Clinical trial NCT02827708
Conditions: Diabetes Diabetes Mellitus, Type 2
Sponsor: Novo Nordisk A/S
Start date: 2016-09-20; Completion date: 2018-05-15
Enrollment: 324 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This trial is conducted globally. The aim of this trial is to investigate efficacy and safety of oral semaglutide versus placebo in subjects with type 2 diabetes and moderate renal impairment.

Detailed description:

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

Protocol documents:
Prot_000.pdf: 
Cover Page for Protocol 
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT02827708 
Sponsor trial ID: 
NN9924-4234 
Official title of study: 
Efficacy and Safety of Oral Semaglutide Versus Placebo in 
Subjects with Type 2 Diabetes and Moderate Renal Impairment 
Document date: 
13-December-2018 
 


Link
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List of contents
Protocol ...............................................................................................................................................
Appendix A - Monitoring of Calcitonin ...........................................................................................
Appendix B - Adverse events requiring additional data collection................................................
Attachment I and II............................................................................................................................
Protocol amendment 1 - Sweden.......................................................................................................
Protocol amendment 2 - Global ........................................................................................................
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
Oral semaglutide
Trial ID: NN9924-4234
Clinical Trial Report
Appendix 16.1.1
13 December 2018
1.0
Final
16.1.1 Protocol and protocol amendments
CONFIDENTIAL
Redacted protocol 
Lncludes redaction of personal identifiable DQGFRPSDQ\
FRQILGHQWLDOinformation. 
. 


Protocol
CONFIDENTIAL
Date:
06 April 2016
Novo Nordisk
Trial ID: NN9924-4234
Version:
1.0
UTN: U1111-1176-9230
Status:
Final
EudraCT no.: 2015-005326-19
Page:
1 of 129
Protocol
Trial ID: NN9924-4234
PIONEER 5 – renal impairment
Efficacy and safety of oral semaglutide versus placebo in subjects with 
type 2 diabetes and moderate renal impairment
A 26-week randomised, double-blind, placebo-controlled trial
Trial phase: 3a
Protocol originator
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol
CONFIDENTIAL
Date:
06 April 2016
Novo Nordisk
Trial ID: NN9924-4234
Version:
1.0
UTN: U1111-1176-9230
Status:
Final
EudraCT no.: 2015-005326-19
Page:
2 of 129
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............................................................................23
3.1
Background information..............................................................................................................23
3.1.1
Type 2 diabetes mellitus ............................................................................................23
3.1.2
Glucagon-like peptide-1 ............................................................................................23
3.1.3
Oral semaglutide........................................................................................................23
3.1.4
Nonclinical data.........................................................................................................24
3.1.4.1
Semaglutide.........................................................................................24
3.1.4.2
SNAC ..................................................................................................25
3.1.5
Clinical data for oral semaglutide..............................................................................26
3.1.5.1
Pharmacokinetics ................................................................................26
3.1.5.2
Efficacy ...............................................................................................27
3.1.5.3
Safety...................................................................................................27
3.2
Rationale for the trial...................................................................................................................28
4
Objectives and endpoints........................................................................................................................30
4.1
Objectives ....................................................................................................................................30
4.1.1
Primary objective.......................................................................................................30
4.1.2
Secondary objectives .................................................................................................30
4.2
Endpoints .....................................................................................................................................30
4.2.1
Primary endpoint........................................................................................................30
4.2.2
Secondary endpoints..................................................................................................30
4.2.2.1
Confirmatory secondary endpoints .....................................................30
4.2.2.2
Supportive secondary endpoints..........................................................30
5
Trial design ..............................................................................................................................................33
5.1
Type of trial .................................................................................................................................33
5.2
Rationale for trial design..............................................................................................................34
5.3
Treatment of subjects...................................................................................................................34
5.3.1
Dosing instructions ....................................................................................................35
5.3.2
Background medication.............................................................................................35
5.3.2.1
Basal insulin dose adjustment .............................................................36
5.4
Treatment after discontinuation of trial product ..........................................................................36
5.5
Rationale for treatment ................................................................................................................37
6
Trial population.......................................................................................................................................38
6.1
Number of subjects......................................................................................................................38
6.2
Inclusion criteria ..........................................................................................................................38
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
06 April 2016
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Trial ID: NN9924-4234
Version:
1.0
UTN: U1111-1176-9230
Status:
Final
EudraCT no.: 2015-005326-19
Page:
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6.3
Exclusion criteria.........................................................................................................................39
6.4
Rescue criteria..............................................................................................................................40
6.5
Criteria for premature discontinuation of trial product................................................................41
6.6
Withdrawal from trial ..................................................................................................................41
6.7
Subject replacement.....................................................................................................................41
6.8
Rationale for trial population.......................................................................................................41
7
Milestones.................................................................................................................................................43
8
Methods and assessments .......................................................................................................................44
8.1
Visit procedures...........................................................................................................................44
8.1.1
Screening, visit 1........................................................................................................44
8.1.2
Fasting visits ..............................................................................................................45
8.1.3
Randomisation and trial product administration........................................................45
8.1.4
End-of-treatment (visit 13) and Follow-up (visit 14).................................................46
8.1.5
Premature discontinuation of trial product and follow-up (visit 13A and visit 
14A) ...........................................................................................................................46
8.1.6
Withdrawal from trial ................................................................................................47
8.1.7
Investigator assessments............................................................................................47
8.2
Subject related information/assessments .....................................................................................48
8.2.1
Demography...............................................................................................................48
8.2.2
Diabetes history and diabetes complications .............................................................48
8.2.3
Concomitant illness and medical history...................................................................48
8.2.4
Concomitant medication............................................................................................49
8.2.5
Childbearing potential................................................................................................49
8.2.6
Tobacco use ...............................................................................................................50
8.3
Efficacy assessments....................................................................................................................50
8.3.1
Laboratory assessments for efficacy..........................................................................50
8.3.1.1
Fasting plasma glucose........................................................................51
8.3.2
Self-measured plasma glucose (SMPG) ....................................................................51
8.3.2.1
Basal insulin dose adjustment .............................................................52
8.3.3
Body weight and height .............................................................................................52
8.3.4
Waist circumference ..................................................................................................52
8.3.5
Patient reported outcomes questionnaires..................................................................53
8.4
Safety assessments.......................................................................................................................53
8.4.1
Adverse events...........................................................................................................53
8.4.1.1
Medication error..................................................................................54
8.4.1.2
Adverse events requiring additional data collection ...........................54
8.4.2
Physical examination.................................................................................................55
8.4.3
Vital signs ..................................................................................................................55
8.4.4
Eye examination ........................................................................................................55
8.4.5
Electrocardiogram (12-lead)......................................................................................56
8.4.6
Laboratory assessments for safety .............................................................................56
8.4.6.1
Blood samples for safety.....................................................................56
8.4.6.2
Urine samples for safety......................................................................57
8.4.7
Pregnancy testing.......................................................................................................58
8.4.8
Anti-semaglutide antibodies ......................................................................................58
8.4.9
Hypoglycaemic episodes ...........................................................................................58
8.5
Laboratory assessments ...............................................................................................................61
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
06 April 2016
Novo Nordisk
Trial ID: NN9924-4234
Version:
1.0
UTN: U1111-1176-9230
Status:
Final
EudraCT no.: 2015-005326-19
Page:
4 of 129
8.6
Other assessments........................................................................................................................62
8.6.1
Pharmacokinetics.......................................................................................................62
8.6.1.1
Semaglutide PK sampling...................................................................62
8.6.1.2
SNAC PK sampling ............................................................................63
8.6.2
Subject diary ..............................................................................................................63
8.7
Subject compliance......................................................................................................................63
9
Trial supplies ...........................................................................................................................................65
9.1
Trial products...............................................................................................................................65
9.2
Labelling......................................................................................................................................66
9.3
Storage .........................................................................................................................................66
9.4
Drug accountability and destruction............................................................................................66
9.5
Auxiliary supplies........................................................................................................................67
10 Interactive voice/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.......................................................................................................73
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 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
17 Statistical considerations ........................................................................................................................92
17.1
Sample size calculation................................................................................................................94
17.2
Definition of analysis sets............................................................................................................95
17.3
Primary endpoint..........................................................................................................................98
17.3.1
Primary analysis for the primary estimand ................................................................98
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
06 April 2016
Novo Nordisk
Trial ID: NN9924-4234
Version:
1.0
UTN: U1111-1176-9230
Status:
Final
EudraCT no.: 2015-005326-19
Page:
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17.3.2
Primary analysis for the secondary estimand.............................................................99
17.3.3
Sensitivity analyses....................................................................................................99
17.3.3.1
Pattern mixture models......................................................................100
17.3.3.2
Other sensitivity analyses..................................................................101
17.3.3.3
Assessment of sensitivity analyses....................................................101
17.4
Secondary endpoints..................................................................................................................101
17.4.1
Confirmatory secondary endpoints..........................................................................101
17.4.2
Supportive secondary endpoints ..............................................................................102
17.4.2.1
Efficacy endpoints.............................................................................102
17.4.2.2
Safety endpoints................................................................................104
17.4.2.3
Pharmacokinetic endpoints................................................................108
17.5
Interim analysis..........................................................................................................................108
17.6
Pharmacokinetic and/or pharmacodynamic modelling..............................................................108
17.7
Patient reported outcomes..........................................................................................................109
18 Ethics......................................................................................................................................................110
18.1
Benefit-risk assessment of the trial............................................................................................110
18.1.1
Risks and precautions ..............................................................................................110
18.1.2
Benefits....................................................................................................................112
18.1.3
Risk and benefit conclusion.....................................................................................113
18.2
Informed consent .......................................................................................................................113
18.3
Data handling.............................................................................................................................114
18.4
Information to subjects during trial............................................................................................114
18.5
Premature termination of the trial and/or trial site.....................................................................114
19 Protocol compliance..............................................................................................................................115
19.1
Protocol deviations ....................................................................................................................115
19.2
Prevention of missing data.........................................................................................................115
20 Audits and inspections ..........................................................................................................................116
21 Critical documents ................................................................................................................................117
22 Responsibilities......................................................................................................................................119
23 Reports and publications......................................................................................................................120
23.1
Communication of results..........................................................................................................120
23.1.1
Authorship ...............................................................................................................121
23.1.2
Site-specific publication(s) by investigator(s) .........................................................121
23.2
Investigator access to data and review of results.......................................................................121
24 Retention of clinical trial documentation and human biosamples....................................................122
24.1
Retention of clinical trial documentation...................................................................................122
24.2
Retention of human biosamples.................................................................................................122
25 Institutional Review Boards/Independent Ethics Committees and regulatory authorities............124
26 Indemnity statement .............................................................................................................................125
27 References..............................................................................................................................................126
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
06 April 2016
Novo Nordisk
Trial ID: NN9924-4234
Version:
1.0
UTN: U1111-1176-9230
Status:
Final
EudraCT no.: 2015-005326-19
Page:
6 of 129
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:
06 April 2016
Novo Nordisk
Trial ID: NN9924-4234
Version:
1.0
UTN: U1111-1176-9230
Status:
Final
EudraCT no.: 2015-005326-19
Page:
7 of 129
Table of Figures
Page
Figure 5–1
Trial design.............................................................................................................................33
Figure 12–1
Reporting of AEs....................................................................................................................77
Figure 17–1
Graphical illustration of the testing procedure .......................................................................95
Figure 17–2
ADA classification of hypoglycaemia..................................................................................107
Table of Tables
Page
Table 5–1
Treatment of subjects..............................................................................................................34
Table 5–2
Increase of basal insulin dose .................................................................................................36
Table 5–3
Reduction of basal insulin dose..............................................................................................36
Table 9–1
Investigational medicinal products.........................................................................................65
Table 9–2
Storage conditions for investigational medicinal products.....................................................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 for sample size calculation................................................................................94
Table 17–2
Calculated powers for individual hypotheses.........................................................................95
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
06 April 2016
Novo Nordisk
Trial ID: NN9924-4234
Version:
1.0
UTN: U1111-1176-9230
Status:
Final
EudraCT no.: 2015-005326-19
Page:
8 of 129
List of abbreviations
AACE
American Association of Clinical Endocrinologists
ADA
American Diabetes Association
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
AUC
area under the curve
BG
blood glucose
BMI
body mass index
CK
creatine kinase
CKD
Chronic Kidney Disease 
CKD-EPI
Chronic Kidney Disease Epidemiology 
Collaboration
CLAE
clinical laboratory adverse event
Cmax
maximum concentration
CRF
case report form
CRP
c-reactive protein
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
EOT
end-of-treatment
FAS
full analysis set
FDA
U.S. Food and Drug Administration
FPG
fasting plasma glucose
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
06 April 2016
Novo Nordisk
Trial ID: NN9924-4234
Version:
1.0
UTN: U1111-1176-9230
Status:
Final
EudraCT no.: 2015-005326-19
Page:
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FSFV
first subject first visit
GCP
Good Clinical Practice
GFR
glomerular filtration rate
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
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
MMRM
mixed model for repeated measurements
NPH
Neutral Protamine Hagedorn
NSTEMI
non-ST elevation acute myocardial infarction 
NYHA
New York Heart Association
P
phone contact
PG
plasma glucose
PK
pharmacokinetics
PRO
patient reported outcome
SAE
serious adverse event
SAS
safety analysis set
s.c.
subcutaneous(ly)
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Protocol
CONFIDENTIAL
Date:
06 April 2016
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Trial ID: NN9924-4234
Version:
1.0
UTN: U1111-1176-9230
Status:
Final
EudraCT no.: 2015-005326-19
Page:
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SGLT-2
sodium-glucose co-transporter-2
SMPG
self-measured plasma glucose
SNAC
sodium N-[8-(2-hydroxybenzoyl) amino]caprylate
STEMI
ST-elevation acute myocardial infarction
SU
sulfonylurea
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
U
unit
UNL
Upper Normal Limit
UTN
Universal Trial Number
V
visit
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Protocol
CONFIDENTIAL
Date:
06 April 2016
Novo Nordisk
Trial ID: NN9924-4234
Version:
1.0
UTN: U1111-1176-9230
Status:
Final
EudraCT no.: 2015-005326-19
Page:
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1
Summary
Objectives and endpoints:
Primary objective
To compare the effect of once-daily dosing of 14 mg oral semaglutide versus placebo, both in 
combination with metformin and/or sulfonylurea, basal insulin alone or metformin in combination 
with basal insulin on glycaemic control in subjects with type 2 diabetes mellitus and moderate renal 
impairment.
