Clinical trial NCT03021187
Conditions: Diabetes Diabetes Mellitus, Type 2
Sponsor: Novo Nordisk A/S
Start date: 2017-02-02; Completion date: 2018-08-22
Enrollment: 731 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This trial is conducted globally. The aim of the trial is to investigate the efficacy and safety of oral semaglutide versus placebo in subjects with Type 2 Diabetes Mellitus treated with insulin. All subjects should continue their pre-trial insulin therapy (basal, basal-bolus or premixed regimen including combinations of soluble insulins) throughout the trial. Subjects treated with metformin in addition to insulin treatment must continue their metformin treatment throughout the entire trial.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None arm 4: None
Interventions: intervention 1: semaglutide intervention 2: semaglutide intervention 3: semaglutide intervention 4: placebo
Intervention descriptions: intervention 1: Oral semaglutide administered once-daily for 52 weeks as an add-on to the subjects' pre-trial insulin treatment intervention 2: Oral semaglutide (3 mg followed by 7 mg) administered once-daily for 52 weeks as an add-on to the subjects' pre-trial insulin treatment intervention 3: Oral semaglutide (3 mg followed by 7 mg and finally 14 mg) administered once-daily for 52 weeks as an add-on to the subjects' pre-trial insulin treatment intervention 4: Oral semaglutide placebo administered once-daily for 52 weeks as an add-on to the subjects' pre-trial insulin treatment

Protocol documents:
Prot_000.pdf: 
Cover Page for Protocol 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT03021187 
Sponsor trial ID: 
NN9924-4280 
Official title of study: 
PIONEER 8 – Insulin add-on 
Efficacy and Safety of Oral Semaglutide versus Placebo in 
Subjects with Type 2 Diabetes Mellitus treated with insulin A 
52-week, randomised, double-blind, placebo-controlled trial
Document date: 
 February 2019 


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CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
19 August 2016
1RYR1RUGLVN
Trial ID: NN9924-4280
Version:
1.0
UTN: U1111-1180-3637 
Status:
Final
EudraCT no.: 2016-000988-16 
Page:
1 of 130
Protocol
Trial ID: NN9924-4280
PIONEER 8 – Insulin add-on
Efficacy and Safety of Oral Semaglutide versus Placebo 
in Subjects with Type 2 Diabetes Mellitus treated with insulin
A 52-week, randomised, placebo-controlled trial, double-blinded during the initial 26 weeks
Trial phase: 3a
Protocol originator
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol
CONFIDENTIAL
Date:
19 August 2016
1RYR1RUGLVN
Trial ID: NN9924-4280
Version:
1.0
UTN: U1111-1180-3637 
Status:
Final
EudraCT no.: 2016-000988-16 
Page:
2 of 130
Table of Contents
Page
Table of Contents..............................................................................................................................................2
Table of Figures................................................................................................................................................7
Table of Tables..................................................................................................................................................7
List of abbreviations.........................................................................................................................................8
1
Summary..................................................................................................................................................11
2
Flow chart ................................................................................................................................................15
3
Background information and rationale for the trial............................................................................22
3.1
Background information..............................................................................................................22
3.1.1
Type 2 diabetes mellitus ............................................................................................22
3.1.2
Glucagon-like peptide-1 ............................................................................................22
3.1.3
Oral semaglutide........................................................................................................23
3.1.4
Nonclinical data.........................................................................................................23
3.1.4.1
Semaglutide.........................................................................................23
3.1.4.2
SNAC ..................................................................................................24
3.1.5
Clinical data for oral semaglutide..............................................................................25
3.1.5.1
Pharmacokinetics ................................................................................25
3.1.5.2
Efficacy ...............................................................................................26
3.1.5.3
Safety...................................................................................................26
3.2
Rationale for the trial...................................................................................................................27
4
Objective(s) and endpoint(s) ..................................................................................................................28
4.1
Objective(s)..................................................................................................................................28
4.1.1
Primary objective.......................................................................................................28
4.1.2
Secondary objective(s)...............................................................................................28
4.2
Endpoints .....................................................................................................................................28
4.2.1
Primary endpoint........................................................................................................28
4.2.2
Secondary endpoints..................................................................................................28
4.2.2.1
Confirmatory secondary endpoints .....................................................28
4.2.2.2
Supportive secondary efficacy endpoints............................................28
4.2.2.3
Supportive secondary pharmacokinetic endpoint................................29
4.2.2.4
Supportive secondary safety endpoints...............................................29
5
Trial design ..............................................................................................................................................31
5.1
Type of trial .................................................................................................................................31
5.2
Rationale for trial design..............................................................................................................32
5.3
Treatment of subjects...................................................................................................................33
5.3.1
Dosing instructions ....................................................................................................34
5.3.2
Background medication.............................................................................................34
5.3.3
Total daily insulin dose adjustments during the trial.................................................34
5.3.3.1
At randomisation (V2) ........................................................................34
5.3.3.2
During the fixed insulin treatment period ...........................................35
5.3.3.3
During the adjustable insulin treatment period ...................................35
5.3.3.4
Insulin titration guideline ....................................................................35
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
19 August 2016
1RYR1RUGLVN
Trial ID: NN9924-4280
Version:
1.0
UTN: U1111-1180-3637 
Status:
Final
EudraCT no.: 2016-000988-16 
Page:
3 of 130
5.4
Treatment after discontinuation of trial product ..........................................................................37
5.5
Rationale for treatment ................................................................................................................37
6
Trial population.......................................................................................................................................39
6.1
Number of subjects......................................................................................................................39
6.2
Inclusion criteria ..........................................................................................................................39
6.3
Exclusion criteria.........................................................................................................................40
6.4
Rescue criteria..............................................................................................................................41
6.5
Criteria for premature discontinuation of trial product................................................................42
6.6
Withdrawal from trial ..................................................................................................................42
6.7
Subject replacement.....................................................................................................................43
6.8
Rationale for trial population.......................................................................................................43
7
Milestones.................................................................................................................................................44
8
Methods and assessments .......................................................................................................................45
8.1
Visit procedures...........................................................................................................................45
8.1.1
Screening, visit 1........................................................................................................45
8.1.2
Fasting visits ..............................................................................................................46
8.1.3
Randomisation and trial product administration........................................................46
8.1.4
End-of-treatment (visit 18) and Follow-up (visit 19).................................................47
8.1.5
Premature discontinuation of trial product and follow-up (visits 18A and 19A) ......47
8.1.6
Withdrawals...............................................................................................................48
8.1.7
Investigator assessments............................................................................................48
8.2
Subject related information/assessments .....................................................................................49
8.2.1
Demography...............................................................................................................49
8.2.2
Diabetes history and diabetes complications .............................................................49
8.2.3
Hypoglycaemia unawareness.....................................................................................49
8.2.4
Concomitant illness and medical history...................................................................49
8.2.5
Concomitant medication............................................................................................50
8.2.6
Childbearing potential................................................................................................51
8.2.7
Tobacco use ...............................................................................................................51
8.3
Efficacy assessments....................................................................................................................51
8.3.1
Laboratory assessments for efficacy..........................................................................51
8.3.1.1
Fasting plasma glucose........................................................................52
8.3.2
Self-measured plasma glucose (SMPG) ....................................................................52
8.3.2.1
Self-measured plasma glucose profile.................................................52
8.3.2.2
7-point self-measured plasma glucose profile.....................................53
8.3.3
Body weight and height .............................................................................................53
8.3.4
Waist circumference ..................................................................................................53
8.3.5
Patient reported outcomes questionnaires..................................................................54
8.3.6
Basal insulin dose adjustment....................................................................................55
8.3.6.1
At randomisation (V2) ........................................................................55
8.3.6.2
During the fixed insulin treatment period ...........................................55
8.3.6.3
During the adjustable insulins treatment period..................................55
8.4
Safety assessments.......................................................................................................................55
8.4.1
Adverse Events ..........................................................................................................55
8.4.1.1
Medication error..................................................................................56
8.4.1.2
Adverse events requiring additional data collection ...........................56
8.4.2
Physical examination.................................................................................................57
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
19 August 2016
1RYR1RUGLVN
Trial ID: NN9924-4280
Version:
1.0
UTN: U1111-1180-3637 
Status:
Final
EudraCT no.: 2016-000988-16 
Page:
4 of 130
8.4.3
Vital signs ..................................................................................................................57
8.4.4
Eye examination ........................................................................................................58
8.4.5
Electrocardiogram (12-lead)......................................................................................58
8.4.6
Laboratory assessments for safety .............................................................................58
8.4.7
Pregnancy testing.......................................................................................................59
8.4.8
Hypoglycaemic episodes ...........................................................................................60
8.5
Laboratory assessments ...............................................................................................................62
8.6
Other assessments........................................................................................................................63
8.6.1
Pharmacokinetics.......................................................................................................63
8.6.2
Subject diary ..............................................................................................................64
8.7
Subject compliance......................................................................................................................64
9
Trial supplies ...........................................................................................................................................65
9.1
Trial products...............................................................................................................................65
9.2
Labelling......................................................................................................................................66
9.3
Storage .........................................................................................................................................66
9.4
Drug accountability and destruction............................................................................................67
9.5
Auxiliary supplies........................................................................................................................67
10 Interactive web response system............................................................................................................68
11 Randomisation procedure and breaking of blinded codes..................................................................69
11.1
Breaking of blinded codes ...........................................................................................................69
12 Adverse events, technical complaints and pregnancies .......................................................................70
12.1
Definitions ...................................................................................................................................70
12.1.1
Adverse event ............................................................................................................70
12.1.2
Serious adverse event.................................................................................................71
12.1.3
Non-serious adverse event.........................................................................................72
12.1.4
Medication errors.......................................................................................................72
12.1.5
Adverse events requiring additional data collection..................................................73
12.1.6
Technical complaints.................................................................................................74
12.2
Reporting of adverse events.........................................................................................................75
12.3
Follow-up of adverse events........................................................................................................78
12.4
Technical complaints and technical complaint samples ..............................................................79
12.4.1
Reporting of technical complaints .............................................................................79
12.4.2
Collection, storage and shipment of technical complaint samples ............................79
12.5
Pregnancies..................................................................................................................................80
12.5.1
Pregnancies in female subjects ..................................................................................80
12.6
Precautions and/or overdose ........................................................................................................81
12.7
Committees related to safety........................................................................................................82
12.7.1
Novo Nordisk safety committee ................................................................................82
12.7.2
Event adjudication committee....................................................................................82
13 Case report forms....................................................................................................................................86
13.1
Corrections to case report forms..................................................................................................86
13.2
Case report form flow..................................................................................................................87
14 Monitoring procedures ...........................................................................................................................88
15 Data management....................................................................................................................................90
16 Computerised systems.............................................................................................................................91
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
19 August 2016
1RYR1RUGLVN
Trial ID: NN9924-4280
Version:
1.0
UTN: U1111-1180-3637 
Status:
Final
EudraCT no.: 2016-000988-16 
Page:
5 of 130
17 Statistical considerations ........................................................................................................................91
17.1
Sample size calculation................................................................................................................93
17.2
Definition of analysis sets............................................................................................................96
17.3
Primary endpoint..........................................................................................................................98
17.3.1
Primary analysis for the primary estimand ................................................................99
17.3.2
Primary analysis for the secondary estimand.............................................................99
17.3.3
Sensitivity analyses..................................................................................................100
17.3.3.1
Pattern mixture models......................................................................101
17.3.3.2
Other sensitivity analyses..................................................................101
17.3.3.3
Assessment of sensitivity analyses....................................................102
17.4
Secondary endpoints..................................................................................................................102
17.4.1
Confirmatory secondary endpoints..........................................................................102
17.4.2
Supportive secondary endpoints ..............................................................................102
17.4.2.1
Efficacy endpoints.............................................................................102
17.4.2.2
Safety endpoints................................................................................105
17.4.2.3
Pharmacokinetic endpoints................................................................109
17.5
Interim analysis..........................................................................................................................109
17.6
Pharmacokinetic and/or pharmacodynamic modelling..............................................................109
17.7
Patient reported outcomes..........................................................................................................109
18 Ethics......................................................................................................................................................111
18.1
Benefit-risk assessment of the trial............................................................................................111
18.1.1
Benefits....................................................................................................................113
18.1.2
Risk and benefit conclusion.....................................................................................114
18.2
Informed consent .......................................................................................................................114
18.3
Data handling.............................................................................................................................115
18.4
Information to subjects during trial............................................................................................115
18.5
Premature termination of the trial and/or trial site.....................................................................115
19 Protocol compliance..............................................................................................................................116
19.1
Protocol deviations ....................................................................................................................116
19.2
Prevention of missing data.........................................................................................................116
20 Audits and inspections ..........................................................................................................................117
21 Critical documents ................................................................................................................................118
22 Responsibilities......................................................................................................................................120
23 Reports and publications......................................................................................................................121
23.1
Communication of results..........................................................................................................121
23.1.1
Authorship ...............................................................................................................122
23.1.2
Site-specific publication(s) by investigator(s) .........................................................122
23.2
Investigator access to data and review of results.......................................................................122
24 Retention of clinical trial documentation............................................................................................123
24.1
Retention of clinical trial documentation...................................................................................123
25 Institutional Review Boards/Independent Ethics Committees and regulatory authorities............124
26 Indemnity statement .............................................................................................................................125
27 References..............................................................................................................................................127
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
19 August 2016
1RYR1RUGLVN
Trial ID: NN9924-4280
Version:
1.0
UTN: U1111-1180-3637 
Status:
Final
EudraCT no.: 2016-000988-16 
Page:
6 of 130
Appendix A
Calcitonin monitoring
Appendix B 
Adverse events requiring additional data collection
Attachment I  Global list of key staff and relevant departments and suppliers 
Attachment II Country list of key staff and relevant departments
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
19 August 2016
1RYR1RUGLVN
Trial ID: NN9924-4280
Version:
1.0
UTN: U1111-1180-3637 
Status:
Final
EudraCT no.: 2016-000988-16 
Page:
7 of 130
Table of Figures
Page
Figure 5–1
Trial design.............................................................................................................................32
Figure 12–1
Reporting of AEs....................................................................................................................77
Figure 17–1
Graphical illustration of the closed testing procedure ............................................................95
Figure 17–2
ADA classification of hypoglycaemia..................................................................................108
Table of Tables
Page
Table 5-1
Overview of treatment of subjects..........................................................................................33
Table 5-2
Increase of insulin dose ..........................................................................................................36
Table 5-3
Decrease of insulin dose.........................................................................................................37
Table 9-1
Investigational medicinal products.........................................................................................65
Table 9-2
Storage conditions ..................................................................................................................66
Table 12-1
Adverse events requiring completion of specific event forms and/or are subject to event 
adjudication ............................................................................................................................74
Table 12-2
Adverse events for adjudication .............................................................................................83
Table 17-1
Assumptions used in the sample size calculation...................................................................94
Table 17-2
Calculated powers for individual hypotheses.........................................................................94
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
19 August 2016
1RYR1RUGLVN
Trial ID: NN9924-4280
Version:
1.0
UTN: U1111-1180-3637 
Status:
Final
EudraCT no.: 2016-000988-16 
Page:
8 of 130
List of abbreviations
AACE
American Association of Clinical Endocrinologists
ADA
American Diabetes Association
AE
adverse event
AESI
adverse event of special interest
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 
CLAE
clinical laboratory adverse event
CK
creatine kinase
CKD
Chronic Kidney Disease 
CKD-EPI
Chronic Kidney Disease Epidemiology 
Collaboration
CLAE
clinical laboratory adverse event
Cmax
maximum concentration
CRF
case report form
CTR
clinical trial report
DPP-4
dipeptidyl peptidase-4
DUN
dispensing unit number
EAC
event adjudication committee
ECG
electrocardiogram
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
19 August 2016
1RYR1RUGLVN
Trial ID: NN9924-4280
Version:
1.0
UTN: U1111-1180-3637 
Status:
Final
EudraCT no.: 2016-000988-16 
Page:
9 of 130
EOT
end-of-treatment
FAS
full analysis set
FDA
U.S. Food and Drug Administration
FPG
fasting plasma glucose
FSFV
first subject first visit
GCP
Good Clinical Practice
GLP-1
glucagon-like peptide-1
GLP-1 RA
glucagon-like peptide-1 receptor agonist
HbA1c
glycosylated haemoglobin
HDL
high-density lipoprotein
ICH
International Conference on Harmonisation of 
Technical Requirements for Registration of 
Pharmaceuticals for Human Use
ICMJE
International Committee of Medical Journal Editors
IEC
independent ethics committee
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
MEN 2 
Multiple Endocrine Neoplasia Type 2
MI
myocardial infarction
MMRM
mixed model for repeated measurements
MTC 
medullary thyroid carcinoma
n
number of randomised subjects
NIMP
non-investigational medicinal product
NYHA
New York Heart Association
OAD
oral antidiabetic drug
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
19 August 2016
1RYR1RUGLVN
Trial ID: NN9924-4280
Version:
1.0
UTN: U1111-1180-3637 
Status:
Final
EudraCT no.: 2016-000988-16 
Page:
10 of 130
P
phone contact
PG
plasma glucose
PIONEER
Peptide InnOvatioN for Early diabEtes tReatment
PK
pharmacokinetics
PRO
patient reported outcome
SAE
serious adverse event
SAP
statistical analysis plan
SAS
safety analysis set
s.c.
subcutaneous(ly)
SDV
source data verification
SGLT-2
sodium-glucose co-transporter-2
SmPC
summary of product characteristics
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
TE
treatment effect
TEAE
treatment-emergent adverse events
tmax
time to reach maximum observed concentration
TMM
Trial Materials Manual
U
unit
UNL
upper normal limit
UTN
Universal Trial Number
V
visit
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
19 August 2016
1RYR1RUGLVN
Trial ID: NN9924-4280
Version:
1.0
UTN: U1111-1180-3637 
Status:
Final
EudraCT no.: 2016-000988-16 
Page:
11 of 130
1
Summary
Objectives and endpoints:
Primary objective
To compare the effect of once-daily dosing of three dose levels of oral semaglutide (3, 7 and 14 mg) 
versus placebo on glycaemic control in subjects with type 2 diabetes mellitus treated with insulin.
Secondary objectives
To compare the effect of once-daily dosing of three dose levels of oral semaglutide (3, 7 and 14 mg) 
versus placebo on body weight in subjects with type 2 diabetes mellitus treated with insulin.
To compare the safety and tolerability of once-daily dosing of three dose levels of oral semaglutide 
(3, 7 and 14 mg) versus placebo in subjects with type 2 diabetes mellitus treated with insulin.
Primary endpoint
Change from baseline to week 26 in HbA1c
Key secondary endpoints
Change from baseline to week 26 in body weight (kg)
Change from baseline to week 52 in:
!
HbA1c
!
Body weight (kg)
Change from baseline to week 26 and week 52 in:
!
Fasting plasma glucose (FPG)
If a subject after week 26 and week 52 achieves (yes/no):
!
HbA1c < 7.0% (53 mmol/mol) (American Diabetes Association (ADA) target)
Number of treatment-emergent adverse events (TEAEs) during exposure to trial product, assessed 
up to approximately 57 weeks
Number of treatment-emergent severe or blood glucose-confirmed symptomatic hypoglycaemic 
episodes during exposure to trial product, assessed up to approximately 57 weeks
Trial design:
This is a 52-week, randomised, placebo-controlled, four-armed, parallel-group, multicentre, 
multinational trial, double-blinded during the initial 26 weeks after which the randomisation details 
will be revealed to selected Novo Nordisk personnel. Investigators and subjects will be blinded 
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
19 August 2016
1RYR1RUGLVN
Trial ID: NN9924-4280
Version:
1.0
UTN: U1111-1180-3637 
Status:
Final
EudraCT no.: 2016-000988-16 
Page:
12 of 130
throughout the trial. The trial will compare the efficacy and safety of three dose levels of once-daily 
oral semaglutide versus placebo in subjects with type 2 diabetes mellitus treated with insulin.
Subjects will be randomised 1:1:1:1 manner to receive one of the following treatments:
!
3 mg oral semaglutide once-daily
!
7 mg oral semaglutide once-daily
!
14 mg oral semaglutide once-daily
!
placebo once-daily
The total trial duration for the individual subject will be approximately 59 weeks. The trial includes 
a 2-week screening period followed by a 52-week randomised treatment period and a 5-week 
follow-up period. The 52-week randomised treatment period is split into two treatment periods; an 
initial 26-week period where the insulin treatment is restricted, followed by a 26-week period where 
the insulin treatment is adjustable without any restrictions. 
Trial population:
Number of subjects planned to be randomised: 720
Inclusion criteria:
1. Informed consent obtained before any trial-related activities. Trial-related activities are any 
procedures that are carried out as part of the trial, including activities to determine suitability for 
the trial.
2. Male or female, age above or equal to 18 years at the time of signing informed consent.
For Japan only: Male or female, age above or equal to 20 years at the time of signing informed 
consent.
3. Diagnosed with type 2 diabetes mellitus ≥ 90 days prior to the day of screening.
4. HbA1c of 7.0-9.5% (53-80 mmol/mol) (both inclusive).
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
19 August 2016
1RYR1RUGLVN
Trial ID: NN9924-4280
Version:
1.0
UTN: U1111-1180-3637 
Status:
Final
EudraCT no.: 2016-000988-16 
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5. Stable treatment with one of the following insulin regimens (minimum 10 IU/day) ≥ 90 days 
prior to the day of screening. Maximum 20% change in total daily dose is acceptable:
!
Basal insulin alone
!
Basal and bolus insulin in any combination
!
Premixed insulin including combinations of soluble insulins 
Concomitant treatment with stable daily dose of metformin (≥ 1500 mg or maximum tolerated 
dose as documented in the subject medical record) ≥ 90 days prior to the day of screening is 
allowed.
For Japan only: Concomitant treatment with metformin is only allowed in combination with 
basal insulin alone (not in combination with basal-bolus or premixed insulin including 
combinations of soluble insulins).
Key exclusion criteria:
1. Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing 
potential and not using an adequate contraceptive method (adequate contraceptive measure as 
required by local regulation or practice).
For Greece only: adequate contraceptive measures are defined as combined hormonal 
contraception (containing oestrogen and progesterone), which suppress ovulation (oral, 
intravaginal, percutaneous), progesterone-only hormonal contraception which suppress 
ovulation (oral, injectable, implantable), intrauterine device, hormone-releasing intrauterine 
system, bilateral tubal occlusion, partner with vasectomy, sexual abstinence.
For Japan only: Adequate contraceptive measures are abstinence (not having sex), diaphragm, 
condom (by the partner), intrauterine device, sponge, spermicide or oral contraceptives.
2. Any disorder, which in the investigator’s opinion might jeopardise subject’s safety or 
compliance with the protocol.
3. Family or personal history of Multiple Endocrine Neoplasia Type 2 (MEN 2) or Medullary 
Thyroid Carcinoma (MTC).
4. History of pancreatitis (acute or chronic).
5. 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).
6. Any of the following: myocardial infarction (MI), stroke or hospitalisation for unstable angina 
or transient ischaemic attack within the past 180 days prior to the day of screening and 
randomisation.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
19 August 2016
1RYR1RUGLVN
Trial ID: NN9924-4280
Version:
1.0
UTN: U1111-1180-3637 
Status:
Final
EudraCT no.: 2016-000988-16 
Page:
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7. Classified as being in New York Heart Association (NYHA) Class IV.
8. Planned coronary, carotid or peripheral artery revascularisation known on the day of screening.
9. Renal impairment defined as estimated Glomerular Filtration Rate (eGFR) <60 mL/min/1.73 m2
as per Chronic Kidney Disease Epidemiology Collaboration formula (CKD-EPI).
10. Treatment with any medication for the indication of diabetes or obesity other than stated in the 
inclusion criteria in a period of 90 days before the day of screening. An exception is short-term 
change of insulin treatment for acute illness for a total of ≤ 14 days.
11. Known hypoglycaemic unawareness according to Clarke’s questionnaire. 
12. Proliferative retinopathy or maculopathy requiring acute treatment. Verified by fundus 
photography or dilated fundoscopy performed within 90 days prior to randomisation.
13. History or presence of malignant neoplasms within the last 5 years (except basal and squamous 
cell skin cancer and carcinoma in situ).
14. Subjects with alanine aminotransferase (ALT) > 2.5 x upper normal limit (UNL).
Key assessments:
Efficacy
!
HbA1c
!
FPG
!
Body weight
Safety
!
Adverse events
!
Hypoglycaemic episodes
Trial products:
Investigational medicinal products:
!
Test product : semaglutide 3 mg, 7 mg and 14 mg tablets
!
Reference therapy: semaglutide placebo tablets
CONFIDENTIAL


Protocol
UTN: U1111-1180-3637 
Date:
19 August 2016
Status:
Final
1RYR1RUGLVN
Trial ID: NN9924-4280
EudraCT no.: 2016-000988-16 
Version:
1.0
Page:
15 of 130
2
Flow chart
Trial Periods
Scree-
ninga
Ran-
domi-
sation
Treatment period 1
Fixed insulin treatment period 
Treatment period 2
Adjustable insulin treatment 
period 
End-
of-
treatm
ent 
EoT
Fol-
low-
upb
EoT 
pre-
mature  
disconti
nua-
tionc
Follow-up 
premature 
discon-
tinuationc
Visit (V), Phone (P)
V1
V2
P3
V4
V5
P6
P7
V8
P9 V10
V11d
P12 V13
P14 V15 P16 V17
V18
V19
V18A
V19A
Timing of visit
(weeks)
up to
-2
0
2
4
8
10
12
14
16
20
26
29
32
35
38
41
45
52
57
Day of 
disconti
nuation 
of trial 
product
5 weeks 
after day of 
discontinuat
ion of trial 
product
Visit window
(days)
-7
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+3
+3
+3
SUBJECT RELATED
INFO/ASSESS-MENTS
Informed consent
x
In/exclusion criteria
x
x
Concomitant medication
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Demography
x
Childbearing potential
x
Tobacco use
x
Concomitant illness and 
medical history
x
Diagnosis of 
diabetes/diabetes 
complications
x
Hypoglycaemic 
unawareness
x


Protocol
UTN: U1111-1180-3637 
Date:
19 August 2016
Status:
Final
1RYR1RUGLVN
Trial ID: NN9924-4280
EudraCT no.: 2016-000988-16 
Version:
1.0
Page:
16 of 130
Trial Periods
Scree-
ninga
Ran-
domi-
sation
Treatment period 1
Fixed insulin treatment period 
Treatment period 2
Adjustable insulin treatment 
period 
End-
of-
treatm
ent 
EoT
Fol-
low-
upb
EoT 
pre-
mature  
disconti
nua-
tionc
Follow-up 
premature 
discon-
tinuationc
Visit (V), Phone (P)
V1
V2
P3
V4
V5
P6
P7
V8
P9 V10
V11d
P12 V13
P14 V15 P16 V17
V18
V19
V18A
V19A
Timing of visit
(weeks)
up to
-2
0
2
4
8
10
12
14
16
20
26
29
32
35
38
41
45
52
57
Day of 
disconti
nuation 
of trial 
product
5 weeks 
after day of 
discontinuat
ion of trial 
product
Visit window
(days)
-7
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+3
+3
+3
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
x
x
x
x
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
x
x
Self-measured plasma 
glucose, once or twice 
dailye
x
x
x
x
x
x
x
x
x
x
x
x
x
7-point profilef
x
x
x


Protocol
UTN: U1111-1180-3637 
Date:
19 August 2016
Status:
Final
1RYR1RUGLVN
Trial ID: NN9924-4280
EudraCT no.: 2016-000988-16 
Version:
1.0
Page:
17 of 130
Trial Periods
Scree-
ninga
Ran-
domi-
sation
Treatment period 1
Fixed insulin treatment period 
Treatment period 2
Adjustable insulin treatment 
period 
End-
of-
treatm
ent 
EoT
Fol-
low-
upb
EoT 
pre-
mature  
disconti
nua-
tionc
Follow-up 
premature 
discon-
tinuationc
Visit (V), Phone (P)
V1
V2
P3
V4
V5
P6
P7
V8
P9 V10
V11d
P12 V13
P14 V15 P16 V17
V18
V19
V18A
V19A
Timing of visit
(weeks)
up to
-2
0
2
4
8
10
12
14
16
20
26
29
32
35
38
41
45
52
57
Day of 
disconti
nuation 
of trial 
product
5 weeks 
after day of 
discontinuat
ion of trial 
product
Visit window
(days)
-7
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+3
+3
+3
Lipids
x
x
x
x
x
Height
x
Body weight
x
x
x
x
x
x
x
x
x
x
x
Waist circumference
x
x
x
x
x
x
Total daily insulin doseg
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
PRO questionnaires
x
x
x
x
SAFETY
Eye examinationh
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 testi
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Calcitonin
x
x
x
x
x
x
x
x
Biochemistryj
x
x
x
x
x
x
x
x
x
x
x
Haematology
x
x
x
x
x
x
x
x
x
x
Adverse eventsk
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x


Protocol
UTN: U1111-1180-3637 
Date:
19 August 2016
Status:
Final
1RYR1RUGLVN
Trial ID: NN9924-4280
EudraCT no.: 2016-000988-16 
Version:
1.0
Page:
18 of 130
Trial Periods
Scree-
ninga
Ran-
domi-
sation
Treatment period 1
Fixed insulin treatment period 
Treatment period 2
Adjustable insulin treatment 
period 
End-
of-
treatm
ent 
EoT
Fol-
low-
upb
EoT 
pre-
mature  
disconti
nua-
tionc
Follow-up 
premature 
discon-
tinuationc
Visit (V), Phone (P)
V1
V2
P3
V4
V5
P6
P7
V8
P9 V10
V11d
P12 V13
P14 V15 P16 V17
V18
V19
V18A
V19A
Timing of visit
(weeks)
up to
-2
0
2
4
8
10
12
14
16
20
26
29
32
35
38
41
45
52
57
Day of 
disconti
nuation 
of trial 
product
5 weeks 
after day of 
discontinuat
ion of trial 
product
Visit window
(days)
-7
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+3
+3
+3
Hypoglycaemic episodes
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Technical complaints
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
OTHER 
ASSESSMENTS
Semaglutide PK 
samplingl
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 dosing instructions
x
x
x
x
x
x
x
x
x
Attend visit fastingm
x
x
x
x
x
x
x
x
x
x
x
Handout and instruct in 
BG meter use
x


Protocol
UTN: U1111-1180-3637 
Date:
19 August 2016
Status:
Final
1RYR1RUGLVN
Trial ID: NN9924-4280
EudraCT no.: 2016-000988-16 
Version:
1.0
Page:
19 of 130
Trial Periods
Scree-
ninga
Ran-
domi-
sation
Treatment period 1
Fixed insulin treatment period 
Treatment period 2
Adjustable insulin treatment 
period 
End-
of-
treatm
ent 
EoT
Fol-
low-
upb
EoT 
pre-
mature  
disconti
nua-
tionc
Follow-up 
premature 
discon-
tinuationc
Visit (V), Phone (P)
V1
V2
P3
V4
V5
P6
P7
V8
P9 V10
V11d
P12 V13
P14 V15 P16 V17
V18
V19
V18A
V19A
Timing of visit
(weeks)
up to
-2
0
2
4
8
10
12
14
16
20
26
29
32
35
38
41
45
52
57
Day of 
disconti
nuation 
of trial 
product
5 weeks 
after day of 
discontinuat
ion of trial 
product
Visit window
(days)
-7
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+3
+3
+3
Handout ID card
x
Dispense and/or collect 
diary
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Footer
Description
xa
Screening assessments should be performed up to 2 weeks prior to randomisation and the subject can be randomised as 
soon as all inclusion and exclusion criteria are confirmed. The screening assessment must not exceed 3 weeks prior to 
randomisation (V2).
xb
V19 (Follow-up 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 V19.
xc
V18A and V19A are only applicable for subjects who have discontinued trial product prematurely.
xd
V11 is the concluding visit in the Restricted or fixed insulin treatment period as well the first visit in the Adjustable 


Protocol
UTN: U1111-1180-3637 
Date:
19 August 2016
Status:
Final
1RYR1RUGLVN
Trial ID: NN9924-4280
EudraCT no.: 2016-000988-16 
Version:
1.0
Page:
20 of 130
Footer
Description
insulin treatment period. 
xe
SMPG measurements should for all subjects be performed fasting (for six hours) before breakfast for 3 consecutive 
days prior to the phone/site visit.
For subjects on twice daily basal or twice daily premixed insulin including combinations of soluble insulins an 
additional SMPG measurement should be performed before dinner on the same 3 consecutive days. These additional 
SMPGs measurements need not be in a fasting state.
For the SMPG measurements performed prior to V11 and V18 one of the three SMPG measurements will be part of the
7-point profile.
xf
7-point profile – SMPG measurements should be taken as follows: before breakfast, 90 minutes after start of breakfast, 
before lunch, 90 minutes after start of lunch, before dinner, 90 minutes after start of dinner, and at bedtime. The 7-point 
profile should preferably be taken within the week prior to the visit.
xg
Total daily insulin dose can be adjusted during the trial. 
The total daily insulin dose is the sum of all daily insulin doses (i.e. any basal, bolus and premixed insulin dose
including combinations of soluble insulins) taken during the day.
At randomisation, the pre-randomisation total daily dose of insulin should be reduced by 20%. 
From V5 to P9, the total daily insulin dose should be adjusted by titration of the basal doses or doses of premixed 
insulin including combinations of soluble insulins based on 3 SMPGs prior to each visit. However, the total daily dose 
should not be adjusted titrated above the pre-randomisation dose.
From V11 and until end of the trial, the total daily insulin dose can be adjusted without restrictions by titration of the 
basal doses or doses of premixed insulin including combinations of soluble insulins based on 3 SMPGs prior to each 
visit.
xh
Fundus photography or 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.
xi
For women of child-bearing potential: Urine pregnancy test should also be performed at any time during the trial if a 


Protocol
UTN: U1111-1180-3637 
Date:
19 August 2016
Status:
Final
1RYR1RUGLVN
Trial ID: NN9924-4280
EudraCT no.: 2016-000988-16 
Version:
1.0
Page:
21 of 130
Footer
Description
menstrual period is missed, and/or according to local regulations/law.
xj
At V1 only, ALT, creatinine and eGFR will be assessed as part of Biochemistry.
xk
Adverse events reporting includes adverse events form 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.
xl
No PK sampling should be done for visits occurring after V19A (subjects who have discontinued trial product 
prematurely).
xm
Fasting for blood sampling is defined as no food or liquid within the last 8 hours prior to blood sampling, however, 
water is allowed up until 2 hours prior to blood sampling. Trial product must be taken after blood sampling. Other oral 
medication can be taken 30 minutes after trial product. Injectable medications can be administered after blood 
sampling.


