Furthermore 
it has been specified which factors to include in the imputation model for both week 26 and 
week 52 in case the model is not estimable.
!
For the MMRM analyses, it has been specified that for subjects who do not have post-
baseline assessments for planned visits available in the on-treatment without rescue 
medication period, the baseline value will be carried forward to the first planned visit, if the 
first planned visit do not fall later than 8 weeks after randomisation, to ensure that all 
randomised subjects will contribute to the statistical analyses.
!
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, imputation of missing data in the analyses for the 
hypothetical estimand has been specified to use a sequential imputation approach assuming 
data are MAR.
!
The protocol pre-specified statistical analyses of body weight loss ≥ 10% will be omitted 
due to low number of such episodes across treatment groups (based on review of blinded 
data).
!
A clarification of the ‘no hypoglycaemia’ component in the composite binary endpoint has 
been added.
!
It has been specified which assessments will be analysed on logarithmic scale.
!
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.
!
It has been specified that all safety laboratory results (except amylase and lipase) are safety 
assessments and not safety endpoints as written in the trial protocol.
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Statistical Analysis Plan
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Date:
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Trial ID: NN9924-4281
Version:
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UTN: U1111-1181-4048
Status:
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!
For free fatty acids assessments done by the 
 all assessments are 
considered invalid due to the samples being stored at ambient temperature, hence these 
results will not be reported
!
The protocol pre-specified statistical analyses of severe or BG-confirmed symptomatic 
hypoglycaemia episodes will be omitted due to low number of such episodes across 
treatment groups (based on review of blinded data).
!
Because PRO endpoints will be further evaluated in a separate PRO report, it has been 
specified that SF-36v2 (acute version) will be analysed using the primary analysis of the 
treatment policy estimand only, and DTR-QoL will be analysed for both the treatment 
policy estimand and the hypothetical estimand for the CTR.
!
The responder analyses for SF-36v2 (acute version) and DTR-QoL will not be included in 
the CTR, but in a separate PRO report.
CONFIDENTIAL


Statistical Analysis Plan
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Date:
05 October 2018
Novo Nordisk
Trial ID: NN9924-4281
Version:
1.0
UTN: U1111-1181-4048
Status:
Final
Page:
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4
References
1 Ministry of Health, Labour and Welfare. Draft Guideline for Clinical Evaluation of Hypoglycaemic Agents. 19 May 
2015.
2 Little RJA, Rubin DB. Statistical analysis with missing data: New York: John Wiley & Sons. 1987.
3 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.
4 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.
5 Maruish ME, (Ed.). User's manual for the SF-36v2 Health Survey (3rd ed.). Lincoln, RI: QualityMetric Incorporated. 
2011.
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Oral Semaglutide
PIONEER 1-10
Clinical Trial Report
Appendix 16.1.9
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16.1.9.1 Pre-defined MedDRA search – list of preferred terms
Table of contents
Page
16.1.9.1 Pre-defined MedDRA search – list of preferred terms......................................................................2
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