Secondary objectives
To compare the effect of once-daily dosing of 14 mg oral semaglutide versus placebo, both in 
combination with metformin and/or sulfonylurea, basal insulin alone or metformin in combination 
with basal insulin on body weight in subjects with type 2 diabetes mellitus and moderate renal 
impairment.
To compare the safety and tolerability of once-daily dosing of 14 mg oral semaglutide versus 
placebo, both in combination with metformin and/or sulfonylurea, basal insulin alone or metformin 
in combination with basal insulin in subjects with type 2 diabetes mellitus and moderate renal 
impairment.
Primary endpoint
Change from baseline to week 26 in glycosylated haemoglobin (HbA1c).
Key secondary endpoints
Change from baseline to week 26 in body weight (kg).
Change from baseline to week 26 in fasting plasma glucose.
If a subject after week 26 achieves (yes/no):
!
HbA1c < 7.0% (53 mmol/mol) American Diabetes Association target.
Number of treatment-emergent adverse events during exposure to trial product, assessed up to 
approximately 31 weeks.
Number of treatment-emergent severe or blood glucose-confirmed symptomatic hypoglycaemic 
episodes during exposure to trial product, assessed up to approximately 31 weeks.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
06 April 2016
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Trial ID: NN9924-4234
Version:
1.0
UTN: U1111-1176-9230
Status:
Final
EudraCT no.: 2015-005326-19
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Trial design:
This is a 26-week, randomised, double-blind, placebo-controlled, parallel-group, multicentre, 
multinational trial with 2 arms comparing the efficacy and safety of oral semaglutide with placebo 
in subjects with type 2 diabetes mellitus and moderate renal impairment.
Subjects will be randomised 1:1 to receive one of the following treatments:
!
14 mg oral semaglutide once-daily
!
placebo once-daily
The total trial duration for the individual subject will be approximately 33 weeks. The trial includes 
a 2-week screening period, followed by a 26-week randomised treatment period and a follow-up 
period of 5 weeks.
Trial population:
Number of subjects planned to be randomised: 324
Inclusion criteria:
!
Informed consent obtained before any trial-related activities. Trial-related activities are any 
procedures that are carried out as part of the trial, including activities to determine suitability for 
the trial.
!
Male or female, age above or equal to 18 years at the time of signing informed consent. 
!
Diagnosed with type 2 diabetes mellitus ≥ 90 days prior to day of screening.
!
HbA1c of 7.0-9.5% (53-80 mmol/mol) (both inclusive).
!
Moderate renal impairment defined as estimated glomerular filtration rate of 
30-59 mL/min/1.73 m2 as per Chronic Kidney Disease Epidemiology Collaboration formula.
!
Stable daily dose(s) within 90 days prior to the day of screening of any of the following 
treatment regimens:
–
1-2 of the following oral anti-diabetic drugs:
- Metformin ≥ 1500 mg or maximum tolerated dose documented in the subject medical 
record), 
- Sulfonylurea (≥ half of the maximum approved dose according to local label or maximum 
tolerated dose as documented in subject medical record)
–
Basal insulin alone (20% change in total daily dose of insulin glargine, insulin detemir, 
insulin degludec or NPH insulin)
or
–
Metformin (≥ 1500 mg or maximum tolerated dose documented in the subject medical 
record) in combination with basal insulin (20% change in total daily dose of insulin 
glargine, insulin detemir, insulin degludec or NPH insulin)
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Protocol
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Date:
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Trial ID: NN9924-4234
Version:
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UTN: U1111-1176-9230
Status:
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Key exclusion criteria:
!
Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing 
potential and not using an adequate contraceptive method (adequate contraceptive measure as 
required by local regulation or practice). 
For certain specific countries: Additional specific requirements apply.
!
Any disorder, which in the investigator’s opinion might jeopardise subject’s safety or 
compliance with the protocol.
!
Family or personal history of Multiple Endocrine Neoplasia Type 2 or Medullary Thyroid 
Carcinoma.
!
History of pancreatitis (acute or chronic).
!
History of major surgical procedures involving the stomach potentially affecting absorption of 
trial product (e.g. subtotal and total gastrectomy, sleeve gastrectomy, gastric bypass surgery).
!
Any of the following: myocardial infarction, stroke or hospitalisation for unstable angina or 
transient ischaemic attack within the past 180 days prior to the day of screening and 
randomisation.
!
Subjects presently classified as being in New York Heart Association Class IV.
!
Planned coronary, carotid or peripheral artery revascularisation known on the day of screening.
!
Subjects with alanine aminotransferase > 2.5 x upper normal limit.
!
Rapidly progressing renal disease (e.g. such as acute glomerulonephritis) as judged by the 
investigator or known nephrotic albuminuria (> 2200 mg/24 hours or > 2200 mg/g).
!
Use of systemic immunosuppressive treatment within 90 days prior to screening.
!
Treatment with any medication for the indication of diabetes or obesity other than stated in the 
inclusion criteria in a period of 90 days before the day of screening. An exception is short-term
insulin treatment for acute illness for a total of ≤ 14 days.
!
Known hypoglycaemic unawareness and/or recurrent severe hypoglycaemic episodes as judged 
by the investigator.
!
Proliferative retinopathy or maculopathy requiring acute treatment. Verified by fundus 
photography or dilated fundoscopy performed within 90 days prior to randomisation.
!
History or presence of malignant neoplasms within the last 5 years (except basal and squamous 
cell skin cancer and carcinoma in situ).
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
06 April 2016
Novo Nordisk
Trial ID: NN9924-4234
Version:
1.0
UTN: U1111-1176-9230
Status:
Final
EudraCT no.: 2015-005326-19
Page:
14 of 129
Key assessments:
Efficacy
!
HbA1c
!
Fasting plasma glucose
!
Body weight
!
Pharmacokinetics sampling
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, 0 mg tablets
CONFIDENTIAL


Protocol
UTN: U1111-1176-9230
Date:
06 April 2016
Status:
Final
Novo Nordisk
Trial ID: NN9924-4234
EudraCT no.: 2015-005326-19
Version:
1.0
Page:
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2
Flow chart
Trial Periods
Screeninga
Randomisation
Treatment
End of treatment 
(EoT)
Follow-upb
EoT premature 
discontinuationc
Follow-up 
premature 
discontinuationc
Visit (V), Phone (P)
V1
V2
P3
V4
V5
P6d
P7d
P8d
P9d
V10
P11d
V12
V13
V14
V13A
V14A
Timing of visit (weeks)
Up to -2 
weeks
0
2
4
8
10
11
12
13
14
16
20
26
31
Day of 
discontinuation 
of trial product
5 weeks after 
discontinuation 
of trial product 
(last dose)
Visit window (days)
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+3
+3
+3
SUBJECT RELATED
INFO/ASSESSMENTS
Informed consent
X
In/exclusion criteria
X
X
Concomitant medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Demography
X
Tobacco use
X
Concomitant illness and 
Medical history
X


Protocol
UTN: U1111-1176-9230
Date:
06 April 2016
Status:
Final
Novo Nordisk
Trial ID: NN9924-4234
EudraCT no.: 2015-005326-19
Version:
1.0
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Trial Periods
Screeninga
Randomisation
Treatment
End of treatment 
(EoT)
Follow-upb
EoT premature 
discontinuationc
Follow-up 
premature 
discontinuationc
Visit (V), Phone (P)
V1
V2
P3
V4
V5
P6d
P7d
P8d
P9d
V10
P11d
V12
V13
V14
V13A
V14A
Timing of visit (weeks)
Up to -2 
weeks
0
2
4
8
10
11
12
13
14
16
20
26
31
Day of 
discontinuation 
of trial product
5 weeks after 
discontinuation 
of trial product 
(last dose)
Visit window (days)
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+3
+3
+3
Diagnosis of diabetes/
diabetes complications
X
Renal impairment history
X
History of cardiovascular 
disease 
X
History of gallbladder 
disease
X
History of gastrointestinal 
disease 
X
Randomisation
X
Criteria for premature 
discontinuation of trial 
product
X
X
X
X
X
X
X
X
X
X


Protocol
UTN: U1111-1176-9230
Date:
06 April 2016
Status:
Final
Novo Nordisk
Trial ID: NN9924-4234
EudraCT no.: 2015-005326-19
Version:
1.0
Page:
17 of 129
Trial Periods
Screeninga
Randomisation
Treatment
End of treatment 
(EoT)
Follow-upb
EoT premature 
discontinuationc
Follow-up 
premature 
discontinuationc
Visit (V), Phone (P)
V1
V2
P3
V4
V5
P6d
P7d
P8d
P9d
V10
P11d
V12
V13
V14
V13A
V14A
Timing of visit (weeks)
Up to -2 
weeks
0
2
4
8
10
11
12
13
14
16
20
26
31
Day of 
discontinuation 
of trial product
5 weeks after 
discontinuation 
of trial product 
(last dose)
Visit window (days)
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+3
+3
+3
EFFICACY
HbA1c
X
X
X
X
X
X
X
X
Fasting plasma glucose
X
X
X
X
X
X
X
Semaglutide PKe
X
X
X
X
X
X
X
SNAC PKe, f
X
X
X
Lipids 
X
X
X
X
Height
X
Body weight 
X
X
X
X
X
X
X
Waist circumference 
X
X
X
X
Self measured plasma 
X
X
X
X
X
X


Protocol
UTN: U1111-1176-9230
Date:
06 April 2016
Status:
Final
Novo Nordisk
Trial ID: NN9924-4234
EudraCT no.: 2015-005326-19
Version:
1.0
Page:
18 of 129
Trial Periods
Screeninga
Randomisation
Treatment
End of treatment 
(EoT)
Follow-upb
EoT premature 
discontinuationc
Follow-up 
premature 
discontinuationc
Visit (V), Phone (P)
V1
V2
P3
V4
V5
P6d
P7d
P8d
P9d
V10
P11d
V12
V13
V14
V13A
V14A
Timing of visit (weeks)
Up to -2 
weeks
0
2
4
8
10
11
12
13
14
16
20
26
31
Day of 
discontinuation 
of trial product
5 weeks after 
discontinuation 
of trial product 
(last dose)
Visit window (days)
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+3
+3
+3
glucoseg
PRO questionnaires 
X
X
X
X
CRP
X
X
X
X
SAFETY 
Eye examinationh
X 
Physical examination 
X
X
X
ECG 
X
X
X
X
X
Vital signs 
X
X
X
X
X
X
X
X
X
Pregnancy testi
X 
X
X
X
X
X
X
X
X
X
Calcitonin 
X
X
X
X
X
X


Protocol
UTN: U1111-1176-9230
Date:
06 April 2016
Status:
Final
Novo Nordisk
Trial ID: NN9924-4234
EudraCT no.: 2015-005326-19
Version:
1.0
Page:
19 of 129
Trial Periods
Screeninga
Randomisation
Treatment
End of treatment 
(EoT)
Follow-upb
EoT premature 
discontinuationc
Follow-up 
premature 
discontinuationc
Visit (V), Phone (P)
V1
V2
P3
V4
V5
P6d
P7d
P8d
P9d
V10
P11d
V12
V13
V14
V13A
V14A
Timing of visit (weeks)
Up to -2 
weeks
0
2
4
8
10
11
12
13
14
16
20
26
31
Day of 
discontinuation 
of trial product
5 weeks after 
discontinuation 
of trial product 
(last dose)
Visit window (days)
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+3
+3
+3
Biochemistryj
X
X
X
X
X
X
X
X
X
Haematology 
X
X
X
X
X
X
X
X
Antibodiesk
X
X
X
X
X
X
X
X
Adverse eventsl
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hypoglycaemic episodes 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Technical complaints
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis 
X
X
X
X
Urinary 
albumin:creatinine ratiom
X
X
X
X
TRIAL MATERIAL 


Protocol
UTN: U1111-1176-9230
Date:
06 April 2016
Status:
Final
Novo Nordisk
Trial ID: NN9924-4234
EudraCT no.: 2015-005326-19
Version:
1.0
Page:
20 of 129
Trial Periods
Screeninga
Randomisation
Treatment
End of treatment 
(EoT)
Follow-upb
EoT premature 
discontinuationc
Follow-up 
premature 
discontinuationc
Visit (V), Phone (P)
V1
V2
P3
V4
V5
P6d
P7d
P8d
P9d
V10
P11d
V12
V13
V14
V13A
V14A
Timing of visit (weeks)
Up to -2 
weeks
0
2
4
8
10
11
12
13
14
16
20
26
31
Day of 
discontinuation 
of trial product
5 weeks after 
discontinuation 
of trial product 
(last dose)
Visit window (days)
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+3
+3
+3
IWRS call 
X
X
X
X
X
X
X
X
Dispensing visit 
X
X
X
X
X
Drug accountability 
X
X
X
X
X
X
X
REMINDERS 
Attend visit fastingn
X
X
X
X
X
X
X
Basal insulin dosed
X
X
X
X
X
X
X
X
X
X
X
X
Training in trial product 
dosing instructions
X
X
X
X
X
Handout and instruct in 
blood glucose meter use 
X
Handout ID card 
X


Protocol
UTN: U1111-1176-9230
Date:
06 April 2016
Status:
Final
Novo Nordisk
Trial ID: NN9924-4234
EudraCT no.: 2015-005326-19
Version:
1.0
Page:
21 of 129
Trial Periods
Screeninga
Randomisation
Treatment
End of treatment 
(EoT)
Follow-upb
EoT premature 
discontinuationc
Follow-up 
premature 
discontinuationc
Visit (V), Phone (P)
V1
V2
P3
V4
V5
P6d
P7d
P8d
P9d
V10
P11d
V12
V13
V14
V13A
V14A
Timing of visit (weeks)
Up to -2 
weeks
0
2
4
8
10
11
12
13
14
16
20
26
31
Day of 
discontinuation 
of trial product
5 weeks after 
discontinuation 
of trial product 
(last dose)
Visit window (days)
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+3
+3
+3
Dispense and/or collect
diary 
X
X
X
X
X
X
X
X
X
X
Dispense containers for 
urine sample collection
X
X
X
Footer
Description
xa
Subject can be randomised as soon as all inclusion and exclusion criteria are confirmed. The screening assessment must not exceed 2 weeks prior to 
randomisation (V2).
xb
Subjects who have discontinued trial product prematurely, are not required to attend V14 (Follow-up).
xc
V13A and V14A are only applicable for subjects who have discontinued trial product prematurely.