Protocol
CONFIDENTIAL
Date:
19 August 2016
1RYR1RUGLVN
Trial ID: NN9924-4280
Version:
1.0
UTN: U1111-1180-3637 
Status:
Final
EudraCT no.: 2016-000988-16 
Page:
22 of 130
3
Background information and rationale for the trial
The trial will be conducted in compliance with this protocol, ICH GCP1 and applicable regulatory 
requirements, and in accordance with the Declaration of Helsinki2. 
For Mexico only: The above will include the following responsibilities for the head of the 
Institution/Health Care Establishment, Ethics, Research and, when applicable, Biosafety 
Committees and sponsor within their scope of responsibility: 
a) Investigation follow-up;
b) Damages to health arising from the investigation development; as well as those arising from 
interruption or advanced suspension of treatment due to non-attributable reasons to the Subject; 
c) Timely compliance of the terms in which the authorization of a research for health in human 
beings had been issued; 
d) To present in a timely manner the information required by the Health Authority.
In this document, the term investigator refers to the individual responsible for the overall conduct of
the clinical trial at a trial site.
3.1
Background information
3.1.1
Type 2 diabetes mellitus 
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 hyperglycaemia3. Despite the availability of several 
anti-diabetic drugs, a significant proportion of subjects with T2DM do not achieve the 
recommended targets for glycaemic control4,5.
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 islets6, 7. Subjects 
with T2DM have a decreased incretin effect8, 9. However, the insulinotropic action of GLP-1 and 
thus, the ability to lower BG levels, is preserved when GLP-1 is administered at supraphysiological 
levels10. In addition, supraphysiological levels of GLP-1 induce reduction in body weight11. 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 regulation12, 13. Physiologically, GLP-1 also has a 
pronounced inhibitory effect on gastric emptying; however this effect seems to diminish upon 
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
19 August 2016
1RYR1RUGLVN
Trial ID: NN9924-4280
Version:
1.0
UTN: U1111-1180-3637 
Status:
Final
EudraCT no.: 2016-000988-16 
Page:
23 of 130
chronic exposure11, 13. These mechanisms of action make GLP-1 receptor agonists (GLP-1 RA) an 
attractive pharmacological treatment for T2DM14, 15.
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 
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 2616. 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 whereto 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 development17. 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.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
19 August 2016
1RYR1RUGLVN
Trial ID: NN9924-4280
Version:
1.0
UTN: U1111-1180-3637 
Status:
Final
EudraCT no.: 2016-000988-16 
Page:
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Thyroid C-cell tumours in rodents
Treatment-related non-genotoxic proliferative changes in the thyroid C-cells of mice and rats were 
observed in 2-year carcinogenicity studies with semaglutide; thyroid hyperplasia was preceded by 
an increase in serum calcitonin. C-cell changes have not been observed in long-term studies in non-
human primate. The observed pattern of effects in mice and rats and lack of these effects in the non-
human primate and in man suggest that the mechanism by which semaglutide acts on the thyroid C-
cells in rodents is the same as has been demonstrated for other GLP-1 RAs, including liraglutide. 
According to this mechanism, C-cell hyperplasia is mediated by the GLP-1 receptor and is not 
associated with RET (re-arranged during transfection) gene activation and rodents appear to be 
particularly sensitive, whereas humans are not. The relevance for human subjects is currently 
unknown, but considered to be low18.
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 1119 and the IB for oral administration of 
semaglutide (NN9924), edition 720, 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.
 
 
 
 
 