Protocol
UTN: U1111-1176-9230
Date:
06 April 2016
Status:
Final
Novo Nordisk
Trial ID: NN9924-4234
EudraCT no.: 2015-005326-19
Version:
1.0
Page:
22 of 129
xd
Only applicable for subjects on basal insulin: At randomisation the dose of basal insulin should be reduced by 20%. From week 10 to week 16 (P6 to P11)
the dose can be up-titrated based on 3 SMPGs prior to each visit (see xg) according to Section 5.3.2.1. From week 20 (V12) and until follow-up the basal 
insulin dose should be recorded according to Section 8.3.2.1
xe
No PK sampling should be done for visits occurring after V14A (subjects who have discontinued trial product prematurely).
xf
Samples should be taken for all subjects 25 (± 5) minutes and 40 (± 5) minutes post dosing.
xg
Only applicable for subjects on basal insulin: Pre-breakfast SMPG values should be measured fasting (for at least 6 hours) once-daily for 3 consecutive days 
prior to the phone contact/site 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 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
At randomisation, the antibody sampling must be done pre-dose. No antibody sampling should be done for visits occurring after V14A (subjects who have 
discontinued trial product prematurely).
xl
Adverse events reporting includes adverse events from the first trial-related activity after the subject has signed the informed consent at V1. Pre-existing
conditions identified as a result of the screening procedures should be reported as medical history.
xm
Subjects should collect a first morning urine sample both on the day prior to the visit and on the day of the visit.
xn
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:
06 April 2016
Novo Nordisk
Trial ID: NN9924-4234
Version:
1.0
UTN: U1111-1176-9230
Status:
Final
EudraCT no.: 2015-005326-19
Page:
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3
Background information and rationale for the trial
The trial will be conducted in compliance with this protocol, ICH GCP1 and applicable regulatory 
requirements, and in accordance with the Declaration of Helsinki2.
In this document, the term investigator refers to the individual responsible for the overall conduct of 
the clinical trial at a trial site.
3.1
Background information
3.1.1
Type 2 diabetes mellitus
Type 2 diabetes mellitus (T2DM) is a progressive metabolic disease primarily characterised by 
abnormal glucose metabolism. The pathogenesis is heterogeneous involving environmental, 
lifestyle and genetic factors leading to chronic hyperglycaemia caused by peripheral tissue insulin 
resistance, impaired insulin secretion due to abnormal beta-cell function and abnormal glucose 
metabolism in the liver3.
Optimal glycaemic control is the treatment goal in subjects with T2DM in order to prevent long-
term complications associated with chronic hyperglycaemia4. Despite the availability of several 
anti-diabetic drugs, a significant proportion of subjects with T2DM do not achieve the 
recommended targets for glycaemic control5, 6.
3.1.2
Glucagon-like peptide-1
Glucagon-like peptide-1 (GLP-1) is an incretin hormone with a glucose-dependent stimulatory 
effect on insulin and inhibitory effect on glucagon secretion from the pancreatic islets7, 8. 
Subjects with T2DM have a decreased incretin effect9-12. However, the insulinotropic action of 
GLP-1 and thus, the ability to lower blood glucose levels, is preserved when GLP-1 is administered 
at supraphysiological levels13. In addition, supraphysiological levels of GLP-1 induce reduction in 
body weight14. GLP-1 is a physiological regulator of appetite and food intake and GLP-1 receptors 
are present in several areas of the brain involved in appetite regulation15, 16. 
Physiologically, GLP-1 also has a pronounced inhibitory effect on gastric emptying; however this 
effect seems to diminish upon chronic exposure14-16. These mechanisms of action make glucagon-
like peptide-1 receptor agonists (GLP-1 RAs) an attractive pharmacological treatment for T2DM17-
19.
3.1.3
Oral semaglutide
Semaglutide is a long-acting GLP-1 RA structurally similar to liraglutide (Victoza®), a once-daily 
GLP-1 RA developed by Novo Nordisk and approved worldwide for the treatment of T2DM. 
Compared to human native GLP-1, which has a short half-life, the semaglutide molecule has three 
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
06 April 2016
Novo Nordisk
Trial ID: NN9924-4234
Version:
1.0
UTN: U1111-1176-9230
Status:
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EudraCT no.: 2015-005326-19
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minor but important modifications ensuring protraction of its action: amino acid substitutions at 
position 8 (alanine to alfa-aminoisobutyric acid, a synthetic amino acid) and position 34 (lysine to 
arginine) and acylation of the peptide backbone with a spacer and C-18 fatty di-acid chain to lysine 
in position 2620. The fatty di-acid side chain and the spacer mediate strong binding to albumin, 
thereby reducing renal clearance. The amino acid substitution at position 8 makes semaglutide less 
susceptible to degradation by dipeptidyl peptidase-4 (DPP-4). The change in position 34 from a 
lysine to an arginine is included to have only one lysine in the sequence 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 is based on the 
 concept developed by 
SNAC facilitates the absorption of semaglutide in a strictly time- and size-dependent manner, 
primarily via the transcellular route. The available data for semaglutide co-formulated with SNAC 
support that the absorption takes place in the stomach in a localised, buffered environment in close 
proximity of the tablet erosion. The absorption process is hampered if dosed with food, liquid or in 
the presence of significant stomach content. 
The absorption enhancement requires co-formulation between semaglutide and SNAC. Throughout 
this document “oral semaglutide” will refer to the drug product, that is, semaglutide co-formulated 
with 300 mg SNAC.
3.1.4
Nonclinical data
3.1.4.1
Semaglutide
The nonclinical programme for semaglutide was designed according to the ICH M3 guideline21 to 
support the clinical development. The standard nonclinical data package required to support phase 3 
clinical trials has been completed. In addition, 2-year carcinogenicity studies and a pre- and 
postnatal development toxicity study have been completed. Semaglutide was generally well 
tolerated in animals (mice, rats and cynomolgus monkeys). Two potential safety issues have been 
identified and these are detailed below.
Thyroid C-cell tumours in rodents
Treatment-related non-genotoxic proliferative changes in the thyroid C-cells of mice and rats were 
observed in 2-year carcinogenicity studies with semaglutide; thyroid hyperplasia was preceded by 
an increase in serum calcitonin. C-cell changes have not been observed in long-term studies in non-
human primate. The observed pattern of effects in mice and rats and lack of these effects in the non-
human primate and in man suggest that the mechanism by which semaglutide acts on the thyroid C-
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
06 April 2016
Novo Nordisk
Trial ID: NN9924-4234
Version:
1.0
UTN: U1111-1176-9230
Status:
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EudraCT no.: 2015-005326-19
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cells in rodents is the same as has been demonstrated for other GLP-1 RAs, including liraglutide. 
According to this mechanism, C-cell hyperplasia is mediated by the GLP-1 receptor and is not 
associated with RET (re-arranged during transfection) gene activation and rodents appear to be 
particularly sensitive, whereas humans are not. The relevance for human subjects is currently 
unknown, but considered to be low22.
Embryo−foetal development toxicity
Semaglutide caused embryo-foetal development toxicity in the rat through a GLP-1 receptor 
mediated effect on the inverted yolk sac placenta leading to impaired nutrient supply to the 
developing embryo. Primates do not have an inverted yolk sac placenta which makes this 
mechanism unlikely to be of relevance to humans and cynomolgus monkeys. In the developmental 
toxicity studies in cynomolgus monkey, a marked maternal body weight loss associated with the 
pharmacological effect of semaglutide coincided with increased early foetal loss; however, there 
was no indication of a teratogenic potential of semaglutide in this species.
A review of the results from the nonclinical studies can be found in the Investigator’s Brochure for 
subcutaneous (s.c.) administration of semaglutide (NN9535), edition 1023 and the Investigator’s
Brochure for oral administration of semaglutide (NN9924), edition 624, or any updates of these
documents.
3.1.4.2
SNAC
SNAC was developed as an absorption-enhancing excipient for the oral route of administration. The 
nonclinical programme to support clinical phase 3 development and marketing authorisation 
application submission has been conducted including a 26-week carcinogenicity study in transgenic 
rasH2 mice and a 2-year carcinogenicity study in Sprague-Dawley rats.
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
06 April 2016
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Trial ID: NN9924-4234
Version:
1.0
UTN: U1111-1176-9230
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The carcinogenicity studies demonstrated that SNAC was not carcinogenic to the transgenic rasH2 
mouse or the Sprague-Dawley rat. The doses tested covered total exposures of SNAC in plasma (in 
terms of area under the curve [AUC]) of 2-fold in the mouse and up to 44-fold in the rat when 
compared to the mean total exposure of SNAC in humans following a clinical dose of 300 mg 
SNAC/day.
A review of the SNAC results from the nonclinical studies can be found in the Investigator’s 
Brochure for oral administration of semaglutide (NN9924), edition 624, or any updates hereof.
3.1.5
Clinical data for oral semaglutide
A comprehensive clinical pharmacology programme including 12 trials has been completed, as well 
as a 26-week phase 2 dose-finding trial involving more than 600 subjects with T2DM.
For details on the individual trials, please see the Investigator’s Brochure for oral administration of 
semaglutide (NN9924) edition 624, or any updates hereof.
3.1.5.1
Pharmacokinetics
In the multiple-dose trial (NN9924-3991), oral semaglutide has demonstrated a long mean terminal 
half-life (t½) ranging from 153 to 161 hours (~1 week) and a median time to reach maximum 
observed concentration (tmax) ranging from 1 to 2 hours in healthy subjects. 
In multiple-dose pharmacokinetics (PK) trials, the exposure to oral semaglutide increased with 
increasing dose. Overall, the pharmacokinetic properties of semaglutide appeared similar in healthy 
subjects and in subjects with T2DM.
Exposure of semaglutide exhibits a substantially greater dose-to-dose variation following oral 
administration compared to s.c. administration. However, when administered orally once-daily the
PK properties of semaglutide, i.e. low clearance and long half-life, will limit the variation in 
exposure at steady state.
Data obtained following investigation of different dosing conditions for oral semaglutide have 
demonstrated that subjects should take the oral semaglutide tablet in the morning in a fasting state 
and at least 30 minutes before the first meal of the day. 
Drug-drug interaction investigations have explored the effect of oral semaglutide on the exposure to 
lisinopril, warfarin, metformin and digoxin as well as the effect of omeprazole on oral semaglutide 
and SNAC. It was demonstrated that oral semaglutide did not change the exposure to lisinopril, 
warfarin or digoxin, but increased the exposure to metformin when taken simultaneously. The 
increase in exposure to metformin may be related to delayed gastric emptying caused by 
semaglutide as observed for other GLP-1 RAs. Further, it was demonstrated that the exposure to 
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
06 April 2016
Novo Nordisk
Trial ID: NN9924-4234
Version:
1.0
UTN: U1111-1176-9230
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EudraCT no.: 2015-005326-19
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semaglutide appeared to be slightly higher when administered with omeprazole in comparison to 
semaglutide alone, but the effect was not statistically significant or considered clinically relevant.
In subjects with mild to end-stage renal impairment, the exposure to semaglutide appeared similar 
in subjects with normal and impaired renal function, whereas the exposure to SNAC was greater in 
subjects with impaired renal function than in subjects with normal renal function. The maximum 
concentration (Cmax) of SNAC appeared similar in subjects with normal and impaired renal 
function. The renal clearance of all SNAC metabolites was decreased in subjects with renal 
impairment.
In subjects with mild to severe hepatic impairment, the exposure to semaglutide appeared to be 
unaffected by the degree of hepatic impairment, whereas the exposure to SNAC (in terms of both 
AUC and Cmax) was increased for subjects with hepatic impairment as compared to subjects with 
normal hepatic function.
All tablets of oral semaglutide contain 300 mg of SNAC regardless of the semaglutide dose. SNAC 
is rapidly absorbed with a median tmax ranging from 0.35−0.5 hours in healthy subjects and from 
0.52−1.43 hours in subjects with T2DM. It is extensively metabolised and no accumulation of 
SNAC has been observed in clinical trials.
3.1.5.2
Efficacy
The efficacy of oral semaglutide in adult subjects with T2DM was investigated in a 26-week phase 
2 dose-finding trial (NN9924-3790). In this trial, placebo or one of the following doses of oral 
semaglutide were administered once-daily: 2.5, 5, 10, 20 and 40 mg.
Results from the trial showed that oral semaglutide effectively lowered glycosylated haemoglobin 
(HbA1c) and body weight. Placebo-adjusted reductions in HbA1c were dose-dependent and
statistically significant for all oral semaglutide treatment arms at week 26 (range: -0.40% to -
1.59%). Placebo-adjusted reductions in body weight were dose-dependent and statistically 
significant for oral semaglutide treatment doses of 10 mg and above at week 26 (range: -3.61 kg 
to -6.98 kg).
3.1.5.3
Safety
In the clinical trials completed so far, no unexpected safety findings have been identified for oral 
semaglutide administered up to 40 mg once daily. Consistent with other GLP-1 RAs, commonly 
reported AEs included nausea and vomiting, most of them were mild to moderate in severity. In line 
with findings for other GLP-1 RAs, an increase in heart rate and serum levels of lipase and amylase 
has also been observed in subjects exposed to oral semaglutide.
CONFIDENTIAL


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Trial ID: NN9924-4234
Version:
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UTN: U1111-1176-9230
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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 Investigator’s Brochure for oral administration of semaglutide 
(NN9924) edition 624, 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. Nevertheless, treatment with more efficacious injectable therapies such as GLP-1 
RAs and insulin are rarely added during the early stages of the disease. Oral semaglutide is the first 
GLP-1 RA in development in a tablet formulation and it has the potential of becoming a new 
attractive treatment option early in the treatment cascade due to its effects on both hyperglycaemia 
and body weight.
Considering that T2DM is often associated with renal impairment, anti-diabetic treatment options 
for this group of patients are limited. Chronic renal impairment is a slowly progressing condition 
and has multiple causes. The most common cause of chronic kidney disease (CKD) is diabetes 
mellitus and is found in about 40% of all patients with T2DM, and the second most common cause 
is hypertension.25, 26
A useful and recommended estimate of renal function can be obtained by estimated glomerular 
filtration rate (eGFR) and it can be categorised based on the Chronic Kidney Disease Epidemiology 
Collaboration (CKD-EPI) equation27. A normal glomerular filtration rate (GFR) varies according to 
many factors, including sex, age, body size and race. A number of formulas to estimate GFR on the 
basis of serum creatinine levels and the above factors have been developed. CKD is divided into 
five stages using a patient’s GFR28. Stage 1 is characterised by kidney damage with normal or 
increased GFR (≥ 90 mL/min/1.73 m2). Stage 2 is characterised by mild reduction in GFR 
(60-89 mL/min/1.73 m2) and stage 3 is characterised by moderate reduction in GFR 
(30-59 mL/min/1.73 m2). Guidelines distinguish between stage 3A (45-59 mL/min/1.73 m2) and 
stage 3B (30-44 mL/min/1.73 m2)29, 30. Stage 4 is characterised by severe reduction in GFR
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(15-29 mL/min/1.73 m2) and stage 5 is characterised by end-stage renal disease (GFR 
< 15 mL/min/1.73 m2, or permanent renal replacement therapy).
In many countries metformin is contraindicated in patients with moderate, severe or end-stage renal 
impairment due to concerns of increased risk of lactic acidosis, despite current data indicate that the 
overall risk of lactic acidosis associated with metformin is low. Most treatment guidelines propose 
that metformin should be used with caution at eGFR below 45 mL/min/1.73 m2 and discontinued 
when eGFR is below 30 mL/min/1.73 m2 or in clinical situations in which there is an increased risk 
of lactic acidosis31, 32. Sodium-glucose co-transporter-2 (SGLT-2)-inhibitors have compromised 
efficacy and restricted use, and dose reductions are required for all DPP-4 inhibitors except for 
linagliptin in subjects with renal impairment. Sulfonylurea (SU) may have an increased risk of 
hypoglycaemia in case of renal impairment and thiazolidinediones can cause fluid retention, which 
implies that these drugs should be used with caution in this population31, 32. Therefore, there is a 
need for additional treatment options and to establish the efficacy and safety of novel anti-diabetic 
treatments such as oral semaglutide in patients with T2DM and moderate renal impairment.
The purpose of this 26-week phase 3a trial is to establish efficacy and safety data of the highest 
dose (14 mg) of oral semaglutide versus placebo as add on to metformin and/or SU, basal insulin 
alone or metformin in combination with basal insulin in subjects with T2DM and moderate renal 
impairment. The safety and efficacy of oral semaglutide in subjects with mild renal impairment will 
be established based on data from other PIONEER trials.
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4
Objectives and endpoints
4.1
Objectives
4.1.1
Primary objective
To compare the effect of once-daily dosing of 14 mg oral semaglutide versus placebo, both in 
combination with metformin and/or sulfonylurea, basal insulin alone or metformin in combination 
with basal insulin on glycaemic control in subjects with type 2 diabetes mellitus and moderate renal 
impairment.
4.1.2
Secondary objectives
To compare the effect of once-daily dosing of 14 mg oral semaglutide versus placebo, both in 
combination with metformin and/or sulfonylurea, basal insulin alone or metformin in combination 
with basal insulin on body weight in subjects with type 2 diabetes mellitus and moderate renal 
impairment.
To compare the safety and tolerability of once-daily dosing of 14 mg oral semaglutide versus 
placebo, both in combination with metformin and/or sulfonylurea, basal insulin alone or metformin 
in combination with basal insulin in subjects with type 2 diabetes mellitus and moderate renal 
impairment.
4.2
Endpoints
Baseline refers to randomisation, and week 26 refers to 26 weeks after randomisation.
4.2.1
Primary endpoint
Change from baseline to week 26 in glycosylated haemoglobin (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 endpoints
Key supportive secondary endpoints prospectively selected for disclosure (e.g. clinicaltrials.gov and 
EudraCT) are marked with an asterisk (*).
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Supportive secondary efficacy endpoints
Change from baseline to week 26 in: 
!
Fasting plasma glucose (FPG)* 
!
Body weight (%) 
!
Body mass index (BMI) 
!
Waist circumference
!
Fasting lipid profile (total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density 
lipoprotein (HDL) cholesterol and triglycerides)
!
C-reactive protein (CRP)
!
Patient-reported outcomes (PROs)
–
Short Form (SF)-36v2TM (acute version) health survey
–
Diabetes Treatment Satisfaction Questionnaire – status version (DTSQs)
If a subject after week 26 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 
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Supportive secondary safety endpoints
!
Number of treatment-emergent adverse events (TEAEs) during exposure to trial product, 
assessed up to approximately 31 weeks*
!
Number of treatment-emergent severe or blood glucose-confirmed symptomatic hypoglycaemic 
episodes during exposure to trial product, assessed up to approximately 31 weeks*
!
Treatment-emergent severe or blood glucose-confirmed symptomatic hypoglycaemic episodes 
during exposure to trial product, assessed up to approximately 31 weeks (yes/no)
Change from baseline to week 26 in:
!
Haematology
!
Biochemistry
!
Estimated glomerular filtration rate (eGFR) as per Chronic Kidney Disease Epidemiology 
Collaboration formula (CKD-EPI)
!
Calcitonin
!
Urinalysis
!
Urinary albumin to creatinine ratio
!
Pulse
!
Systolic blood pressure
!
Diastolic blood pressure
!
Electrocardiogram (ECG) evaluation
!
Physical examination
Any occurrence of anti-semaglutide antibodies (yes/no) up to approximately 31 weeks:
!
Anti-semaglutide binding antibodies
!
Anti-semaglutide neutralising antibodies
!
Anti-semaglutide binding antibodies cross reacting with native GLP-1
!
Anti-semaglutide neutralising antibodies cross reacting with native GLP-1
Anti-semaglutide binding antibodies up to approximately 31 weeks:
!
Anti-semaglutide binding antibody levels.
Supportive secondary pharmacokinetic endpoints
!
Semaglutide plasma concentrations for population PK analyses
!
SNAC plasma concentrations
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5
Trial design
5.1
Type of trial
This is a 26-week, randomised, double-blind, placebo-controlled, parallel-group, multicentre,
multinational trial with 2 arms comparing the efficacy and safety of oral semaglutide with placebo 
in subjects with T2DM and moderate renal impairment.
Subjects inadequately controlled on metformin and/or SU, basal insulin alone or metformin in 
combination with basal insulin will be randomised 1:1 to receive one of the following treatments:
!
14 mg oral semaglutide once-daily
!
placebo once-daily
as add-on to their background medication.
Randomisation will be stratified according to renal function and antidiabetic background 
medication at screening (see Section 11) to ensure an even distribution of the two treatment arms 
within each stratum.
To maintain the blinding of the trial, all tablets containing oral semaglutide or placebo will be
identical with regards to visual appearance.
The total trial duration for the individual subject will be approximately 33 weeks. The trial includes 
a 2-week screening period, followed by a 26-week randomised treatment period and a follow-up 
period of 5 weeks.
The trial design is illustrated in Figure 5–1.
Figure 5–1
Trial design
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5.2
Rationale for trial design
The trial has been designed as a parallel-group, 2-armed trial to ensure a direct comparison between
oral semaglutide and placebo. The placebo arm has been chosen to ensure assay sensitivity by 
demonstrating glycaemic effect of oral semaglutide compared to placebo and to establish safety of 
oral semaglutide versus placebo in subjects with T2DM and moderate renal impairment.
Subjects will be randomised between the two treatment arms and the trial will be double-blinded. 
The randomisation will be stratified based on renal function and anti-diabetic background 
medication at screening to ensure an even distribution of the two treatment arms within strata.
The 26-week treatment duration is considered sufficient to ensure adequate time to compare the full 
effect on glycaemic control and body weight after dose escalation of oral semaglutide and 
adjustment of the basal insulin dose in a placebo-controlled trial.
The 5-week follow-up period is included to allow for wash-out of semaglutide and to prevent 
interference in the antibody assay.
5.3
Treatment of subjects
Treatment of subjects is summarised in Table 5–1.
Table 5–1
Treatment of subjects
Trial periods
Screening
Treatment 
period 1
Treatment 
period 2
Treatment 
period 3
Follow-up
First visit in each period
V1
V2
V4
V5
V13
Duration of each period
2 weeks
4 weeks
4 weeks
18 weeks
5 weeks
Treatment arm
N
Oral semaglutide
162
Screening
3 mg
7 mg
14 mg
Follow-up
Placebo
162
Screening
Placebo
Placebo
Placebo
Follow-up
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 once-daily and follow a fixed 
4-week dose escalation regimen until reaching the maximum treatment dose of 14 mg once-daily, as 
illustrated in Table 5–1. To mitigate the risk of gastrointestinal AEs it is important to follow the 
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fixed 4-week dose escalation intervals. The dose must not be changed during the course of the trial 
once the 14 mg 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.
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. The tablets can be taken with up to half a glass of water (approximately 
120 mL/4 fluid oz). The tablets must be swallowed whole by the subject and must not be broken or 
chewed (see Table 9–2). Furthermore, other oral medication can be taken 30 minutes after 
administration of trial product.
5.3.2
Background medication
After signing the informed consent, subjects must continue their anti-diabetic background 
medication (metformin alone, SU alone or in combination with metformin, basal insulin alone or in 
combination with metformin) throughout the entire trial. Metformin and SU must be maintained at 
the same dose level as given at trial entrance and with the same frequency during the entire
treatment period. For subjects on basal insulin (insulin glargine, insulin detemir, insulin degludec or 
NPH insulin) the dose should be reduced at randomisation to minimise the risk of hypoglycaemic
episodes when introducing an additional anti-diabetic agent (see Section 5.3.2.1). However, if a
subject has unacceptable hypoglycaemia on a background medication of SU or basal insulin during 
the trial, the dose of SU or basal insulin can be reduced. Finally, the background medication may be 
adjusted if rescue medication (see Section 6.4) is needed or a safety concern related to the 
background medication arises. If a subject experience persistent decline in renal function (eGFR 
available at randomisation, week 4, 8, 14, 26 and at the follow-up visit) on a background medication 
of metformin the treatment with metformin should be adjusted/discontinued according to the current 
approved local label or guideline due to the risk of lactic acidosis.
In addition, all background medication:
!
is considered to be non-investigational medicinal product
!
will not be provided by Novo Nordisk, except if required by local regulations
!
should be used in accordance with standard of care and current approved label for patients with 
moderate renal impairment in the individual country 
!
should not exceed the maximum approved dose in the individual country
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5.3.2.1
Basal insulin dose adjustment
Subjects on basal insulin should have the total daily insulin dose reduced by 20% at randomisation. 
Further reductions may be needed during the trial and in particular during escalation of oral 
semaglutide. After having reached the maximum dose of oral semaglutide (14 mg), basal insulin 
can be up-titrated by the investigator from week 10 to week 16 (P6 to P11) based on the lowest of 
three fasting (for at least 6 hours) pre-breakfast self-measured plasma glucose (SMPGs) values; 
preferably measured on three consecutive days prior to each phone contact/site visit (please see 
Table 5–2). However, the basal insulin dose should not be increased above the dose taken prior 
to randomisation. Increasing the basal insulin dose before week 10 should be avoided, unless 
required to control acute hyperglycaemia or to prevent acute diabetic complications (see Section 6.4
for further details).