 
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 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.
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 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 720, 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 7, 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 them were mild to moderate 
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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 
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 720, or 
any updates hereof.
For an assessment of benefits and risks of the trial, see Section 18.1.
3.2
Rationale for the trial
Many patients with T2DM are not in glycaemic control with the currently marketed oral anti-
diabetic drugs (OADs). 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 due to its effects 
on both hyper glycaemia and body weight. 
Insulin treatment in T2DM can be a very efficacious treatment, but in a number of patients optimal
glycaemic control is not reached due to weight gain, risk of hypoglycaemia or reluctance to the 
increase insulin dose. The purpose of the present trial is to investigate whether combining oral 
semaglutide with insulin treatment may help patients with T2DM to reach glycaemic control as well 
as lead to weight loss or weight stabilisation.
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4
Objective(s) and endpoint(s)
4.1
Objective(s)
4.1.1
Primary objective
To compare the effect of once-daily dosing of three dose levels of oral semaglutide (3, 7 and 14 mg) 
versus placebo on glycaemic control in subjects with type 2 diabetes mellitus treated with insulin.
4.1.2
Secondary objective(s)
To compare the effect of once-daily dosing of three dose levels of oral semaglutide (3, 7 and 14 mg) 
versus placebo on body weight in subjects with type 2 diabetes mellitus treated with insulin.
To compare the safety and tolerability of once-daily dosing of three dose levels of oral semaglutide 
(3, 7 and 14 mg) versus placebo in subjects with type 2 diabetes mellitus treated with insulin.
4.2
Endpoints
Baseline refers to randomisation, and week 26 and week 52 refers to 26 weeks 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
Change from baseline to week 26 in body weight (kg)
4.2.2.2
Supportive secondary efficacy endpoints
Key supportive secondary endpoints prospectively selected for disclosure (e.g. clinicaltrials.gov and 
EudraCT) are marked with an asterisk (*).
Change from baseline to week 52 in:
!
HbA1c*
!
Body weight (kg)*
Change from baseline to week 26 and week 52 in:
!
Fasting plasma glucose (FPG)*
!
7-point self-measured plasma glucose (SMPG) profile
–
Mean 7-point profile
–
Mean postprandial increment (over all meals)
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!
Body weight (%)
!
Body mass index (BMI)
!
Waist circumference
!
Fasting lipid profile (total cholesterol, low density lipoprotein [LDL] cholesterol, high density 
lipoprotein [HDL] cholesterol, triglycerides)
!
Patient-reported outcomes (PROs)
–
Short Form (SF)-36v2TM (acute version) health survey
–
Impact of Weight on Quality of Life (IWQOL-Lite)
–
Diabetes Treatment Satisfaction Questionnaire (DTSQs)
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)
!
Weight loss ≥ 3% 
!
Weight loss ≥ 5% 
!
Weight loss ≥ 10% 
!
HbA1c  < 7.0% (53 mmol/mol) without hypoglycaemia (treatment-emergent severe or blood 
glucose-confirmed symptomatic hypoglycaemia) and no weight gain 
!
HbA1c reduction ≥ 1.0%-point (10.9 mmol/mol) and weight loss ≥ 3%
Time to event:
!
Time to rescue medication
Change from baseline to weeks 26 and 52 in:
!
Total daily insulin dose (IU)
4.2.2.3
Supportive secondary pharmacokinetic endpoint
!
Semaglutide plasma concentrations for population PK analyses
4.2.2.4
Supportive secondary safety endpoints
!
Number of treatment-emergent adverse events (TEAEs) during exposure to trial product, 
assessed up to approximately 26 and 57* weeks 
!
Number of treatment-emergent severe or blood glucose-confirmed symptomatic 
hypoglycaemic episodes during exposure to trial product, assessed up to approximately 26 
and 57* weeks 
!
Treatment-emergent severe or blood glucose confirmed symptomatic hypoglycaemic 
episodes during exposure to trial product, assessed up to approximately 26 and 57 weeks 
(yes/no)
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Change from baseline to week 26 and 52 in:
!
Haematology
!
Biochemistry
!
Calcitonin
!
Pulse
!
Systolic blood pressure
!
Diastolic blood pressure
!
Electrocardiogram (ECG) category
!
Physical examination 
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5
Trial design
5.1
Type of trial
This is a 52-week, randomised, placebo-controlled, four-armed, parallel-group, multicentre, 
multinational trial, double-blinded during the initial 26 weeks. The trial will compare the efficacy 
and safety of three dose levels of once-daily oral semaglutide versus placebo in subjects with 
T2DM treated with insulin.
Subjects will be randomised in a 1:1:1:1 manner to receive one of the following treatments:
!
3 mg oral semaglutide once-daily
!
7 mg oral semaglutide once-daily
!
14 mg oral semaglutide once-daily
!
oral semaglutide placebo once-daily
Randomisation will be stratified based on:
Descent:
!
Japanese subject 
!
Non-Japanese subject
Background metformin medication at screening:
!
Metformin
!
No metformin
Background insulin medication at screening:
!
Basal insulin
!
Basal-bolus insulin alone
!
Premixed insulin including combinations of soluble insulins
All tablets containing oral semaglutide or placebo are identical with regards to visual appearance to 
maintain the blinding of the trial.
The total trial duration for the individual subject will be approximately 59 weeks. The trial includes 
a 2-week screening period followed by a 52-week randomised treatment period and a 5-week 
follow-up period. The 52-week randomised treatment period is split into two treatment periods; an 
initial 26-week fixed insulin treatment period where the insulin treatment is restricted, followed by 
a 26-week period where the insulin treatment is adjustable without any restrictions (see Section 
5.3.3). 
The first 26 weeks of the trial is double-blinded. Because the week 26 trial results will be reported 
before the trial is completed, the randomisation details will be revealed to selected Novo Nordisk 
personnel after all subjects have completed 26 weeks treatment. Following the end of trial, results 
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from the entire trial period will be reported. Investigators and subjects will be blinded throughout 
the entire trial. All subjects consent to the full trial length when they sign the informed consent.
The trial design is illustrated in Figure 5–1.
Figure 5–1
Trial design
5.2
Rationale for trial design
The trial has been designed as a parallel-group, four-armed placebo-controlled trial to ensure a 
direct comparison between three dose levels of oral semaglutide and placebo. Subjects will be 
randomised in a 1:1:1:1 manner between the four treatment arms and the trial will be double-
blinded for the initial 26 weeks. The randomisation will be stratified based on descent and 
background metformin medication and background insulin medication at screening (see Section 
11.1). The stratification is to ensure an even distribution of the four treatment arms within strata.
The confirmatory endpoints are defined after 26 weeks of treatment. This is considered sufficient 
time to compare the effect on glycaemic control and body weight after oral semaglutide dose 
escalation up till week 8 and insulin dose adjustments ending at week 16. Regarding insulin 
adjustment see section 5.3.3 and 5.5. Furthermore, at 26 weeks the extent of missing data, use of 
rescue medication or premature treatment discontinuation is expected to be limited. This allows for 
a robust estimation of the effect of oral semaglutide on HbA1c and body weight.
Supportive secondary efficacy endpoints defined at both 26 and 52 weeks will ensure capture of a 
number of relevant efficacy measures to support the primary results. 
The 5-week follow-up period is included to allow for wash-out of semaglutide. The total trial 
duration of 52 weeks of exposure to trial product will ensure adequate time to evaluate the long 
term safety of oral semaglutide in combination with insulin in subjects with T2DM.
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5.3
Treatment of subjects
Treatment of subjects is summarised in Table 5-1.
Table 5-1
Overview of treatment of subjects
Trial periods
Screening
Restricted or fixed insulin 
treatment period
Adjustable 
insulin 
treatment period
Follow-up
Screening
Dose escalation /Maintenance
Maintenance
Follow-up
First visit in each period
V1
V2
V4
V5
V11
V19
Duration of each period
(total 60 weeks)
2 weeks
4 weeks
4 weeks
18 weeks
26 weeks
5 weeks
Treatment arm
n
Semaglutide 3 mg
tablet
180
Screening
3 mg
3 mg
3 mg
3 mg
Follow-up
Semaglutide 7 mg
tablet
180
Screening
3 mg
7 mg
7 mg
7 mg
Follow-up
Semaglutide 14 mg
tablet
180
Screening
3 mg
7 mg
14 mg
14 mg
Follow-up
Placebo
180
Screening
Placebo
Placebo
Placebo
Placebo
Follow-up
The following trial products will be supplied by Novo Nordisk A/S, Denmark: 
!
Semaglutide, 3 mg, 7 mg and 14 mg, tablets
!
Semaglutide placebo, tablets
Oral semaglutide treatment
Oral semaglutide is a long-acting GLP-1 RA to be administered orally once-daily. Subjects 
randomised to oral semaglutide will initiate treatment with 3 mg oral semaglutide once-daily. 
Subjects randomised to the 7 and 14 mg treatment arms will continue treatment with 4-week dose-
escalation step(s) until maintenance dose is reached, as illustrated in Table 5-1. 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 during the course of the trial once the maintenance dose of oral 
semaglutide has been reached.
Placebo treatment
Subjects randomised to placebo will follow the same directions as outlined for the oral semaglutide 
treatment i.e. tablets administered orally once-daily. 
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5.3.1
Dosing instructions
Oral semaglutide/semaglutide placebo
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. Trial product can be taken with up to half a glass of water (approximately 120 
mL/4 fluid oz). The tablets must be swallowed whole by the subject and must not be broken or 
chewed (see Table 9-2). Furthermore, other oral medication can be taken 30 minutes after 
administration of the oral trial product.
5.3.2
Background medication
In this trial, oral semaglutide or placebo will be added to an existing background medication of an 
insulin regimen alone or in combination with metformin treatment.  
After signing the informed consent, all subjects should continue their pre-trial insulin therapy 
(basal, basal-bolus or premixed regimen including combinations of soluble insulins) throughout the 
trial. For insulin treatment, see section 5.3.3.1. Subjects treated with metformin in addition to 
insulin treatment must continue their metformin treatment throughout the entire trial. Metformin 
treatment must be maintained at the stable, pre-trial dose and at the same frequency during the 
entire treatment period. 
If a subject has unacceptable hypoglycaemia during the course of the trial, the total daily insulin 
dose can be reduced at any time during the trial. However, the background medication may be 
adjusted if rescue medication is needed or a safety concern related to the background medication 
arises. 
In addition, all background medication (both metformin and insulin):
!
is considered to be non-investigational medicinal product (NIMP)
!
will not be provided by Novo Nordisk A/S, except if required by local regulations. 
!
should be used in accordance with standard of care and current approved label in the 
individual country
!
must not exceed the maximum approved dose in the individual country
5.3.3
Total daily insulin dose adjustments during the trial
The total daily insulin dose is the sum of all daily insulin doses (i.e. any basal, bolus and premixed 
insulin including combinations of soluble insulins) taken during the day.
5.3.3.1
At randomisation (V2)
To minimise the risk of hypoglycaemic episodes when introducing an additional anti-diabetic agent, 
an initial 20% reduction in total daily insulin dose is recommended at randomisation for all subjects. 
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5.3.3.2
During the fixed insulin treatment period
Increasing the total daily insulin dose before V5 should be avoided, unless required to prevent acute 
diabetic complications. However, decreasing insulin doses before V5 to prevent hypoglycaemia, is 
allowed.
After a subject has reached the maintenance dose of oral semaglutide, the total daily insulin doses
can be adjusted by the investigator from V5 until and including phone contact 9 (P9) by titration of 
either the basal insulin doses or doses of premixed insulin including combinations of soluble 
insulins  according to the insulin titration guideline (5.3.3.4). Bolus insulin doses can be titrated at 
the investigators discretion. However, the total daily insulin doses should not be adjusted above 
the dose recorded at V2 (i.e. pre-randomisation dose). There are no restrictions on decreasing the 
insulin doses.
After P9 the total daily insulin dose should remain fixed until V11, unless required to prevent acute 
diabetic complications or the subject has met rescue criteria (see Section 6.4).
V11 is the concluding visit in the Restricted or fixed insulin treatment period as well the first visit in 
the Adjustable insulin treatment period. 
5.3.3.3
During the adjustable insulin treatment period
From V11 to end of trial there are no restrictions on adjustments of the total daily insulin dose. 
Thus, the total daily insulin dose can be adjusted by the investigator by either titration of the basal 
doses or doses of premixed insulin including combinations of soluble insulins according to the 
insulin titration guideline (section 5.3.3.4). Bolus insulin doses can be titrated at investigators 
discretion.
5.3.3.4
Insulin titration guideline
Insulin titration should be based on the lowest of three self-measured plasma glucose (SMPG) 
values; preferably measured on three consecutive days prior to each phone contact/site visit and 
according to Table 5-2 and Table 5-3. The aim of the insulin titration should be to obtain a fasting 
plasma glucose level between 4.0 and 5.5 mmol/L (71-99 mg/dL) and an HbA1c level below 7.0% 
(53 mmol/mol).
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In addition:
!
For subjects on once-daily basal insulin or once-daily premixed insulin including 
combinations of soluble insulins regimens, titration should be based on the lowest of three 
fasting pre-breakfast SMPG values taken after at least 6 hours of fasting.
!
For subjects on twice-daily basal or twice-daily premixed insulin including combinations of 
soluble insulins regimens, titration should be done for each dosing separately:
o
The morning dosing should be titrated based on the lowest of three pre-dinner SMPG 
values
o
The evening dosing should be based on the lowest of three fasting pre-breakfast 
fasting SMPG values
!
For subjects on a basal-bolus insulin regimen, the basal insulin should be adjusted as above, 
and the bolus insulin dose should be adjusted at the discretion of the investigator
All subjects should continue to measure SMPG values regularly throughout the trial. Subjects will 
be instructed to inform the investigator in case of hypoglycaemia or hyperglycaemia.
Table 5-2
Increase of insulin dose
Lowest of 3 pre-breakfast/pre-dinner SMPG values 
Titration of dose of basal or premixed insulin including 
combinations of soluble insulins IU (*)
mmol/L
mg/dL
4.0 – 5.5
71 – 99
No titration
5.6 – 7.0
100 – 126
+2
7.1 – 8.0
127 – 144
+4
8.1 – 9.0
145 – 162
+6
>9.0
>162
+8
(*)
!
V5 to P9 (both included): The total daily insulin dose should not be adjusted above the dose taken prior to randomisation, 
recorded at V2 as pre-randomisation dose.   
!
V11 to V18: No restrictions on maximum total daily insulin doses 
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Table 5-3
Decrease of insulin dose
Lowest of 3 pre-breakfast/pre-dinner SMPG values 
Titration of dose of basal or premixed insulin 
including combinations of soluble insulins IU (*)
mmol/L
mg/dL
< 3.1
< 56
-4 
(for doses >45 IU, suggest dose reduction of 10%)
3.1 – 3.9
56 – 70
-2
(for doses >45 IU, suggest dose reduction of 5%)
(*) Entire trial:  No restrictions on minimum total daily insulin doses
5.4
Treatment after discontinuation of trial product
When discontinuing trial product, either at the scheduled end-of-treatment visit (see Section 8.1.4) 
or if trial product is discontinued prematurely (see Section 8.1.5), the subject should have the 
insulin dose adjusted or be switched to a suitable marketed product, both at the discretion of the 
investigator. After discontinuation of trial product, GLP-1 RAs are not allowed before completion 
of the follow-up visit 5 weeks after the last date on trial product. Throughout the protocol, last date 
on trial product is defined as date of the subject’s last dosage of trial product.
As this trial is a phase 3a trial, oral semaglutide will not be available for prescription until after 
marketing authorisation.
5.5
Rationale for treatment  
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 phase 2 dose-
finding trial (NN9924-3790). This regimen is expected to have the optimal benefit-risk profile for 
further development for treatment of T2DM in the PIONEER programme. 
In one of the four arms, oral semaglutide will be dose escalated to the highest dose (14 mg) to 
investigate and establish the maximum efficacy and safety in subjects with T2DM treated with 
insulin alone or in combination with metformin. 
The present trial includes a placebo arm. The use of a placebo group is necessary to demonstrate 
that oral semaglutide together with non-pharmacological interventions such as diet, exercise and 
behaviour modifications are more effective than the same non-pharmacological interventions on 
their own. Specifically for this trial, glycaemic control in the placebo arm may also potentially be 
achieved by intensification of insulin treatment. Therefore, in order to estimate the true glucose 
lowering effect of oral semaglutide after 26 weeks, for all subjects, the insulin dose should be 
titrated with the restriction not to exceed the baseline total daily insulin dose and then be fixed 
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during the 10 weeks leading up to visit V11 (i.e. week 26) when the primary endpoint will be 
evaluated.
The recommended 20% decrease in subjects’ total daily insulin dose at randomisation as well as the 
initial 8-week period during which insulin should not be increased are set to protect subjects 
randomised to active treatment arms against potential hypoglycaemic episodes. 
The insulin titration from visit V5 to P9 (weeks 8-16) is set to allow all subjects who may benefit 
from this, to get back to their pre-randomisation insulin dose-level. This will alleviate a possible 
hyperglycaemic effect of the initial insulin dose reduction in subjects randomised to the placebo 
arm. 
During the second trial period (from week 26 to end of trial) insulin treatment may be adjusted 
without restrictions in order to estimate the long term safety of adding oral semaglutide to freely 
adjustable insulin treatment.
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6
Trial population
6.1
Number of subjects 
Number of subjects planned to be screened: 
1200
Number of subjects planned to be randomised:
720
For Mexico only: Approximately 40 subjects planned to be randomised.
Number of subjects expected to complete the trial on or off trial product:
576
6.2
Inclusion criteria
For an eligible subject, all inclusion criteria must be answered “yes”. 
1. Informed consent obtained before any trial-related activities. Trial-related activities are any 
procedures that are carried out as part of the trial, including activities to determine suitability for 
the trial.
2. Male or female, age above or equal to 18 years at the time of signing informed consent.
For Japan only: Male or female, age above or equal to 20 years at the time of signing informed 
consent.
3. Diagnosed with type 2 diabetes mellitus ≥ 90 days prior to the day of screening.
4. HbA1c of 7.0-9.5% (53-80 mmol/mol) (both inclusive).
5. Stable treatment with one of the following insulin regimens (minimum 10 IU/day) ≥ 90 days 
prior to the day of screening. Maximum 20% change in total daily dose is acceptable:
!
Basal insulin alone
!
Basal and bolus insulin in any combination
!
Premixed insulin including combinations of soluble insulins 
Concomitant treatment with stable daily dose of metformin (≥ 1500 mg or maximum tolerated 
dose as documented in the subject medical record) ≥ 90 days prior to the day of screening is 
allowed.
For Japan only: Concomitant treatment with metformin is only allowed in combination with 
basal insulin alone (not in combination with basal-bolus or premixed insulin including 
combinations of soluble insulins).
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6.3
Exclusion criteria
For an eligible subject, all exclusion criteria must be answered “no”. 
1. Known or suspected hypersensitivity to trial product(s) or related products.
2. Previous participation in this trial. Participation is defined as signed informed consent.
3. Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing 
potential and not using an adequate contraceptive method (adequate contraceptive measure as 
required by local regulation or practice).
For Greece only: adequate contraceptive measures are defined as combined hormonal 
contraception (containing oestrogen and progesterone), which suppress ovulation (oral, 
intravaginal, percutaneous), progesterone-only hormonal contraception which suppress 
ovulation (oral, injectable, implantable), intrauterine device, hormone-releasing intrauterine 
system, bilateral tubal occlusion, partner with vasectomy, sexual abstinence.
For Japan only: Adequate contraceptive measures are abstinence (not having sex), diaphragm, 
condom (by the partner), intrauterine device, sponge, spermicide or oral contraceptives.
4. Receipt of any investigational medicinal product within 90 days before screening.
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 and potentially affecting absorption 
of trial product (e.g. subtotal and total gastrectomy, sleeve gastrectomy, gastric bypass surgery).
9. Any of the following: myocardial infarction (MI), stroke or hospitalisation for unstable angina 
or transient ischaemic attack within the past 180 days prior to the day of screening and 
randomisation.
10. Classified as being in New York Heart Association (NYHA) Class IV.
11. Planned coronary, carotid or peripheral artery revascularisation known on the day of screening.
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12. Renal impairment defined as estimated Glomerular Filtration Rate (eGFR) <60 mL/min/1.73 m2
as per Chronic Kidney Disease Epidemiology Collaboration formula (CKD-EPI).
13. Treatment with any medication for the indication of diabetes or obesity other than stated in the 
inclusion criteria in a period of 90 days before the day of screening. An exception is short-term 
change of insulin treatment for acute illness for a total of ≤ 14 days.
14. Known hypoglycaemic unawareness according to Clarke’s questionnaire. 
15. Proliferative retinopathy or maculopathy requiring acute treatment. Verified by fundus 
photography or dilated fundoscopy performed within 90 days prior to randomisation.
16. History or presence of malignant neoplasms within the last 5 years (except basal and squamous 
cell skin cancer and carcinoma in situ).
17. Subjects with alanine aminotransferase (ALT) > 2.5 x upper normal limit (UNL).
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 as well as the effect of insulin up-titration from week 8 
to week 16 (V5 to P9), a rescue criteria will be applied from week 16 (P9) 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 (i.e. intensification of anti-
diabetic background medication and/or initiation of new anti-diabetic medication):
!
11.1 mmol/L (200 mg/dL) from week 16 (P9) to end of treatment 
In addition, subject should be offered rescue medication if:
!
HbA1c (at central laboratory) > 8.5% (69.4 mmol/mol) from week 26 (V11) 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 the investigators’s discretion. Increase of insulin dose 
should be first choice. Second choice should be add-on to randomised treatment and according to 
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ADA/European Association for the Study of Diabetes guidelines21, 22 (excluding GLP1-RAs, DPP-4 
inhibitors and amylin analogues). 
Rescue medication and any changes hereto should be captured on the concomitant medication form 
in the electronic case report form (eCRF), see Section 8.2.5.
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, see appendix B. 
The subject must be prematurely discontinued from the 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 (IMP)
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 8.1.5 for procedures to be performed for subjects discontinuing trial product 
prematurely.
6.6
Withdrawal from trial
The subject may withdraw consent at will at any time. The subject’s request to withdraw from the 
trial must always be respected. Only subjects who withdraw consent should be considered as 
withdrawn from trial.
See Section 8.1.6 for procedures to be performed for subjects withdrawing consent.  
For Mexico only: Should the subject, his/her family members, parents or legal representative 
decide to withdraw the consent for participation in the trial, the subject will be entitled to receive 
appropriate, free of charge medical care and/or trial drug during the follow up period of the 
protocol when it will be available with certainty that no untoward medical consequences of the 
subject´s participation in the research occurred.
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6.7
Subject replacement
Subjects who withdraw consent or discontinue trial product prematurely will not be replaced. 
6.8
Rationale for trial population 
The trial population will include subjects with T2DM treated with stable doses of insulin alone or in 
combination with stable treatment with metformin for at least 90 days prior to screening. 
Background medication must be stable as changes in the background medication shortly before trial 
participation may potentially impact the trial interpretation.
The HbA1c limits of 7.0-9.5% (53-80 mmol/mol) have been chosen to include subjects needing 
intensification of their anti-diabetic medication. The upper limit will ensure that subjects with 
severely uncontrolled T2DM are not enrolled in this placebo-controlled trial as the expected 
beneficial non-pharmacological effects merely from participation in the trial may not be sufficient 
in these individuals to justify inclusion. 
No BMI or blood pressure restrictions will be applied. Subjects with liver test abnormalities (ALT > 
2.5 × UNL) will be excluded to avoid potential confounding of liver safety assessments. In addition, 
subjects with moderate, severe or end-stage renal impairment will be excluded in this trial, as the 
safety and efficacy of oral semaglutide in subjects with renal impairment are addressed in another 
dedicated phase 3a clinical trial. The eligibility criteria allow for enrolment of a trial population 
resembling the target population of T2DM patients treated with insulin in common practice. In 
addition, FPG and HbA1c will be monitored throughout the trial and rescue medication should be 
initiated in subjects with persistent, unacceptable hyperglycaemia.
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Version:
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7
Milestones
Planned duration of recruitment period:
20 weeks
Planned FSFV:
02-Feb-2017
Planned LSLV:
09-Aug-2018
End of trial is defined as 
LSLV
Recruitment:
The screening and randomisation rate will be followed closely via the IWRS in order to estimate 
when to stop screening. All investigators will be notified immediately when the recruitment period 
ends, after which no further subjects may be screened and the IWRS will be closed for further 
screening.
Trial registration:
Information of the trial will be disclosed at clinicaltrials.gov and novonordisk-trials.com and the 
Clinical Trials Information JapicCTI site clinicaltrials.jp. According to the Novo Nordisk Code of 
Conduct for Clinical Trial Disclosure23, it will also be disclosed according to other applicable 
requirements such as those of the International Committee of Medical Journal Editors (ICMJE)24, 
the Food and Drug Administration Amendment Act (FDAAA)25, European Commission 
Requirements26,27 and other relevant recommendations or regulations. If a subject requests to be 
included in the trial via the Novo Nordisk e-mail contact at these web sites, Novo Nordisk may 
disclose the investigator’s contact details to the subject. As a result of increasing requirements for 
transparency, some countries require public disclosure of investigator names and their affiliations.
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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 (see Section 2) for number and timing of visits and specific assessments to be 
performed. 
Each subject will attend 12 site visits and 7 phone contacts. It is the responsibility of the 
investigator to ensure that all site visits 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 log of staff and a delegation of task(s) list at site. Investigator must 
sign the log of staff and the delegation of task(s) at site prior to the delegation of tasks.
The investigator must keep a subject screening log, a subject identification code list and a subject 
enrolment log. Only subjects who have signed the informed consent form should be included on the 
logs. The subject screening log and subject enrolment log may be combined in one log. 
8.1.1
Screening, visit 1
At screening, subjects will be provided with a card stating that they are participating in a trial and 
giving contact address(es) and telephone number(s) of relevant trial site staff. Subjects should be 
instructed to return the card to the investigator at the last trial visit or to destroy the card after the 
last visit.
A screening session must be made in the IWRS. Each subject will be assigned a unique 6-digit 
subject number which will remain the same throughout the trial.
Once all data relating to V1 have been obtained, these must be reviewed, dated and signed by the 
investigator and/or documented in medical records to assess that the subject is eligible to continue 
in the trial.
It is the investigator’s responsibility to ensure that the subject knows how to use the pen correctly.
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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 or 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.
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. 
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.
Fasting samples:
!
fasting plasma glucose (FPG)
!
fasting lipid profile (total cholesterol, low-density lipoprotein (LDL) cholesterol, high-
density lipoprotein (HDL) cholesterol, triglycerides)
!
semaglutide PK
8.1.3
Randomisation and trial product administration
Eligible subjects will be randomised into one of four treatment arms. The randomisation session 
must be performed in the IWRS which will allocate the dispensing unit number (DUN) of trial 
product to be dispensed to the subject.
All V2 assessments must be performed before administration of first dose of trial product.
Trial products (see Section 9) will be dispensed to the subject by the site, hospital pharmacy or 
equivalent at each site visit during the trial from randomisation to last visit before the End-of-
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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.
Date of first administration of trial product will be captured in the eCRF.
8.1.4
End-of-treatment (visit 18) and Follow-up (visit 19)
Subjects, who stay on trial product throughout the trial, must attend the End-of-treatment visit 
(V18) 52 weeks after randomisation and the Follow-up visit (V19) 5 weeks after the last date on 
trial product. V19 has a +3 days visit window. A completion call must be performed in the IWRS 
after completion of visit 18 (see Section 10).
In case the subject cannot be reached (by clinic visit or phone contact) at the scheduled visit 19, the 
site should consult the contacts provided by the subject (e.g. close relatives), relevant physicians, 
medical records and locator agencies (if allowed according to local law) to collect health status. If 
no health status can be collected, the subject should be considered lost to follow up and this should 
be specified in the end-of-trial form. 
8.1.5
Premature discontinuation of trial product and follow-up (visits 18A and 19A)
Subjects, who discontinue trial product prematurely, should attend visit 18A scheduled to take place 
on the day of discontinuation of trial product (+ 3 days visit window). Visit 19A 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 18A (see Section 10).
If premature discontinuation of trial product is decided during a scheduled visit, the visit will be 
converted into a V18A and trial procedures must be performed accordingly.
Subjects should continue with the originally scheduled site contacts after visit 19A and up to and 
including visit 19. If necessary, in order to retain the subject in the trial, site visits can be replaced 
by phone contacts after V19A. However, if a subject is unable or unwilling to attend all subsequent 
visit(s), the investigator should at least aim to have the subject attend V11 (week 26) and End-of-
treatment (V18) (week 52) as these visits should be performed for all subjects, if at all possible 
(except subjects who withdraw informed consent, see Section 8.1.6). 
Subjects, who only agree to attend or provide health status at the planned V18, should not be 
considered withdrawn from the trial. In case the subject cannot be reached (by clinic visit or phone 
contact) at the scheduled V18, the site should consult the contacts provided by the subject (e.g. 
close relatives), relevant physicians, medical records and locator agencies (if allowed according to 
local law) to collect health status. If no health status can be collected, the subject should be 
considered lost to follow-up and this should be specified in the end-of-trial form. 
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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 8.1.6).
8.1.6
Withdrawals
If a subject considers withdrawing from the trial, the investigator must aim to undertake procedures 
for visit 18A as soon as possible and visit 19A should be scheduled 5 weeks (+3 days visit window) 
after the last date on trial product, if the subject agrees to it.
The end-of-trial form must be completed and final drug accountability must be performed even if 
the subject is not able to come to the trial site. A treatment discontinuation session must be made in 
the IWRS (see Section 10). The case book must be signed. 
Although a subject is not obliged to give his/her reason(s) for withdrawing consent, the investigator 
must make a reasonable effort to ascertain the reason(s), while fully respecting the subject’s rights. 
Where the reasons are obtained, the primary reason for withdrawing consent must be specified in 
the end-of-trial form in the eCRF.
8.1.7
Investigator assessments
Review of diaries, Patient Reported Outcomes (PROs), laboratory reports, ECGs and fundus 
photography or 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.
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In case of abnormal clinically significant findings found as a result of screening procedures 
conducted at V1 or assessments revealing baseline conditions at V2, the investigator must state a 
comment in the subject’s medical record and record this in the medical history/concomitant illness 
form in the eCRF. 
The Investigator or his/her delegate must collect and review the PROs and diaries for completeness 
and to ensure that AEs are reported. 
8.2
Subject related information/assessments 
8.2.1
Demography
Demography will be recorded in the eCRF at screening and consists of:
!
Date of birth (according to local regulation)
!
Sex
!
Ethnicity (according to local regulation)
!
Race (according to local regulation)
8.2.2
Diabetes history and diabetes complications 
Diabetes history and diabetes complications will be recorded on a disease specific form at screening 
and consists of:
!
Date of diagnosis of type 2 diabetes 
!
Information regarding diabetes complications including date of onset
–
Diabetic retinopathy
–
Diabetic neuropathy
–
Diabetic nephropathy
Please note that macroangiopathy (including peripheral arterial disease) should be reported on the 
disease specific form History of cardiovascular disease (see Section 8.2.4).
8.2.3
Hypoglycaemia unawareness 
Information on hypoglycaemia unawareness will be recorded at screening according to Clarke’s 
questionnaire, question 828. The investigator must ask the subject in the following way: “To what 
extent can you tell by your symptoms that your blood glucose is low?” The subject can answer 
never, rarely, sometimes, often or always. Subjects answering ‘never, rarely or sometimes’ are 
considered as having impaired awareness of hypoglycaemia.
8.2.4
Concomitant illness and medical history
A concomitant illness is any illness that is present at the start of the trial (V1) or found as a result 
of a screening procedure or other trial procedures performed before exposure to trial product.
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Medical history is a medical event that the subject has experienced in the past. Only relevant 
medical history as judged by the investigator should be reported.
The information collected for concomitant illness and medical history should include diagnosis, 
date of onset and date of resolution or continuation, as applicable.
The following must be recorded in the eCRF on the disease specific forms only, i.e. not on the 
medical history/concomitant illness form:
!
History of cardiovascular disease (CVD) (e.g. ischaemic heart disease, MI, heart failure 
incl. NYHA class, hypertension, stroke, peripheral arterial disease)
!
History of gallbladder disease (e.g. gallstone, cholecystitis, cholecystectomy)
!
History of gastrointestinal disease (e.g. gastroesophageal reflux disease, ulcer disease, 
chronic gastritis)
Any change to a concomitant illness should be recorded during the trial. A clinically significant 
worsening of a concomitant illness must be reported as an AE (see Section 12).
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.
8.2.5
Concomitant medication
A concomitant medication is any medication, other than the trial products, which is taken during 
the trial, including the screening and follow-up periods. 
Details of any concomitant medication must be recorded at the first visit. Changes in concomitant 
medication must be recorded at each visit as they occur.
The information collected for each concomitant medication includes
!
trade name or generic name
!
indication
!
start date and stop date or continuation
!
only applicable for anti-diabetic medication:
–
start date of current dose and total daily insulin dose (basal, bolus and premixed insulin
including combinations of soluble insulins)
–
start date of current dose and total daily dose of metformin
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.
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8.2.6
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 an adequate 
contraceptive method throughout the trial and until 5 weeks after end of treatment. 
For Japan only: Adequate contraceptive measures are abstinence (not having sex), diaphragm, 
condom (by the partner), intrauterine device, sponge, spermicide or oral contraceptives.
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
8.2.7
Tobacco use 
Details of tobacco use must be recorded at V1. Smoking is defined as smoking at least one cigarette 
or equivalent daily. 
Smoking status:
!
Never smoked
!
Previous smoker, smoking stop date
!
Current smoker
8.3
Efficacy assessments
8.3.1
Laboratory assessments for efficacy
For overall 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 lipid profile: 
!
Total cholesterol
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!
LDL-cholesterol
!
HDL-cholesterol
!
Triglycerides
Other parameters
!
Semaglutide PK (see Section 8.6.1)
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 laboratory 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 V1, 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. In case a hypoglycaemic episode is 
suspected, 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 meters provided by Novo Nordisk A/S should be used for the 
measurements required in the protocol.
Subjects should be instructed in how to record the results of the SMPG values in the diaries. The 
record of each SMPG value should include date, time and value. All data from the diary must be 
transcribed into the eCRF during or following the contact. If obtained via phone and a discrepancy 
is later detected between the diary and the SMPG data obtained at the phone contact, the values in 
the eCRF must be corrected.
Occasional review by the investigator of the values stored in the memory of the BG meter and 
correct reporting of these in the diary is advised in order to ensure adequacy of the data reported in 
the trial database. 
8.3.2.1
Self-measured plasma glucose profile
During the trial subjects should perform SMPG measurements for 3 consecutive days prior to 
selected site visits or phone contacts according to flowchart (see Section 2). The investigator will 
use the SMPGs to monitor subjects with respect to the need for insulin titration. 
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The SMPG measurements should be done pre-breakfast in a fasting state (defined as six hours). For 
subjects on twice daily basal or twice daily premixed insulin including combinations of soluble 
insulins regimen an additional pre-dinner SMPG should be done. Pre-dinner SMPGs are not 
required to be done in a fasting state. All SMPG data obtained at a telephone contact will be entered 
into the eCRF during or following the telephone contact. When the subject comes in for the 
following site visit and if there is a discrepancy between the diary and the SMPG data obtained at 
the telephone contact the diary will be considered source data and the values in the eCRF must be 
corrected.
For the SMPG measurements performed prior to V11 and V18 one of the three SMPG 
measurements will be part of the 7-point profile.
8.3.2.2
7-point self-measured plasma glucose profile
The subject will be instructed to perform a 7-point SMPG profile three times during the trial period 
(see Section 2) using the BG meter provided for the trial. The 7-point SMPG profile should be 
performed on a day where the subject does not anticipate unusual strenuous exercise. The 7-point 
profile should preferably be taken within a week prior to the visit.
The record of each SMPG measurement should include the following seven time points:
!
before breakfast
!
90 minutes after start of breakfast
!
before lunch
!
90 minutes after start of lunch
!
before dinner
!
90 minutes after start of dinner
!
at bedtime
8.3.3
Body weight and height
Body weight must be measured and recorded in the eCRF in kilogram or pound (kg or lb), with one 
decimal (with an empty bladder, without shoes and only wearing light clothing). The body weight 
should be assessed on the same calibrated weighing scale equipment throughout the trial, if 
possible.
Height is measured without shoes in centimetres or inches and recorded in the eCRF to nearest 
½ cm or ¼ inch.
8.3.4
Waist circumference
The waist circumference is defined as the minimal abdominal circumference located midway 
between the lower rib margin and the iliac crest.
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The measurement of waist circumference must be performed and recorded in the eCRF. Waist 
circumference is measured in the horizontal plane and rounded up or down to the nearest ½ cm or ¼ 
inches 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 survey29, 30, 31, 32, 33
!
IWQOL-Lite Clinical Trial Version34, 35
!
Diabetes Treatment Satisfaction Questionnaire – status version (DTSQs)36
The questionnaires must be completed by the subject as specified in the flow chart, see Section 2, 
preferably before any other trial-related activities for that visit. It takes approximately fifteen 
minutes to complete the three questionnaires. Subjects should be given the opportunity to complete 
the questionnaires by themselves without interruption. The completed questionnaires must be 
reviewed for potential adverse events and missing data while the subject is still at the site. All 
results from the PRO questionnaires must be transferred into the eCRF.
The questionnaires SF-36v2™, IWQOL-Lite Clinical Trial Version and DTSQ are commonly used 
PRO instruments, also in the T2DM area. 
All the questionnaires will be translated to local languages, and also be linguistically validated 
before being handed out to the subjects participating in the trial. 
SF-36 acute version
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.
Impact of Weight on Quality of Life questionnaire (IWQOL-Lite) Clinical Trial Version
The IWQOL-Lite for Clinical Trials was adapted from the IWQOL-Lite and measures the health 
related quality of life. The IWQOL- Lite Clinical Trial Version contains 22 items.
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Diabetes Treatment Satisfaction Questionnaire – status version
The Diabetes Treatment Satisfaction Questionnaire – status version (DTSQs) questionnaire will be 
used to assess subject’s treatment satisfaction. This questionnaire contains 8 items that measures the 
treatment satisfaction for subjects’ diabetes treatment in terms of convenience, flexibility and 
general feelings regarding treatment.
8.3.6
Basal insulin dose adjustment
8.3.6.1
At randomisation (V2)
The investigator should at V2 record the subject’s daily doses of insulin (basal, bolus and premixed 
insulin including combinations of soluble insulins) on the day prior to the visit in the CRF. The 
prescribed dose after dose reduction should also be recorded in the eCRF.
8.3.6.2
During the fixed insulin treatment period
The investigator should at all visits and phone contacts review and record subject’s daily doses of
basal, bolus and premixed insulin including combinations of soluble insulins on the day prior to the 
visit as specified in sections 2 and 5.3.3. From V5 to P9 (both included) the investigator should also 
review and record the results of subject’s SMPG measurements prior to each visit and based on 
these, titration guidance will be provided (see section 5.3.3). However, maximum total daily insulin 
dose in this treatment period is restricted and should not exceed the dose prior to randomisation as 
recorded at visit 2. All adjustments of insulin doses will be captured in the eCRF including reason 
for any deviation from guidance. 
After P9 and until V11 the insulin doses should not be adjusted. 
8.3.6.3
During the adjustable insulins treatment period
From V11 and until and including the follow-up visit the investigator should review and record 
subject’s daily insulin doses (basal, bolus and premixed insulin including combinations of soluble 
insulins) on the day prior to the visit as specified in sections 2 and 5.3.3. 
From V11 to V18 (both included) the investigator should review and record results of subject’s 
SMPG measurements prior to each visit and based on these, titration guidance will be provided (see 
section 5.3.3). There are no restrictions on insulin dose in this period. All adjustments of insulin 
dose will be captured in the eCRF including reason for any deviation from guidance.
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. 
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8.4.1.1
Medication error
If a medication error is observed during the trial, the following information is required and a 
specific event form must be completed in the eCRF in addition to the AE form (see Section 8.4.1.2, 
12.1.5 and appendix B): 
!
Trial product(s) involved 
!
Classification of medication error
!
Whether the subject experienced any hypoglycaemic episode and/or adverse event(s) as a 
result of the medication error 
!
Suspected primary reason for the medication error 
For definition of medication errors, see Section 12.1.4 and appendix B.
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 (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
!
Lactic acidosis
!
Creatine kinase (CK) > 10x UNL
!
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.
*Please note that in case of a hepatic event defined as aminotransferase (ALT) or aspartate 
aminotransferase (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.
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See Section 12 and appendix B for details about the additional information to report. 
Note that additional assessments will be required according to appendix B in case of: 
!
suspicion of acute pancreatitis
!
suspicion of hypersensitivity reaction
!
increased levels of creatine kinase
!
increased levels of aminotransferase
In case any of these events fulfil the criteria for a serious adverse event, please report accordingly, 
see Section 12.
8.4.2
Physical examination
A physical examination will be performed by the investigator according to local procedure (see 
Section 2 and 8.1.7). A physical examination must include:
!
General appearance
!
Head, ears, eyes, nose, throat, neck
!
Thyroid gland
!
Respiratory system
!
Cardiovascular system
!
Gastrointestinal system including mouth
!
Musculoskeletal system
!
Central and peripheral nervous system
!
Skin
!
Lymph node palpation
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 the subject has been 
resting for 5 minutes in a sitting position.
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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 practice. Results of the fundus photography or dilated 
fundoscopy will be interpreted by the investigator (see Section 8.1.7).
If fundus photography or dilated fundoscopy has been performed within 90 days prior to 
randomisation, the procedure does not need to be repeated, unless worsening of visual function 
since the last examination. The results must be available prior to randomisation.
If the fundus photography or dilated fundoscopy is performed before the subject has signed the 
informed consent form, it must be documented in the medical records that the reason for performing 
the procedure was not related to this trial.
8.4.5
Electrocardiogram (12-lead)
12-lead ECG will be performed as per flowchart (see Section 2) and the assessment must be 
reviewed as described in Section 8.1.7 by the investigator. The ECGs will also undergo central 
assessment and the investigator must forward the ECGs to the central ECG reader as soon as 
possible.
If the central ECG evaluation of a baseline ECG is suggestive of a prior MI, the investigator will be 
notified. The investigator should consider if an update of the History of CVD form is required.
If the central ECG evaluation of a post-baseline ECG is suggestive of new MI, the investigator will 
be notified and a confirmatory ECG should be performed. Unless already done, the investigator 
should report this as 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:
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Haematology:
!
Haemoglobin
!
Haematocrit
!
Leucocytes
!
Thrombocytes
!
Differential count (eosinophils, neutrophils, basophils, lymphocytes and monocytes)
Biochemistry: 
!
Alanine aminotransferase (ALT)
!
Albumin
!
Alkaline phosphatase (ALP)
!
Amylase
!
Aspartate aminotransferase (AST)
!
Bilirubin, total
!
Calcium, total
!
Creatinine 
!
eGFR per CKD-EPI37
!
Creatine kinase (CK)
!
Lipase
!
Potassium
!
Sodium
!
Urea
Hormones:
!
Calcitonin
In case any calcitonin value at any time during the trial is ≥ 10 ng/L, the algorithm in appendix A 
must be followed.
8.4.7
Pregnancy testing
Females of childbearing potential will have a urine dip-stick pregnancy test performed at site as 
specified in Section 2 or as required by local law. For definition of female of non-childbearing 
potential and contraceptive methods, see Section 8.2.6.
In case a menstrual period is missed or if pregnancy is suspected between the scheduled visits, a 
urine pregnancy test should be performed. Investigator should instruct the subject to contact the site 
in case the pregnancy test is positive. At V2, females of childbearing potential will be provided with 
a urine dip-stick pregnancy test.
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8.4.8
Hypoglycaemic episodes
Plasma glucose (PG) should always be measured and recorded when a hypoglycaemic episode is 
suspected.
All PG values:
!
≤ 3.9 mmol/L (70 mg/dL) or 
!
> 3.9 mmol/L (70 mg/dL) occurring in conjunction with hypoglycaemic symptoms 
should be reported in the diary according to the instructions below throughout the trial from V1 to 
V19.
Upon onset of a hypoglycaemic episode the subject is recommended to measure PG every 15 
minutes until the SMPG value is > 3.9 mmol/L (70 mg/dL) and/or symptoms have been resolved in 
accordance to current guidelines38.
A SMPG value ≤3.9 mmol/L (70 mg/dL) or hypoglycaemic symptoms must trigger a 
hypoglycaemic episode form to be completed by the subject. Repeated SMPG measurements and/or 
symptoms will per default be considered as one hypoglycaemic episode until a succeeding SMPG 
value is > 3.9 mmol/L (70 mg/dL) and/or symptoms have been resolved. One hypoglycaemic 
episode form is to cover these measurements and/or symptoms
In case of several low SMPG values within the hypoglycaemic episode, the lowest value is the one 
that will be reported as the SMPG value for the hypoglycaemic episode but the start time of the 
episode will remain as the time for the first SMPG value and/or symptom.
The record should include the following information: 
!
Start date and time of the hypoglycaemic episode.
!
Stop date and time of the hypoglycaemic episode (stop time is the first time the PG value is 
> 3.9 mmol/L (70 mg/dL) and/or symptoms have been resolved).
If a stop date and time is not reported, a hypoglycaemic episode will cover a period of 60 
minutes.
!
The PG level before treating the episode (if available) and any follow up measurements. 
The lowest value measured during the hypoglycaemic episode will be reported as the PG value 
for the episode, the remaining values will be kept as source data in the diary.
!
Whether the episode was symptomatic (Yes/No).
A hypoglycaemic episode starting without symptoms should be updated to symptomatic if the 
subject experiences symptoms later during the episode. 
!
Whether the subject was able to treat him/herself.
If the severity of a hypoglycaemic episode aggravates, only one hypoglycaemic episode should 
be reported reflecting the most severe degree of hypoglycaemia.
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!
Date and time of last trial product administration and for pen-injection and selected anti-
diabetic medications prior to the episode, date and time as well as dose must be collected.
!
Date and time of last main meal (not including snacks) prior to the episode.
!
Whether the episode occurred in relation to physical activity.
!
Change in any concomitant illness.
!
Any sign of fever and/or other acute disease.
!
Whether the subject was asleep when the episode occurred.
–
If yes, whether the symptoms of the episode woke up the subject.
The answer to the question: "Was the subject able to treat him/herself?" must be answered "No" for 
an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or 
take other corrective actions. PG concentrations may not be available during an event, but 
neurological recovery following the return of PG to normal is considered sufficient evidence that 
the event was induced by a low PG concentration39.
Oral carbohydrates must not be given if the subject is unconscious.
If the question "Was the subject able to treat him/herself?" is answered "No", the following 
information should be recorded by the subject:
!
Who assisted in the treatment of the hypoglycaemic episode (i.e. medical person or non-
medical person)?
!
Where the treatment was administered (in clinic/emergency room/hospital or other. If the 
subject was treated in clinic/emergency room/hospital, whether they were transported in an 
ambulance or not)
!
Type of treatment provided by another person (i.e. oral carbohydrates, glucagon, IV glucose 
or other)
!
Were symptoms alleviated after administration of treatment?
!
Factors contributing to the episode (i.e. physical activity, missed meal, diet change, 
medication error (i.e. overdose, mix-up between products, incorrect use of device), other 
factors not listed or unknown)
!
Did the subject experience seizure?
!
Was the subject unconscious/comatose?
!
Did the subject experience any of the following symptoms39
–
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)
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–
General malaise: headache or malaise (feeling discomfort/unease)
!
Other symptoms
The Investigator must review the diary for low SMPG values not reported as hypoglycaemic 
episodes (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 data40, 41.
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. IgE anti-semaglutide 
antibodies and PK samples will be analysed by Novo Nordisk and a special laboratory (see Section
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, semaglutide plasma concentration results will not be available to the investigator during 
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the trial. These results will be provided to the investigator upon request after the completion of the 
clinical trial report (CTR).
The laboratory provides results to the trial sites in the units preferred by the trial sites while the 
results that are transferred to the trial database will always be in SI units.
The laboratory equipment may provide analyses not requested in the protocol but produced 
automatically in connection with the requested analyses according to specifications in the laboratory 
standard operating procedures. Such data will not be transferred to the trial database, but abnormal 
values will be reported to the investigator. The investigator must review all laboratory results for 
concomitant illnesses and AEs and report these according to Section 8.2.5 and Section 12.
For Mexico only: Descriptions of assay methods, laboratory supplies and procedures for obtaining 
samples will be described in a trial specific laboratory manual provided by the central laboratory ). 
Laboratory samples will be destroyed at the latest at the completion of the CTR, or according to 
local regulations. 
8.6
Other assessments
8.6.1
Pharmacokinetics
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. 
The exact date and time for sampling the blood for PK analysis must be recorded on the lab 
requisition form.
The date and time of the latest trial product administration prior to the visit must be recorded by the 
subject in the subject diary and transcribed to the eCRF by the investigator.
Blood samples for PK assessments 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.
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8.6.2
Subject diary
The diaries should be handed out at the visits described in the flow chart (see Section 2). The 
recordings must be reviewed as described in Section 8.1.7 and transcribed to the eCRF at the 
following visit.
Entries in the diaries are only to be made by the subject, unless otherwise specified.
The investigator should instruct the subject in recording the following data in the diary:
!
date of first trial product administration
!
date and time of last trial product administration prior to visits with PK sampling
!
date and total daily dose of insulin (basal, bolus and premixed insulin including 
combinations of soluble insulins ) on the day prior to V2 and prior to each visit including
follow-up visit 
!
hypoglycaemic episodes
!
changes in concomitant medication
!
AEs
!
SMPG measurements (on 3 consecutive days prior to selected clinic visits and phone 
contacts (see Section 8.3.2)
!
SMPG 7-point profile (prior to selected clinic visits (see Section 8.3.2.1))
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. The subject will be 
asked to return all used, partly used and unused trial product during the trial as instructed by the 
investigator. The investigator must assess the amount of trial products returned compared to what 
was dispensed at the previous visits 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. 
9.1
Trial products
The following trial products are considered as IMPs and will be provided by Novo Nordisk A/S, 
Denmark:
Table 9-1
Investigational medicinal products
Trial product
Strength
Dosage form
Route of 
administration
Container/
delivery device 
Semaglutide 3 mg tablet
3 mg
Tablet
Oral
Dosepacka
Semaglutide 7 mg tablet
7 mg
Semaglutide 14 mg tablet
14 mg
Placebo tablet
NA
a One dosepack contains one blister card with 7 tablets
Metformin, insulins and rescue medication are considered non-investigational medicinal products 
and will not be supplied by Novo Nordisk. However, during the 52-week treatment period and the 5 
weeks follow-up period, the patients de-facto cost (actual patient cost, not covered by the Health 
Authorities/any insurance) of metformin and insulins will be reimbursed if required by local 
legislation and institutional review board (IRB)/independent ethics committee (IEC) approval. 
For Japan only: During the treatment period, all anti-diabetic medication including pre-trial OADs 
will be reimbursed by Novo Nordisk Japan according to the local requirement.
For Russia only: Maintaining subjects on the basal insulin subjects were using at trial entry is 
important for the integrity of the trial. Therefore, if governmental supply of the subjects basal 
insulin ceases, leaving subjects without the option to continue on background basal insulin, then 
Novo Nordisk may reimburse the cost of maintaining the subject on the trial entry basal insulin for 
the time the subject is included in the trial, or until supply of the basal insulin is re-instituted, if this 
occurs earlier. Novo Nordisk will only reimburse the basal insulin as long as the subject is included
in the trial.
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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 1342 local regulations and trial 
requirements.
Each trial site will be supplied with sufficient trial product for the trial on an ongoing basis 
controlled by the IWRS. Trial products will be distributed to the trial sites according to enrolment 
and randomisation. 
9.3
Storage 
Storage conditions of the trial products are outlined in Table 9-2.
Table 9-2
Storage conditions
The investigator must ensure that trial product is kept under proper storage conditions and record 
and evaluate the temperature. The investigator must inform Novo Nordisk immediately if any trial 
product has been stored outside specified conditions (e.g. outside temperature range). Additional 
details regarding handling of temperature deviations can be found in the TMM.
Trial product that has been stored improperly must not be dispensed to any subject before it has 
been evaluated and approved for further use by Novo Nordisk. The investigator must take 
appropriate action to ensure correct storage.
For Japan only: The head of the study site or the trial product storage manager if assigned by the 
head of the study site must ensure the availability of proper storage conditions, record and evaluate 
the temperature.
Trial product
Storage conditions
(not-in-use)
In-use conditions
Semaglutide 3 mg tablet
Do not store above 30ºC (86ºF)
Do not freeze
Do not refrigerate
Store in the original package
Take the tablet immediately after 
dispensation from blister card
Take the tablets whole: Do not 
break or chew
Semaglutide 7 mg tablet
Semaglutide 14 mg tablet
Placebo tablet
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9.4
Drug accountability and destruction
Drug accountability of all trial products received at site is the responsibility of the investigator.
For Japan only: Drug accountability is the responsibility of the head of the study site or the trial 
product storage manager if assigned by the head of the study site.
Subjects must be instructed to return all used, partly used and unused trial products including empty 
packaging material as instructed by the investigator.
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.
Destruction of trial products can be performed on an ongoing 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 A/S in accordance with the TMM:
•
BG meter and BG meter auxiliaries
For Japan only: The trial sites are allowed to purchase and supply themselves with auxiliary 
supplies, if possible. BG meters must be the same model as supplied by Novo Nordisk.
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10
Interactive web response system
A trial-specific IWRS will be set up which can be accessed at any time via the internet or telephone. 
Access to the IWRS must be restricted to and controlled by authorised persons. 
IWRS is used for: 
!
Screening
!
Screening failure
!
Randomisation
!
Medication arrival
!
Dispensing
!
Dispensing verification (when barcode scanner is used)
!
Treatment discontinuation
!
Completion
!
Code break
!
Drug accountability
!
Data change
IWRS user manuals will be provided to each trial site. DUNs will be allocated using the IWRS. It is 
important to dispense the exact allocated DUNs to a subject.
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11 Randomisation procedure and breaking of blinded codes
The trial is a double-blinded trial. A randomisation session will be carried out for all subjects using 
the IWRS. 
At the randomisation visit (V2), subjects meeting all eligibility criteria will be randomised to one of 
four parallel treatment arms as described in Section 5.1.
Randomisation will be stratified based on the factors listed below to ensure an even distribution of 
the four treatment arms within strata.
!
Descent:
–
Japanese subject
–
Non-Japanese subject
!
Background metformin medication at screening
–
Metformin
–
No metformin
!
Background insulin medication at screening:
–
Basal insulin
–
Basal-bolus insulin
–
Premixed insulin including combinations of soluble insulins
11.1
Breaking of blinded codes
The IWRS will notify Novo Nordisk (monitor and the Global Safety department) immediatelyafter 
the code is broken.
The code for a particular subject may be broken in a medical emergency if knowing the actual 
treatment would influence the treatment of the subject. Whenever a code is broken the person 
breaking the code must print the Code BreakConfirmation Notification generated by the IWRS, 
record the reason, and sign and date the document.
When the code is broken, the treatment allocation will be accessible to the investigator and the 
Novo Nordisk Global Safety department. If the 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8.1.5). A treatment discontinuation session must be completed in the IWRS.
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12 Adverse events, technical complaints and pregnancies
12.1
Definitions
12.1.1
Adverse event 
According to ICH, 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 8.4.8. 
The following three definitions are used when assessing an AE:
!
Severity 
–
Mild – no or transient symptoms, no interference with the subject's daily activities.
–
Moderate – marked symptoms, moderate interference with the subject' 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.
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–
Unlikely – The event is most likely related to aetiology other than the trial product.
•
Final outcome
–
Recovered/resolved – The subject has fully recovered, or by medical or surgical 
treatment the condition has returned to the level observed at the first trial-related activity 
after the subject signed the informed consent.
–
Recovering/resolving – The condition is improving and the subject is expected to 
recover from the event. This term is only applicable if the subject has completed the trial 
or has died from another AE.
–
Recovered/resolved with sequelae – The subject has recovered from the condition, but 
with lasting effect due to a disease, injury, treatment or procedure. If a sequela meets an 
SAE criterion, the AE must be reported as an SAE.
–
Not recovered/not resolved – The condition of the subject has not improved and the 
symptoms are unchanged, or the outcome is not known.
–
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 adverse events must always be reported as an SAE using the important medical event 
criterion if no other seriousness criteria are applicable:
!
suspicion of transmission of infectious agents via the trial product 
!
risk of liver injury defined as ALT or AST >3 x UNL and total bilirubin >2 x UNL, where 
no alternative aetiology exists (Hy's law).
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. 
!
Wrong route of administration
!
Administration of an overdose with the intention to cause harm (e.g. suicide attempt), misuse or 
abuse of trial product.
!
Accidental administration of a higher dose than intended. A higher dose is a dose of at least one 
tablet more than the intended dose; however, the administered dose must deviate from the 
intended dose to an extent where clinical consequences for the trial subject were likely to 
happen as judged by the investigator, although they did not necessarily occur.
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Medication errors must be reported on an AE form and a specific event form, see Section 8.4.1.1, 
12.1.5 and appendix B.
12.1.5
Adverse events requiring additional data collection
AEs requiring additional data collection are AEs where the additional data will benefit the 
evaluation of the product safety. A number of adverse events that always require additional data 
collection have been pre-specified. See appendix B for details about these events and the additional 
information to report.
Some events in this trial will be adjudicated by an independent external committee as described in 
Section 12.7.2.
Table 12-1 lists AEs that require completion of specific event forms in the eCRFs and/or are subject 
to event adjudication.
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Table 12-1
Adverse events requiring completion of specific event forms and/or are subject 
to event adjudication
Event
Specific event form
Event adjudication
Death
No
Yes
Acute coronary syndrome (myocardial infarction or 
unstable angina pectoris requiring hospitalisation)
Yes
Yes
Cerebrovascular event (stroke or transient ischaemic 
attack)
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
Creatine kinase (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 aminotransferase (ALT) or aspartate aminotransferase (AST) > 3 
x UNL and total bilirubin > 2 x UNL, where no alternative aetiology exists (Hy's law), this must be reported as an SAE 
using the important medical event criterion if no other seriousness criteria are applicable.
For details about specific event forms, see Section 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
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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 (V19) for subjects on trial product OR until the end 
of trial (V18 or V19A, 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 safety information form (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, 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.
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Timelines for initial reporting of AEs:
The investigator must complete the following forms in the eCRF within the specified timelines:
!
SAEs: The AE form within 24 hours and the SIF within 5 calendar days of the 
investigator's first knowledge of the SAE.
Both forms must be signed within 7 calendar days from the date the information was entered in 
the eCRF. 
For SAEs requiring reporting on a specific event form: In addition to the above, the specific 
event form within 14 calendar days from the investigators 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 12.7.2. The investigator should 
preferably provide the medical documentation within 4 weeks of event identification 
according to instructions in the event adjudication site manual. 
If the eCRF is unavailable, the concerned AE information must be reported on a paper AE form and 
sent to Novo Nordisk by fax, e-mail or courier within the same timelines as stated above. When the 
eCRF becomes available again, the investigator must enter the information on the form into the 
eCRF.
Contact details (fax, telephone, e-mail and address) are provided in the investigator trial master file.
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AE identified
Does the AE require 
a specific event 
form?
Is the AE subject to 
adjudication and/or 
is the outcome 
fatal?
AE form < 24 hours
SIF < 5 calendar days
Specific event form 
For SAEs:
< 14 calendar days
Is the AE serious or 
non-serious?
AE form
Adjudication form
< 14 calendar days
Source data < 4 weeks
Non-serious
Serious
No
Yes
Yes
Queries and follow-up 
requests to be resolved 
< 14 calendar days
Timelines are for the completion of forms from the time of investigator’s awareness.
AE: Adverse event  SAE: Serious adverse event  SIF: Safety Information form 
No additional action
No additional action
No
Figure 12–1
Reporting of AEs
Novo Nordisk assessment of AE expectedness: 
Novo Nordisk assessment of expectedness is performed according to the following reference 
documents: IB for oral Semaglutide (NN9924)20; current versions and any updates thereto.
Reporting of trial product-related SUSARs by Novo Nordisk:
Novo Nordisk will notify the investigator of trial product-related suspected unexpected serious 
adverse reactions (SUSARs) in accordance with local requirements and ICH1. In addition, the 
investigator will be informed of any trial-related SAEs that may warrant a change in any trial 
procedure.
In accordance with regulatory requirements, Novo Nordisk will inform the regulatory authorities, 
including EMA, of trial product-related SUSARs. In addition, Novo Nordisk will inform the 
IRBs/IECs of trial product-related SUSARs in accordance with local requirement and 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 
non-investigational medicinal product or concomitant medication in the trial, it is important that the 
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suspected relationship is reported to Novo Nordisk, e.g. in the alternative aetiology section on the 
SIF. Novo Nordisk may need to report this AE to relevant regulatory authorities.
12.3
Follow-up of adverse events
The investigator must record follow-up information by updating the medical records and the forms 
in the eCRF.
Follow-up information must be reported to Novo Nordisk according to the following:
!
SAEs: All SAEs must be followed until the outcome of the event is “recovered/resolved”, 
“recovered/resolved with sequelae” or “fatal”, and until all queries have been resolved. 
Cases of chronic conditions, cancer or AEs ongoing at time of death (where death is due to 
another AE) may be closed with the outcome “recovering/resolving” or “not recovered/not 
resolved”. Cases can be closed with the outcome of “recovering/resolving” when the subject 
has completed the follow-up period and is expected by the investigator to recover.
The SAE follow-up information should only include new (e.g. corrections or additional) 
information and must be reported within 24 hours of the investigator’s first knowledge of the 
information. This is also the case for previously non-serious AEs which subsequently become 
SAEs. 
!
Non-serious AEs: Non-serious AEs must be followed until the outcome of the event is 
“recovering/resolving”, “recovered/resolved” or “recovered/resolved with sequelae” or until 
the end of the follow-up period stated in the protocol, whichever comes first, and until all 
queries related to these AEs have been resolved. Cases of chronic conditions, cancer or AEs 
ongoing at time of death (where death is due to another AE) may be closed with the 
outcome “recovering/resolving” or “not recovered/not resolved”. Cases can be closed with 
the outcome of “recovering/resolving” when the subject has completed the follow-up period 
and is expected by the investigator to recover.
!
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.
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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
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 the Customer Complaint Center, Novo Nordisk.
Contact details (fax, e-mail and address) are provided in Attachment I to the protocol.
The investigator must assess whether the technical complaint is related to any AEs or SAEs.
Technical complaints must be reported on a separate technical complaint form: 
!
One technical complaint form must be completed for each affected DUN
!
If DUN is not available, a technical complaint form for each code 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 the 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.
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The investigator must ensure that the technical complaint sample contains the code 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).
The investigator must follow the pregnancy until the pregnancy outcome and the newborn infant is 
one month of age.
The investigator must report information about the pregnancy, pregnancy outcome and health of the 
newborn infant(s), as well as AEs in connection with the pregnancy and AEs in the foetus and 
newborn infant.
The following must be collected and reported by the investigator to Novo Nordisk - electronically 
(e.g. in PDF format), or by fax or courier:
1. Reporting of pregnancy information
Information about the pregnancy and pregnancy outcome/health of the newborn infant(s) has to 
be reported on Maternal Form 1A and 1B, respectively. 
When the pregnancy outcome is abnormal (i.e. congenital anomalies, foetal death including 
spontaneous abortion and/or any anomalies of the foetus observed at gross examination or 
during autopsy), and/or when a congenital anomaly is diagnosed within the first month, further 
information has to be reported for the female subject on Maternal Form 2. In addition, 
information from the male partner has to be reported on the Paternal Form, after an informed 
consent has been obtained from the male partner. 
Initial reporting and follow-up information must be reported within 14 calendar days of the 
investigator's first knowledge of initial or follow-up information. 
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2. Reporting of AE information
The investigator has to report AEs in connection with the pregnancy as well as in the foetus and 
newborn infant(s). The SAEs that must be reported include abnormal outcome, such as foetal 
death (including spontaneous abortion), congenital anomalies (including those observed at gross 
examination or during autopsy of the foetus), as well as other pregnancy complications fulfilling 
the criteria of an SAE.
Forms and timelines for reporting AEs:
Non-serious AEs: 
!
AE forma within 14 calendar days of the investigator's first knowledge of the initial or 
follow-up information to the non-serious AE.
SAEs: 
!
AE forma within 24 hours of the investigator's first knowledge of the SAE. 
!
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.
a
It must be clearly stated in the AE diagnosis field on the AE form if the event occurred in 
the subject, foetus or newborn infant. If the AE occurred in the foetus or newborn infant, the 
AE can only be reported on paper AE and safety information form.
Any queries or follow-up requests from Novo Nordisk to non-serious AEs, SAEs and pregnancy 
forms must be responded to by the investigator within 14 calendar days from the date of receipt of 
the request, unless otherwise specified in the follow-up request.
12.6
Precautions and/or overdose
There are no specific antidotes to semaglutide. Treatment of an overdose should be symptomatic.
There is a potential risk of hypoglycaemia during dosing with semaglutide. The typical signs and 
symptoms of a non-severe hypoglycaemia include: hunger, slight headache, nausea, light-
headedness, palpitations and sweating. Symptoms of non-severe hypoglycaemia should be treated 
by ingestion of carbohydrates. 
Severe hypoglycaemia resulting in loss of consciousness should be treated according to best 
available medical practise. 
One case of accidental overdose of oral semaglutide was reported in the NN9924-3692 trial. The 
subject accidentally took the trial product 
 and was thus treated with 20 mg of 
oral semaglutide.  The subject did not report any symptoms and treatment was continued without 
any change. 
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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.
12.7
Committees related to safety
12.7.1
Novo Nordisk safety committee
Novo Nordisk will constitute an internal oral semaglutide safety committee to perform ongoing 
safety surveillance. 
12.7.2
Event adjudication committee
An independent external event adjudication committee (EAC) is established to perform validation 
of selected AEs according to pre-defined diagnostic criteria. The validation is based on review of 
pre-defined clinical data related to the specific AE. Pre-defined clinical data consist of copies of 
source documents collected and delivered by the investigational sites.
The EAC is composed of permanent members covering required medical specialities. EAC 
members must disclose any potential conflicts of interest and must be independent of Novo 
Nordisk. 
The events are reviewed by the EAC in a blinded manner. The EAC will have no authorisations to 
impact on trial conduct, trial protocol or amendments.
The EAC works in accordance with written guidelines included in the EAC Charter describing in 
details the composition, tasks, responsibilities and work processes of the committee.
The events outlined in Table 12-2 have been selected for adjudication in order to obtain an external 
independent validation of the diagnosis. In addition, cardiovascular events are being adjudicated 
according to FDA requirements51.
The EAC will review copies in English (translated if necessary) of medical documentation received 
in the adjudication packages (e.g. x-ray, ECGs, ultrasound images, discharge summaries, pathology 
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. 
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The AEs for adjudication are listed in Table 12-2:
Table 12-2
Adverse events for adjudication
Events
Description
Adjudication outcome
Death*
! All-cause death
! Cardiovascular death 
(including undetermined 
cause of death)
! Non-Cardiovascular death
Acute Coronary Syndrome
! Acute Coronary Syndrome conditions include: 
! ST-elevation acute myocardial infarction 
(STEMI)
! Non-ST elevation acute myocardial infarction 
(NSTEMI)
! Silent MI 
! Unstable angina pectoris (UAP) requiring 
hospitalisation
! Acute myocardial 
infarction (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
! Transient Ischaemic Attack (TIA) is defined as 
a transient episode (< 24 hours) of focal 
neurological dysfunction caused by brain, spinal 
cord, or retinal ischaemia, without acute 
infarction
! Ischaemic stroke
! Haemorrhagic stroke
! Undetermined stroke
! TIA
Heart failure requiring 
hospitalisation
Hospitalisation with a primary diagnosis of heart 
failure (new episode or worsening of existing heart 
failure)
! Heart failure requiring 
hospitalisation
Acute pancreatitis
The diagnosis of acute pancreatitis requires two of 
the following three features:
! Abdominal pain consistent with acute 
pancreatitis (acute onset of a persistent, severe, 
epigastric pain often radiating to the back)
! Serum lipase activity (and/or amylase activity) 
at least three times greater than the upper limit
of normal (UNL)
! Characteristic findings of acute pancreatitis on 
imaging
Acute pancreatitis
! Mild
! Moderately severe
! Severe
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Malignant neoplasm
Malignant neoplasms are defined as
! neoplasms in which abnormal cells divide 
without control and can invade nearby tissues 
and/or spread to other parts of the body through 
the blood and lymph systems
Thyroid neoplasms are excluded from this event 
category
! Malignant neoplasm
Thyroid disease, if malignant 
thyroid neoplasm or C-cell 
hyperplasia
Malignant thyroid neoplasms are defined as 
! thyroid neoplasms in which abnormal cells 
divide without control and can invade nearby 
tissues and/or spread to other parts of the body 
through the blood and lymph systems
! C-cell hyperplasia, defined as hyperplasia of the 
parafollicular C-cells of the thyroid gland
! Malignant thyroid 
neoplasm
! C-cell hyperplasia
Acute kidney injury
Acute kidney injury43 is defined as any of the 
following (not graded):
! Increase in serum creatinine by ≥ 0.3 mg/dL 
(≥26.5 μmol/L) within 48 hours, or
! Increase in serum creatinine to ≥ 1.5 times 
baseline, which is known or presumed to have 
occurred within the prior 7 days, or
! Urine volume < 0.5 mL/kg/h for 6 hours
! Acute kidney injury
Lactic acidosis
! Lactic acidosis is characterised 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:
o
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
o
AEs with fatal outcome
!
Screening: 
o
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.
o
All ECGs will be centrally read. If the central reading conclusion is suggestive of new 
MI, the ECG adjudication form will be populated for sites to complete for all post-
baseline ECGs.
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!
EAC identified events:
o
The EAC can decide to have an AE adjudicated even if not initially reported as an event 
for adjudication by the investigator.
Event adjudication will be performed for AEs in randomised subjects including AEs with an onset 
date during the screening period. Event adjudication will not be performed for AEs in screening 
failures.
AEs for adjudication must be reported according to Section 12.2. In addition, the specific 
adjudication form should be completed within 14 calendar days of the investigator's first knowledge 
of the AE and all relevant predefined documents provided within 4 weeks according to instructions 
in the event adjudication site manual.
The assessment made by the EAC will be included in the clinical trial report as well as assessments 
made by the investigator. However, the adjudication made by an EAC, given its independent 
analysis of each event, will be attributed with greater importance of the two. 
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13 Case report forms 
Novo Nordisk will provide a system for the eCRF. This system and support services to the system 
will be provided by an external supplier.
Ensure that all relevant questions are answered and that no empty data field exists. If a test or an 
assessment has not been done and will not be available, or if the question is irrelevant (e.g. is not 
applicable), indicate this according to the data entry instructions.
The following will be provided as paper case report forms (CRF):
!
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 
Monitoring will be conducted under a risk based approach.
During the course of the trial, the monitor will visit the trial site to ensure that the protocol is 
adhered to, that all issues have been recorded, to perform source data verification and to monitor 
drug accountability. The first monitoring visit will be performed as soon as possible after FSFV at 
the trial site and no later than 4 weeks after. The monitoring visit intervals will depend on the 
outcome of the remote monitoring of the eCRFs, the trial site's recruitment rate and the compliance 
of the trial site to the protocol and Good Clinical Practice (GCP), but will not exceed 12 weeks until 
LSLV at the trial site (for trial sites with active subjects (defined as subjects in screening, treatment 
or follow-up)).
The monitor must be given direct access to all source documents (original documents, data and 
records). Direct access includes permission to examine, analyse, verify and reproduce any record(s) 
and report(s) that are important to the evaluation of the trial. If the electronic medical record does 
not have a visible audit trail, the investigator must provide the monitor with signed and dated 
printouts. In addition the relevant trial site staff should be available for discussions at monitoring 
visits and between monitoring visits (e.g. by telephone).
All data must be verifiable in source documentation other than the eCRF.
For all data recorded the source document must be defined in a source document agreement at each 
trial site. There must only be one source defined at any time for any data element.
Source data generated by the trial site can be corrected by another person than the person entering 
the source data if accepted by local regulations; any correction must be explained, signed and dated 
by the person making the correction.
The original of the completed diaries and/or PROs must not be removed from the trial site, unless 
they form part of the CRF and a copy is kept at the site.
The monitor will ensure that the eCRFs are completed and that paper CRFs are collected.
The following data will be source data verified for screening failures:
!
Date for obtaining informed consent.
!
Reason for screening failure
Monitors will review the subject's medical records and other source data (e.g. the diaries and PROs) 
to ensure consistency and/or identify omissions compared to the eCRF. If discrepancies are found, 
the investigator must be questioned about these.
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A follow-up letter (paper or electronic) will be sent to the investigator following each monitoring 
visit. This should address any action to be taken.
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15 Data management
Data management is the responsibility of Novo Nordisk. Data management may be delegated under 
an agreement of transfer of responsibilities to a Contract Research Organisation (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.
17 Statistical considerations
There will be a partial database lock performed when all subjects have completed the first 26 
weeks. After the entire 57 weeks a database lock will be performed. Data from the first 26 weeks 
will be reported separately before the entire trial is finalised. Data from the entire trial will be 
analysed and reported as a 57 week trial.
General considerations
If necessary, a statistical analysis plan may be written in addition to the protocol, including a more 
technical and detailed elaboration of the statistical analyses. The statistical analysis plan will be 
finalised before the partial database lock.
The first 26 weeks of the trial is double-blinded. Because the week 26 trial results will be reported 
before the trial is completed, the randomisation details will be revealed to selected Novo Nordisk 
personnel after subjects have completed 26 weeks treatment. Following the end of trial, results from 
the entire trial period will be reported. Investigators and subjects will be blinded throughout the 
entire trial.
Data from all sites will be analysed and reported together.
In statistical analyses where stratification is included, the background metformin medication at 
screening (metformin/no metformin) and background insulin medication (basal insulin/basal-bolus 
insulin/premixed insulin including combinations of soluble insulins) will be included based on the 
actual information collected through the eCRF. In case of missing eCRF information the 
information collected from the IWRS system will be used. The information regarding descent 
(Japanese/non-Japanese) will be included based on country details from the IWRS. In the statistical 
analyses, stratification factors refer to the background metformin medication at screening and the 
background insulin medication at screening. Descent (Japanese/non-Japanese) will be included in 
the statistical analyses as part of region.
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.
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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.
Results from a statistical analysis will as a minimum be presented by the estimated treatment 
contrasts for the below three 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 7 mg vs. placebo
!
Oral semaglutide 3 mg vs. placebo
If no statistical analysis is specified, data will be presented using relevant summary statistics.
Primary and secondary estimands
Two estimands addressing different aspects of the trial objective will be defined; a primary de-facto 
(effectiveness) estimand and a secondary de-jure (efficacy) estimand: 
!
Primary estimand
–
de-facto treatment difference at week 26 for all randomised subjects
The primary de-facto estimand assesses the expected glycaemic benefit in a future population that 
results from subjects initiating treatment with oral semaglutide including potential rescue 
medication(s). 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 treatment adherence 
reflects the behaviour of the target population. Accordingly, data collected regardless of 
discontinuation of trial product or initiation of rescue medication(s) will be used to draw inference.
!
Secondary estimand 
–
de-jure treatment difference at week 26 for all randomised subjects if all subjects 
adhered to treatment and did not initiate rescue medication
The secondary de-jure estimand assesses the glycaemic benefit a future subject is expected to 
achieve if initiating and continuing treatment with oral semaglutide. It is considered a clinically 
relevant estimand as it provides information to treating clinicians about the expected glycaemic 
efficacy of oral semaglutide for purposes of treating individual subjects. Generalisation of this 
estimand depends among other things on the extent to which the adherence to trial product 
administration in this trial reflects the behaviour of the target population. Accordingly, only data 
collected prior to discontinuation of trial product or initiation of rescue medication will be used to 
draw inference. This will avoid confounding from rescue medication.
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Missing data considerations at week 26
When estimating the primary estimand, the proportion of missing data, i.e. data that do not exist 
even though subjects are intended to stay in the trial regardless of treatment status and initiation of 
rescue medication, 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 secondary estimand, the proportion of subjects with missing data is expected 
to be higher (20%) since data collected after discontinuation of trial product or initiation of rescue 
medication(s) will be set to missing. The proportion of 20% is based on the oral semaglutide phase 
2 trial (NN9924-3790), that indicates that a low starting dose with gradual dose escalation 
diminishes gastrointestinal AEs compared with more aggressive dosing regimens. Across treatment 
arms the main reasons for missing data are expected to be early treatment discontinuation due to 
gastrointestinal AEs and eventually initiation of rescue medication. Initiation of rescue medication 
is expected to be more frequent in the placebo arm and in the oral semaglutide 3 mg arm than for 
the two highest dose levels of oral semaglutide. A higher proportion of subjects are expected to 
discontinue treatment due to AEs in the oral semaglutide 14 mg arm, compared to the other 
treatment arms. So overall the frequency of missing data is expected to be similar across treatment 
arms.
Descriptive summaries and graphical representation of extent, reason(s) for and pattern of missing 
data will be presented by treatment arm.
17.1
Sample size calculation
Both the primary endpoint, change from baseline to week 26 in HbA1c and the confirmatory 
secondary endpoint, change from baseline to week 26 in body weight are planned to be tested for 
superiority of oral semaglutide vs. placebo at each dose level (3 mg, 7 mg, and 14 mg).
The sample size calculation is made to ensure a power of at least 90% to jointly confirm HbA1c
superiority of oral semaglutide vs. placebo at each dose level out of the six pre-specified 
confirmatory hypotheses shown in in Figure 17–1. The closed testing procedure described in Bretz 
et al.44 is used to control the overall type I error at a nominal two-sided 5% level. The statistical 
testing strategy is built on the following two principles:
!
Within a dose level, glycaemic effect must be established in terms of HbA1c superiority 
before testing for added benefits in terms of body weight superiority.
!
Glycaemic effect in terms of HbA1c superiority must be established on all higher dose levels 
before continuing testing hypotheses on lower dose levels.
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The sample size is calculated using the calcPower function in the R package, gMCP45 using 10000 
simulations. All of the six pre-specified confirmatory tests are assumed to be independent. Since 
some of the tests are positively correlated, the assumption of independence is viewed as 
conservative.
The sample size assumptions for treatment effects (TE), adjusted treatment effects and the standard 
deviations are given 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).
Since the equalising effect of rescue medication will be included in the primary analysis as well as a 
conservative approach for handling of missing data will be performed, an adjustment in treatment 
effect will be implemented for the 10% of subjects who are expected to discontinue trial product or 
initiate rescue medication and for the 10% of subjects who are expected to have actual missing data. 
The treatment effects used in the sample size calculation will be adjusted according to a 75% 
smaller effect in these subjects. The adjusted treatment effects for testing superiority are defined as 
0.8×TE + 0.2×TE×0.25.
Table 17-1
Assumptions used in the sample size calculation
Oral semaglutide vs. placebo
HbA1c
Body weight
Treatment dose
14 mg
7 mg
3 mg
14 mg
7 mg
3 mg
Treatment effect (TE)
-0.8%-points
-0.60%-points
-0.45%-points
-3.0 kg
-2.0 kg
-1.0 kg
Adjusted TE, superiority
-0.68%-points -0.51%-points
-0.38%-points
-2.55 kg
-1.70 kg
-0.85 kg
Standard deviation
1.1%s
1.1%s
1.1%
4.0 kg
4.0 kg
4.0 kg
With the above assumptions, allocating 180 subjects to each of the oral semaglutide arms and the 
placebo arm provides 90% power to confirm HbA1c superiority of oral semaglutide vs. placebo at 
all dose levels. Calculated powers for individual hypotheses are presented in Figure 17–1. In total 
4×180 = 720 subjects are planned to be randomised.
Table 17-2
Calculated powers for individual hypotheses
Statistical test
HbA1c superiority
Body weight superiority
Treatment dose
14 mg
7 mg
3 mg
14 mg
7 mg
3 mg
Power (%)
> 99
99
90
> 99
96
47
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Figure 17–1
Graphical illustration of the closed testing procedure
The overall significance level of α = 0.05 (two-sided) is initially allocated to the HbA1c superiority test on the highest 
dose level. The local significance level (α-local) will be reallocated if a hypothesis is confirmed according to the weight 
given by the directed edges between nodes (hypotheses). The sample size is based on the hypotheses in the dark boxes.
 = 0.05
HbA1c (%-point)
Superiority
 = 0
Body weight (kg)
Superiority
 = 0
HbA1c (%-point)
Superiority
1 2
⁄
1 2
⁄
1
 = 0
Body weight (kg)
Superiority
 = 0
HbA1c (%-point)
Superiority
1 2
⁄
1 2
⁄
1
 = 
Body weight (kg)
Superiority
1
Oral semaglutide 7 mg
vs. placebo
Oral semaglutide 3 mg
vs. placebo
Oral semaglutide 14 mg
vs. placebo
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17.2
Definition of analysis sets
The following analysis sets will be defined:
Full analysis set (FAS): Includes all randomised subjects. Subjects in the FAS will contribute to 
the evaluation “as randomised”.
Safety analysis set (SAS): Includes all subjects exposed to at least one dose of trial product. 
Subjects in the SAS will contribute to the evaluation based on the trial product received for the 
majority of the period where they were on treatment. This will be referred to as contributing to the 
evaluation “as treated”.
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 (V19) for subjects on trial product
!
The latest occurring visit of the end-of-treatment visit (V18) or the follow-up premature 
discontinuation visit (V19A), 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
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On-treatment: This observation period represents the time period where subjects are considered 
treated with the trial product. The observation period is a subset of the in-trial observation period. It 
starts at the date of first dose of trial product. Two slightly different end dates will be needed to 
cover all assessments appropriately. For adjudicated events, ECGs and AEs including 
hypoglycaemic episodes, the observation period ends at the first date of any of the following:
!
The follow-up visit (V19)
!
The follow-up prematurely discontinuation visit (V19A)
!
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 end date is 
the first date of any of the following:
!
The last dose of trial product + 3 days
!
Initiation of rescue medication
The in-trial observation period will be the primary observation period for estimating the primary 
estimand. The on-treatment without rescue medication observation period will be the primary 
observation period when estimating the secondary estimand. The on-treatment observation period 
will be considered supportive for evaluating efficacy. Safety will be evaluated based on the in-trial 
and the on-treatment observation periods.
Data points collected outside an observation period will be treated as missing in the analysis. 
Baseline data will always be included in an observation period. For adjudicated events, the onset 
date will be the EAC adjudicated onset date.
Before data are locked for statistical analysis and the randomisation code is broken, a review of all 
data will take place. Any decision to exclude either a subject or single observations from the 
statistical analysis is the joint responsibility of the members of the Novo Nordisk study group. 
Exclusion of data from analyses should be used restrictively and normally no data should be 
excluded from the FAS. The subjects or observations to be excluded, and the reasons for their 
exclusion must be documented and signed by those responsible before database lock. The subjects 
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and observations excluded from analysis sets, and the reason for this, will be described in the 
clinical trial report.
Confirmatory hypotheses
For the primary HbA1c endpoint and the confirmatory secondary body weight endpoint the 
following confirmatory one-sided hypotheses are planned to be tested at each dose level of oral 
semaglutide versus placebo. Let the mean treatment difference be defined as μ = (oral semaglutide 
minus placebo):
!
HbA1c superiority
–
H0: μ ≥ 0.0 %-point against HA: μ < 0.0 %-point
!
Body weight superiority
–
H0: μ ≥ 0.0 kg against HA: μ < 0.0 kg
Operationally the hypotheses will be evaluated by two-sided tests at the 5% significance level.
Multiplicity and criteria for confirming hypotheses
The type I error for testing the six confirmatory hypotheses related to the HbA1c and body weight 
endpoints will be preserved in the strong sense at 5% (two-sided) using the weighted Bonferroni-
based closed testing procedure described in Bretz et al.44 and outlined in Figure 17–1.
The first hypothesis to be tested is superiority of HbA1c at the highest dose level. It will be tested at 
the overall significance level (5%) while allocating 0% local significance level to the remaining of 
the hypotheses. For this hypothesis, and in general, if a hypothesis is confirmed, then the 
significance level will be reallocated according to the weight and the direction of the edges going 
from the confirmed hypothesis to the next hypotheses as specified in Figure 17–1. Each of the 
following hypotheses will be tested at their updated local significance level (α-local). This process 
will be repeated until no further hypotheses can be confirmed.
Superiority will be considered confirmed if the mean treatment difference is supporting the 
corresponding alternative hypothesis and the two-sided p-value from the primary analysis of the 
primary estimand is strictly below its local two-sided significance level as defined by the closed 
testing procedure in Figure 17–1. This is equivalent to using a one-sided p-value (nominal α = 
0.025) and a one-sided 2.5% overall significance level in the closed testing procedure.
17.3
Primary endpoint
The primary endpoint is change from baseline to week 26 in HbA1c.
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17.3.1
Primary analysis for the primary estimand
The primary estimand will be estimated based on the FAS using week 26 measurements from the 
in-trial observation period. The primary statistical analysis will be a pattern mixture model using 
multiple imputation to handle missing data assuming that the missing data mechanism is missing at 
random (MAR) within the groups used for imputation. Imputation of missing data at week 26 will 
be done within 8 groups of subjects defined by randomised treatment arm, and whether subjects at 
week 26; (i) have discontinued treatment or initiated rescue medication or (ii) 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 region, stratification factors and the interaction 
between the stratification factors categorical fixed effects and baseline HbA1c measurement 
as a covariate will be fitted to observed values of the change from baseline in HbA1c at week 
26.
!
The estimated parameters for location and dispersion will be used to impute 100 values for 
each subject with missing week 26 data based on region, stratification factors, the 
interaction between the stratification factors and baseline HbA1c. Thus, 100 complete data 
sets will be generated including observed and imputed values.
Analysis used for confirming superiority versus placebo at week 26:
For each of the 100 (now complete) imputed data sets the change from baseline to week 26 in 
HbA1c will be analysed using an ANCOVA with treatment, stratification factors , the interaction 
between the stratification factors and region as categorical fixed effects and baseline HbA1c as 
covariate. The results obtained from analysing the datasets will be combined using Rubin’s rule46 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% confidence intervals and unadjusted 
two-sided p-values for testing no difference from zero will be presented.
17.3.2
Primary analysis for the secondary estimand
The secondary estimand will be estimated based on the FAS using post-baseline measurements up 
to and including week 26 from the on-treatment without rescue medication observation period. The 
primary analysis for the secondary estimand will be 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 
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variables. The independent effects included in the model will be treatment, stratification factors, the 
interaction between the stratification factors and region as categorical fixed effects and baseline 
HbA1c as a covariate, all nested within visit. An unstructured covariance matrix for HbA1c
measurements within the same subject will be employed, assuming measurements from different 
subjects are independent.
The MMRM is a well-established method that accounts for the uncertainty pertaining to missing 
data. This analysis assumes that the missing data mechanism is MAR. Under this assumption the 
statistical behaviour of the missing data (given the observed responses and model fixed effects and 
covariates) is assumed to be same as the observed data. 
17.3.3
Sensitivity analyses
To investigate the robustness of the primary analysis results, complementary and separate analyses 
will be performed for the primary and secondary estimand. In line with EMA recommendations47
and with a report from the US National Research Council48, these analyses will primarily evaluate 
the sensitivity of the results due to the impact of missing data. 
The evaluation of the robustness of the primary analysis results will primarily be based on a pattern 
mixture model approach using multiple imputation. An overview of the sensitivity analyses for each 
of the estimands are specified below followed by a more detailed description of the three different 
pattern mixture models used. Finally, one additional sensitivity analysis for the primary analysis 
will be described that is not based on the pattern mixture model approach, see Section 17.3.3.2.
Sensitivity analyses for the primary estimand
The estimation of the primary estimand will be repeated using the following sensitivity analyses:
!
A comparator multiple imputation analysis based on FAS using the in-trial observation 
period
!
A comparator multiple imputation analysis differentiating between reasons for discontinuing 
treatment prematurely based on FAS using the in-trial observation period
!
A tipping-point multiple imputation analysis based on FAS using the in-trial observation 
period
!
An MMRM analysis (the primary analysis for the secondary estimand) based on FAS using 
the in-trial observation period
Sensitivity analyses for the secondary estimand
The estimation of the secondary estimand will be repeated using the following sensitivity analyses:
!
A comparator multiple imputation analysis based on FAS using the on-treatment without 
rescue medication observation period.
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!
A comparator multiple imputation analysis based on FAS using the on-treatment observation 
period. This sensitivity analysis aims to compare oral semaglutide versus placebo for 
subjects who adhere to treatment regardless of whether or not rescue medication has been 
initiated.
!
A comparator multiple imputation analysis differentiating between reasons for discontinuing 
treatment prematurely based on FAS using the on-treatment without rescue medication 
observation period.
!
A tipping-point multiple imputation analysis based on FAS using the on-treatment without 
rescue medication observation period.
17.3.3.1
Pattern mixture models
Common for the three pattern mixture model sensitivity analyses is that they all aim to stress-test 
the primary HbA1c results by changing the assumptions for part or all missing data in the oral 
semaglutide treatment arms, while maintaining the missing at random data assumption for the 
placebo arm:
!
Comparator multiple imputation analysis: In this sensitivity analysis missing data at week 
26 for all subjects will be imputed to resemble the distribution of the week 26 values 
observed in the placebo treatment arm. In effect this imputation approach removes the 
treatment difference between oral semaglutide and placebo for all subjects randomised to 
oral semaglutide, given that oral semaglutide is better than placebo.
!
Comparator multiple imputation analysis differentiating between reasons for discontinuing 
treatment prematurely: In this sensitivity analysis only missing data at week 26 for subjects 
who discontinue oral semaglutide treatment due to treatment related AEs will be imputed to 
resemble the distribution of the week 26 values observed in the placebo treatment arm. 
Treatment related AEs are defined as AEs classified as possible or probable related to trial 
product as reported by the investigator. In effect this imputation approach removes the 
treatment difference between oral semaglutide and placebo for this selected group of 
subjects randomised to oral semaglutide.
!
Tipping-point multiple imputation analysis: In this sensitivity analysis, missing data will 
first be imputed according to the primary analysis. Secondly, for all oral semaglutide 
treatment arms a penalty will be added to the imputed values at week 26. The approach is to
gradually increase this penalty until all confirmed HbA1c conclusions from the primary 
analysis are changed. For each hypothesis tested the specific value of the penalty that 
reverses the conclusion will be used to evaluate the robustness of the primary analysis 
results. 
17.3.3.2
Other sensitivity analyses
The following additional sensitivity analysis will be specified:
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!
Last observation carried forward analysis: This sensitivity analysis will be based on the 
FAS using the on-treatment without rescue medication observation period. The change from 
baseline to week 26 in HbA1c will be analysed by a linear normal model (ANCOVA) with 
treatment, stratification factors, the interaction between the stratification factors and region 
as categorical fixed effects and baseline HbA1c as a covariate. 
17.3.3.3
Assessment of sensitivity analyses
The results from the sensitivity analyses will be collectively used to interpret the robustness of the 
trial results for HbA1c. Due to sensitivity analyses inherent conservative nature, it will not be a 
requirement that all confirmatory hypotheses are consistently confirmed across the sensitivity 
analyses. Thus, no absolute success criteria will be pre-defined for each sensitivity analysis. The 
sensitivity results in totality will be used to substantiate the credibility of the trial results.
17.4
Secondary endpoints
17.4.1
Confirmatory secondary endpoints 
Change from baseline to week 26 in body weight (kg) will be a confirmatory secondary endpoint. 
The primary and secondary estimands will be estimated using the same approaches as described for 
the primary HbA1c endpoint. Baseline body weight will be used a covariate instead of baseline 
HbA1c in both the multiple imputation and MMRM analysis models. 
Superiority will be considered confirmed if the mean treatment difference is supporting the 
corresponding hypothesis and the two-sided p-value from the analysis of the primary estimand is 
strictly below its local two-sided significance level resulting from the closed testing procedure in 
Figure 17–1. Sensitivity analyses similar to the ones pre-specified for the primary HbA1c endpoint 
will be made to evaluate the robustness of the body weight results.
17.4.2
Supportive secondary endpoints
17.4.2.1
Efficacy endpoints
The below supportive secondary efficacy endpoints will be evaluated for:
!
The primary estimand based on FAS using the in-trial observation period
!
The secondary estimand based on FAS using the on-treatment without rescue medication 
observation period
No sensitivity analyses are planned for these supportive secondary efficacy endpoints.
Continuous efficacy endpoints
Change from baseline to week 52 in:
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!
HbA1c
!
Body weight (kg)
Change from baseline to week 26 and week 52 in:
!
FPG
!
Body weight (%)
!
BMI
!
Waist circumference
!
Fasting lipid profiles (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides)
!
Total daily insulin dose (IU)
!
Patient-reported outcomes (see Section 17.7 for further details)
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 week 52 in the below derived endpoints from the SMPG 7-
point 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. Fasting lipid profile 
endpoints will be log-transformed prior to analysis with the associated log-transformed baseline 
value as a covariate.
For evaluation of the primary estimand the analyses will be performed separately for week 26 and 
week 52. For the analysis at week 52, the imputation of missing data will be further differentiated 
by whether subjects have discontinued treatment or initiated rescue medication prior to week 26 or 
at or after week 26. This will result in imputation of missing data within 16 groups of subjects 
instead of the 8 groups as described for the week 26 evaluation in Section 17.3.1. If less than five 
subjects have available data in one of the 16 groups, the imputation will be made within the 8 
groups specified for the primary evaluation. The frequency of missing data is expected to be slightly 
larger at week 52 compared to week 26. The rate of missing data is expected to decline over time.
For evaluation of the secondary estimand the MMRM based primary analysis will include all 
scheduled post-baseline measurement up to and including week 26 (or up to and including week 52 
for change from baseline to week 52 endpoints). From this model the estimated treatment contrasts 
at week 26 (or at week 52 for change from baseline to week 52 endpoints) will be presented with 
95% confidence intervals and two-sided p-values for test of no difference.
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Binary efficacy endpoints
If a subject after week 26 and after week 52 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 weight gain
!
HbA1c reduction ≥ 1 %-point (10.9 mmol/mol) and weight loss ≥ 3 %
The above binary endpoints will be analysed separately using a logistic regression model with 
treatment, stratification factors, the interaction between the stratification factors and region as fixed 
effects and baseline response as covariate (i.e. baseline HbA1c for binary HbA1c endpoints, baseline 
weight for weight endpoints and both baseline HbA1c and baseline weight for the binary endpoints 
that combines both parameters). 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 17.3.1 for the primary estimand and by 
treatment group assuming MAR and as described in Section 17.3.2 for the secondary 
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 rule46.
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.
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The endpoint will be described and compared for oral semaglutide versus placebo using likelihood 
ratio tests obtained from a Cox proportional hazards model with treatment, stratification factors, the 
interaction between the stratification factors and region as categorical fixed effects and baseline 
HbA1c as a covariate. From this analysis the estimated Hazard ratios for each of the oral 
semaglutide dose levels versus placebo will be presented together with 95% confidence intervals 
and two sided p values for test of no difference.  
17.4.2.2
Safety endpoints
The safety endpoints will be evaluated based on SAS using the on-treatment observation period and 
based on SAS using the in-trial observation period unless otherwise stated. The following endpoints 
are used to support the safety objectives.
Adverse events 
!
Number of TEAEs during exposure to trial product, assessed up to approximately 26 and 57 
weeks
All AEs will be coded using the most recent version of the Medical Dictionary for Regulatory 
Activities (MedDRA) coding. 
A treatment-emergent AE is defined as an AE with onset in the on-treatment observation period 
(see definition of observation periods in Section 17.2).
TEAEs will be summarised in terms of the number of subjects with at least one event (N), the 
percentage of subjects with at least one event (%), the number of events (E) and the event rate per 
100 patient years of observation time (R) for the on-treatment observation period. Supportive 
summaries of AEs will be made for the in-trial observation period. The development over time in 
gastrointestinal AEs will be presented graphically.
Other safety endpoints
Change from baseline to week 26 and week 52 in:
!
Amylase
!
Lipase
!
Pulse
!
Systolic blood pressure
!
Diastolic blood pressure
The above safety endpoints will be evaluated using the primary analysis for the primary estimand 
based on SAS using the in-trial observation period and using the primary analysis for the secondary 
estimand based on SAS using the on-treatment observation period. Endpoints will be analysed 
separately as described above for continuous efficacy endpoints. Results will be presented at week 
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26 and at week 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 week 52 in:
!
Haematology 
!
Biochemistry (except for amylase and lipase)
!
Calcitonin
!
ECG evaluation
!
Physical examination
The above safety endpoints will be summarised descriptively by treatment arm and visit. 
Categorical safety endpoints will be summarised as counts and relative frequencies. Calcitonin will 
also be presented by gender.
Hypoglycaemia
!
Number of treatment-emergent severe or BG confirmed symptomatic hypoglycaemic 
episodes during exposure to trial product, assessed up to approximately 26 and 57 weeks
!
Treatment-emergent severe or BG confirmed symptomatic hypoglycaemic episodes during 
exposure to trial product, assessed up to approximately 26 and 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 12.7).
Nocturnal hypoglycaemic episodes: episodes occurring between 00:01 and 05:59 both inclusive.
Hypoglycaemic episodes are classified according to the Novo Nordisk classification of 
hypoglycaemia and the ADA classification of hypoglycaemia (see Figure 17–2).
Novo Nordisk classification of hypoglycaemia
In normal physiology, symptoms of hypoglycaemia occur below a PG level of 3.1 mmol/L 
(56 mg/dL)49. Therefore, Novo Nordisk has included hypoglycaemia with PG levels below this cut-
off point in the definition of BG-confirmed hypoglycaemia.
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Novo Nordisk uses the following classification in addition to the ADA classification:
!
Severe or BG-confirmed symptomatic hypoglycaemia: An episode that is severe according 
to the ADA classification38 or BG confirmed by a PG value < 3.1 mmol/L (56 mg/dL) with
symptoms consistent with hypoglycaemia.
ADA classification of hypoglycaemia
!
Severe hypoglycaemia: An episode requiring assistance of another person to actively 
administer carbohydrate, glucagon, or take other corrective actions. PG concentrations may 
not be available during an event, but neurological recovery following the return of PG to 
normal is considered sufficient evidence that the event was induced by a low PG 
concentration.
!
Asymptomatic hypoglycaemia: An episode not accompanied by typical symptoms of 
hypoglycaemia, but with a measured PG concentration ≤ 3.9 mmol/L (70 mg/dL).
!
Documented symptomatic hypoglycaemia: An episode during which typical symptoms of 
hypoglycaemia are accompanied by a measured PG concentration ≤ 3.9 mmol/L 
(70 mg/dL).
!
Pseudo-hypoglycaemia: An episode during which the person with diabetes reports any of the 
typical symptoms of hypoglycaemia with a measured PG concentration > 3.9 mmol/L 
(70 mg/dL) but approaching that level.
!
Probable symptomatic hypoglycaemia: An episode during which symptoms of 
hypoglycaemia are not accompanied by a PG determination but that was presumably caused 
by a PG concentration ≤ 3.9 mmol/L (70 mg/dL).
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Hypoglycaemic 
episode 
PG ≤ 3.9 mmol/L 
(70 mg/dL) 
or 
Alleviation of 
symptoms 
or
Seizure, coma or 
fatal 
SMPG
measurement
Asymptomatic 
hypoglycaemia
Documented 
symptomatic 
hypoglycaemia
Pseudo-
hypoglycaemia
Probable 
symptomatic 
hypoglycaemia
No
Yes
No measurement 
with symptoms
PG > 3.9 mmol/L 
(70 mg/dL)
with symptoms
PG ≤3.9 mmol/L 
(70 mg/dL)
with symptoms
PG ≤3.9 mmol/L 
(70 mg/dL)
without symptoms
No
Yes
Note: Glucose measurements are performed with capillary blood calibrated to plasma equivalent glucose values
PG: plasma glucose  SMPG: Self-measured plasma glucose  
Subject 
able to 
treat him/
herself
Severe 
hypoglycaemia
(ADA 2013)
Figure 17–2
ADA classification of hypoglycaemia
Data on treatment-emergent hypoglycaemic episodes will be presented in terms of the number of 
subjects with at least one episode, the percentage of subjects with at least one episode (%), the total 
number of episodes and the episode rate per 100 patient years of observation time.
Analysis of severe or BG-confirmed symptomatic hypoglycaemic endpoints
The number of treatment-emergent severe or BG-confirmed symptomatic hypoglycaemic episodes 
in the on-treatment period will be analysed using a negative binomial regression model with a log-
link function and the logarithm of the duration of the subject’s on-treatment observation period as 
offset. The model will include treatment, stratification factors, the interaction between the 
stratification factors and region as fixed factors and baseline HbA1c as covariate.
The binary endpoint showing whether a subject has at least one treatment-emergent severe or BG-
confirmed symptomatic hypoglycaemic episode will be analysed using a logistic regression model 
with treatment, stratification factors, the interaction between the stratification factors and region as 
fixed factors and baseline HbA1c as covariate.
The number of treatment-emergent severe or BG-confirmed symptomatic hypoglycaemic episodes 
will be presented by time using summary statistics.
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17.4.2.3
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 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.
17.7
Patient reported outcomes
PRO endpoints
Change from baseline to week 26 and week 52 in:
!
SF-36v2™ (acute version) health survey: Scores from the 8 domains and summary of the 
physical component score and the mental component score
!
IWQOL-Lite Clinical Trial Version: Total score of the 22 items
!
DTSQs: Individual items and treatment satisfaction score (6 of the 8 items summed)
The PRO questionnaire endpoints will be evaluated using the primary analysis for the primary 
estimand based on FAS using the in-trial observation period and using the primary analysis for the 
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secondary estimand based on FAS using the on-treatment without rescue medication period. Scores 
will be analysed separately as the other continuous efficacy endpoints with the associated baseline 
response as a covariate.
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18 Ethics
18.1
Benefit-risk assessment of the trial
Risks and precautions
The nonclinical safety programme of oral semaglutide has not revealed any safety issues precluding 
use in humans. 
The sections below describe the important identified and potential risks and precautions associated 
with oral semaglutide treatment. These are based on findings in nonclinical studies and clinical 
trials with oral semaglutide as well as other GLP-1 RAs. For each of these risks and precautions, 
mitigating actions have been implemented to minimise the risks for subjects enrolled in this trial.
Identified risks
Gastrointestinal adverse events
Consistent with findings with other GLP-1 RAs, the most frequently reported AEs in clinical trials 
with oral semaglutide have been gastrointestinal disorders (nausea, vomiting, diarrhoea, dyspepsia 
and constipation). Clinical trials have indicated that a low starting dose and gradual dose escalation 
mitigates the risk of gastrointestinal AEs. Consequently, a low starting dose and dose 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.
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 
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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.
Impaired renal function may increase the risk of metformin-associated lactic acidosis when GLP-1 
RAs are co-administered with metformin. As a precaution, serum creatinine will be measured 
regularly. In subjects treated with metformin who experience prolonged or severe nausea and 
vomiting, the investigator should monitor serum creatinine, and if clinically indicated, withhold 
metformin until resolution of renal dysfunction.
The use of the background medication should be in accordance with the current approved labels.
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 treatment50,51,52. Risk factors for these events 
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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 progression53,54 even in intensively treated patients who experienced early worsening51. 
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, or as required by local law.
General precautions 
All subjects will be included after a thorough evaluation with regards to in- and exclusion criteria 
defined in order to ensure that subjects are eligible for trial treatment. There are also strict 
glyacemic rescue criteria in place to ensure acceptable glycaemic control during the trial. If rescue 
medication is required, it should be in accordance with ADA/European Association for the Study of 
Diabetes21, 22 (excluding GLP-1 RAs, DPP-4 inhibitors, amylin analogues and SGLT-2 inhibitors).
It is the responsibility of the investigator to ensure the best possible care according to the principles 
outlined in Diabetes Care 2016 Standards of Medical Care in Diabetes55.
Further details with regards to safety of oral semaglutide are described in the current edition of the 
IB for oral semaglutide (NN9924), or any updates thereto.
18.1.1
Benefits
In this trial subjects will be randomised to one of four treatment arms involving a treatment regimen 
anticipated to be equally or more efficacious than the treatment they receive 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 Type 2 
diabetes.
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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.
18.1.2
Risk and benefit conclusion 
The safety profile for oral semaglutide generated from the clinical and nonclinical development 
programme has not revealed any safety issues that would prohibit administration of oral 
semaglutide in accordance with the planned clinical trial.
The phase 2 results indicate that oral semaglutide will provide clinically relevant improvements in 
glycaemic control and body weight.
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 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 
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requirements. The written informed consent must be signed and personally dated by the person who 
seeks the informed consent before any trial-related activity.
If information becomes available that may be relevant to the subject’s willingness to continue 
participating in the trial, the investigator must inform the subject in a timely manner and a revised 
written subject information must be provided and a new informed consent must be obtained.
In order to avoid missing data, the subjects will be informed about the importance of completing the 
trial also if the subjects discontinue from trial product.
18.3
Data handling
If the subject withdraws from the trial or is lost to follow up, then the subject’s data will be handled 
as follows:
!
Data already collected and any data collected at the end-of-trial visit including follow-up 
visit will be retained by Novo Nordisk, entered into the database and used for the clinical 
trial report. 
!
Safety events will be reported to Novo Nordisk and regulatory authorities according to 
local/national requirements.
If data is used, it will always be in accordance with local regulations and IRBs/IECs.
18.4
Information to subjects during trial
All written information to subjects must be sent to IRB/IEC for approval/favourable opinion and to 
regulatory authorities for approval or notification according to local regulations.
18.5
Premature termination of the trial and/or trial site
Novo Nordisk, the IRBs/IECs or a regulatory authority may decide to stop the trial, part of the trial 
or a trial site at any time, but agreement on procedures to be followed must be obtained.
If the trial is suspended or prematurely terminated, the investigator must inform the subjects 
promptly and ensure appropriate therapy and follow-up. The investigator and/or Novo Nordisk must 
also promptly inform the regulatory authorities and IRBs/IECs and provide a detailed written 
explanation. 
If, after the termination of the trial, the benefit-risk analysis changes, the new evaluation must be 
provided to the IRBs/IECs in case it has an impact on the planned follow-up of subjects who have 
participated in the trial. If it has an impact, the actions needed to inform and protect the subjects 
should be described.
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19 Protocol compliance
19.1
Protocol deviations
Deviations from the protocol should be avoided.
If deviations do occur, the investigator must inform the monitor and the implications of the 
deviation must be reviewed and discussed.
Deviations must be documented and explained in a protocol deviation by stating the reason, date 
and the action(s) taken. Some deviations, for which corrections are not possible, can be 
acknowledged and confirmed via edit checks in the eCRF or via listings from the trial database.
Documentation on protocol deviations must be kept in the investigator’s trial master file and 
sponsor trial master file.
19.2
Prevention of missing data
The importance of subject retention will be addressed by Novo Nordisk in the training and 
communication with the trial sites. 
The subjects will be carefully informed about the trial procedures before signing informed consent, 
so that they know the implications of participating in the trial.  
Close surveillance of subject retention will be performed throughout the trial by Novo Nordisk with 
focus on reasons for premature discontinuation of trial product or withdrawal of consent to secure 
early mitigations in collaboration with the trial sites. 
The investigator will make every effort to ensure that all assessments are performed and data is 
collected. If missing data does occur the reason will be collected via the protocol deviation process, 
see Section 19.1. Novo Nordisk will monitor protocol deviations on an on-going basis throughout 
the trial followed by appropriate actions (e.g. re-training of site staff).
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20 Audits and inspections
Any aspect of the clinical trial may be subject to audits conducted by Novo Nordisk or inspections 
from domestic or foreign regulatory authorities or from IRBs/IECs. Audits and inspections may 
take place during or after the trial. The investigator and the site staff as well as Novo Nordisk staff 
have an obligation to cooperate and assist in audits and inspections. This includes giving auditors 
and inspectors direct access to all source documents and other documents at the trial site relevant to 
the clinical trial. This includes permission to examine, analyse, verify and reproduce any record(s) 
and report(s) that are relevant to the evaluation of the trial.
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21 Critical documents
Before a trial site is allowed to start screening subjects, written notification from Novo Nordisk 
must be received and the following documents must be available to Novo Nordisk:
!
Regulatory approval and/or acknowledgement of notification as required 
!
Approval/favourable opinion from IRBs/IECs clearly identifying the documents reviewed as 
follows: protocol, any protocol amendments, subject information/informed consent form, 
any other written information to be provided to the subject and subject recruitment materials
!
List of IRB/IEC members and/or constitution (or a general assurance number/statement of 
compliance)
!
Curricula vitae of investigator and sub-investigator(s) (current, dated and signed - must 
include documented GCP training or a certificate)
!
Signed receipt of Investigator’s Brochure for oral semaglutide
!
Signed and dated Agreement on Protocol
!
Signed and dated Agreement on Protocol Amendment, if applicable
!
Contract, signed by the investigator and/or appropriate parties on behalf of the investigator’s 
site and Novo Nordisk
For Japan only: A seal is accepted as signature
!
Source document agreement
!
Central laboratory certification and normal ranges
!
Insurance statement, if applicable
!
Financial disclosure form from investigator and sub-investigator(s)
!
For US trial sites: verification under disclosures per Code of Federal Regulations (CFR) of 
Financial Conflict of Interest
!
For US trial sites: FDA form 1572 must be completed and signed by the investigator at each 
site
FDA form 1572:
For US sites:
!
Intended for US sites
!
Conducted under the IND
!
All US investigators, as described above, will sign FDA Form 1572
For sites outside the US:
!
Intended for participating sites outside of the US
!
Not conducted under the IND
!
All investigators outside of the US will not sign FDA form 1572
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Novo Nordisk will analyse and report data from all sites together if more than one site is involved in 
the trial.
By signing the protocol agreement, each investigator agrees to comply fully with ICH GCP1, 
applicable regulatory requirements and the Declaration of Helsinki2.
By signing the protocol agreement, each investigator also agrees to allow Novo Nordisk to make 
investigator’s name and information about site name and address publically available if this is 
required by national or international regulations.
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22 Responsibilities
The investigator is accountable for the conduct of the trial at his/her site and must ensure adequate 
supervision of the conduct of the trial at the trial site. If any tasks are delegated, the investigator 
must maintain a log of appropriately qualified persons to whom he/she has delegated specified trial-
related duties. The investigator must ensure that there is adequate and documented training for all 
staff participating in the conduct of the trial. It is the investigator’s responsibility to supervise the 
conduct of the trial and to protect the rights, safety, and well-being of the subjects.
A qualified physician, who is an investigator or a sub-investigator for the trial, must be responsible 
for all trial-related medical decisions.
The investigator will follow instructions from Novo Nordisk when processing data.
The investigator is responsible for filing essential documents (i.e. those documents which 
individually and collectively permit evaluation of the conduct of a trial and the quality of the data 
produced) in the investigator trial master file. The documents including the subject identification 
code list must be kept in a secure locked facility, so no unauthorized persons can get access to the 
data. 
The investigator will take all necessary technical and organisational safety measures to prevent 
accidental or wrongful destruction, loss or deterioration of data. The investigator will prevent any 
unauthorised access to data or any other processing of data against applicable law. The investigator 
must be able to provide the necessary information or otherwise demonstrate to Novo Nordisk that 
such technical and organisational safety measures have been taken.
During any period of unavailability, the investigator must delegate responsibility for medical care of 
subjects to a specific qualified physician who will be readily available to subjects during that time.
If the investigator is no longer able to fulfil the role as investigator (e.g. if he/she moves or retires), 
a new investigator will be appointed in consultation with Novo Nordisk. 
The investigator and other site personnel must have sufficient English skills according to their 
assigned task(s).
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23 Reports and publications
The information obtained during the conduct of this trial is considered confidential, and may be 
used by or on behalf of Novo Nordisk for regulatory purposes as well as for the general 
development of the trial product. All information supplied by Novo Nordisk in connection with this 
trial shall remain the sole property of Novo Nordisk and is to be considered confidential 
information. 
No confidential information shall be disclosed to others without prior written consent from Novo 
Nordisk. Such information shall not be used except in the performance of this trial. The information 
obtained during this trial may be made available to other physicians who are conducting other 
clinical trials with the trial product, if deemed necessary by Novo Nordisk. Provided that certain 
conditions are fulfilled, Novo Nordisk may grant access to information obtained during this trial to 
researchers who require access for research projects studying the same disease and/or trial product 
studied in this trial.
Novo Nordisk may publish on its clinical trials website a redacted clinical trial report for this trial.
One or two investigators will be appointed by Novo Nordisk to review and sign the clinical trial 
report (signatory investigator) on behalf of all participating investigators. The signatory 
investigator(s) will be appointed based upon the criteria defined by the International Committee of 
Medical Journal Editors for research publications56. 
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 Disclosure 23.
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 Editors56 (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
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.  
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1RYR1RUGLVN
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Version:
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Status:
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25 Institutional Review Boards/Independent Ethics Committees and 
regulatory authorities
IRB/IEC:
Written approval or favourable opinion must be obtained from IRB/IEC prior to commencement of 
the trial.
During the trial, the investigator or Novo Nordisk, as applicable, must promptly report the 
following to the IRB/IEC, in accordance with local requirements: updates to IB, unexpected SAEs 
where a causal relationship cannot be ruled out, protocol amendments according to local 
requirements, deviations to the protocol implemented to eliminate immediate hazards to the 
subjects, new information that may affect adversely the safety of the subjects or the conduct of the 
trial (including new benefit-risk analysis in case it will have an impact on the planned follow-up of 
the subjects), annually written summaries of the trial status and other documents as required by the 
local IRB/IEC.
The investigator must ensure submission of the clinical trial report synopsis to the IRB/IEC.
Protocol amendments must not be implemented before approval or favourable opinion according to 
local regulations, unless necessary to eliminate immediate hazards to the subjects.
The investigator must maintain an accurate and complete record of all submissions made to the 
IRB/IEC. The records must be filed in the investigator trial master file and copies must be sent to 
Novo Nordisk.
Regulatory Authorities:
Regulatory authorities will receive the clinical trial application, protocol amendments, reports on 
SAEs, and the clinical trial report according to national requirements.
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26 Indemnity statement
Novo Nordisk carries product liability for its products, and liability as assumed under the special 
laws, acts and/or guidelines for conducting clinical trials in any country, unless others have shown 
negligence.
Novo Nordisk assumes no liability in the event of negligence, or any other liability of the sites or 
investigators conducting the trial, or by persons for whom the said site or investigator are 
responsible.
Novo Nordisk accepts liability in accordance with:
For France only: 
The French Public Health Code article L 1121-10 (law n° 2004-806 of 9 August 2004 art. 88 I, IX 
Journal Officiel of 11 August 2004. "The sponsor is responsible for identification of the harmful 
consequences of the biomedical research for the person lending himself thereto and for 
indemnification of his beneficiaries, except in case of proof, incumbent on it, that the prejudice is 
not attributable to his fault of or the fault of any intervening party, without the sponsor's being 
entitled to call on acts by a third party or the voluntary withdrawal of the person who had initially 
consented to cooperating in the research.”
For Mexico only: 
a) Novo Nordisk carries product liability for its products assumed under the special laws, 
acts/and/or guidelines for conducting trials in any country, including those applicable
provisions on the Mexican United States. If the subject feels that something goes wrong during 
the course of this trial, the subject should contact the trial staff in the first instance. 
b) If during their participation in the trial the subject experiences a disease or injury that, 
according to the trial doctor and the sponsor, is directly caused by the trial medication and/or a 
trial procedure that otherwise would not have been part of his/her regular care, the subject will 
receive from the Institution or Medical Care Establishment and free of charge, the appropriate 
medical treatment as required. 
c) In this case, the costs resulting from such treatment as well as the costs of any indemnification 
established by law will be covered by the trial sponsor in accordance with the terms provided by 
all applicable regulations; even if the subject discontinues his/her participation in the trial by 
his own will or by a decision from the investigator. 
d) By signing the informed consent, the subject will not renounce to any compensation or 
indemnification he/she may be entitled to by law, nor will he/she will incur any additional 
expense as a result of his/her participation in the trial; any additional expense resulting from 
the subject’s participation in the trial will be covered by the trial sponsor.
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For Poland only:
Novo Nordisk carries liability for the Trial exclusively in the scope defined by the applicable laws 
and in particular by the Civil Code and the Pharmaceutical Law dated 6 September 2001 (uniform 
version Journal of Laws of 2008 No. 45 item 271 with amendments). In order to support potential 
claims for liability attributable to the Trial, Novo Nordisk and Investigator are covered by the 
Insurance Policy issued according to applicable Polish law.
For Russia only: 
Federal law of 12 April 2010 No. 61-FZ ‘On Medicinal Drugs’ Circulation.
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Protocol
CONFIDENTIAL
Date:
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27 References
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2.
World Medical Association. 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.
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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 
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5.
Ford ES, Li C, Little RR, Mokdad AH. Trends in A1C concentrations among U.S. adults 
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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.
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Kieffer TJ, Habener JF. The glucagon-like peptides. Endocr Rev. 1999;20(6):876-913.
8.
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.
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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.
10.
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.
11.
Meier JJ. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. 
Nat Rev Endocrinol. 2012;8(12):728-42.
12.
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.
13.
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.
14.
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.
15.
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.
16.
Nauck MA, Petrie JR, Sesti G, Mannucci E, Courreges JP, Atkin S, et al. The once-weekly 
human GLP-1 analogue semaglutide provides significant reductions in HbA1c and body 
weight in patients with type 2 diabetes. EASD abstract. 2012.
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CONFIDENTIAL
Date:
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Version:
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UTN: U1111-1180-3637 
Status:
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17.
EMA. 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). 2009 2009.
18.
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.
19.
Investigator's Brochure for s.c. Semaglutide (NN9535), Edition 11 or any updates hereof. 
2016.
20.
Investigators brochure for oral semaglutide (NN9924), edition 7 or any updates hereof. 2016 
2016.
21.
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.
22.
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.
23.
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.
24.
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.
25.
U.S. Department of Health and Human Services, Food and Drug Administration. Food and 
Drug Administration Amendments Act of 2007. 27 September 2007.
26.
The European Parliament and the Council of the European Council. Directive 2001/20/EC 
of the European Parliament and of the Councill of 4 April 2001 on the approximation of the 
laws, regulations and administrative provisions of the Member States relating to the 
implementation of good clinical practice in the conduct of clinical trials on medicinal 
products for human use, article 11. Official Journal of the European Communities. 1 May 
2001.
27.
The European Parliament and the Council of the European Council. Regulation (EC) No 
726/2004 of the European Parliament and of the Council of 31 March 2004 laying down 
Community procedures for the authorisation and supervision of medicinal products for 
human and veterinary use and establishing a European Medicines Agency, article 57. 
Official Journal of the European Communities. 2004.
28.
Clarke WL, Cox DJ, Gonder-Frederick LA, Julian D, Schlundt D, Polonsky W. Reduced 
awareness of hypoglycemia in adults with IDDM. A prospective study of hypoglycemic 
frequency and associated symptoms. Diabetes Care. 1995;18(4):517-22.
29.
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.
30.
Ware JE, Kosinski M, Dewey JE. How to Score Version Two of the SF-36 Health Survey. 
3rd ed: Lincoln RI: QualityMetric, Incorporated. 2000.
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Version:
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31.
Turner-Bowker DM, Bartley PJ, Ware JE. SF-36® Health Survey and "SF" Bibliography. 
Lincoln, Rhode Island: QualityMetric Incorporated; 2002.
32.
Hill AJ. The psychology of food craving. Proc Nutr Soc. 2007;66(2):277-85.
33.
Hill AJ, Heaton-Brown L. The experience of food craving: a prospective investigation in 
healthy women. J Psychosom Res. 1994;38(8):801-14.
34.
Hill AJ, Weaver CF, Blundell JE. Food craving, dietary restraint and mood. Appetite. 
1991;17(3):187-97.
35.
Hill AJ, Rogers PJ, Blundell JE. Techniques for the experimental measurement of human 
eating behaviour and food intake: a practical guide. Int J Obes Relat Metab Disord. 
1995;19(6):361-75.
36.
Bradley C. Diabetes Treatment Satisfaction Questionnaire. In: Bradley C, editor. Handbook 
of Psychology and Diabetes. Chur, Switzerland: Harwood Academic Publishers; 1994. p. 
111-32.
37.
National Kidney F. KDOQI Clinical Practice Guideline for Diabetes and CKD: 2012 
Update. Am J Kidney Dis. 2012;60(5):850-86.
38.
Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, et al. Hypoglycemia 
and diabetes: a report of a workgroup of the American Diabetes Association and the 
Endocrine Society. Diabetes Care. 2013;36(5):1384-95.
39.
McAulay V, Deary IJ, Frier BM. Symptoms of hypoglycaemia in people with diabetes. 
Diabet Med. 2001;18(9):690-705.
40.
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.
41.
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.
42.
European Commission. The Rules Governing Medicinal Products in the European Union, 
Volume 4, Annex 13, Investigational Medicinal Products. Brussels, February 2010.
43.
KDIGO. KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney international 
supplements. 2012;2(1):1-138.
44.
Bretz F, Posch M, Glimm E, Klinglmueller F, Maurer W, Rohmeyer K. Graphical 
approaches for multiple comparison procedures using weighted Bonferroni, Simes, or 
parametric tests. Biometrical Journal. 2011;53(6):894-913.
45.
Rohmeyer K, Klinglmueller F. gMCP: Graph Based Multiple Test Procedures. R package 
version 0.8-8. 10/3/2014 2014.
46.
Little RJA, Rubin DB. Statistical analysis with missing data: New York: John Wiley & 
Sons. 1987.
47.
European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP). 
Guideline on Missing Data in Confirmatory Clinical Trials (EMA/CPMP/EWP/1776/99 
Rev. 1). 2 Jul 2010.
48.
National Academy of Sciences (NAS). The Prevention and Treatment of Missing Data in 
Clinical Trials. Washington D.C.: The National Academies Press. 2010.
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Protocol
CONFIDENTIAL
Date:
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Version:
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Status:
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49.
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.
50.
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.
51.
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.
52.
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.
53.
Intensive blood-glucose control with sulphonylureas or insulin compared with conventional 
treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK 
Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352(9131):837-53, Erratum 
1999; 354: 602.
54.
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.
55.
Standards of Medical Care in Diabetes-2016: Summary of Revisions. Diabetes Care. 
2016;39 Suppl 1:S4-5.
56.
International Committee of Medical Journal Editors. Recommendations for the Conduct, 
Reporting, Editing and Publication of Scholarly Work in Medical Journals. 2013.
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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
CONFIDENTIAL
Date:
19 August 2016
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Trial ID: NN9924-4280
Version:
1.0
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Status:
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1
Background
Treatment with GLP-1 receptor agonists has shown to be associated with thyroid C-cell changes in 
rodents but not in non-human primates. The human relevance of this finding is unknown. However, 
based on the findings in rodents, monitoring of serum calcitonin (a sensitive biomarker for C-cell 
activation) is currently being performed in clinical trials with semaglutide.
While there is general agreement on the clinical interpretation of substantially elevated calcitonin 
levels (greater than 100 ng/L) as likely indicative of C-cell neoplasia, the interpretation of values 
between upper normal range (5.0 and 8.4 ng/L for women and men, respectively) and 100 ng/L is 
less clear with regards to indication of disease.
There are several known confounding factors affecting calcitonin levels, e.g.:
!
renal dysfunction
!
smoking
!
autoimmune thyroiditis
!
several drug classes (e.g. proton pump inhibitors, beta-blockers, H2-blockers and 
glucocorticoids)
Physiology of C-cell activation in various clinical conditions and in different patient populations 
(i.e. with various co-morbidities) is poorly understood. There may be various clinical conditions not 
identified so far which mildly or moderately affect calcitonin secretion by C-cells.
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Protocol - Appendix A
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2
Calcitonin monitoring
A blood sample will be drawn at pre-specified trial visits for measurement of calcitonin.
In case a subject has a calcitonin value ≥ 10 ng/L the algorithm outlined in Figure 1 and described 
below should be followed. The algorithm applies for all calcitonin values in the trial.
Calcitonin < 10ng/L
Calcitonin  ≥ 10 ng/L and 
< 50 ng/L
Calcitonin  ≥ 50 ng/L and 
< 100 ng/L
Calcitonin  ≥ 100 ng/L
Evaluation of 
calcitonin results
Calcitonin  ≥ 10 ng/L and 
last measurement in the 
trial
No action
●Investigate potential confounding 
factors
●Continue sampling of calcitonin 
according to protocol
●Refer to thyroid specialist
●Discontinue trial product
●Refer to thyroid specialist
●Refer to thyroid specialist
Figure 1
Flow of calcitonin monitoring
2.1
Calcitonin ≥ 100 ng/L  
Action: The subject must immediately be referred to a thyroid specialist for further evaluation and 
the trial product must be discontinued (see protocol Section 6.5 premature discontinuation of trial 
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Protocol - Appendix A
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Version:
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product). The subject should remain in the trial, however, all medications suspected to relate to this 
condition must be discontinued until diagnosis has been established.
Background: These values were found in 9 (0.15%) of a population of 5817 patients with thyroid 
nodular disease1. All of these patients were diagnosed with medullary thyroid carcinoma 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 medullary thyroid carcinoma, it is common clinical practice to 
explore the family history of medullary thyroid carcinoma or multiple endocrine neoplasia 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.
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Protocol - Appendix A
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Date:
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Version:
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Background: Calcitonin values from 20-50 ng/L were found in up to 1% of subjects of the 
population of 5817 patients with thyroid nodular disease1. The predictive value of a C-cell anomaly 
for this calcitonin level was 8.3%. However, the likelihood of having a medullary carcinoma >1 cm 
with calcitonin in this range is extremely low.
For calcitonin values between 10-20 ng/L Costante et al1 identified 216 (3.7%) patients. One patient 
out of the 216 had a subsequent basal (unstimulated) calcitonin of 33 ng/L, and had C-cell 
hyperplasia at surgery. Two other studies used a cut-off of calcitonin > 10 ng/L to screen for C-cell 
disease, but they do not provide sufficient information on patients with basal calcitonin > 10 and <
20 ng/L to allow conclusions2,3.
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Protocol - Appendix A
CONFIDENTIAL
Date:
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References
1 Costante G, Meringolo D, Durante C, Bianchi D, Nocera M, Tumino S et al. Predictive value of serum calcitonin 
levels for preoperative diagnosis of medullary thyroid carcinoma in a cohort of 5817 consecutive patients with 
thyroid nodules. J Clin Endocrinol Metab 2007; 92(2):450-455.
2 Scheuba C, Kaserer K, moritz A, drosten R. Sporadic hypercalcitoninemia: clinica and therapeutic consequences. 
Endocrine Related Cancer 2009; 16(1):243-253.
3 Verga U, Ferrero S, Vicentini L, Brambilla T, Cirello V, Muzza M et al. Histopathological and molecular studies in 
patients with goiter and hypercalcitoninemia: reactive or neoplastic C-cell hyperplasia? Endocr Relat Cancer 2007; 
14(2):393-403.
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Protocol - Appendix B
CONFIDENTIAL
Date:
19 August 2016
1RYR1RUGLVN
Trial ID: NN9924-4280
Version:
1.0
UTN: U1111-1180-3637
Status:
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Appendix B
Adverse events requiring additional data collection
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol - Appendix B
CONFIDENTIAL
Date:
19 August 2016
1RYR1RUGLVN
Trial ID: NN9924-4280
Version:
1.0
UTN: U1111-1180-3637
Status:
Final
EudraCT No.: 2016-000988-16
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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. 
Note: Use of wrong dispensing unit number (DUN) is not considered a medication error.
!
Wrong route of administration.
!
Administration of an overdose with the intention to cause harm (e.g. suicide attempt), 
misuse or abuse of trial product.
!
Accidental administration of a higher dose than intended. A higher dose is a dose of at least 
one tablet more than the intended dose; however the administered dose must deviate from 
the intended dose to an extent where clinical consequences for the trial subject were likely 
to happen as judged by the investigator, although they did not necessarily occur.
!
Lactic acidosis
!
Creatine kinase (CK) > 10 x upper normal limit (UNL)
!
Hepatic event 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.
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
19 August 2016
1RYR1RUGLVN
Trial ID: NN9924-4280
Version:
1.0
UTN: U1111-1180-3637
Status:
Final
EudraCT No.: 2016-000988-16
Page:
3 of 8
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:
19 August 2016
1RYR1RUGLVN
Trial ID: NN9924-4280
Version:
1.0
UTN: U1111-1180-3637
Status:
Final
EudraCT No.: 2016-000988-16
Page:
4 of 8
!
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 8.1.5).
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
19 August 2016
1RYR1RUGLVN
Trial ID: NN9924-4280
Version:
1.0
UTN: U1111-1180-3637
Status:
Final
EudraCT No.: 2016-000988-16
Page:
5 of 8
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:
19 August 2016
1RYR1RUGLVN
Trial ID: NN9924-4280
Version:
1.0
UTN: U1111-1180-3637
Status:
Final
EudraCT No.: 2016-000988-16
Page:
6 of 8
!
Relevant immunological tests performed
!
Treatment given for the reaction
!
Previous history of similar reaction
!
Risk or confounding factors identified
1.8.1
Assessments in case of suspicion of hypersensitivity reaction
In case of suspicion of a severe immediate systemic hypersensitivity reaction3to the trial product, 
the subject must be discontinued from trial product but should remain in the trial (see protocol 
Section6.5and 8.1.5).
If suspicion of a hypersensitivity reaction occurs, the subjects should be instructed to contact the 
site staff as soon as possible for further guidance.
To assist in the diagnostic evaluation it is recommended to draw a blood sample for measurement of 
tryptase (total and/or mature tryptase, local assessment) within 3 hours of onset of the 
hypersensitivity reaction, and if this is achieved, a tryptase sample should also be drawn at V14A.
Furthermore, a blood sample for assessment of anti-semaglutide IgE antibodies should be drawn as 
soon as possible after the event and at V14A and sent to central laboratory. Tryptase concentrations, 
if available, should be included in the specific event form when reporting the AE.
In case of suspicion of immune complex disease3, the subject must be discontinued from trial 
product but should remain in the trial (see protocol Section 6.5 and 8.1.5). It is recommended to 
draw a blood sample for local assessment of complement levels (C3 and C4) to assist in the 
diagnostic evaluation. Complement level results should be included in the specific event form when 
reporting the AE.
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:
19 August 2016
1RYR1RUGLVN
Trial ID: NN9924-4280
Version:
1.0
UTN: U1111-1180-3637
Status:
Final
EudraCT No.: 2016-000988-16
Page:
7 of 8
!
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:
19 August 2016
1RYR1RUGLVN
Trial ID: NN9924-4280
Version:
1.0
UTN: U1111-1180-3637
Status:
Final
EudraCT No.: 2016-000988-16
Page:
8 of 8
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.
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
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CONFIDENTIAL