In case of hypoglycaemia please see Table 5–3 for guidance on basal insulin dose reduction.
The basal insulin dose should otherwise remain stable during the trial.
Table 5–2
Increase of basal insulin dose
Lowest of 3 pre-breakfast SMPGs
Adjustment of total daily dose of basal insulin*
(during week 10 to week 16)
U
mmol/L
mg/dL
4.0 - 5.5
71 - 99
No adjustment
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
*Basal insulin dose should not be increased above the dose taken prior to randomisation
Table 5–3
Reduction of basal insulin dose
Lowest of 3 pre-breakfast SMPGs
Adjustment of total daily dose of basal insulin*
U
mmol/L
mg/dL
< 3.1
< 56
-4
(for doses > 45 U, suggest dose reduction of 10%)
3.1 - 3.9
56 - 70
-2
(for doses > 45 U, suggest dose reduction of 5%)
*No restrictions on minimum basal insulin doses
Subjects on basal insulin should continue to measure SMPG values regularly throughout the trial. 
Subjects will be instructed to inform the investigator in case of hypoglycaemia.
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 be switched to 
a suitable marketed product at the discretion of the investigator. After discontinuation of trial 
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product, GLP-1 RAs are not allowed before completion of the follow-up visit 5 weeks after the last 
date on trial product (to avoid interference with the antibody assay for oral semaglutide).
Throughout the protocol, last date on trial product is defined as date of the subject’s last dosage of 
trial product.
As this trial is a phase 3a trial, oral semaglutide will not be available for prescription until after 
marketing authorisation.
5.5
Rationale for treatment
For phase 3 development of 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. This regimen is expected to have the optimal benefit-risk profile 
for further development for treatment of T2DM in the PIONEER programme.
In this trial oral semaglutide will be dose escalated to the highest dose (14 mg) to investigate and 
establish the efficacy and safety of the highest dose of oral semaglutide in subjects with moderate 
renal impairment.
Placebo has been selected as comparator as most other oral anti-diabetic drugs approved for 
treatment of T2DM have restrictions or limitations for use in subjects with impaired renal function, 
and in order to establish the safety and efficacy of oral semaglutide vs placebo.
The duration of randomised treatments is considered adequate to collect sufficient data on efficacy 
and safety in accordance with the trial objectives. 
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6
Trial population
6.1
Number of subjects 
Number of subjects planned to be screened: 540
Number of subjects planned to be randomised: 324
Number of subjects expected to complete the trial on or off trial product: 292
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. 
3. Diagnosed with type 2 diabetes mellitus ≥ 90 days prior to day of screening.
4. HbA1c of 7.0-9.5% (53-80 mmol/mol) (both inclusive).
5. Moderate renal impairment defined as estimated glomerular filtration rate of 
30-59 mL/min/1.73 m2 as per Chronic Kidney Disease Epidemiology Collaboration formula
(CKD-EPI).
6. Stable daily dose(s) within 90 days prior to the day of screening of any of the following 
treatment regimens:
–
1-2 of the following oral anti-diabetic drugs:
- Metformin ≥ 1500 mg or maximum tolerated dose documented in the subject medical 
record), 
- Sulfonylurea (≥ half of the maximum approved dose according to local label or maximum 
tolerated dose as documented in subject medical record)
–
Basal insulin alone (20% change in total daily dose of insulin glargine, insulin detemir, 
insulin degludec or NPH insulin) 
or
–
Metformin (≥ 1500 mg or maximum tolerated dose documented in the subject medical 
record) in combination with basal insulin (20% change in total daily dose of insulin 
glargine, insulin detemir, insulin degludec or NPH insulin)
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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 Sweden only: Adequate contraceptive measures are: oral (except low-dose gestagen 
(lynestrenol and norestisteron)), injectable, or implanted hormonal contraceptives, intrauterine 
device, intrauterine system (for example, progestin-releasing coil), vasectomised male (with 
appropriate postvasectomy documentation of the absence of sperm in the ejaculate).
For The United Kingdom only: Adequate contraceptive measures are defined as established use 
of oral, intravaginal, transdermal combined estrogen and progestogen hormonal methods of 
contraception; oral, injected or implanted progestogen only hormonal methods of 
contraception; placement of an intrauterine device or intrauterine hormone releasing system, 
bilateral tubal occlusion, barrier methods of contraception (condom or occlusive cap with 
spermicidal foam/gel/film/cream/suppository), female sterilisation, vasectomised partner (where 
partner is sole partner of subject), or true abstinence (when in line with preferred and usual 
lifestyle).
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 or Medullary Thyroid 
Carcinoma.
7. History of pancreatitis (acute or chronic).
8. History of major surgical procedures involving the stomach potentially affecting absorption of 
trial product (e.g. subtotal and total gastrectomy, sleeve gastrectomy, gastric bypass surgery).
9. Any of the following: myocardial infarction, stroke or hospitalisation for unstable angina or 
transient ischaemic attack within the past 180 days prior to the day of screening and 
randomisation.
10. Subjects presently classified as being in New York Heart Association (NYHA) Class IV.
11. Planned coronary, carotid or peripheral artery revascularisation known on the day of screening.
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12. Subjects with alanine aminotransferase (ALT) > 2.5 x upper normal limit (UNL).
13. Rapidly progressing renal disease (e.g. such as acute glomerulonephritis) as judged by the 
investigator or known nephrotic albuminuria (> 2200 mg/24 hours or > 2200 mg/g).
14. Use of systemic immunosuppressive treatment within 90 days prior to screening.
15. Treatment with any medication for the indication of diabetes or obesity other than stated in the 
inclusion criteria in a period of 90 days before the day of screening. An exception is short-term 
insulin treatment for acute illness for a total of ≤ 14 days.
16. Known hypoglycaemic unawareness and/or recurrent severe hypoglycaemic episodes as judged 
by the investigator.
17. Proliferative retinopathy or maculopathy requiring acute treatment. Verified by fundus 
photography or dilated fundoscopy performed within 90 days prior to randomisation.
18. History or presence of malignant neoplasms within the last 5 years (except basal and squamous 
cell skin cancer and carcinoma in situ).
6.4
Rescue criteria
Subjects with persistent and unacceptable hyperglycaemia should be offered treatment 
intensification. To allow time for dose escalation to maximum dose of trial product, dose
adjustment of basal insulin, and to observe the expected effect of treatment on glycaemic 
parameters, rescue criteria will be applied from week 12 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 value (at the central laboratory) should be 
obtained by calling the subject for a re-test. If the confirmatory FPG value 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):
!
13.3 mmol/L (240 mg/dL) from week 12 to end of week 16
!
11.1 mmol/L (200 mg/dL) from week 17 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 investigator’s discretion as add-on to randomised treatment and according to 
ADA/European Association for the Study of Diabetes guidelines31, 32 (excluding GLP-RAs, 
DPP-4 inhibitors and amylin analogues). For subjects with basal insulin as part of their background 
medication, increase of basal insulin dose should be first choice.
Rescue medication and any changes hereto should be captured on the concomitant medication form 
in the electronic case report form (eCRF), see Section 8.2.4. Rescue medication is considered to be
non-investigational medicinal product and will not be provided by Novo Nordisk.
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6.5
Criteria for premature discontinuation of trial product 
All efforts should be made to keep the subject on trial product. However, the subject may be 
prematurely discontinued from trial product at the discretion of the investigator due to a safety 
concern.
The subject must be prematurely discontinued from trial product if the following applies:
1. Safety concern related to trial product or unacceptable intolerability
2. Included in the trial in violation of the inclusion and/or exclusion criteria
3. Pregnancy
4. Intention of becoming pregnant
5. Simultaneous participation in another clinical trial of an approved or non-approved 
investigational medicinal product
6. Calcitonin ≥ 100 ng/L
If a criterion for premature discontinuation of trial product is met, trial product should not be re-
initiated but subjects should continue with the scheduled site contacts.
See Section 8.1.5 for procedures to be performed for subjects discontinuing trial product 
prematurely.
6.6
Withdrawal from trial
The subject may withdraw consent at will at any time. The subject’s request to withdraw from the 
trial must always be respected. Only subjects who withdraw consent should be considered as 
withdrawn from trial.
See Section 8.1.6 for procedures to be performed for subjects withdrawing consent.
6.7
Subject replacement
Subjects who withdraw consent or discontinue trial product prematurely will not be replaced.
6.8
Rationale for trial population 
The trial population will include subjects with T2DM and moderate renal impairment treated with 
stable doses of metformin and/or SU, basal insulin alone or metformin in combination with basal 
insulin for at least 90 days prior to screening as changes in the background medication shortly 
before trial participation may potentially impact the data 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 treatment. The upper limit will ensure that subjects with severely dysregulated T2DM 
are not enrolled in this placebo-controlled trial. In addition, FPG and HbA1c will be monitored
throughout the trial and rescue medication should be initiated in subjects with persistent, 
unacceptable hyperglycaemia. Subjects with moderate renal impairment (eGFR of 
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30 - 59 mL/min/1.73 m2 as per CKD-EPI) will be included due to the objective of the trial. No BMI 
or blood pressure restrictions will be applied. Subjects with liver test abnormalities (ALT > 2.5 x 
UNL) will be excluded to avoid potential confounding of liver safety assessments. Subjects with 
hypoglycaemia unawareness will be excluded due to the increased risk of hypoglycaemia for 
subjects with moderate renal impairment treated with SU or basal insulin. Overall, the eligibility 
criteria will allow for enrolment of a relatively broad trial population resembling the target 
population in common practice.
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7
Milestones
Planned duration of recruitment period
First Subject First Visit (FSFV) – Last Subject First Visit (LSFV): 
36 weeks
Planned FSFV:
20-Sep-2016
Planned Last Subject Last Visit (LSLV):
22-Jan-2018
End of trial is defined as LSLV.
Recruitment:
The screening and randomisation rate will be followed closely via the interactive web response 
system (IWRS) in order to estimate when to stop screening. All investigators will be notified 
immediately when the recruitment period ends, after which no further subjects may be screened and 
the IWRS will be closed for further screening.
Trial registration:
Information of the trial will be disclosed at clinicaltrials.gov and novonordisk-trials.com. According 
to the Novo Nordisk Code of Conduct for Clinical Trial Disclosure33, it will also be disclosed 
according to other applicable requirements such as those of the International Committee of Medical 
Journal Editors (ICMJE)34, the Food and Drug Administration Amendment Act (FDAAA)35, 
European Commission Requirements36, 37 and other relevant recommendations or regulations. If a 
subject requests to be included in the trial via the Novo Nordisk e-mail contact at these web sites, 
Novo Nordisk may disclose the investigator’s contact details to the subject. As a result of increasing 
requirements for transparency, some countries require public disclosure of investigator names and 
their affiliations.
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8
Methods and assessments
8.1
Visit procedures
The following sections describe the assessments and procedures. These are also included in the flow 
chart (see Section 2). Informed consent must be obtained before any trial related activity, see 
Section 18.2.
Refer to flowchart (Section 2) for number and timing of visits and specific assessments to be 
performed.
Each subject will attend 8 site visits and 1 phone contact. Subjects taking basal insulin as 
background medication will have to attend 5 additional phone contacts (P6, P7, P8, P9 and P11) 
during the treatment period to adjust their basal insulin (see Section 5.3.2.1). It is the responsibility 
of the investigator to ensure that all visits/contacts occur according to the flow chart (see Section 2).
Planned visits can be conducted and re-scheduled within the allowed visit window. If a visit is 
missed and it is not possible to re-schedule, every effort should be made to ensure information is 
collected at a phone 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.
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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. Note that for all subjects, the required fasting period is longer at 
visits with PK sampling (see Section 8.6.1).
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:
!
FPG
!
fasting lipid profile (total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides)
!
SNAC PK
!
semaglutide PK
8.1.3
Randomisation and trial product administration
Eligible subjects will be randomised into one of two 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.
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Trial product (see Section 9) will be dispensed to the subject by the site, hospital pharmacy or 
equivalent at each site visit during the trial from randomisation to last visit before the end-of-
treatment visit (see Section 2). The investigator must document that subjects are 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 13) and Follow-up (visit 14)
Subjects, who stay on trial product throughout the trial, must attend the end-of-treatment visit (V13) 
26 weeks after randomisation and the follow-up visit (V14) 5 weeks after the last date on trial 
product (+3 days visit window). A completion call must be performed in the IWRS after completion 
of V13 (see Section 10).
In case the subject cannot be reached (by clinic visit or phone contact) at the scheduled V14, 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 (visit 13A and visit 14A)
Subjects, who discontinue trial product prematurely, should attend V13A scheduled to take place on 
the day of discontinuation of trial product (+3 days visit window). V14A 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 V13A (see Section 10).
If premature discontinuation of trial product is decided during a scheduled visit, the visit will be 
converted into a V13A and trial procedures must be performed accordingly.
Subjects should continue with the originally scheduled site contacts after V14A and up to and 
including V13. If necessary, in order to retain the subject in the trial, site visits can be replaced by 
phone contacts after V14A. 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 V13 (end-of-treatment) as this 
visit should be performed for all subjects, if at all possible (except subjects who withdraw informed 
consent, see Section 8.1.6).