Protocol Amendment 1.0
CONFIDENTIAL
Date:
06 October 2016
1RYR1RUGLVN
Trial ID: NN9924-4280
Version:
1.0
UTN: U1111-1180-3637
Status:
Final
EudraCT No.: 2016-000988-16
Page:
1 of 4
Protocol Amendment
no 1
to Protocol, final version 1.0
dated 19 August 2016
Trial ID: NN9924-4280
PIONEER 8 – Insulin add-on
Efficacy and safety of oral semaglutide versus Placebo in 
Subjects with type 2 diabetes Mellitus treated with
insulin
A 52-week, randomised, placebo-controlled trial, double-blinded during the initial 26 weeks
Trial phase: 3a
Applicable to Canada
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 1.0
CONFIDENTIAL
Date:
06 October 2016
1RYR1RUGLVN
Trial ID: NN9924-4280
Version:
1.0
UTN: U1111-1180-3637
Status:
Final
EudraCT No.: 2016-000988-16
Page:
2 of 4
Table of Contents   
Page
Table of Contents..............................................................................................................................................2
1
Introduction including rationale for the protocol amendment.............................................................3
2
Changes......................................................................................................................................................3
2.1
Changes to section 1 Summary......................................................................................................3
2.2
Changes to section 6.3 Exclusion criteria......................................................................................3
2.3
Changes to section 8.2.6 Childbearing potential............................................................................4
CONFIDENTIAL


Protocol Amendment 1.0
CONFIDENTIAL
Date:
06 October 2016
1RYR1RUGLVN
Trial ID: NN9924-4280
Version:
1.0
UTN: U1111-1180-3637
Status:
Final
EudraCT No.: 2016-000988-16
Page:
3 of 4
1
Introduction including rationale for the protocol amendment
This protocol amendment was issued to incorporate changes requested by Health Canada on 30 
September 2016 to the study protocol version 1.0 dated 19 August 2016. 
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
2
Changes
2.1
Changes to section 1 Summary
Key exclusion criteria
1. Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing 
potential and not using an adequate contraceptive method (adequate contraceptive measure 
as required by local regulation or practice). 
Greece only: adequate contraceptive measures are defined as combined hormonal
contraception (containing oestrogen and progesterone), which suppress ovulation (oral, 
intravaginal, percutaneous), progesterone-only hormonal contraception which suppress 
ovulation (oral, injectable, implantable), intrauterine device, hormone-releasing intrauterine 
system, bilateral tubal occlusion, partner with vasectomy, sexual abstinence.
For Japan only: Adequate contraceptive measures are abstinence (not having sex), 
diaphragm,
condom (by the partner), intrauterine device, sponge, spermicide or oral contraceptives.
For Canada only: adequate contraceptive measures are defined as combined hormonal 
contraception (containing oestrogen and progesterone), which suppress ovulation (oral, 
intravaginal, percutaneous), progesterone-only hormonal contraception which suppress 
ovulation (oral, injectable, implantable), intrauterine device, hormone-releasing 
intrauterine system, bilateral tubal occlusion, partner with vasectomy, sexual abstinence.
2.2
Changes to section 6.3 Exclusion criteria
Exclusion criteria
3. Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing
CONFIDENTIAL