Subjects, who only agree to attend or provide health status at the planned V13, should not be 
considered withdrawn from the trial. In case the subject cannot be reached (by clinic visit or phone 
contact) at the scheduled V13, 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 
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local law) to collect health status. If no health status can be collected, the subject should be 
considered lost to follow-up and this should be specified in the end-of-trial form.
In summary, subjects should stay in the trial irrespective of lack of adherence to randomised 
treatment, lack of adherence to visit schedule, missing assessments or trial product discontinuation 
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
Withdrawal from trial
If a subject considers withdrawing from the trial, the investigator must aim to undertake procedures 
for V13A as soon as possible and V14A should be scheduled 5 weeks (+3 days visit window) after 
the last date on trial product, if the subject agrees to it.
The end-of-trial form must be completed, and final drug accountability must be performed even if 
the subject is not able to come to the trial site. A treatment discontinuation session must be made in 
the IWRS (see Section 10). The case book must be signed.
Although a subject is not obliged to give his/her reason(s) for withdrawing consent, the investigator 
must make a reasonable effort to ascertain the reason(s), while fully respecting the subject’s rights. 
Where the reasons are obtained, the primary reason for withdrawing consent must be specified in 
the end-of-trial form in the eCRF.
8.1.7
Investigator assessments
Review of diaries, PROs, laboratory reports, ECGs and fundus photography/dilated fundoscopy
must be documented either on the documents or in the subject’s medical record.
If clarification of entries or discrepancies in the diary or PROs is needed, the subject must be 
questioned and a conclusion made in the subject’s medical record. Care must be taken not to bias 
the subject.
The documents must be retained at the site as source documentation.
For ECGs, physical examinations and eye examinations, the evaluations must follow the categories:
!
Normal
!
Abnormal
–
Was the result clinically significant? (yes/no)
The evaluation should be based on investigator’s judgement.
For laboratory report values outside the reference range, the investigator must specify whether the 
value is clinically significant or not clinically significant. All laboratory printouts must be signed 
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and dated by the investigator prior to the following visit. The signed laboratory report is retained at 
the site as source documentation.
In case of abnormal clinically significant findings found as a result of screening procedures 
conducted at V1 or assessments revealing baseline conditions at V2, the investigator must state a 
comment in the subject’s medical record and record this in the medical history/concomitant illness 
form in the eCRF. 
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
Please note that diabetic nephropathy should be reported on the disease specific form Renal 
impairment history and that macroangiopathy (including peripheral arterial disease) should be 
reported on the disease specific form History of cardiovascular disease (see Section 8.2.3).
8.2.3
Concomitant illness and medical history
A concomitant illness is any illness that is present at the start of the trial (V1) or found as a result 
of a screening procedure or other trial procedures performed before exposure to trial product.
Medical history is a medical event that the subject has experienced in the past. Only relevant 
medical history as judged by the investigator should be reported.
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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:
!
Renal impairment history (e.g. hypertension, diabetes, chronic glomerulonephritis incl. date of 
diagnosis)
!
History of cardiovascular disease (e.g. ischaemic heart disease, myocardial infarction, heart 
failure incl. NYHA class, hypertension, stroke, peripheral arterial disease)
!
History of gallbladder disease (e.g. gallstone, cholecystitis, cholecystectomy)
!
History of gastrointestinal disease (e.g. gastroesophageal reflux disease, ulcer disease, chronic 
gastritis)
Any change to a concomitant illness should be recorded during the trial. A clinically significant 
worsening of a concomitant illness must be reported as an AE (see Section 12).
It must be possible to verify the subject’s medical history in source documents such as subject’s 
medical record. If a subject is not from the investigators own practice; the investigator must make 
reasonable effort to obtain a copy of subject’s medical record from relevant party e.g. primary 
physician. The investigator must document any attempt to obtain external medical information by 
noting the date(s) when information was requested and who has been contacted.
8.2.4
Concomitant medication
A concomitant medication is any medication, other than the trial 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 dose
If a change is due to an AE, then this must be reported according to Section 12. If the change 
influences the subject’s eligibility to continue in the trial, the monitor must be informed.
8.2.5
Childbearing potential
It must be recorded in the eCRF whether female subjects are of childbearing potential.
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Pregnancy testing must be performed on female subjects of childbearing potential as described in 
Section 8.4.7. Female subjects of childbearing potential must be instructed to use adequate 
contraceptive methods throughout the trial and until 5 weeks after end of treatment.
For Sweden only: Adequate contraceptive measures are: oral (except low-dose gestagen 
(lynestrenol and norestisteron)), injectable, or implanted hormonal contraceptives, intrauterine 
device, intrauterine system (for example, progestin-releasing coil), vasectomised male (with 
appropriate postvasectomy documentation of the absence of sperm in the ejaculate).
For The United Kingdom only: Adequate contraceptive measures are defined as established use of 
oral, intravaginal, transdermal combined estrogen and progestogen hormonal methods of 
contraception; oral, injected or implanted progestogen only hormonal methods of contraception; 
placement of an intrauterine device or intrauterine hormone releasing system, bilateral tubal 
occlusion, barrier methods of contraception (condom or occlusive cap with spermicidal 
foam/gel/film/cream/suppository), female sterilisation, vasectomised partner (where partner is sole 
partner of subject), or true abstinence (when in line with preferred and usual lifestyle).
Female of non-childbearing potential is defined as:
!
Female who has undergone a hysterectomy, bilateral oophorectomy or bilateral tubal ligation 
!
Postmenopausal defined as no menses for 12 months without an alternative medical cause
!
Other medical reasons preventing childbearing potential
8.2.6
Tobacco use
Details of tobacco use must be recorded at V1. Smoking is defined as smoking at least one cigarette 
or equivalent daily.
Smoking status:
!
Never smoked
!
Previous smoker, smoking stop date
!
Current smoker
8.3
Efficacy assessments
8.3.1
Laboratory assessments for efficacy
For overall laboratory process see Section 8.5.
Blood samples will be drawn according to flow chart (see Section 2) and will be analysed at the 
central laboratory to determine levels of the following efficacy laboratory parameters:
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Glucose metabolism:
!
HbA1c
!
FPG (see Section 8.3.1.1)
Fasting lipid profile:
!
Total cholesterol
!
LDL-cholesterol
!
HDL-cholesterol
!
Triglycerides
Other parameters:
!
CRP
!
Semaglutide PK (see Section 8.6.1.1)
!
SNAC PK (see Section 8.6.1.2)
8.3.1.1
Fasting plasma glucose
FPG is measured at central laboratory in order to evaluate glycaemic control. The subject must 
attend these visits fasting (see Section 8.1.2).
A central FPG result ≤ 3.9 mmol/L (70 mg/dL) in relation to planned fasting visits should not be 
reported as a hypoglycaemic episode but as a clinical laboratory adverse event (CLAE) at the 
discretion of the investigator (see Section 12.1.1).
8.3.2
Self-measured plasma glucose (SMPG)
At V2, subjects will be provided with a blood glucose meter including auxiliaries as well as 
instructions for use. The subjects will be instructed in how to use the device, and the instruction will 
be repeated as necessary during the trial.
The blood glucose 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 blood glucose meter provided by Novo Nordisk should be used for the measurements 
required in the protocol.
All subjects should use the provided blood glucose meter for SMPG measurements in relation to 
hypoglycaemic episodes. For subjects with basal insulin as background medication fasting SMPG 
values should also be measured prior to insulin adjustment as outlined in Section 5.3.2.1 and 
Section 8.3.2.1.
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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 blood glucose 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
Basal insulin dose adjustment
For subjects on basal insulin as background medication the investigator should at V2 record the 
subject’s total daily dose of basal insulin prior to the visit and after dose reduction in the eCRF.
The investigator should from week 10 to week 16 (P6 to P11) review the subject’s basal insulin 
dose as specified in Section 2 and Section 5.3.2. Results of the subject’s SMPG measurements and 
total daily dose of basal insulin prior to each contact will be transcribed into the eCRF and based on 
these, dose adjustment guidance will be provided. Reason for deviation from dose adjustment 
guidance will be recorded in the eCRF. All adjustments of basal insulin dose level will be captured 
in the eCRF. From V12 and until follow-up the investigator should record the subject’s total daily 
dose of basal insulin prior to each visit in the eCRF.
8.3.3
Body weight and height
Body weight must be measured and recorded in the eCRF in kilogram or pound (kg or lb), with one 
decimal (with an empty bladder, without shoes and only wearing light clothing). The body weight 
should be assessed on the same calibrated weighing scale equipment throughout the trial, if 
possible.
Height is measured without shoes in centimetres or inches and recorded in the eCRF to nearest 
½ cm or ¼ inch.
8.3.4
Waist circumference
The waist circumference is defined as the minimal abdominal circumference located midway 
between the lower rib margin and the iliac crest.
The measurement of waist circumference must be performed and recorded in the eCRF. Waist 
circumference is measured in the horizontal plane and rounded up or down to the nearest ½ cm or 
¼ inches using a non-stretchable measuring tape. The same measuring tape should be used 
throughout the trial.
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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
PROs will be assessed using the questionnaires:
!
Short Form (SF)-36v2™(acute version) health survey38-40
!
Diabetes Treatment Satisfaction Questionnaire – status version (DTSQs)41
The questionnaires must be completed by the subject as specified in the flow chart, see Section 2, 
preferably before any other trial-related activities for that visit. It takes approximately ten minutes 
to complete the two questionnaires. Subjects should be given the opportunity to complete the 
questionnaires by themselves without interruption. The completed questionnaires must be reviewed 
for potential AEs and missing data while the subject is still at the site. All results from the PRO 
questionnaires must be transferred into the eCRF.
All the questionnaires will be translated to local languages, and also be linguistically validated 
before being handed out to the subjects participating in the trial. 
Short Form (SF)-36v2TM (acute version) health survey
The Short Form (SF)-36v2™(acute version) health survey measures the individual overall health 
related quality of life on 8 domains; Physical functioning, Role physical, Bodily pain, General 
health, Vitality, Social functioning, Role emotional and Mental health. The acute version’s 
questions are based on a recall period of one week. The Short Form (SF)-36v2™(acute version) 
health survey contains 36 items.
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.
8.4
Safety assessments
8.4.1
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, 
Section 12.1.5 and appendix B):
!
Trial products involved
!
Classification of medication error
!
Whether the subject experienced any hypoglycaemic episode and/or AE(s) as a result of the 
medication error 
!
Suspected primary reason for the medication error 
For definition of medication errors, see Section 12.1.4 and appendix B.
8.4.1.2
Adverse events requiring additional data collection 
For the following AEs additional data collection is required and specific event forms must be 
completed in the eCRF in addition to the AE form:
!
Acute coronary syndrome (myocardial infarction or hospitalisation for unstable angina)
!
Cerebrovascular event (stroke or transient ischaemic attack)
!
Heart failure
!
Pancreatitis
!
Neoplasm (excluding thyroid neoplasm)
!
Thyroid disease (including thyroid neoplasm)
!
Renal event
!
Hypersensitivity reaction
!
Acute gallstone disease
!
Medication error
!
Lactic acidosis
!
Creatine kinase (CK) > 10 x UNL
!
Hepatic event defined as:
–
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 > 3x UNL and total bilirubin 
> 2x UNL, where no alternative aetiology exists (Hy's law), this must be reported as an SAE using 
the important medical event criterion if no other seriousness criteria are applicable.
See Section 12 and appendix B for details about the additional information to report.
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Note that additional assessments will be required according to appendix B in case of:
!
suspicion of acute pancreatitis
!
suspicion of hypersensitivity reaction
!
increased levels of CK
!
increased levels of aminotransferase
In case any of these events fulfil the criteria for a SAE, please report accordingly, see Section 12.
8.4.2
Physical examination
A physical examination will be performed by the investigator according to local procedure (see 
Section 2 and Section 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 resting for 5 minutes in a 
sitting position.
8.4.4
Eye examination 
Fundus photography or dilated fundoscopy will be performed as per flow chart (see Section 2) by 
the investigator or according to local practise. Results of the fundus photography or dilated 
fundoscopy will be interpreted by the investigator (see Section 8.1.7).
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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 flow chart (see Section 2) and the assessment must be 
reviewed as described in Section 8.1.7 by the investigator. The ECGs will also undergo central 
assessment and the investigator must forward the ECGs to the central ECG reader as soon as 
possible.
If the central ECG evaluation of a baseline ECG is suggestive of a prior myocardial infarction, the 
investigator will be notified. The investigator should consider if an update of the History of 
cardiovascular disease form is required.
If the central ECG evaluation of a post-baseline ECG is suggestive of new myocardial infarction, 
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 myocardial infarction 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.
8.4.6.1
Blood samples for safety
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 as per CKD-EPI42
!
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.
Other parameters:
!
Anti-semaglutide antibodies (see Section 8.4.8)
8.4.6.2
Urine samples for safety
Urine sampling will be according to flow chart (see Section 2). For the specified visits subjects will 
be asked to collect a first morning urine sample both on the day prior to the visit and on the day of 
the visit and bring the samples to the site. For information on collection, storage and transport to the 
site please refer to the laboratory manual. Urine samples from the day of the visit will be analysed 
at the central laboratory to determine levels of the following safety laboratory parameters:
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!
Urinary albumin to creatinine ratio
!
Urinalysis by dip-stick:
–
Leucocytes
–
Erythrocytes
–
Nitrit
The additional urine sample collected the day before the visit will be analysed at the central 
laboratory for urinary albumin to creatinine ratio only.
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 8.2.5.