Protocol Amendment 1.0
CONFIDENTIAL
Date:
06 October 2016
1RYR1RUGLVN
Trial ID: NN9924-4280
Version:
1.0
UTN: U1111-1180-3637
Status:
Final
EudraCT No.: 2016-000988-16
Page:
4 of 4
potential and not using an adequate contraceptive method (adequate contraceptive measure as
required by local regulation or practice).
For Greece only: adequate contraceptive measures are defined as combined hormonal
contraception (containing oestrogen and progesterone), which suppress ovulation (oral,
intravaginal, percutaneous), progesterone-only hormonal contraception which suppress
ovulation (oral, injectable, implantable), intrauterine device, hormone-releasing intrauterine
system, bilateral tubal occlusion, partner with vasectomy, sexual abstinence.
For Japan only: Adequate contraceptive measures are abstinence (not having sex), diaphragm,
condom (by the partner), intrauterine device, sponge, spermicide or oral contraceptives.
For Canada only: adequate contraceptive measures are defined as combined hormonal 
contraception (containing oestrogen and progesterone), which suppress ovulation (oral, 
intravaginal, percutaneous), progesterone-only hormonal contraception which suppress ovulation 
(oral, injectable, implantable), intrauterine device, hormone-releasing intrauterine system, bilateral 
tubal occlusion, partner with vasectomy, sexual abstinence.
2.3
Changes to section 8.2.6 Childbearing potential
8.2.6 Childbearing potential
Contraceptive methods
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 an adequate
contraceptive method throughout the trial and until 5 weeks after end of treatment.
For Japan only: Adequate contraceptive measures are abstinence (not having sex), diaphragm,
condom (by the partner), intrauterine device, sponge, spermicide or oral contraceptives.
For Canada only: adequate contraceptive measures are defined as combined hormonal 
contraception (containing oestrogen and progesterone), which suppress ovulation (oral, 
intravaginal, percutaneous), progesterone-only hormonal contraception which suppress ovulation 
(oral, injectable, implantable), intrauterine device, hormone-releasing intrauterine system, bilateral 
tubal occlusion, partner with vasectomy, sexual abstinence.
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
22 November 2016
1RYR1RUGLVN
Trial ID: NN9924-4280
Version:
2.0
UTN: U1111-1180-3637
Status:
Final
EudraCT No.: 2016-000988-16
Page:
1 of 18
Protocol amendment
no 2
to Protocol, final version 1
dated 19 August 2016
Trial ID: NN9924-4280
Efficacy and Safety of Oral Semaglutide versus Placebo in 
Subjects with Type 2 Diabetes Mellitus treated with insulin
A 52-week, randomised, and double-blind, placebo-controlled trial, double-blinded 
during the initial 26 weeks
Trial phase: 3a
Applicable to all countries
Amendment originator:
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol Amendment no 2
CONFIDENTIAL
Date:
22 November 2016
1RYR1RUGLVN
Trial ID: NN9924-4280
Version:
2.0
UTN: U1111-1180-3637
Status:
Final
EudraCT No.: 2016-000988-16
Page:
2 of 18
Table of Contents   
Page
Table of Contents..............................................................................................................................................2
1
Introduction including rationale for the protocol amendment.............................................................4
1.1
Additional eye examinations and additional data collection on diabetic retinopathy....................4
1.2
Investigator’s responsibility in ensuring evaluation and management of certain risk factors 
and complications ..........................................................................................................................4
1.3
Clarification of the criteria for completion, withdrawal and lost to follow-up..............................5
1.4
Week 26 reporting of trial results ..................................................................................................5
1.5
Clarification of insulin titration guideline......................................................................................5
1.6
Other minor adjustments, clarifications and correction of typographical errors............................5
1.6.1
Physical examination...................................................................................................5
1.6.2
Phrasing of background insulin medication.................................................................5
1.6.3
Rescue medication.......................................................................................................6
1.6.4
Statistical considerations..............................................................................................6
1.6.5
Reporting of technical complaints ...............................................................................6
1.6.6
Other ............................................................................................................................6
2
Changes......................................................................................................................................................7
2.1
Summary........................................................................................................................................7
2.2
Protocol title...................................................................................................................................7
2.3
Section 2 Flow chart ......................................................................................................................7
2.4
Section 4.2.2.4  Supportive secondary safety endpoints................................................................8
2.5
Section 5.1 Type of trial ................................................................................................................8
2.6
Section 5.2 Rationale for trial design.............................................................................................9
2.7
Section 5.3.3.4 Insulin titration guideline......................................................................................9
2.8
Section 6.6 Withdrawal from trial ...............................................................................................10
2.9
Section 8.1.4 End-of-treatment (visit 18) and Follow-up (visit 19).............................................10
2.10
Section 8.1.5 Premature discontinuation of trial product and follow-up (visits 18A and 
19A) .............................................................................................................................................11
2.11
Section 8.1.6.1 Lost to follow-up.................................................................................................11
2.12
Section 8.4.1.2  Adverse events requiring additional data collection..........................................12
2.13
Section 8.4.2  Physical examination ............................................................................................12
2.14
Section 8.4.4  Eye examination....................................................................................................13
2.15
Section 11 Randomisation procedure and breaking of blinded codes .........................................13
2.16
Section 12.1.5  Adverse events requiring additional data collection...........................................13
2.17
Section 12.1.6 Technical complaints ...........................................................................................13
2.18
Section 17 Statistical considerations............................................................................................13
2.19
Section 17.1 Sample size calculation...........................................................................................14
2.20
Section 17.2 Definition of analysis sets.......................................................................................14
2.21
Section 17.3.1 Primary analysis for the primary estimand ..........................................................14
2.22
Section 17.4.2.1 Efficacy endpoints (Binary efficacy endpoints)................................................15
2.23
Section 17.4.2.2 Safety endpoints................................................................................................15
2.24
Section 18.1 Benefit-risk assessment of the trial.........................................................................16
2.26
Appendix B, Section 1 Adverse events requiring additional data collection...............................17
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
22 November 2016
1RYR1RUGLVN
Trial ID: NN9924-4280
Version:
2.0
UTN: U1111-1180-3637
Status:
Final
EudraCT No.: 2016-000988-16
Page:
3 of 18
2.27
Appendix B, section 1.8.1 Assessments in case of suspicion of hypersensitivity reaction .........18
2.28
Appendix B, new section 1.4.1 Diabetic retinopathy ..................................................................18
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
22 November 2016
1RYR1RUGLVN
Trial ID: NN9924-4280
Version:
2.0
UTN: U1111-1180-3637
Status:
Final
EudraCT No.: 2016-000988-16
Page:
4 of 18
1
Introduction including rationale for the protocol amendment
This protocol amendment introduces: 
1. Additional eye examinations and additional data collection on diabetic retinopathy
2. Investigator’s responsibility in ensuring evaluation and management of certain risk factors and
complications
3. Clarification of the criteria for completion, withdrawal and lost to follow-up
4. Week 26 reporting of trial results
5. Other minor corrections and clarifications
1.1
Additional eye examinations and additional data collection on diabetic retinopathy 
Updated protocol Sections: 2, 4.2.2.4, 8.4.1.2, 8.4.4, 12.1.5, 17.2, 17.4.2.2, 18.1 and Appendix B.
Transient worsening of diabetic retinopathy is a recognised complication in selected patients with 
diabetes after initiation of intensive antidiabetic treatment50,51,52. 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. 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 placeboref  x1. 
The majority of the related adverse events were moderate in severity and did not lead to premature 
discontinuation of trial product. 
, additional eye examinations 
have been implemented in alltrials in the PIONEER programme. Also, to further understand this 
safety signal, additional information will be collected for all diabetic retinopathy events reported 
during the trial. The information will be collected not only from new subjects enrolled by the time 
of this amendment, but also from already enrolled subjects to the extent that the information is 
available.Furthermore, information to the investigators and subjects related to diabetic retinopathy 
has been added to the protocol (see Section 18) and the subject information. 
1.2
Investigator’s responsibility in ensuring evaluation and management of certain risk 
factors and complications
Updated protocol Section: 8.4.2, 8.4.4 and 18.1.
, text is added to highlight the investigator’s responsibility in 
relation to further evaluation of potential incidental thyroid nodules discovered at the physical 
examination.
In addition, text is added to highlight the investigator’s responsibility in ensuring evaluation and 
management of cardiovascular risk factors and microvascular complications such as diabetic kidney 
disease and diabetic retinopathy.
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
22 November 2016
1RYR1RUGLVN
Trial ID: NN9924-4280
Version:
2.0
UTN: U1111-1180-3637
Status:
Final
EudraCT No.: 2016-000988-16
Page:
5 of 18
1.3
Clarification of the criteria for completion, withdrawal and lost to follow-up
Updated protocol Sections: 6.6, 8.1.4, 8.1.5 and 8.1.6.1.
The criteria for subject completion, -withdrawal and -lost to follow-up respectively are clarified and 
have been made consistent across sections. Lost to follow-up is considered a subcategory to 
withdrawal from trial. In addition, it is emphasised that as soon as contact to a subject is lost, efforts 
must be made to regain contact and the efforts must continue until the subject’s 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
Week 26 reporting of trial results
Updated protocol sub-title and Sections: 1, 5.1, 5.2 and 17.
The protocol is revised to reflect that Novo Nordisk will not report data from the first 26 weeks of 
the trial in a separate interim clinical trial report (CTR). The trial will be blinded for investigators, 
subjects and Novo Nordisk throughout the trial.
1.5
Clarification of insulin titration guideline
Updated protocol Section: 5.3.3.4.
The protocol section on insulin titration is updated to accommodate guidance regarding subjects 
who may be included in the trial on a three times daily premixed insulin regimen. Also a minor 
revision of the wording regarding subjects on a basal and bolus insulin regimen is done. 
Furthermore, wording is added to the end of the section to underline that in the interest of subject 
safety, clinical judgement must always overrule the protocol titration guidelines if deemed 
necessary by the investigator.
1.6
Other minor adjustments, clarifications and correction of typographical errors
1.6.1
Physical examination
Updated protocol sub-title and Sections: 2, 4.2.2.4 and 17.4.2.2.
Physical examination will be performed at week 52 only.
1.6.2
Phrasing of background insulin medication
Updated protocol Sections: 5.1, 5.3.3.4, 11 and 17 and Protocol metadata template for consistency 
with inclusion criteria no. 5.
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
22 November 2016
1RYR1RUGLVN
Trial ID: NN9924-4280
Version:
2.0
UTN: U1111-1180-3637
Status:
Final
EudraCT No.: 2016-000988-16
Page:
6 of 18
1.6.3
Rescue medication
Updated protocol Section: 18.1 for alignment with Section 6.4.
1.6.4
Statistical considerations
Updated protocol Sections: 17.3.1 and 17.4.2.1.
For the pattern mixture model using multiple imputation, the number of imputations will be 
increased from 100 to 1000 data sets, to ensure a greater precision of the estimates. In addition, an 
error in the number of groups used for imputation is corrected.
1.6.5
Reporting of technical complaints
Updated protocol Section: 12.1.6.
1.6.6
Other
Updated protocol and appendix B for correction and clarification of minor typographical errors.
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
22 November 2016
1RYR1RUGLVN
Trial ID: NN9924-4280
Version:
2.0
UTN: U1111-1180-3637
Status:
Final
EudraCT No.: 2016-000988-16
Page:
7 of 18
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
Summary
This is a 52-week, randomised, double-blind, placebo-controlled, four-armed, parallel-group, 
multicentre, multinational trial, double-blinded during the initial 26 weeks after which the 
randomisation details will be revealed to selected Novo Nordisk personnel. Investigators and 
subjects will be blinded throughout the trial. The trial will compare the efficacy and safety of three 
dose levels of once-daily oral semaglutide versus placebo in subjects with type 2 diabetes mellitus 
treated with insulin. 
2.2
Protocol title
A 52-week, randomised, and double-blind, placebo-controlled trial, double-blinded during the 
initial 26 weeks
2.3
Section 2 Flow chart
Trial Periods
Scr
ee-
nin
ga
Ran-
dom
i-
satio
n
Treatment period 1
Fixed insulin treatment period 
Treatment period 2
Adjustable insulin 
treatment period 
En
d-
of-
trea
tme
nt 
Eo
T
Fol
-
low
-
upb
EoT
pre-
mat
ure  
disc
onti
nua-
tionc
Follo
w-up 
premat
ure 
discon
-
tinuati
onc
Visit (V), 
Phone (P)
V1
V2
P3
V4 V5 P6
P7
V8 P9 V10
V11 P12 V13 P14 V15P16 V17
V1
8
V1
9
V18
A
V19A
Timing of 
visit
(weeks)
up 
to
-2
0
2
4
8
1
0
1
2
1
4
1
6
2
0
2
6
2
9
3
2
3
5
3
8
4
1
4
5
52
57
Day 
of 
disc
onti
nuat
ion 
of 
trial 
prod
uct
5 
weeks 
after 
day of 
discon
tinuati
on of 
trial 
produc
t
Visit window
(days)
-7
±
3
±
3
±
3
±
3
±
3
±
3
±
3
±
3
±
3
±
3
±
3
±
3
±
3
±
3
±
3
±3
+3
+3
+3
SAFETY
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
22 November 2016
1RYR1RUGLVN
Trial ID: NN9924-4280
Version:
2.0
UTN: U1111-1180-3637
Status:
Final
EudraCT No.: 2016-000988-16
Page:
8 of 18
Eye 
examinationh
x
x
x
Physical 
examination
x
x
x
x
Footer
Description
xh
Fundus photography or 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 or dilated fundoscopy must be performed again:
!
at V18 or within 5 weeks thereafter for subjects completing treatment
!
at V18A or within 5 weeks thereafter, and again within 5 weeks prior to V18, for
subjects who have prematurely discontinued trial product
2.4
Section 4.2.2.4
Supportive secondary safety endpoints
Change from baseline to week 26 and 52 in:
!
Haematology
!
Biochemistry
!
Calcitonin
!
Pulse
!
Systolic blood pressure
!
Diastolic blood pressure
!
Electrocardiogram (ECG) category
!
Physical examination (week 52 only)
!
Eye examination category (week 52 only)
2.5
Section 5.1 Type of trial
This is a 52-week, randomised, double-blind, placebo-controlled, four-armed, parallel-group, 
multicentre, multinational trial, double-blinded during the initial 26 weeks.
Background insulin medication at screening:
!
Basal insulin
!
Basal and -bolus insulin in any combination alone
!
Premixed insulin including combinations of soluble insulins
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
22 November 2016
1RYR1RUGLVN
Trial ID: NN9924-4280
Version:
2.0
UTN: U1111-1180-3637
Status:
Final
EudraCT No.: 2016-000988-16
Page:
9 of 18
The first 26 weeks of the trial is double-blinded. Because the week 26 trial results will be reported 
before the trial is completed, the randomisation details will be revealed to selected Novo Nordisk 
personnel after all subjects have completed 26 weeks treatment. Following the end of trial, results 
from the entire trial period will be reported. Investigators and subjects will be blinded throughout 
the entire trial. All subjects consent to the full trial length when they sign the informed consent.
2.6
Section 5.2 Rationale for trial design
The trial has been designed as a parallel-group, four-armed placebo-controlled trial to ensure a 
direct comparison between three dose levels of oral semaglutide and placebo. Subjects will be 
randomised in a 1:1:1:1 manner between the four treatment arms and the trial will be double-
blinded throughout the trialfor the initial 26 weeks. The randomisation will be stratified based on 
descent and background metformin medication and background insulin medication at screening (see 
Section 11.1). The stratification is to ensure an even distribution of the four treatment arms within 
strata.
2.7
Section 5.3.3.4 Insulin titration guideline
Insulin titration should be based on the lowest of three self-measured plasma glucose (SMPG) 
values; preferably measured on three consecutive days prior to each phone contact/site visit and 
according to Table 5-2 and Table 5-3. The aim of the insulin titration should be to obtain a fasting 
plasma glucose level between 4.0 and 5.5 mmol/L (71-99 mg/dL) and an HbA1c level below 7.0% 
(53 mmol/mol).
In addition:
!
For subjects on once-daily basal insulin or once-daily premixed insulin including combinations
of soluble insulins regimens, titration should be based on the lowest of three fasting pre-
breakfast SMPG values taken after at least 6 hours of fasting.
!
For subjects on twice-daily basal or twice-daily premixed insulin including combinations of
soluble insulins regimens, titration should be done for each doseing separately:
o
The morning or lunch dose should be titrated based on the lowest of three pre-dinner
SMPG values
o
The evening dose should be based on the lowest of three fasting pre-breakfast fasting
SMPG values
!
For subjects on a regimen of three times daily premixed insulin including combinations of
soluble insulins, titration should be done for each dose separately:
o
The morning dose and the lunch dose should be titrated based on the lowest of three
pre-dinner SMPG values and, at the discretion of the investigator, possibly additional
measurements. For documentation purposes the prescribed morning and lunch doses
should be recorded in the eCRF as the sum of each.
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
22 November 2016
1RYR1RUGLVN
Trial ID: NN9924-4280
Version:
2.0
UTN: U1111-1180-3637
Status:
Final
EudraCT No.: 2016-000988-16
Page:
10 of 18
o
The evening dose should be titrated based on the lowest of three fasting pre-breakfast
fasting SMPG values
!
For subjects on a regimen of basal and -bolus insulin in any combination regimen, the basal
insulin should be adjusted as above, and the bolus insulin dose should be adjusted at the
discretion of the investigator, adhering to the restrictions specified in section 5.3.3.2.
It is recognised that the treatment differs between regions and countries. Likewise, specific 
guidelines are not applicable in certain clinical situations. It is therefore important that other 
information, such as symptoms of hypoglycaemia and /hyperglycaemia, previous response to dose 
adjustments and other indicators of the subject’s level of glycaemic control, is taken into 
consideration when decisions on dose changes are made. Clinical judgement has to be applied to 
avoid increased risk to the subject’s safety and must always overrule guidelines when deemed 
necessary by the investigator.
2.8
Section 6.6
Withdrawal from trial
The subject may withdraw consent at will at any time. The subject’s request to withdraw from the 
trial must always be respected. Only subjects who withdraw consent should be considered as 
withdrawn from trial. A subject who does not complete the trial is also considered withdrawn from 
the trial. Hence, a subject is considered withdrawn if the following applies: 
!
Subject withdrew consent
!
Subject is lost to follow up (only to be used if there is no contact with the subject by the time
of the subject’s last scheduled visit, see sections 8.1.4 - 8.1.6.1)
!
Other (subject deceased or closure of trial site)
2.9
Section 8.1.4
End-of-treatment (visit 18) and Follow-up (visit 19)
At V18, the subject should be reminded about the importance of attending the follow-up visit (V19). 
If the subject, nonetheless, does not attend V19, 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 V19. (For 
subjects who discontinue trial product, see Section 8.1.5) 
In case the subject cannot be reached (by clinic visit or phone contact) at the scheduled visit 19, the 
site should consult the contacts provided by the subject (e.g. close relatives), relevant physicians, 
medical records and locator agencies (if allowed according to local law) to collect health status. If 
no health status can be collected, the subject should be considered lost to follow up and this should 
be specified in the end-of-trial form.
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
22 November 2016
1RYR1RUGLVN
Trial ID: NN9924-4280
Version:
2.0
UTN: U1111-1180-3637
Status:
Final
EudraCT No.: 2016-000988-16
Page:
11 of 18
2.10
Section 8.1.5 Premature discontinuation of trial product and follow-up (visits 18A and 
19A)
Subjects should continue with the originally scheduled site contacts after visit V189A and up to and 
including visit V19 V18. If necessary, in order to retain the subject in the trial, site visits can be 
replaced by phone contacts after V189A. However, if a subject is unable or unwilling to attend all 
subsequent visit(s), the investigator should at least aim to have the subject attend V11 (week 26) 
and End-of-treatment (V18) (week 52) as these visits should be performed for all subjects, if at all 
possible (except subjects who withdraw informed consent, see Section 8.1.6). Subjects, who only 
agree to attend or provide health status at the planned V18, should not be considered withdrawn 
from the trial. In case the subject cannot be reached (by clinic visit or phone contact) at the 
scheduled V18, the site should consult the contacts provided by the subject (e.g. close relatives), 
relevant physicians, medical records and locator agencies (if allowed according to local law) to 
collect health status. If no health status can be collected, the subject should be considered lost to 
follow-up and this should be specified in the end-of-trial form.
A subject who prematurely discontinued trial product is still considered a trial completer if the 
subject attends or is in contact with the site, at the subject’s last scheduled visit. For subjects who 
prematurely discontinue trial product, the last scheduled visit is V18 (or V19A if it is scheduled 
after V18). The site should in due time prepare for establishing contact with the subject within the 
visit window of the scheduled V11 and V18, 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  informed consent from the trial (for withdrawal 
procedures, see Section 8.1.6).
2.11
Section 8.1.6.1
Lost to follow-up
In case contact to the subject is lost during the trial, the site should immediately undertake efforts to 
re-establish contact. If the subject cannot be reached (by clinic visit or phone contact) and the 
subject has consented to it, the site should consult the contacts provided by the subject (e.g. close 
relatives), relevant physicians, medical records and locator agencies (if allowed according to local 
law) in an attempt to regain contact with the subject or to obtain relevant safety information from 
other sources. Efforts to regain contact should continue until the end of the subject’s last scheduled 
visit: V19 for subjects who have completed treatment, whereas for subjects who have discontinued 
trial product prematurely the last visit is V18 (or V19A if it is scheduled after V18). 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). 
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
22 November 2016
1RYR1RUGLVN
Trial ID: NN9924-4280
Version:
2.0
UTN: U1111-1180-3637
Status:
Final
EudraCT No.: 2016-000988-16
Page:
12 of 18
2.12
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 (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
!
Lactic acidosis
!
Creatine kinase (CK) > 10x UNL
!
Hepatic event defined as:
o
ALT or AST > 5x UNL and total bilirubin ≤ 2x UNL
o
ALT or AST > 3x UNL and total bilirubin > 2x UNL*
o
Hepatic event leading to trial product discontinuation
!
Diabetic retinopathy and related complications
*Please note that in case of a hepatic event defined as aminotransferase (ALT) or aspartate
aminotransferase (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.
2.13
Section 8.4.2
Physical examination
A physical examination will be performed by the investigator according to local procedure (see 
Section 2 and 8.1.7). A physical examination must include:
!
General appearance
!
Head, ears, eyes, nose, throat, neck
!
Thyroid gland*
!
Respiratory system
!
Cardiovascular system
!
Gastrointestinal system including mouth
!
Musculoskeletal system
!
Central and peripheral nervous system
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
22 November 2016
1RYR1RUGLVN
Trial ID: NN9924-4280
Version:
2.0
UTN: U1111-1180-3637
Status:
Final
EudraCT No.: 2016-000988-16
Page:
13 of 18
!
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 update s hereofRef 3, and adapted to 
local treatment guidelines if applicable.
2.14
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 practice. Fundoscopy requires pharmacological dilation of 
both pupils.  Results of the fundus photography or dilated fundoscopy will be interpreted by the 
investigator (see Section 8.1.7).
2.15
Section 11 Randomisation procedure and breaking of blinded codes
Background insulin medication at screening:
!
Basal insulin
!
Basal and -bolus insulin in any combination
!
Premixed insulin including combinations of soluble insulins
2.16
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
2.17
Section 12.1.6 Technical complaints
Only technical complaints related to adverse events will be reported in the clinical trial report.  
2.18
Section 17 Statistical considerations
There will be a partial database lock performed when all subjects have completed the first 26 
weeks. After the entire 57 weeks a database lock will be performed. Data from the first 26 weeks 
will be reported separately before the entire trial is finalised. Data from the entire trial will be 
analysed and reported as a 57 week trial.
The blinding of the randomised treatments will be maintained until the database has been released 
for statistical analysis.
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
22 November 2016
1RYR1RUGLVN
Trial ID: NN9924-4280
Version:
2.0
UTN: U1111-1180-3637
Status:
Final
EudraCT No.: 2016-000988-16
Page:
14 of 18
The first 26 weeks of the trial is double-blinded. Because the week 26 trial results will be reported 
before the trial is completed, the randomisation details will be revealed to selected Novo Nordisk 
personnel after subjects have completed 26 weeks treatment. Following the end of trial, results from 
the entire trial period will be reported. Investigators and subjects will be blinded throughout the 
entire trial.
In statistical analyses where stratification is included, the background metformin medication at 
screening (metformin/no metformin) and background insulin medication (basal insulin/basal and-
bolus in any combination/premixed insulin including combinations of soluble insulins) will be 
included based on the actual information collected through the eCRF. 
2.19
Section 17.1 Sample size calculation
With the above assumptions, allocating 180 subjects to each of the oral semaglutide arms and the 
placebo arm provides 90% power to confirm HbA1c superiority of oral semaglutide vs. placebo at 
all dose levels. Calculated powers for individual hypotheses are presented in Table 17-2Figure 17-1. 
In total 4×180 = 720 subjects are planned to be randomised.
2.20
Section 17.2 Definition of analysis sets
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 (V19)
!
the follow-up prematurely discontinuation visit (V19A)
!
the last date on trial product +38 days
!
the end-date for the in-trial observation period
2.21
Section 17.3.1 Primary analysis for the primary estimand
Missing values for each group will be imputed as follows:
!
An analysis of covariance (ANCOVA) with region, stratification factors  and the interaction
between the stratification factors categorical fixed effects and baseline HbA1c measurement
as a covariate will be fitted to observed values of the change from baseline in HbA1c at week
26.
!
The estimated parameters for location and dispersion will be used to impute 100 1000 values
for each subject with missing week 26 data based on region, stratification factors, the
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
22 November 2016
1RYR1RUGLVN
Trial ID: NN9924-4280
Version:
2.0
UTN: U1111-1180-3637
Status:
Final
EudraCT No.: 2016-000988-16
Page:
15 of 18
interaction between the stratification factors and baseline HbA1c. Thus, 100 1000 complete 
data sets will be generated including observed and imputed values.
Analysis used for confirming superiority versus placebo at week 26:
For each of the 100 1000 (now complete) imputed data sets the change from baseline to week 26 in 
HbA1c will be analysed using an ANCOVA with treatment, stratification factors, the interaction 
between the stratification factors and region as categorical fixed effects and baseline HbA1c as 
covariate. The results obtained from analysing the datasets will be combined using Rubin’s rule46 to 
draw inference.
2.22
Section 17.4.2.1 Efficacy endpoints (Binary efficacy endpoints)
For evaluation of the primary estimand the analyses will be performed separately for week 26 and 
week 52. For the analysis at week 52, the imputation of missing data will be further differentiated 
by whether subjects have discontinued treatment or initiated rescue medication prior to week 26 or 
at/ or after week 26. This will result in imputation of missing data within 12 16 groups of subjects 
instead of the 8 groups as described for the week 26 evaluation in Section 17.3.1. If less than five 
subjects have available data in one of the 12 16 groups, the imputation will be made within the 8 
groups specified for the primary evaluation. The frequency of missing data is expected to be slightly 
larger at week 52 compared to week 26. The rate of missing data is expected to decline over time.
!
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
adherence/rescue status assuming MAR and as described in Section 17.3.1 for the primary
estimand and by treatment group assuming MAR and as described in Section 17.3.2 for the
secondary 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 rule46.
2.23
Section 17.4.2.2 Safety endpoints
Other safety endpoints
Change from baseline to week 26 and week 52 in:
!
Haematology
!
Biochemistry (except for amylase and lipase)
!
Calcitonin
!
ECG evaluation
!
Physical examination (week 52 only)
!
Eye examination category (week 52 only)
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
22 November 2016
1RYR1RUGLVN
Trial ID: NN9924-4280
Version:
2.0
UTN: U1111-1180-3637
Status:
Final
EudraCT No.: 2016-000988-16
Page:
16 of 18
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 17.212.7).
2.24
Section 18.1
Benefit-risk assessment of the trial
Othersafety considerations
Diabetic retinopathy complications
A transient worsening of diabetic retinopathy is a recognised complication in selected patients with 
diabetes after initiation of intensive antidiabetic treatment50,51,52. 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 progression53,54even in intensively treated patients who experienced early worsening51. 
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 placeboRefx1. 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 trialRef x2.
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 
glyacemica-related 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 Diabetes guidelines (excluding GLP-1 RAs, DPP-4 inhibitors and, amylin analogues and 
SGLT-2 inhibitors).
It is the responsibility of the investigator to ensure the best possible care of the subject. This 
includes adequate glycaemic control, appropriate risk factor modification such as optimal 
treatment of hypertension, dyslipidaemia and other cardiovascular risk factors, as well as regular 
monitoring and treatment of diabetic kidney disease and diabetic retinopathy (according to the 
principles outlined in Diabetes Care 2016 Standards of Medical Care in Diabetes)Refx2.
2.25
Section 27
References 
Reference numbers will change throughout the updated protocol when new references above are
introduced.
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
22 November 2016
1RYR1RUGLVN
Trial ID: NN9924-4280
Version:
2.0
UTN: U1111-1180-3637
Status:
Final
EudraCT No.: 2016-000988-16
Page:
17 of 18
New references added, see sections 8.4.2 and 18.1. New references in this amendment are marked 
with an x, i.e. Ref x1. The following references are new references:
1. Ref x1; 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.
2. Refx2 ; Diabetes Care. 2016;39 (Suppl. 1).
3. Refx3; 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
Two references are corrected:
39.
Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L et al: 
Hypoglycemia and Diabetes: A Report of a Workgroup of the American Diabetes 
Association and The Endocrine Society. Diabetes Care 2013; 36:1384-1395
McAulay V, Deary IJ, Frier BM. Symptoms of hypoglycaemia in people with 
diabetes. Diabet Med. 2001;18(9):690-705.
51
Hicks KA, Hung HMJ, Mahaffey KW, Mehran R, Nissen SE, Strockbridge NL, et al. 
Standardized Definitions for Cardiovascular and Stroke End Point Events in Clinical 
Trials (Draft). 20 Aug 2014.
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.
2.26
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
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
22 November 2016
1RYR1RUGLVN
Trial ID: NN9924-4280
Version:
2.0
UTN: U1111-1180-3637
Status:
Final
EudraCT No.: 2016-000988-16
Page:
18 of 18
!
Hypersensitivity reaction
!
Acute gallstone disease
!
Medication error
!
Lactic acidosis
!
Creatine kinase (CK) > 10x UNL
!
Hepatic event defined as:
o
ALT or AST > 5x UNL and total bilirubin ≤ 2x UNL
o
ALT or AST > 3x UNL and total bilirubin > 2x UNL*
o
Hepatic event leading to trial product discontinuation
!
Diabetic retinopathy and related complications
2.27
Appendix B, section 1.8.1 Assessments in case of suspicion of hypersensitivity reaction
To assist in the diagnostic evaluation it is recommended to draw a blood sample for measurement of 
tryptase (total and/or mature tryptase, local assessment) within 3 hours of onset of the 
hypersensitivity reaction, and if this is achieved, a tryptase sample should also be drawn at V149A. 
Furthermore, a blood sample for assessment of anti-semaglutide IgE antibodies should be drawn as 
soon as possible after the event and at V149A and sent to central laboratory. 
2.28
Appendix B, new section 1.4.1 Diabetic retinopathy
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
An updated protocol is prepared, which also includes amendment no. 1 for Canada. An updated 
master subject information/informed consent form is also prepared.
CONFIDENTIAL


Protocol Amendment No. 3
CONFIDENTIAL
Date:
15 May 2017
1RYR1RUGLVN
Trial ID: NN9924-4280
Version:
1.0
UTN:U1111-1180-3637
Status:
Final
EudraCT No.:2016-000988-16
Page:
1 of 5
Protocol Amendment
no 3
to Protocol, final version 3.0
dated 22 November 2016
Trial ID:NN9924-4280
PIONEER 8 – Insulin add-on
Efficacy and Safety of Oral Semaglutide versus Placebo in Subjects with Type 2 Diabetes Mellitus 
treated with Insulin
Trial phase: 3a
Applicable to all countries
Amendment originator:
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol Amendment No. 3
CONFIDENTIAL
Date:
15 May 2017
1RYR1RUGLVN
Trial ID: NN9924-4280
Version:
1.0
UTN:U1111-1180-3637
Status:
Final
EudraCT No.:2016-000988-16
Page:
2 of 5
Table of Contents  
Page
Table of Contents........................................................................................................................................2
1
Introduction including rationale for the protocol amendment...........................................................3
1.1
Correction in the Protocol flow chart at Visit 18A .....................................................................3
1.2
Correction in Section 8.1.5 of Protocol......................................................................................3
1.3
Correction Section 17.2 of Protocol...........................................................................................3
2
Changes ................................................................................................................................................4
2.1
Section 2 Flow chart..................................................................................................................4
2.2
Section 8.1.5 Premature discontinuation of trial product and follow up (Visit 18A and 19A)......5
2.3
Section 17.2 Definition of analysis sets .....................................................................................5
CONFIDENTIAL


Protocol Amendment No. 3
CONFIDENTIAL
Date:
15 May 2017
1RYR1RUGLVN
Trial ID: NN9924-4280
Version:
1.0
UTN:U1111-1180-3637
Status:
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EudraCT No.:2016-000988-16
Page:
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1
Introduction including rationale for the protocol amendment
The protocol amendment introduces:
1. Correction in the protocol flow chart at Visit 18A
2. Correction in Section 8.1.5 of protocol
3. Correction in Section 17.2 of protocol
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
1.1
Correction in the Protocol flow chart at Visit 18A
The 7-point SMPG profile was mistakenly missing from visit 18A. The flow chart has been updated 
to include the 7-point SMPG profile at visit 18A.
1.2
Correction in Section 8.1.5 of Protocol
Typographical error has been corrected wherein Visit 18A is corrected to Visit 19A
1.3
Correction Section 17.2 of Protocol
In protocol amendment no 2 dated 22 November 2016, an “Eye Examination Category” was 
mistakenly not included in section 17.2 “Definition of analysis sets”. The “Eye Examination 
Category” is therefore now included in the on-treatment section.
CONFIDENTIAL


Protocol Amendment No. 3
UTN:U1111-1180-3637
Date:
15 May 2017
Status:
Final
1RYR1RUGLVN
Trial ID: NN9924-4280
EudraCT No.:2016-000988-16
Version:
1.0
Page:
4 of 5
2
Changes
2.1
Section 2 Flow chart
Trial Periods
Scree-
ninga
Ran-
domi-
sation
Treatment period 1
Fixed insulin treatment period 
Treatment period 2
Adjustable insulin treatment period 
End-
of-
treatme
nt EoT
Fol-
low-
upb
EoT pre-
mature  
discontin
ua-tionc
Follow-up 
premature 
discon-
tinuationc
Visit (V), Phone (P)
V1
V2
P3
V4
V5
P6
P7
V8
P9
V10
V11
d
P1
2
V1
3
P1
4
V1
5
P1
6
V1
7
V18
V19
V18A
V19A
Timing of visit
(weeks)
up to
-2
0
2
4
8
10
12
14
16
20
26
29
32
35
38
41
45
52
57
Day of 
discontin
uation of 
trial 
product
5 weeks after 
day of 
discontinuatio
n of trial 
product
Visit window
(days)
-7
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+3
+3
+3
SUBJECT RELATED
INFO/ASSESS-MENTS
EFFICACY
7-point profilef
x
x
x
x


Protocol Amendment No. 3
CONFIDENTIAL
Date:
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Trial ID: NN9924-4280
Version:
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EudraCT No.:2016-000988-16
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2.2
Section 8.1.5 Premature discontinuation of trial product and follow up (Visit 18A and 
19A)
Subjects should continue with the originally scheduled site contacts after V18 19A and up to and 
including V18. If necessary, in order to retain the subject in the trial, site visits can be replaced by 
phone contacts after V18 19A. However, if a subject is unable or unwilling to attend all subsequent 
visit(s), the investigator should at least aim to have the subject attend V11 (week 26) and End-of-
treatment (V18) (week 52) as these visits should be performed for all subjects, if at all possible 
(except subjects who withdraw informed consent, see Section 8.1.6. 
2.3
Section 17.2 Definition of analysis sets
On-treatment: This observation period represents the time period where subjects are considered 
treated with the trial product. The observation period is a subset of the in-trial observation period. It 
starts at the date of first dose of trial product. Two slightly different end dates will be needed to 
cover all assessments appropriately. For adjudicated events, ECGs, Eye Examination Category and 
AEs including hypoglycaemic episodes, the observation period ends at the first date of any of the 
following:
!
The follow-up visit (V19)
!
The follow-up prematurely discontinuation visit (V19A)
!
The last date on trial product + 38 days
!
The end-date for the in-trial observation period
CONFIDENTIAL

SAP_001.pdf: 
Cover Page for Statistical analysis plan 
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT03021187 
Sponsor trial ID: 
NN9924-4280 
Official title of study: 
PIONEER 8 – Insulin add-on 
Efficacy and Safety of Oral Semaglutide versus Placebo in 
Subjects with Type 2 Diabetes Mellitus treated with insulin A 
52-week, randomised, double-blind, placebo-controlled trial 
Document date: 
08 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: NN9924-4280
Clinical Trial Report
Appendix 16.1.9
)HEUXDU\

)LQDO
16.1.9 Documentation of statistical methods
CONFIDENTIAL
Redacted VWDWLVWLFDODQDO\VLVSODQ 
Includes redaction of personal identifiable information only. 
. 