In case a menstrual period is missed or if pregnancy is suspected between the scheduled visits, a 
urine pregnancy test should be performed. Investigator should instruct the subject to contact the site 
in case the pregnancy test is positive. At V2, females of childbearing potential will be provided with 
a urine dip-stick pregnancy test.
8.4.8
Anti-semaglutide antibodies
Blood samples will be drawn for measurement of antibodies against semaglutide at selected visits 
(see Section 2). Positive anti-semaglutide binding antibody samples will be further characterised for 
cross reactivity to native GLP-1. Samples which are positive for anti-semaglutide binding 
antibodies will be further characterised for in vitro neutralising effect towards semaglutide. In 
addition, samples which are positive for antibodies cross-reacting with native GLP-1 will be further 
analysed for in vitro neutralising effect towards native GLP-1.
Furthermore, samples drawn at randomisation may be used for calculations of the neutralising effect 
in the in vitro neutralising antibody assays. The in vitro neutralising assays will be performed by 
Novo Nordisk.
At randomisation, the antibody sampling must be done pre-dose.
Antibody samples will be stored as described in Section 24.2.
8.4.9
Hypoglycaemic episodes
Plasma glucose should always be measured and recorded when a hypoglycaemic episode is 
suspected.
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All plasma glucose values:
!
≤ 3.9 mmol/L (70 mg/dL) or 
!
> 3.9 mmol/L (70 mg/dL) occurring in conjunction with hypoglycaemic symptoms
should be reported in the diary according to the instructions below throughout the trial from V1 to 
end of trial.
Upon onset of a hypoglycaemic episode the subject is recommended to measure plasma glucose
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 guidelines43.
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 plasma glucose 
value is > 3.9 mmol/L (70 mg/dL) and/or symptoms have been resolved).
If a stop date and time is not reported, a hypoglycaemic episode will cover a period of 60 
minutes.
!
The plasma glucose level before treating the episode (if available) and any follow up 
measurements. 
The lowest value measured during the hypoglycaemic episode will be reported as the plasma 
glucose value for the episode, the remaining values will be kept as source data 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.
!
Date and time of last trial product administration, and for selected anti-diabetic medications 
administered prior to the episode, date and time as well as dose must be collected.
!
Date and time of last main meal (not including snacks) prior to the episode.
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!
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. Plasma glucose concentrations may not be available during an event, 
but neurological recovery following the return of plasma glucose to normal is considered sufficient 
evidence that the event was induced by a low plasma glucose concentration43.
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 symptoms44 (layman term used in the diary is 
specified in brackets if different from the protocol term)?
–
Autonomic: sweating, trembling, hunger or palpitations (rapid or irregular heart beat)
–
Neuroglycopenic: confusion, drowsiness, speech difficulty, visual disturbances, odd 
behaviour, impaired balance or incoordination (reduced ability to coordinate movement)
–
General malaise: headache or malaise (feeling discomfort/unease)
!
Other symptoms
The Investigator must review the diary for low SMPG values not reported as hypoglycaemic 
episodes (only applicable for subjects on basal insulin as background medication; see Section 2 for 
relevant visits). The subject must be questioned whether any of the low values were severe, i.e. 
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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 data45, 46
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 must also be filled in, see Section 12.
8.5
Laboratory assessments
The laboratory analyses will mainly be performed by a central laboratory. Anti-semaglutide 
antibodies, in vitroneutralising effectto semaglutide and GLP-1, IgE anti-semaglutide antibodies 
and PK samples will be analysed by a special laboratory and Novo Nordisk(see Sections 8.4.8and 
Section8.6.1). For some of the analyses related to suspicion of acute pancreatitis and 
hypersensitivity reactions, 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 on-going basis.
However, anti-semaglutide antibodyresults,semaglutideand SNACplasma concentration results 
will not be available to the investigator during the trial. These results will be provided to the 
investigator upon request after the completion of the clinical trial report.
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.
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The laboratory equipment may provide analyses not requested in the protocol but produced 
automatically in connection with the requested analyses according to specifications in the laboratory 
standard operating procedures. Such data will not be transferred to the trial database, but abnormal 
values will be reported to the investigator. 
The investigator must review all laboratory results for concomitant illnesses and AEs and report 
these according to Section 8.2.3 and Section 12.
Laboratory samples will be destroyed no later than at finalisation of the clinical trial report, or 
according to local regulations, except samples obtained for antibody analysis. Antibody samples 
will be stored as described in Section 24.2.
8.6
Other assessments
8.6.1
Pharmacokinetics
Blood samples will be drawn for assessment of plasma concentration of semaglutide and SNAC at 
selected visits (see Section 2). The semaglutide concentrations will be used for population PK 
analysis.
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 PK responsible laboratory will be provided with the randomisation list and only samples from 
subjects treated with oral semaglutide will be analysed for semaglutide and SNAC plasma 
concentrations.
Semaglutide PK and SNAC PK samples will be stored at the specialised laboratory until final 
clinical trial report in case Novo Nordisk request further analysis of the PK samples.
8.6.1.1
Semaglutide PK sampling
Samples for semaglutide PK can be drawn at any time during the visit. For simplicity it is 
recommended to take the sample for semaglutide PK together with biochemistry samples at all 
visits requiring semaglutide PK.
The date and exact time of the latest trial product administration prior to semaglutide PK sampling 
must be recorded in the diary and entered into the eCRF. The date and time of sampling must be 
recorded on the laboratory requisition form.
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8.6.1.2
SNAC PK sampling
Samples for SNAC PK should be drawn at the following time points in relation to dosing of trial 
product:
!
25 (± 5) minutes post-dosing
!
40 (± 5) minutes post-dosing
At visits with sampling of SNAC PK trial product must be taken at site. The subject must be fasting 
and not take any other oral medication until last sample has been taken. See Section 8.1.2 in case 
the subject attends the visit in a non-fasting state.
The date and exact time of dosing of trial product must be recorded in the medical record and 
entered into the eCRF. The date and exact time of sampling must be recorded at the laboratory 
requisition form.
8.6.2
Subject diary
The diaries should be handed out at the visits described in the flow chart Section 2. The recordings 
must be reviewed as described in Section 8.1.7 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 exact time of last trial product administration on the day prior to sampling of 
semaglutide PK
!
date and total daily dose of basal insulin on the day prior to V2 and prior to each site contact 
from week 10 to follow-up visit (only applicable for subjects on basal insulin as background 
medication)
!
hypoglycaemic episodes
!
changes in concomitant medication
!
AEs
!
SMPG values in relation to hypoglycaemic episodes (all subjects)
!
SMPG values in relation to insulin dose adjustment from week 10 to week 16 (only applicable 
for subjects on basal insulin as background medication)
8.7
Subject compliance
Throughout the trial, the investigator will remind the subjects to follow the trial procedures and 
requirements to ensure subject compliance. 
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Treatment compliance: Will be assessed by monitoring of drug accountability. Prior to visits 
where drug accountability is performed, the subject will be asked to return all used, partly used and 
unused trial products. The investigator must assess the amount of trial products returned compared 
to what was dispensed at the last dispensing visit and, in case of discrepancies, question the subject.
If a subject is found to be non-compliant, the investigator will remind the subject of the importance 
of following the instructions given including taking the trial products as prescribed and should 
document this discussion in the subject’s medical record.
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9
Trial supplies
Trial supplies comprise trial products and auxiliary supplies. Additional details regarding trial 
supplies can be found in the Trial Materials Manual.
Trial products must not be dispensed to any person not included in the trial.
9.1
Trial products
The following trial products are considered as investigational medicinal products and will be 
provided by Novo Nordisk A/S, Denmark:
Table 9–1
Investigational medicinal products
Trial product
Strength
Dosage form
Route of
administration
Container/
delivery device
Semaglutide 3 mg tablet 
3 mg
Tablet
Oral
Dosepacka
Semaglutide 7 mg tablet
7 mg
Semaglutide 14 mg tablet 
14 mg
Placebo tablet 
N/A
aOne dosepack contains one blister card.
Metformin, SU, basal insulin (insulin glargine, insulin detemir, insulin degludec or NPH insulin) 
and rescue medication are considered non-investigational medicinal products and will not be 
supplied by Novo Nordisk. However, metformin, SU and basal insulin (insulin glargine, insulin 
detemir, insulin degludec or NPH insulin) will be reimbursed if required by the country’s regulatory 
authority or institutional review board (IRB)/independent ethics committee (IEC).
“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.”
For semaglutide, the active drug tablets and the corresponding placebo tablets are identical with 
regard to visual appearance; and all semaglutide tablets are visually identical to each other, 
irrespective of dose levels.
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9.2
Labelling
The trial products will be labelled in accordance with Annex 1347, local regulations and trial 
requirements.
Each trial site will be supplied with sufficient trial products for the trial on an on-going basis 
controlled by the IWRS. Trial product will be distributed to the trial sites according to enrolment 
and randomisation.
9.3
Storage
Storage conditions of the trial products are outlined in Table 9–2.
Table 9–2
Storage conditions for investigational medicinal products
Trial product
Storage conditions
(not-in-use)
In-use conditions
Semaglutide 3 mg tablet
Do not store above 30ºC (86ºF)
Do not freeze
Do not refrigerate
Store in the original package
Take the tablet immediately 
after dispensation from 
blister card
Take the tablets whole:
Do not break or chew
Semaglutide 7 mg tablet
Semaglutide 14 mg tablet
Placebo tablet
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 Trial Materials Manual.
Trial product that has been stored improperly must not be dispensed to any subject before it has 
been evaluated and approved for further use by Novo Nordisk. The investigator must take 
appropriate action to ensure correct storage.
9.4
Drug accountability and destruction
Drug accountability of all trial products received at site is the responsibility of the investigator.
Subjects must be instructed to return all used, partly used and unused trial products including empty 
packaging material at each dispensing visit.
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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 on-going basis and will be done according to 
local procedures after accountability is finalised and reconciled by the monitor. Destruction of 
products must be documented in the IWRS.
9.5
Auxiliary supplies
The following will be provided by Novo Nordisk in accordance with the Trial Materials Manual:
•
Blood glucose meters and blood glucose meter auxiliaries
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10
Interactive voice/web response system
A trial-specific IWRS will be set up which can be accessed at any time via the internet or telephone. 
Access to the IWRS must be restricted to and controlled by authorised persons. 
IWRS is used for: 
!
Screening
!
Screening failure
!
Randomisation
!
Medication arrival
!
Dispensing
!
Treatment discontinuation
!
Completion
!
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 
two parallel treatment arms as described in Section 5.1.
Randomisation will be stratified based on two factors; renal function including two levels and 
antidiabetic background medication at screening including 3 levels:
!
Renal function (eGFR 30 - 44 mL/min/1.73 m2 and eGFR 45 - 59 mL/min/1.73 m2 as per CKD-
EPI)
!
Antidiabetic background medication at screening (metformin alone, SU alone or in combination 
with metformin, basal insulin alone or in combination with metformin)
to ensure an even distribution of the two treatment arms within the six strata.
At least 40% of the subjects must be randomised to the low eGFR strata.
Centralised treatment allocation will be applied for this trial.
11.1
Breaking of blinded codes
The IWRS will notify Novo Nordisk (monitor and the Global Safety department) immediately after 
the code is broken.
The code for a particular subject may be broken in a medical emergency if knowing the actual 
treatment would influence the treatment of the subject. Whenever a code is broken the person 
breaking the code must print the Code Break Confirmation Notification generated by the IWRS, 
record the reason, and sign and date the document.
When the code is broken, the treatment allocation will be accessible to the investigator and the 
Novo Nordisk Global Safety department. If IWRS is not accessible at the time of code break the 
IWRS helpdesk should be contacted. Contact details are listed in Attachment I. If the code has been 
broken, the subject 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 IWRS.
The laboratory responsible for antibody and pharmacokinetic analysis and the responsible 
development bioanalysis scientist in Novo Nordisk will have access to the unblinding report in the 
IWRS.
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12 Adverse events, technical complaints and pregnancies
12.1
Definitions
12.1.1
Adverse event
An AE is any untoward medical occurrence in a subject administered a medicinal product, and 
which does not necessarily have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom or disease temporally associated with the use of a product, whether or not 
considered related to the product.
An AE includes:
!
A clinically significant worsening of a concomitant illness.
!
A CLAE: a clinical laboratory abnormality which is clinically significant, i.e. an abnormality 
that suggests a disease and/or organ toxicity and is of a severity that requires active 
management. Active management includes active treatment or further investigations, for 
example change of medicine dose or more frequent follow-up due to the abnormality.
The following should not be reported as AEs:
!
Pre-existing conditions, including those found as a result of screening or other trial procedures 
performed before exposure to trial product (pre-existing conditions should be reported as 
medical history or concomitant illness).
!
Pre-planned procedures unless the condition for which the procedure was planned has worsened 
from the first trial related activity after the subject has signed the informed consent.
!
Non-serious hypoglycaemia is an AE, but is reported on a hypoglycaemic episode form instead 
of on an AE form, see Section 8.4.9.
The following three definitions are used when assessing an AE:
!
Severity
–
Mild - no or transient symptoms, no interference with the subject’s daily activities.
–
Moderate - marked symptoms, moderate interference with the subject’s daily activities.
–
Severe - considerable interference with the subject’s daily activities; unacceptable.
!
Causality
Relationship between an AE and the relevant trial product(s): 
–
Probable - Good reason and sufficient documentation to assume a causal relationship.
–
Possible - A causal relationship is conceivable and cannot be dismissed.
–
Unlikely - The event is most likely related to aetiology other than the trial product.
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!