Statistical Analysis Plan
CONFIDENTIAL
Date:
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Trial ID: NN9924-4280
Version:
1.0
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EudraCT No.: 2016-000988-16
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Statistical Analysis Plan
Trial ID: NN9924-4280
PIONEER 8 – Insulin add-on
Efficacy and Safety of Oral Semaglutide versus Placebo 
in Subjects with Type 2 Diabetes Mellitus treated with insulin
A 52-week, randomised, double-blind, placebo-controlled trial
Trial phase: 3a
Author
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Statistical Analysis Plan
CONFIDENTIAL
Date:
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Trial ID: NN9924-4280
Version:
1.0
UTN: U1111-1180-3637
Status:
Final
EudraCT No.: 2016-000988-16
Page:
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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..........................................................................................5
2
Statistical considerations .....................................................................................................................7
2.1
Sample size calculation .............................................................................................................9
2.2
Definition of analysis sets........................................................................................................10
2.3
Primary endpoint.....................................................................................................................15
2.3.1
Primary analysis for the treatment policy estimand.................................................15
2.3.2
Primary analysis for the hypothetical estimand.......................................................16
2.3.3
Sensitivity analyses................................................................................................16
2.3.3.1
Pattern mixture models.....................................................................17
2.3.3.2
Assessment of sensitivity analyses....................................................17
2.4
Secondary endpoints ...............................................................................................................18
2.4.1
Confirmatory secondary endpoints.........................................................................18
2.4.2
Supportive secondary endpoints .............................................................................18
2.4.2.1
Efficacy endpoints............................................................................18
2.4.2.2
Safety endpoints...............................................................................24
2.4.2.3
Pharmacokinetic endpoints...............................................................28
2.5
Interim analysis.......................................................................................................................28
2.6
Pharmacokinetic and/or pharmacodynamic modelling .............................................................28
2.7
Patient reported outcomes .......................................................................................................28
2.7.1
SF-36v2® (acute version) health survey.................................................................29
2.7.2
Impact of Weight on Quality of Life Clinical Trials Version (IWQOL-Lite-CT).....31
2.7.3
Diabetes Treatment Satisfaction Questionnaire – status version (DTSQs)...............33
2.7.4
Responder analyses................................................................................................34
3
Changes to the statistical analyses planned in the protocol..............................................................35
4
References ..........................................................................................................................................37
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
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Trial ID: NN9924-4280
Version:
1.0
UTN: U1111-1180-3637
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EudraCT No.: 2016-000988-16
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List of abbreviations
AACE
American Association of Clinical Endocrinologists
ADA
American Diabetes Association
AE
adverse event
ANCOVA
analysis of covariance
BG
blood glucose 
BMI
body mass index
BP
bodily pain
CRF
case report form
CTR
clinical trial report
DTSQs
diabetes treatment satisfaction questionnaire – status version
EAC 
event adjudication committee
ECG 
electrocardiogram
eCRF
electronic case report form
EOT
end-of-treatment
FAS 
full analysis set
FPG 
fasting plasma glucose
GH
general health
gMCP 
graph based multiple comparison procedure
HbA1c
glycosylated haemoglobin
HDL
high-density lipoprotein
HRQoL
health-related quality of life
IWQOL-Lite-CT 
impact of weight on quality of life clinical trials version
IWRS
interactive web response system
LDL
low-density lipoprotein
LLoQ
lower limit of quantification
LOCF
last observation carried forward
MAR
missing at random
MCMC
Markov Chain Monte Carlo
MCS
mental component summary
MedDRA
Medical Dictionary for Regulatory Activities
MH
mental health
MI 
multiple imputation
MMRM 
mixed model for repeated measurements
NBS 
norm-based score
PCS
physical component summary
PF
physical functioning
PG
plasma glucose
PIONEER
Peptide InnOvatioN for Early diabEtes tReatment
PK
pharmacokinetics
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
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Novo Nordisk
Trial ID: NN9924-4280
Version:
1.0
UTN: U1111-1180-3637
Status:
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EudraCT No.: 2016-000988-16
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PRO
patient reported outcomes
RP
role physical
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
TE
treatment effect
TEAE 
treatment-emergent adverse events
US
United States
VT
vitality
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
25 September 2018
Novo Nordisk
Trial ID: NN9924-4280
Version:
1.0
UTN: U1111-1180-3637
Status:
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EudraCT No.: 2016-000988-16
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1
Introduction
1.1
Trial information
This is a 52-week, randomised, double-blind, placebo-controlled, four-armed, parallel-group, 
multicentre, multinational trial. The trial will compare the efficacy and safety of three dose levels of 
once-daily oral semaglutide versus placebo in subjects with type 2 diabetes mellitus (T2DM) treated 
with insulin.
Primary objective
To compare the effect of once-daily dosing of three dose levels of oral semaglutide (3, 7 and 14 mg) 
versus placebo on glycaemic control in subjects with T2DM treated with insulin.
Secondary objectives
To compare the effect of once-daily dosing of three dose levels of oral semaglutide (3, 7 and 14 mg) 
versus placebo on body weight in subjects with T2DM treated with insulin.
To compare the safety and tolerability of once-daily dosing of three dose levels of oral semaglutide 
(3, 7 and 14 mg) versus placebo in subjects with T2DM treated with insulin.
Trial design
Subjects will be randomised 1:1:1:1 manner to receive one of the following treatments:
!
3 mg oral semaglutide once-daily
!
7 mg oral semaglutide once-daily
!
14 mg oral semaglutide once-daily
!
placebo once-daily
The total trial duration for the individual subject will be approximately 59 weeks. The trial includes 
a 2-week screening period followed by a 52-week randomised treatment period and a 5-week 
follow-up period. The 52-week randomised treatment period is split into two treatment periods; an 
initial 26-week period where the insulin treatment is restricted followed by a 26-week period where 
the insulin treatment is adjustable without any restrictions. For further details, see the trial protocol.
1.2
Scope of the statistical analysis plan
This statistical analysis plan (SAP) is based on the protocol for trial NN9924-4280 “Efficacy and 
Safety of Oral Semaglutide versus Placebo in Subjects with T2DM treated with insulin”, version 4.0 
(15 May 2017) as well as the Original protocol, version 1.0 (19 August 2016), the Protocol 
amendment no. 1, version 1.0 (06 October 2016), Protocol amendment no. 2, version 2.0 (22 
November 2016), Protocol amendment no. 3, version 3.0 (15 May 2017).
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
25 September 2018
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Trial ID: NN9924-4280
Version:
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UTN: U1111-1180-3637
Status:
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EudraCT No.: 2016-000988-16
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This SAP 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 within 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. 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
25 September 2018
Novo Nordisk
Trial ID: NN9924-4280
Version:
1.0
UTN: U1111-1180-3637
Status:
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EudraCT No.: 2016-000988-16
Page:
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2
Statistical considerations
General considerations
The blinding of the randomised treatments will be maintained until the database has been released 
for statistical analysis. No interim analyses 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 background metformin medication at 
screening (metformin/no metformin) and background insulin medication (basal insulin/basal and 
bolus in any combination/premixed insulin including combinations of soluble insulin(s)) will be 
included based on the actual information collected through the electronic case report form (eCRF). 
In case of missing eCRF information the information collected from the interactive web response 
system (IWRS) will be used. The information regarding descent (Japanese/non-Japanese) will be 
included based on country details from the IWRS. In the statistical analyses, stratification factors 
refer to the background metformin medication at screening and the background insulin medication 
at screening. Descent (Japanese/non-Japanese) will be included in the statistical analyses as part of 
region. The regions are Europe, North America, South America and Asia.
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.
Results from a statistical analysis will as a minimum be presented by the estimated treatment 
contrasts for the below three 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 7 mg vs. placebo
!
Oral semaglutide 3 mg vs. placebo
If no statistical analysis is specified, data will be presented using relevant summary statistics.
The two different estimands defined below will be used for the evaluation of the efficacy endpoints.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
25 September 2018
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Trial ID: NN9924-4280
Version:
1.0
UTN: U1111-1180-3637
Status:
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EudraCT No.: 2016-000988-16
Page:
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Primary and secondary estimands
Two estimands addressing different aspects of the primary trial objective will be defined as follows: 
!
Primary estimand – ‘Treatment policy’
o
treatment difference (oral semaglutide versus placebo) at week 26 for all randomised 
subjects regardless of adherence to randomised treatment and initiation of rescue 
medication
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 
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 treatment adherence 
reflects the behaviour of the target population. Accordingly, data collected regardless of 
discontinuation of trial product or initiation of rescue medication(s) will be used to draw inference.
!
Secondary estimand –‘Hypothetical’ 
o
treatment difference (oral semaglutide versus placebo) at week 26 for all randomised 
subjects if all subjects adhered to treatment and did not initiate rescue medication
The hypothetical estimand assesses the glycaemic benefit a future subject is expected to achieve if 
initiating and continuing treatment with oral semaglutide. It is considered a clinically relevant 
estimand as it provides information to treating clinicians about the expected glycaemic efficacy of 
oral semaglutide for purposes of treating individual subjects. Generalisation of this estimand 
depends among other things on the extent to which the adherence to trial product administration in 
this trial reflects the behaviour of the target population. Accordingly, only data collected prior to 
discontinuation of trial product or initiation of rescue medication will be used to draw inference. 
This will avoid confounding from rescue medication.
Analogously, two estimands are defined for the remaining secondary endpoints.
Missing data considerations at week 26
When estimating the treatment policy estimand, the proportion of missing data, i.e. data that do not 
exist even though subjects are intended to stay in the trial regardless of treatment status and 
initiation of rescue medication is expected to be a 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 hypothetical estimand, the proportion of subjects with missing data is expected 
to be higher (20%) since data collected after discontinuation of trial product or initiation of rescue 
medication(s) will be set to missing. The proportion of 20% is based on the oral semaglutide phase 
2 trial (NN9924-3790), that indicates that a low starting dose with gradual dose escalation 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
25 September 2018
Novo Nordisk
Trial ID: NN9924-4280
Version:
1.0
UTN: U1111-1180-3637
Status:
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EudraCT No.: 2016-000988-16
Page:
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diminishes gastrointestinal adverse events (AEs) compared with more aggressive dosing regimens. 
Across treatment arms the main reasons for missing data are expected to be early treatment 
discontinuation due to gastrointestinal AEs and eventually initiation of rescue medication. Initiation 
of rescue medication is expected to be more frequent in the placebo arm and in the oral semaglutide 
3 mg arm than for the two highest dose levels of oral semaglutide. A higher proportion of subjects 
are expected to discontinue treatment due to AEs in the oral semaglutide 14 mg arm, compared to 
the other treatment arms. So overall the frequency of missing data is expected to be similar across 
treatment arms.
Descriptive summaries and graphical representation of extent, reason(s) for and pattern of missing 
data will be presented by treatment arm.
2.1
Sample size calculation
Both the primary endpoint, change from baseline to week 26 in HbA1c and the confirmatory 
secondary endpoint, change from baseline to week 26 in body weight are planned to be tested for 
superiority of oral semaglutide vs. placebo at each dose level (3 mg, 7 mg, and 14 mg).
The sample size calculation is made to ensure a power of at least 90% to jointly confirm HbA1c
superiority of oral semaglutide vs. placebo at each dose level out of the six pre-specified 
confirmatory hypotheses shown in Table 2-2. The closed testing procedure described in Bretz et al1. 
is used to control the overall type I error at a nominal two-sided 5% level. The statistical testing 
strategy is built on the following two principles:
!
Within a dose level, glycaemic effect must be established in terms of HbA1c superiority 
before testing for added benefits in terms of body weight superiority.
!
Glycaemic effect in terms of HbA1c superiority must be established on all higher dose levels 
before continuing testing hypotheses on lower dose levels.
The sample size is calculated using the calcPower function in the R package graph based multiple 
comparison procedure (gMCP)2 using 10000 simulations. All of the six pre-specified confirmatory 
tests are assumed to be independent. Since some of the tests are positively correlated, the 
assumption of independence is viewed as conservative.
The sample size assumptions for treatment effects (TE), adjusted TE and the standard deviations are 
given 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).
Since the equalising effect of rescue medication will be included in the primary analysis as well as a 
conservative approach for handling of missing data will be performed, an adjustment in TE will be 
implemented for the 10% of subjects who are expected to discontinue trial product or initiate rescue 
medication and for the 10% of subjects who are expected to have actual missing data. The TE used 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
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Trial ID: NN9924-4280
Version:
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UTN: U1111-1180-3637
Status:
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EudraCT No.: 2016-000988-16
Page:
10 of 37
in the sample size calculation will be adjusted according to a 75% smaller effect in these subjects. 
The adjusted TE for testing superiority is defined as 0.8×TE + 0.2×TE×0.25.
Table 2-1
Assumptions used in the sample size calculation
Oral semaglutide vs. placebo
HbA1c
Body weight
Treatment dose
14 mg
7 mg
3 mg
14 mg
7 mg
3 mg
Treatment effect (TE)
-0.8%-points
-0.60%-points
-0.45%-points
-3.0 kg
-2.0 kg
-1.0 kg
Adjusted TE, superiority
-0.68%-points -0.51%-points
-0.38%-points
-2.55 kg
-1.70 kg
-0.85 kg
Standard deviation
1.1%s
1.1%s
1.1%
4.0 kg
4.0 kg
4.0 kg
With the above assumptions, allocating 180 subjects to each of the oral semaglutide arms and the 
placebo arm provides 90% power to confirm HbA1c superiority of oral semaglutide vs. placebo at 
all dose levels. Calculated powers for individual hypotheses are presented in Table 2-2. In total 
4×180 = 720 subjects are planned to be randomised.
Table 2-2
Calculated powers for individual hypotheses
Statistical test
HbA1c superiority
Body weight superiority
Treatment dose
14 mg
7 mg
3 mg
14 mg
7 mg
3 mg
Power (%)
> 99
99
90
> 99
96
47
2.2
Definition of analysis sets
The following analysis sets will be defined:
Full analysis set (FAS): Includes all randomised subjects. Subjects in the FAS will contribute to 
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 they were on treatment. 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 (V19) for subjects on trial product
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
25 September 2018
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Trial ID: NN9924-4280
Version:
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UTN: U1111-1180-3637
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EudraCT No.: 2016-000988-16
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!
The latest occurring visit of the end-of-treatment (EOT) visit (V18) or the follow-up 
premature discontinuation visit (V19A), 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 the trial product. The observation period is a subset of the in-trial observation period. It 
starts at the date of first dose of trial product. Two slightly different end dates will be needed to 
cover all assessments appropriately. For adjudicated events, ECGs, Eye Examination Category and 
AEs including hypoglycaemic episodes, the observation period ends at the first date of any of the 
following:
!
The follow-up visit (V19)
!
The follow-up prematurely discontinuation visit (V19A)
!
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: NN9924-4280
Version:
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UTN: U1111-1180-3637
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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 end date is 
the first date of any of the following:
!
The last dose of trial product + 3 days
!
Initiation of rescue medication
The in-trial observation period will be the primary observation period for estimating the treatment 
policy estimand. The on-treatment without rescue medication observation period will be the 
primary observation period when estimating the hypothetical 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 event adjudication committee (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 and in-trial period. 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 (CTR).
Confirmatory hypotheses
For the primary HbA1c endpoint and the confirmatory secondary body weight endpoint the 
following confirmatory one-sided hypotheses are planned to be tested at each dose level of oral 
semaglutide versus placebo. Let the mean treatment difference be defined as μ = (oral semaglutide 
minus placebo):
!
HbA1c superiority
H0: μ ≥ 0.0 %-point against HA: μ < 0.0 %-point
!
Body weight superiority
H0: μ ≥ 0.0 kg against HA: μ < 0.0 kg
Operationally the hypotheses will be evaluated by two-sided tests at the 5% significance level.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
25 September 2018
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Trial ID: NN9924-4280
Version:
1.0
UTN: U1111-1180-3637
Status:
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EudraCT No.: 2016-000988-16
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Multiplicity and criteria for confirming hypotheses
The type I error for testing the six confirmatory hypotheses related to the HbA1c and body weight 
endpoints will be preserved in the strong sense at 5% (two-sided) using the weighted Bonferroni-
based closed testing procedure described in Bretz et al.1 and outlined in Figure 2-1.
The first hypothesis to be tested is superiority of HbA1c at the highest dose level. It will be tested at 
the overall significance level (5%) while allocating 0% local significance level to the remaining of 
the hypotheses. For this hypothesis, and in general, if a hypothesis is confirmed, then the 
significance level will be reallocated according to the weight and the direction of the edges going 
from the confirmed hypothesis to the next hypotheses as specified in Figure 2-1. Each of the 
following hypotheses will be tested at their updated local significance level (α-local). This process 
will be repeated until no further hypotheses can be confirmed.
Superiority will be considered confirmed if the mean treatment difference is supporting the 
corresponding alternative hypothesis and the two-sided p-value from the primary analysis of the 
treatment policy estimand is strictly below its local two-sided significance level as defined by the 
closed testing procedure in Figure 2-1. This is equivalent to using a one-sided p-value (nominal 
α = 0.025) and a one-sided 2.5% overall significance level in the closed testing procedure.
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Statistical Analysis Plan
CONFIDENTIAL
Date:
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Trial ID: NN9924-4280
Version:
1.0
UTN: U1111-1180-3637
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EudraCT No.: 2016-000988-16
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Figure 2-1
Graphical illustration of the closed testing procedure
The overall significance level of α = 0.05 (two-sided) is initially allocated to the HbA1c superiority test on the highest 
dose level. The local significance level (α-local) will be reallocated if a hypothesis is confirmed according to the weight 
given by the directed edges between nodes (hypotheses). The sample size is based on the hypotheses in the dark boxes.
 = 0.05
HbA1c (%-point)
Superiority
 = 0
Body weight (kg)
Superiority
 = 0
HbA1c (%-point)
Superiority
1 2
⁄
1 2
⁄
1
 = 0
Body weight (kg)
Superiority
 = 0
HbA1c (%-point)
Superiority
1 2
⁄
1 2
⁄
1
 = 
Body weight (kg)
Superiority
1
Oral semaglutide 7 mg
vs. placebo
Oral semaglutide 3 mg
vs. placebo
Oral semaglutide 14 mg
vs. placebo
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
25 September 2018
Novo Nordisk
Trial ID: NN9924-4280
Version:
1.0
UTN: U1111-1180-3637
Status:
Final
EudraCT No.: 2016-000988-16
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2.3
Primary endpoint
The primary endpoint is change from baseline to week 26 in HbA1c.
2.3.1
Primary analysis for the treatment policy estimand
The treatment policy estimand will be estimated based on the FAS using week 26 measurements 
from the in-trial observation period. The primary statistical analysis will be a pattern mixture model 
using multiple imputation (MI) 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 8 groups of subjects defined by randomised treatment arm, and 
whether subjects at week 26; (i) have discontinued treatment or initiated rescue medication or (ii) 
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 region, stratification factors and the interaction 
between the stratification factors as categorical fixed effects and baseline HbA1c
measurement as a covariate will be fitted to observed values of the change from baseline in 
HbA1c at week 26. 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
region
o
interaction between stratification factors
o
stratification factors
!
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. 
Thus, 1000 complete data sets will be generated including observed and imputed values.
Analysis used for confirming superiority versus placebo at week 26:
For each of the 1000 (now complete) imputed data sets the change from baseline to week 26 in 
HbA1c will be analysed using an ANCOVA with treatment, region, stratification factors and the 
interaction between the stratification factors as categorical fixed effects and base line HbA1c as 
covariate. The results obtained from analysing the datasets will be combined using Rubin’s rule3 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% confidence intervals and unadjusted 
two-sided p-values for testing no difference from zero will be presented.
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Statistical Analysis Plan
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Date:
25 September 2018
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Trial ID: NN9924-4280
Version:
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UTN: U1111-1180-3637
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2.3.2
Primary analysis for the hypothetical estimand
The hypothetical 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 primary analysis for the hypothetical estimand will be 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, region,
stratification factors and the interaction between the stratification factors as categorical fixed effects 
and baseline HbA1c as a covariate, all nested within visit. An unstructured covariance matrix for 
HbA1c measurements within the same subject will be employed, assuming measurements from 
different subjects are independent.
For subjects who 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.
From this model the estimated treatment contrasts (each oral semaglutide dose vs. placebo) will be 
presented together with 95% CIs and p-values.
The MMRM is a well-established method that accounts for the uncertainty pertaining to missing 
data. This analysis assumes that the missing data mechanism is MAR. Under this assumption the 
statistical behaviour of the missing data (given the observed responses and model fixed effects and 
covariates) is assumed to be same as the observed data. 
2.3.3
Sensitivity analyses
To investigate the robustness of the primary analysis results, complementary and separate analyses 
will be performed for the treatment policy and hypothetical estimand. In line with EMA 
recommendations4 and with a report from the United States (US) National Research Council5, these 
analyses will primarily evaluate the sensitivity of the results due to the impact of missing data. 
The robustness of the results from the primary analysis is assessed through the following sensitivity 
analyses.
Sensitivity analyses for the treatment policy estimand
The estimation of the treatment policy estimand will be repeated using the following sensitivity 
analyses:
!
A comparator MI analysis based on FAS using the in-trial observation period
!
A comparator MI analysis differentiating between reasons for discontinuing treatment 
prematurely based on FAS using the in-trial observation period
!
A tipping-point MI analysis based on FAS using the in-trial observation period
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Statistical Analysis Plan
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Date:
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Trial ID: NN9924-4280
Version:
1.0
UTN: U1111-1180-3637
Status:
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EudraCT No.: 2016-000988-16
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Sensitivity analysis for the hypothetical estimand
The estimation of the hypothetical estimand will be repeated using the following sensitivity 
analysis:
A tipping-point MI analysis based on FAS using the on-treatment without rescue medication 
observation period.
2.3.3.1
Pattern mixture models
Common for the three pattern mixture model sensitivity analyses is that they all aim to stress-test 
the primary HbA1c results by changing the assumptions for part of or all of the missing data in the 
oral semaglutide treatment arms, while maintaining the MAR data assumption for the placebo arm:
!
Comparator MI analysis: In this sensitivity analysis missing data at week 26 for all subjects 
will be imputed to resemble the distribution of the week 26 values observed in the placebo 
treatment arm. In effect this imputation approach removes the treatment difference between 
oral semaglutide and placebo for all subjects randomised to oral semaglutide, given that oral 
semaglutide is better than placebo.
!
Comparator MI analysis differentiating between reasons for discontinuing treatment 
prematurely: In this sensitivity analysis only missing data at week 26 for subjects who 
discontinue oral semaglutide treatment due to treatment related AEs will be imputed to 
resemble the distribution of the week 26 values observed in the placebo treatment arm. 
Treatment related AEs are defined as AEs classified as having a possible or probable 
relationship to the trial product as reported by the investigator. In effect this imputation 
approach removes the treatment difference between oral semaglutide and placebo for this 
selected group of subjects randomised to oral semaglutide.
!
Tipping-point MI analysis: In this sensitivity analysis, missing data will first be imputed 
according to the primary analysis for the treatment policy estimand, whereas for the 
hypothetical estimand imputation will be done as described below for the binary endpoints 
(see Section 2.4.2.1). Secondly, for all oral semaglutide treatment arms a penalty will be 
added to the imputed values at week 26. The approach is to gradually increase this penalty 
until all confirmed HbA1c conclusions from the primary analysis are reversed. For each 
hypothesis tested the specific value of the penalty that reverses the conclusion will be used 
to evaluate the robustness of the primary analysis results. 
2.3.3.2
Assessment of sensitivity analyses
The results from the sensitivity analyses will be collectively used to interpret the robustness of the 
trial results for HbA1c. Due to sensitivity analyses inherent conservative nature, it will not be a 
requirement that all confirmatory hypotheses are consistently confirmed across the sensitivity 
analyses. Thus, no absolute success criteria will be pre-defined for each sensitivity analysis. The 
sensitivity results in totality will be used to substantiate the credibility of the trial results.
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Statistical Analysis Plan
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Trial ID: NN9924-4280
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2.4
Secondary endpoints
2.4.1
Confirmatory secondary endpoints 
Change from baseline to week 26 in body weight (kg) will be a confirmatory secondary endpoint. 
The treatment policy and hypothetical estimands will be estimated using the same approaches as 
described for the primary HbA1c endpoint. Baseline body weight will be used as a covariate instead 
of baseline HbA1c in both the MI and MMRM analysis models. 
Superiority will be considered confirmed if the mean treatment difference is supporting the 
corresponding hypothesis and the two-sided p-value from the analysis of the treatment policy 
estimand is strictly below its local two-sided significance level resulting from the closed testing 
procedure in Table 2-1. Sensitivity analyses similar to the ones pre-specified for the primary HbA1c
endpoint will be made to evaluate the robustness of the body weight results.
2.4.2
Supportive secondary endpoints
2.4.2.1
Efficacy endpoints
The below supportive secondary efficacy endpoints will be evaluated for:
!
The treatment policy estimand based on FAS using the in-trial observation period
!
The hypothetical estimand based on FAS using the on-treatment without rescue medication 
observation period
No sensitivity analyses are planned for these supportive secondary efficacy endpoints.
Continuous efficacy endpoints
Change from baseline to week 52 in:
!
HbA1c
!
Body weight (kg)
Change from baseline to week 26 and week 52 in:
!
Fasting plasma glucose (FPG)
!
Body weight (%)
!
Body mass index (BMI)
!
Waist circumference
!
Fasting lipid profiles (total cholesterol, low-density lipoprotein (LDL) cholesterol, high-
density lipoprotein (HDL) cholesterol, triglycerides)
!
Total daily insulin dose (IU)
!
Patient reported outcomes (PROs) (see Section 2.7 for further details)
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Statistical Analysis Plan
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BMI will be calculated based on body weight and height based on the formulae:
BMI kg/m2 = body weight (kg)/(height (m) × height (m)) or (kg/m2 = [lb/in2 × 703])
Change from baseline to week 26 and week 52 in the below derived endpoints from the self-
measured plasma glucose (SMPG) 7-point 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. All endpoints, except
HbA1c, body weight, FPG, BMI, waist circumference and endpoints related to 7-point SMPG 
profile and PROs, will be log-transformed prior to analysis with the associated log-transformed 
baseline value as a covariate.
For evaluation of the treatment policy estimand the analyses will be performed separately for week 
26 and week 52. For the analysis at week 52, the imputation of missing data will be further 
differentiated by whether subjects have discontinued treatment or initiated rescue medication prior 
to week 26 or at/after week 26. This will result in imputation of missing data within 12 groups of 
subjects instead of the 8 groups as described for the week 26 evaluation in Section 2.3.1.If data are 
too sparse to fit the model in all 12 groups then the imputation will be done without differentiating 
by time of discontinuation of trial product or initiation of rescue medication in the same way as 
specified for the primary evaluation. The frequency of missing data is expected to be slightly larger 
at week 52 compared to week 26. The rate of missing data is expected to decline over time.
For evaluation of the hypothetical estimand the MMRM based primary analysis will include all 
scheduled post-baseline measurement up to and including week 26 (or up to and including week 52 
for change from baseline to week 52 endpoints). From this model the estimated treatment contrasts 
at week 26 (or at week 52 for change from baseline to week 52 endpoints) will be presented with 
95% confidence intervals and two-sided p-values for test of no difference. For endpoints where the 
first planned visit falls later than 8 weeks after randomisation, the baseline will not be carried 
forward.
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 and after week 52 achieves (yes/no): 
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!
HbA1c < 7.0 % (53 mmol/mol) (American Diabetes Association (ADA) target)
!
HbA1c ≤ 6.5 % (48 mmol/mol) (American Association of Clinical Endocrinologists (AACE) 
target)
!
Body weight loss ≥ 5 %
!
Body weight loss ≥ 10 %
!
HbA1c < 7.0 % (53 mmol/mol) without hypoglycaemia (severe or blood glucose confirmed 
(BG-confirmed)  symptomatic hypoglycaemic episodes) and no weight gain
!
HbA1c reduction ≥ 1 %-point (10.9 mmol/mol) and weight loss ≥ 3 %
When addressing the treatment policy estimand the ‘without hypoglycaemia’ component of the 
composite endpoint will also include non-treatment-emergent events of severe of 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 six binary endpoints will be accounted for using MI techniques. For the 
treatment policy estimand the binary endpoints will be calculated as dichotomisations of the 1000 
MIs underlying the primary MI analysis. For the hypothetical estimand the model will be 
implemented using a sequential imputation approach assuming MAR. The imputation will be done 
as described below:
!
Intermittent missing values in the on-treatment without rescue observation period are 
imputed using a Markov Chain Monte Carlo (MCMC) method, in order to obtain a 
monotone missing data pattern. This imputation is done for each 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 EOT visit. For each treatment group an analysis of covariance model will be 
used to impute missing values at each planned visit. The model will include region, 
stratification factors and the interaction between stratification factors as categorical effects 
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 MIs from the sequential 
imputation.
For both estimands, each of the 1000 data sets will be analysed using a logistic regression model 
with treatment, region, stratification factors and the interaction between stratification factors as 
fixed effects and baseline value as covariate (i.e. baseline HbA1c for binary HbA1c endpoints, 
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Statistical Analysis Plan
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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 
rule3 to draw inference.
For the composite endpoints involving both HbA1c and body weight the imputed data sets will be 
combined by imputation number.
Without hypoglycaemia
For both estimands, missing data in the ‘without hypoglycaemia’ component will be accounted for 
using a multiple imputation approach6 in which the number of events of severe or BG-confirmed 
hypoglycaemia in the missing data period will be imputed. The ‘without hypoglycaemia’ 
component will be calculated as a dichotomization of the sum of the observed and the imputed 
number of episodes covering the observed and missing data periods. 
Treatment policy estimand
Analogously to the primary imputation model for the continuous endpoints, the imputation of 
hypoglycaemic episodes will assume that the missing data are best described by information from 
subjects who are similar in terms of randomised treatment arm and whether subjects at time of 
evaluation; (i) have discontinued treatment or initiated rescue medication or (ii) are still on 
treatment and have not initiated rescue medication (treatment status). I.e. withdrawn subjects or 
subjects who are lost to follow-up are assumed to have the same conditional event rate after 
withdrawal conditional on the observed event rate before withdrawal and on randomised treatment 
and treatment status and the other covariates. For evaluation at week 52, treatment status will be 
differentiated by whether subjects have discontinued trial product or initiated rescue medication 
prior to week 26 or at/after week 26. The imputation will be done as described below:
!
A Bayesian log-linear negative binomial model is fitted to the observed data from the in-trial 
observation period to obtain the posterior distribution of the model parameters. The model 
will include randomised treatment, treatment status, stratification factors and the interaction 
between the stratification factors as fixed factors and baseline HbA1c as a covariate. The 
logarithm of the duration of the subject’s observed data period will be included as offset.
!
Based on the estimated parameters in this model the number of events in the missing data 
period will be imputed conditional on the event rate in the observed data period. 1000 
imputations will be done, sampling from the posterior distribution of the model parameters.
Hypothetical estimand
Imputation of events when addressing the hypothetical estimand will be done in a similar way. 
Subjects who discontinue trial product or initiate recue medication are assumed to have the same 
conditional event rate after discontinuation/rescue initiation conditional on the observed event rate 
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Statistical Analysis Plan
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Date:
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Version:
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before discontinuation/rescue initiation and on randomised treatment and the other covariates. The 
imputation will be done as described below:
!
A Bayesian log-linear negative binomial model is fitted to the observed data from the 
on-treatment without rescue observation period to obtain the posterior distribution of the
model parameters. The model will include randomised treatment, stratification factors and 
the interaction between stratification factors as fixed factors and baseline HbA1c as a 
covariate. The logarithm of the duration of the subject’s observed data perio d will be 
included as offset.
!
Based on the estimated parameters in this model the number of events in the missing data 
period will be imputed conditional on the event rate in the observed data period. 1000 
imputations will be done, sampling from the posterior distribution of the model parameters.
For the composite endpoint the imputed datasets of the three components will be combined by 
imputation number and analysed in the same way as described above for the other binary endpoints.
Time to event endpoints
!
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 and/or 
intensification of anti-diabetic medication initiated at or after randomisation and before (planned) 
end-of-treatment.
Definition of rescue medication: New anti-diabetic medication and/or intensification of anti-
diabetic medication initiated at or after randomisation and before last date on trial product. This is a 
subset of the additional anti-diabetic medication. 
The following rules will be applied based on the insulin and concomitant medication data reported 
by the investigator, to determine whether or not the recorded anti-diabetic medication is new anti-
diabetic medication or intensification of anti-diabetic medication.
1. New anti-diabetic medication: Anti-diabetic medication (4th-level ATC code), 
excluding insulin, that is initiated after randomisation and is new compared to the 
anti-diabetic background medication at randomisation (see above) and with a dosing 
duration of more than 21 days
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Statistical Analysis Plan
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2. Intensification of anti-diabetic medication: 
a.
Insulin: A more than 20% increase in the total dose of insulin after 
randomisation as compared to the total insulin  dose at randomisation and with a 
dosing duration across 2 consecutive visits or more
b. Other anti-diabetic medication: A more than 20% increase in the dose of anti-
diabetic medication after randomisation as compared to the anti-diabetic 
medication dose at randomisation (5th-level ATC code not changed) and with a 
dosing duration of more than 21 days
More than 21 days (or 2 consecutive visits for insulin) are chosen as a minimum duration for the 
medication to be considered as ‘anti-diabetic medication’. This threshold is set to ensure that short-
term durations (i.e., ≤ 21 days (or < 2 visits for insulin)) 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. 
As an initial 20% reduction of the total insulin dose is recommended at the randomisation visit for 
all subjects using insulin as background medication, the background dose is defined as the total 
insulin dose taken before the 20% reduction.
Treatment policy estimand: Time to additional anti-diabetic medication
The analysis used to estimate 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 a Cox proportional hazards model with 
treatment, region, stratification factors and the interaction between stratification factors as 
categorical fixed effects and the baseline HbA1c value as a covariate. From this analysis the 
estimated hazard ratio between oral semaglutide and placebo together with associated two-sided 
95% CIs and unadjusted two-sided p-values will be presented. 
The endpoint aims to address the need of additional anti-diabetic medication regardless of whether 
this is due to lack of effect or related to tolerability of the trial product. Switching to a new anti-
diabetic treatment (excluding insulin) and/or intensification of anti-diabetic medication are also 
considered events and withdrawn subjects or subjects lost to follow-up will be considered as having 
an event (started on additional anti-diabetic medication) on the day of withdrawal. Subjects will be 
censored on the day before the planned end-of-treatment visit. 
Hypothetical estimand: Time to rescue medication
The analysis used to estimate 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. 
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Statistical Analysis Plan
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The endpoint aims to address a lack of effect of treatment with trial product. Only initiation of 
rescue medication (new anti-diabetic medication and/or intensification of anti-diabetic medication) 
as add-on to randomised treatment is considered an event; switching to another anti-diabetic 
treatment is not considered an event (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 on first date 
of trial product, in order to account for all events of rescue medication initiation. 
2.4.2.2
Safety endpoints
The safety endpoints will be evaluated based on SAS using the on-treatment observation period and 
based on SAS using the in-trial observation period unless otherwise stated. The following endpoints 
are used to support the safety objectives.
Adverse events 
!
Number of 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 MedDRA coding. 
A TEAE is defined as an AE with onset in the on-treatment observation period (see definition of 
observation periods in Section 2.2).
TEAEs will be summarised in terms of the number of subjects with at least one event (N), the 
percentage of subjects with at least one event (%), the number of events (E) and the event rate per 
100 patient years of observation time (R) for the on-treatment observation period. Supportive 
summaries of AEs will be made for the in-trial observation period. The development over time in 
gastrointestinal AEs will be presented graphically.
Other safety endpoints
Change from baseline to week 26 and week 52 in:
!
Amylase
!
Lipase
!
Pulse
!
Systolic blood pressure
!
Diastolic blood pressure
The above safety endpoints will be evaluated using the primary analysis for the treatment policy 
estimand based on SAS using the in-trial observation period and using the primary analysis for the 
hypothetical 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 
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at week 26 and at week 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 week 52 in:
!
ECG evaluation
!
Physical examination (week 52 only)
!
Eye examination category (week 52 only)
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 26 and 57 weeks
!
Treatment-emergent severe or BG confirmed symptomatic hypoglycaemic episodes during 
exposure to trial product, assessed up to approximately 26 and 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 2.2).
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 (Figure 2-2).
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Novo Nordisk classification of hypoglycaemia
In normal physiology, symptoms of hypoglycaemia occur below a plasma glucose (PG) level of 3.1 
mmol/L (56 mg/dL).7 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 classificatio n:
!
Severe or BG-confirmed symptomatic hypoglycaemia: An episode that is severe according 
to the ADA classification8 or BG confirmed by a PG value < 3.1 mmol/L (56 mg/dL) with
symptoms consistent with hypoglycaemia.
ADA classification of hypoglycaemia
!
Severe hypoglycaemia: An episode requiring assistance of another person to actively 
administer carbohydrate, glucagon, or take other corrective actions. PG concentrations may 
not be available during an event, but neurological recovery following the return of PG to 
normal is considered sufficient evidence that the event was induced by a low PG 
concentration.
!
Asymptomatic hypoglycaemia: An episode not accompanied by typical symptoms of 
hypoglycaemia, but with a measured PG concentration ≤ 3.9 mmol/L (70 mg/dL).
!
Documented symptomatic hypoglycaemia: An episode during which typical symptoms of 
hypoglycaemia are accompanied by a measured PG concentration ≤ 3.9 mmol/L 
(70 mg/dL).
!
Pseudo-hypoglycaemia: An episode during which the person with diabetes reports any of the 
typical symptoms of hypoglycaemia with a measured PG concentration > 3.9 mmol/L 
(70 mg/dL) but approaching that level.
!
Probable symptomatic hypoglycaemia: An episode during which symptoms of 
hypoglycaemia are not accompanied by a PG determination but that was presumably caused 
by a PG concentration ≤ 3.9 mmol/L (70 mg/dL).
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Hypoglycaemic 
episode 
PG ≤ 3.9 mmol/L 
(70 mg/dL) 
or 
Alleviation of 
symptoms 
or
Seizure, coma or 
fatal 
SMPG
measurement
Asymptomatic 
hypoglycaemia
Documented 
symptomatic 
hypoglycaemia
Pseudo-
hypoglycaemia
Probable 
symptomatic 
hypoglycaemia
No
Yes
No measurement 
with symptoms
PG > 3.9 mmol/L 
(70 mg/dL)
with symptoms
PG ≤3.9 mmol/L 
(70 mg/dL)
with symptoms
PG ≤3.9 mmol/L 
(70 mg/dL)
without symptoms
No
Yes
Note: Glucose measurements are performed with capillary blood calibrated to plasma equivalent glucose values
PG: plasma glucose  SMPG: Self-measured plasma glucose  
Subject 
able to 
treat him/
herself
Severe 
hypoglycaemia
(ADA 2013)
Figure 2-2
ADA classification of hypoglycaemia
Data on treatment-emergent hypoglycaemic episodes will be presented in terms of the number of 
subjects with at least one episode, the percentage of subjects with at least one episode (%), the total 
number of episodes and the episode rate per 100 patient years of observation time.
Analysis of severe or BG-confirmed symptomatic hypoglycaemic endpoints
The number of treatment-emergent severe or BG-confirmed symptomatic hypoglycaemic episodes 
in the on-treatment period will be analysed using a negative binomial regression model with a log -
link function and the logarithm of the duration of the subject’s on-treatment observation period as 
offset. The model will include treatment, region, stratification factors and the interaction between 
the stratification factors as fixed factors and baseline HbA1c as covariate. The estimated rate ratio 
between each oral semaglutide dose and placebo will be presented together with the 95% CI and 
p-value.
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, region, stratification factors and the interaction between the stratification 
factors as fixed factors and baseline HbA1c as covariate. The estimated odds ratio between each oral 
semaglutide dose and placebo will be presented together with the 95% CI and p-value.
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Statistical Analysis Plan
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The number of treatment-emergent severe or BG-confirmed symptomatic hypoglycaemic episodes 
will be presented by time using summary statistics.
2.4.2.3
Pharmacokinetic endpoints
!
Semaglutide plasma concentrations for population pharmacokinetic (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 2.6.
2.5
Interim analysis
No interim analyses or other analyses of unblinded data will be performed before the database is 
locked.
2.6
Pharmacokinetic and/or pharmacodynamic modelling
Data from this trial will be evaluated using population PK analysis and exposure-response for 
semaglutide. The purpose of the population PK analysis will be: 
!
To describe the covariate factors (such as weight, age, gender, race and ethnicity) that 
influence semaglutide exposure
!
To estimate a steady-state exposure level for each subject with PK 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 PK 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 CTR.
2.7
Patient reported outcomes
PRO endpoints
Change from baseline to week 26 and week 52 in:
!
SF-36v2® (acute version) health survey (SF-36v2 (acute version)): Scores from the 8 
domains and summary of the physical component summary (PCS) score and the mental 
component summary (MCS) score
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Statistical Analysis Plan
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!
Impact of weight on quality of life clinical trials version (IWQOL-Lite-CT): Total score and 
scores from the 4 domains 
!
Diabetes treatment satisfaction questionnaire – status version (DTSQs): Individual items and 
treatment satisfaction score (6 of the 8 items summed)
A more detailed description of the handling of the two PRO questionnaires used in this trial is 
provided in the following sections. No multiplicity adjustments will be done for the PRO 
questionnaires.
The PRO questionnaire endpoints will be evaluated using the primary analysis for the treatment 
policy estimand based on FAS using the in-trial observation period and using the primary analysis 
for the hypothetical estimand based on FAS using the on-treatment without rescue medication 
period. Scores will be analysed separately as the other continuous efficacy endpoints with the 
associated baseline value as a covariate.
2.7.1
SF-36v2® (acute version) health survey
The 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 diabetes.9 The 
SF-36v2 (acute version) for adults with a 1-week recall period contains 36 items.
A total of 35 items measure eight domains of functional health and well-being as well as two 
component summary scores: physical functioning (10 items), role limitation due to physical health 
problems (4 items), bodily pain (2 items), general health perceptions (5 items), vitality (4 items), 
social functioning (2 items), role limitations due to emotional problems (3 items) and general 
mental health (5 items), MCS, PCS. 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 
Software10 including the 2009 US general population norm. The most recent version of the 
QualityMetric Health Outcomes™ Scoring Software available at time of licensing was used (i.e. 
Version 5.0). 
Table 2-3 provides an overview of the domains. NBS standardises domain and component scores 
into T-scores using the means and standard deviations from the US general population. Higher 
scores on all domains and component summary measures (PCS and MCS) indicate better 
HRQoL/general health status. Item 2 (i.e. Question 2 in case report form (CRF)) is not included in 
any score. 
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Table 2-3
Overview of domains for SF-36v2 (acute version)
Domain
Items numbers of 
items included in 
domain
Comment
Physical Functioning (PF)
Items 3a-j
Role Limitations Due to Physical Health 
(Role-Physical; RP)
Items 4a-d
Bodily Pain (BP)
Items 7, 8
Both item scores reversed 
General Health Perceptions (General Health; 
GH)
Items 1, 11a-d
Item scores 1, 11b and 11d 
reversed
Vitality (VT)
Items 9a, 9e, 9g, 9i Item scores 9a and 9e 
reversed 
Social Functioning (SF)
Items 6, 10
Item score 6 reversed 
Role Limitations Due To Emotional Problems 
(Role-Emotional; RE)
Items 5a-c
Mental Health (MH)
Items 9b, 9c, 9d, 
9f, 9h
Item scores 9d and 9h 
reversed 
Physical component summary (PCS)
NA
The PCS score is a weighted 
average of the 8 domain 
scores. 
Mental component summary (MCS)
NA
The MCS score is also a 
weighted average of the 8 
domain scores. Weights differ 
from PCS to MCS. 
Missing data at instrument level will be handled using the Maximum Data Recovery method: The 
method applies a value to a domain item rendered missing if at least one of the items in that domain 
has valid data. A domain score is considered missing if all item values in the domain are missing. 
PCS and MCS are calculated when at least seven of the eight domains have valid data, either actual 
or estimated. However, to calculate PCS, the PF domain must be one of the seven domains having 
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valid data. Also, to calculate MCS, the MH domain must be one of the seven domains having valid 
data.
Responder threshold values
The responder threshold values, in terms of T-score points for change from baseline are defined in 
Table 2-4.9
Table 2-4
Responder thresholds for SF-36v2 (acute version)
Domain
Responder threshold
Physical Functioning (PF)
4.3
Role Limitations Due to Physical Health (Role-Physical; RP)
4.0
Bodily Pain (BP)
5.5
General Health Perceptions (General Health; GH)
7.0
Vitality (VT)
6.7
Social Functioning (SF)
6.2
Role Limitations Due To Emotional Problems (Role-Emotional; 
RE)
4.6
Mental Health (MH)
6.7
Physical component summary (PCS)
3.8
Mental component summary (MCS)
4.6
Responder analyses will be based on the responder threshold values and are described in Section 2.7.4.
2.7.2
Impact of Weight on Quality of Life Clinical Trials Version (IWQOL-Lite-CT)
The IWQOL-Lite-CT is designed to assess the impact of changes in weight on patients' quality of 
life within the context of clinical trials. The items of the IWQOL-Lite-CT pertain to physical 
functioning and psychosocial domains and all items employ a 5-point graded response scale (never, 
rarely, sometimes, usually, always; or not at all true, a little true, moderately true, mostly true, 
completely true). The 22-item version of the IWQOL -Lite-CT was completed by patients.
Domain scores
All IWQOL-Lite-CT composite scores range from 0 to 100, with higher scores reflecting better 
levels of functioning. Table 2-5 provides an overview of domains.
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Table 2-5
Overview of domains for IWQOL-Lite-CT 
Domain
Items numbers of items included in domain
Psychosocial
6-8, 10-16, 19, 21, 22
1-5, 17, 18
1-3, 17, 18
4, 5
1-8, 10-19, 21, 22
Physical
Physical Function
Pain/Discomfort
IWQOL-Lite-CT Total
Missing data at instrument level will be handled in the following way. Raw scores for each subscale 
are computed if a minimum of 50% of the items for that subscale are non-missing, and for the 
IWQOL-Lite-CT total score if a minimum of 75% of all items are non-missing.
The scoring is done in three steps:
1. If the minimum number of items are answered for a composite, compute the average of the valid 
item responses for that composite where 1 =”never” or “not at all true” and 5 =”always” or 
“completely true.” This average must be a number between 1 and 5, inclusive.
2. Multiply that average by the total number of items in that composite. The total number of items 
in each IWQOL-Lite-CT composite is as follows: Psychosocial = 13, Physical = 7, Physical 
Function = 5, Pain/Discomfort = 2, IWQOL-Lite-CT Total = 20. Round to the nearest integer.
3. To convert the IWQOL-Lite-CT raw score (as calculated above) to the 0 (worst) to 100 (best) 
metric:
a.
Subtract the raw score from the maximum raw score for each composite. The maximum 
raw scores are as follows: Psychosocial = 13x5 = 65, Physical = 7x5 = 35, Physical 
Function = 5x5 = 25, Pain/Discomfort = 2x5 = 10, IWQOL-Lite-CT Total = 20x5 = 100.
b. Divide the difference in (a) by the raw score range for each composite. The ranges of the 
raw scores are as follows: Psychosocial = 65-13 = 52, Physical = 35-7 = 28, Physical 
Function = 25-5 = 20, Pain/Discomfort = 10-2 = 8, IWQOL-Lite-CT Total = 100-20 = 80.
c.
Multiply the total in (b) by 100.
Responder threshold values
Data from the oral semaglutide phase 3a monotherapy trial (PIONEER 1; NN9924-4233) data were 
used as part of the confirmation of the psychometric properties of IWQOL -Lite-CT in patients with 
T2DM. To estimate potential responder threshold values for the composite scores in IWQOL-Lite-
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CT anchor-based and distribution-based methods were applied to PIONEER 1 data. The resulting 
responder threshold values, in terms of score points for change from baseline are defined in
Table 2-6 9
Table 2-6
Responder thresholds for IWQOL-Lite-CT
Domain
Responder threshold
Psychosocial
10
Physical
8
Physical Function
10
Pain/Discomfort
5
IWQOL-Lite-CT Total
8
Responder analyses will be based on the responder threshold values and are described in Section 2.7.4.
2.7.3
Diabetes Treatment Satisfaction Questionnaire – status version (DTSQs)
The DTSQs questionnaire will be used to assess subject’s treatment satisfaction. This questionnaire 
contains 8 items that measures the treatment satisfaction for subjects’ diabetes treatment in terms of 
convenience, flexibility and general feelings regarding treatment.
Item scores
The DTSQs items are scored on a 7-point graded response scale ranging from 6 to 0. Higher scores 
indicate higher levels of treatment satisfaction for DTSQs items 1, 4 -8. For items 2 and 3 a higher 
score indicates a higher patient perceived experience of hyperglycaemia and hypoglycaemia, 
respectively. Thus, lower scores indicate a perception of BG levels being “none of the time” 
unacceptably high (item 2) or low (item 3). If data are missing for an item, the item score is treated 
as missing. No reversal of item scores will be done.
Treatment satisfaction score
The domain score of total treatment satisfaction (total treatment satisfaction score) is computed by 
adding the six items scores 1, 4-8. The score has a minimum of zero and a maximum of 36. A 
higher treatment satisfaction score indicates a higher level of treatment satisfaction. No reversals of 
items are necessary prior to computing the treatment satisfaction score.
Missing data at instrument level will be handled in the following way. For computing the total 
treatment satisfaction score consisting of six items, missing data from one item is allowed. 
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Scoring algorithm:
!
Step 1: Sum the existing item scores (i.e. either 5 or 6 item scores)
!
Step 2: Divide this sum by the number of existing item scores
!
Step 3: Multiply by 6 (the number of items in the total treatment satisfaction scale)
Responder threshold values
Half of a standard deviation (SD) of the baseline DTSQs item and domain scores were used as 
distribution-based approach defining the responder thresholds. The thresholds are derived from 
baseline DTSQs data across trial arms. Responder analyses will be based on the responder threshold 
values and are described in Section 2.7.4.
2.7.4
Responder analyses
Responder analyses will be conducted for both estimands, for the same time points that are defined 
for the analyses of PRO endpoints and separately for each score.
For descriptive statistics the following subject responder categorization is applied for all relevant 
time points and scores:
!
Responder - improvement: Individual change from baseline in score ≥ positive responder 
threshold 
!
Non-responder - no change: Individual change from baseline in score  > negative responder 
threshold value and < positive responder threshold value
!
Non-responder - worsening: Individual change from baseline in score  ≤ negative responder 
threshold value
The following binary subject responder definition is applied for all relevant time points and scores:
!
Responder: Individual change from baseline in score ≥ positive responder threshold
!
Non-responder: Individual change from baseline in score < positive responder threshold
The binary responder endpoints will be analysed as the other supportive secondary binary efficacy 
endpoints. Estimated proportions and differences in proportions will be reported in addition to odds 
and odds ratios.
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3
Changes to the statistical analyses planned in the protocol
The main analyses were described in the protocol for the trial NN9924-4280. However, 
clarifications, more detailed descriptions of endpoints and analyses are provided in this SAP. The 
changes from the protocol of NN9924-4280 are summarised below:
!
The countries for region in the study have been specified.
!
The primary and secondary estimand names ‘de-facto’ and ‘de-jure’ have been changed to 
‘treatment policy’ and ‘hypothetical’ respectively.
!
Step-wise factor removal from ANCOVA imputation model for primary analy sis.
!
The number of sensitivity analyses has been reduced:
o
The MMRM sensitivity analysis of the treatment policy estimand has been omitted. 
It is considered sufficient to keep just the two current sensitivity analyses to stress 
test the primary results. 
o
Three MI sensitivity analyses of the hypothetical estimand have been omitted. It is 
considered sufficient to keep the tipping point sensitivity analysis for the secondary 
analysis of the hypothetical estimand as it can be considered as a progressive stress-
testing to assess how severe the departures from MAR must be to reverse the 
conclusions from the primary MMRM analysis used to address the hypothetical 
estimand.
o
The last observation carried forward (LOCF) sensitivity analysis specified in the trial 
protocol has been omitted, as it is not realistic that subjects with missing data would 
have had stable results from the point of drop out to trial completion.
!
It has been specified which assessments will be analysed on logarithmic scale.
!
The statistical analysis of the two binary effect endpoints: HbA1c reduction ≥ 1 %-point 
(10.9 mmol/mol); and body weight loss ≥ 3 %, have been omitted, because they are being 
analysed as a part of the two composite binary effect endpoints.
!
For the binary efficacy endpoints, it has been specified with more details how missing data 
in the analyses for both the treatment policy estimand and hypothetical estimand will be 
imputed.
!
A clarification of the ‘without hypoglycaemia’ component in composite binary endpoints 
has been added. The specification on how to analyses the binary component ‘without 
hypoglycaemia’ in the composite endpoint ‘HbA1c < 7.0 % (53 mmol/mol) without 
hypoglycaemia (severe or BG-confirmed symptomatic hypoglycaemia) and no weight gain’ 
has not been described in the statistical section of the protocol. The specification is therefore 
included in the SAP.
!
The definitions of rescue medication and additional anti-diabetic medication used for the 
time-to-event endpoints were added along with discussion on additional anti-diabetic 
medication. Furthermore, the accompanying statistical analyses have been further clarified.
!
All PROs (SF-36v2 (acute version), IWQOL-Lite-CT, and DTSQs) will be analysed 
statistically. SF-36v2 (acute version) using the primary analysis for the treatment policy 
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estimand. IWQOL-Lite-CT and DTSQs using both the primary analysis for the treatment 
policy estimand and the hypothetical estimand.
!
The responder analyses and the primary analysis for the hypothetical estimand of SF 36v2 
(acute version) will be presented in a report separate from and after finalisation of the CTR.
!
In addition to the total score, four domain scores will be analysed for IWQOL-Lite-CT.
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Statistical Analysis Plan
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4
References
1.
Bretz F, Posch M, Glimm E, Klinglmueller F, Maurer W, Rohmeyer K. Graphical 
approaches for multiple comparison procedures using weighted Bonferroni, Simes, or 
parametric tests. Biometrical Journal. 2011;53(6):894-913.
2.
Rohmeyer K, Klinglmueller F. gMCP: Graph Based Multiple Test Procedures. R package 
version 0.8-8. 3 Oct 2014.
3.
Little R, Rubin D. Statistical analysis with missing data. Sons. JW, editor. New York.: John 
Wiley & Sons. 1987.
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(CHMP) EMACfMPfHU. Guideline on Missing Data in Confirmatory Clinical Trials 
(EMA/CPMP/EWP/1776/99 Rev. 1). 7/2/2010 2010.
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National Academy of Sciences (NAS). The Prevention and Treatment of Missing Data in 
Clinical Trials. Washington D.C.: The National Academies Press. 2010.
6.
Bagger JI, Knop FK, Lund A, Vestergaard H, Holst JJ, Vilsbøll T. Impaired regulation of 
the incretin effect in patients with type 2 diabetes. J Clin Endocrinol Metab. 2011;96(3):737-
45.
7.
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.
8.
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.
9.
Maruish ME, (Ed.). User's manual for the SF-36v2 Health Survey (3rd ed.). Lincoln, RI: 
QualityMetric Incorporated. 2011.
10.
Fehnel S, Qin S, Williams V, RTI Health Solutions. Psychometric Evaluation of the 
IWQOL-Lite-CT in Overweight and Obese Patients With Type 2 Diabetes (RTI-HS Project 
No. 0303824.003). IWQOL-Lite-CT Scoring and Responder definitions (v. 1.0 Final). In: 
Meincke H, Novo Nordisk A/S, editors. 17 May 2018.
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Oral Semaglutide
PIONEER 1-10
Clinical Trial Report
Appendix 16.1.9
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16.1.9.1 Pre-defined MedDRA search – list of preferred terms
Table of contents
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16.1.9.1 Pre-defined MedDRA search – list of preferred terms......................................................................2
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Trial: NN9924-4280 
Documentation of Statistical methods, Version 1.0 dated 08 February 2019  
Overview of deleted pages 
Pages 
Section 
Title 
40-249 
16.1.9.1 
Pre-defined MedDRA search – list of preferred terms