Final outcome
–
Recovered/resolved - The subject has fully recovered, or by medical or surgical treatment 
the condition has returned to the level observed at the first trial-related activity after the 
subject signed the informed consent.
–
Recovering/resolving - The condition is improving and the subject is expected to recover 
from the event. This term is only applicable if the subject has completed the trial or has died 
from another AE.
–
Recovered/resolved with sequelae - The subject has recovered from the condition, but 
with lasting effect due to a disease, injury, treatment or procedure. If a sequela meets an 
SAE criterion, the AE must be reported as an SAE.
–
Not recovered/not resolved - The condition of the subject has not improved and the 
symptoms are unchanged, or the outcome is not known.
–
Fatal - This term is only applicable if the subject died from a condition related to the 
reported AE. Outcomes of other reported AEs in a subject before he/she died should be 
assessed as "recovered/resolved", "recovering/resolving", "recovered/resolved with 
sequelae" or "not recovered/not resolved". An AE with fatal outcome must be reported as an 
SAE.
–
Unknown - This term is only applicable if the subject is lost to follow-up.
12.1.2
Serious adverse event
A serious adverse event (SAE) is an experience that at any dose results in any of the following:
!
Death.
!
A life-threateninga experience.
!
In-patient hospitalisationb or prolongation of existing hospitalisation.
!
A persistent or significant disability or incapacityc.
!
A congenital anomaly or birth defect.
!
Important medical events that may not result in death, be life threateninga or require 
hospitalisationb may be considered an SAE when - based on appropriate medical judgement -
they may jeopardise the subject and may require medical or surgical intervention to prevent one 
of the outcomes listed in the definition of SAEd.
a
The term "life threatening" in the definition of SAE refers to an event in which the subject was 
at risk of death at the time of the event. It does not refer to an event which hypothetically might 
have caused death if it was more severe.
b
The term "hospitalisation" is used when a subject:
–
Is admitted to a hospital or in-patient, irrespective of the duration of physical stay, or 
–
Stays at the hospital for treatment or observation for more than 24 hours
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Medical judgement must always be exercised, and when in doubt, the hospital contact should be 
regarded as a hospitalisation. Hospitalisations for administrative, trial related and social 
purposes do not constitute AEs and should therefore not be reported as AEs or SAEs. Hospital 
admissions for surgical procedures, planned before trial inclusion, are not considered AEs or 
SAEs.
c
A substantial disruption of a subject’s ability to conduct normal life functions (e.g. following the 
event or clinical investigation the subject has significant, persistent or permanent change, 
impairment, damage or disruption in his/her body function or structure, physical activity and/or 
quality of life).
d
For example intensive treatment in an emergency room or at home of allergic bronchospasm, 
blood dyscrasia or convulsions that do not result in hospitalisation, or development of drug 
dependency or drug abuse.
The following AEs must always be reported as an SAE using the important medical event criterion
if no other seriousness criteria are applicable:
!
suspicion of transmission of infectious agents via the trial product
!
risk of liver injury defined as ALT or AST > 3 x UNL and total bilirubin > 2 x UNL, where no 
alternative aetiology exists (Hy's law).
Additional assessments should be made for events meeting the criterion of Hy’s law as stated above 
(see appendix B).
12.1.3
Non-serious adverse event
A non-serious AE is any AE which does not fulfil the definition of an SAE.
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12.1.4
Medication errors
A medication error concerning trial products is defined as:
!
Administration of wrong drug.
Note: Use of wrong DUN is not considered a medication error.
!
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.
Medication errors must be reported on an AE form and a specific event form, see Section 8.4.1.1, 
Section 12.1.5 and appendix B.
12.1.5
Adverse events requiring additional data collection
AEs requiring additional data collection are AEs where the additional data will benefit the 
evaluation of the product safety. A number of AEs that always require additional data collection 
have been pre-specified. See appendix B for details about these events and the additional 
information to report.
Some events in this trial will be adjudicated by an independent external committee as described in 
Section 12.7.2.
Table 12–1 lists AEs that require completion of specific event forms in the eCRFs and/or are 
subject to event adjudication.
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Table 12–1
Adverse events requiring completion of specific event forms and/or are subject 
to event adjudication
Event
Specific
event form
Event
adjudication
Death
No
Yes
Acute coronary syndrome (myocardial infarction or 
hospitalisation for unstable angina)
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
CK > 10 x UNL
Yes
No
Hepatic event defined as:
!
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.
Yes
No
*Please note that in case of a hepatic event defined as ALT or AST > 3 x UNL and total bilirubin > 2 x UNL, where no 
alternative aetiology exists (Hy's law), this must be reported as an SAE using the important medical event criterion if no 
other seriousness criteria are applicable.
For details about specific event forms, see Section 8.4.1.2, Section 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.
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Examples of technical complaints:
!
The physical or chemical appearance of trial products (e.g. discoloration, particles or 
contamination)
!
All packaging material including labelling
Only technical complaints related to AEs will be reported in the clinical trial report.
12.2
Reporting of adverse events
All events meeting the definition of an AE must be collected and reported. This includes events 
from the first trial-related activity after the subject has signed the informed consent until the end of 
the post-treatment follow-up period (V14) for subjects on trial product or until the end of trial (V13
or V14A, whichever comes last) for the subjects who have discontinued trial product prematurely.
Events for withdrawn subjects will be collected and reported until last trial related contact with the 
subject. The events must be recorded in the applicable eCRF forms in a timely manner, see 
timelines below and Figure 12–1.
During each contact with the trial site staff, the subject must be asked about AEs and technical 
complaints, for example by asking: ”Have you experienced any problems since the last contact?”
All AEs, either observed by the investigator or subject, must be reported by the investigator and 
evaluated.
All AEs must be recorded by the investigator on an AE form. The investigator should report the 
diagnosis, if available. If no diagnosis is available, the investigator should record each sign and 
symptom as individual AEs using separate AE forms.
For SAEs, a safety information form must be completed in addition to the AE form. A safety 
information form is a form to collect supplementary clinical information. If several symptoms or 
diagnoses occur as part of the same clinical picture, one safety information form can be used to 
describe all the SAEs.
AEs requiring additional data collection must be reported using both the AE form and the specific 
event form. A specific event form is a form tailored to collect specific information related to the 
individual event. See appendix B for details about the events and the additional information to 
report.
In case any of these events fulfil the criteria for seriousness in Section 12.1 then the event should be 
reported as serious.
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Some events will undergo event adjudication by the EAC, please refer to Section 12.7.2. For AEs 
qualifying for event adjudication, the adjudication form will also have to be completed in the eCRF. 
The adjudication form is a checklist of clinical data to be provided from the site.
For all non-serious AEs, the applicable forms should be signed when the event is resolved or at the 
end of the trial at the latest.
Timelines for initial reporting of AEs:
The investigator must complete the following forms in the eCRF within the specified timelines:
!
SAEs: The AE form within 24 hours and the safety information form within 5 calendar days 
of the investigator's first knowledge of the SAE.
Both forms must be signed within 7 calendar days from the date the information was entered in 
the eCRF.
For SAEs requiring reporting on a specific event form: In addition to the above, the specific 
event form within 14 calendar days from the investigator’s first knowledge of the AE.
!
Events for adjudication: The adjudication form should be completed within 14 calendar days 
of the investigator’s first knowledge of the AE, see Section 12.7.2. The investigator should 
preferably provide the medical documentation within 4 weeks of event identification according 
to instructions in the event adjudication site manual.
If the eCRF is unavailable, the concerned AE information must be reported on a paper AE form and 
sent to Novo Nordisk by fax, e-mail or courier within the same timelines as stated above. When the 
eCRF becomes available again, the investigator must enter the information on the form into the 
eCRF.
Contact details (fax, telephone, e-mail and address) are provided in the investigator trial master file.
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AE identified
Does the AE require 
a specific event 
form?
Is the AE subject to 
adjudication and/or 
is the outcome 
fatal?
AE form < 24 hours
SIF < 5 calendar days
Specific event form 
For SAEs:
< 14 calendar days
Is the AE serious or 
non-serious?
AE form
Adjudication form
< 14 calendar days
Source data < 4 weeks
Non-serious
Serious
No
Yes
Yes
Queries and follow-up 
requests to be resolved 
< 14 calendar days
Timelines are for the completion of forms from the time of investigator’s awareness.AEs 
requiring specific event forms are described in Section 12.1.4, 12.1.5 and appendix B.AEs 
for adjudication are described in Section 12.7.2
AE: Adverse event  SAE: Serious adverse event  SIF: Safety Information form 
No additional action
No additional action
No
Figure 12–1
Reporting of AEs
Novo Nordisk assessment of AE expectedness:
Novo Nordisk assessment of expectedness is performed according to the following reference 
document: Investigator’s Brochure, oral semaglutide (NN9924), edition 624, or any updates hereof.
Reporting of trial product-related SUSARs by Novo Nordisk:
Novo Nordisk will notify the investigator of trial product-related suspected unexpected serious 
adverse reactions (SUSARs) in accordance with local requirements and ICH GCP1. In addition, the 
investigator will be informed of any trial-related SAEs that may warrant a change in any trial 
procedure.
In accordance with regulatory requirements, Novo Nordisk will inform the regulatory authorities, 
including European Medicines Agency, of trial product-related SUSARs. In addition, Novo Nordisk 
will inform the IRBs/IECs of trial product-related SUSARs in accordance with local requirement 
and ICH GCP1, unless locally this is an obligation of the investigator.
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 
safety information form. Novo Nordisk may need to report this AE to relevant regulatory 
authorities.
12.3
Follow-up of adverse events
The investigator must record follow-up information by updating the medical records and the forms 
in the eCRF.
Follow up information must be reported to Novo Nordisk according to the following:
!
SAEs: All SAEs must be followed until the outcome of the event is “recovered/resolved”, 
“recovered/resolved with sequelae” or “fatal”, and until all queries have been resolved. Cases of 
chronic conditions, cancer or AEs ongoing at time of death (where death is due to another AE) 
may be closed with the outcome “recovering/resolving” or “not recovered/not resolved”. Cases 
can be closed with the outcome of “recovering/resolving” when the subject has completed the 
follow-up period and is expected by the investigator to recover.
The SAE follow-up information should only include new (e.g. corrections or additional) 
information and must be reported within 24 hours of the investigator’s first knowledge of the 
information. This is also the case for previously non-serious AEs which subsequently become 
SAEs.
!
Non-serious AEs: Non-serious AEs must be followed until the outcome of the event is 
“recovering/resolving”, “recovered/resolved” or “recovered/resolved with sequelae” or until the 
end of the follow-up period stated in the protocol, whichever comes first, and until all queries 
related to these AEs have been resolved. Cases of chronic conditions, cancer or AEs ongoing at 
time of death (where death is due to another AE) may be closed with the outcome 
“recovering/resolving” or “not recovered/not resolved”. Cases can be closed with the outcome 
of “recovering/resolving” when the subject has completed the follow-up period and is expected 
by the investigator to recover.
The investigator must ensure that the recording of the worst case severity and seriousness of an 
event is kept throughout the trial. A worsening of an unresolved AE must be reported as follow up 
with re-assessment of severity and/or seriousness of the event.
Queries or follow-up requests from Novo Nordisk must be responded to within 14 calendar days
from the date of receipt of the request, unless otherwise specified in the follow-up request.
SAEs after end of trial: If the investigator becomes aware of an SAE with a suspected causal 
relationship to the investigational medicinal product occurring to a subject after the subject has 
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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 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 Customer Complaint 
Center, Novo Nordisk, within the same timelines as stated above. When the eCRF becomes 
available again, the investigator must enter the information on the technical complaint form in the 
eCRF.
12.4.2
Collection, storage and shipment of technical complaint samples
The investigator must collect the technical complaint sample and notify the monitor within 5 
calendar days of obtaining the sample at trial site. The monitor must coordinate the shipment to 
Customer Complaint Center, Novo Nordisk (the address is provided in Attachment I) and ensure 
that the sample is sent as soon as possible. A copy of the technical complaint form must be included 
in the shipment of the sample. If several samples are returned in one shipment, the individual 
sample and the corresponding technical complaint form must be clearly separated.
The investigator must ensure that the technical complaint sample contains the code number and, if 
available, the DUN. All parts of the DUN should be returned.
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If the technical complaint sample is unobtainable, the investigator must specify on the technical 
complaint form why it is unobtainable.
Storage of the technical complaint sample must be done in accordance with the conditions 
prescribed for the product.
12.5
Pregnancies in female subjects
Female subjects must be instructed to notify the investigator immediately if they become pregnant 
during the trial. The investigator must report any pregnancy in subjects who have received trial 
product(s).
The investigator must follow the pregnancy until the pregnancy outcome and the newborn infant is 
one month of age.
The investigator must report information about the pregnancy, pregnancy outcome and health of the 
newborn infant(s), as well as AEs in connection with the pregnancy and AEs in the foetus and 
newborn infant.
The following must be collected and reported by the investigator to Novo Nordisk - electronically 
(e.g. in PDF format), or by fax or courier:
1. Reporting of pregnancy information
Information about the pregnancy and pregnancy outcome/health of the newborn infant(s) has to 
be reported on Maternal Form 1A and 1B, respectively. 
When the pregnancy outcome is abnormal (i.e. congenital anomalies, foetal death including 
spontaneous abortion and/or any anomalies of the foetus observed at gross examination or 
during autopsy), and/or when a congenital anomaly is diagnosed within the first month, further 
information has to be reported for the female subject on Maternal Form 2. In addition, 
information from the male partner has to be reported on the Paternal Form, after an informed 
consent has been obtained from the male partner.
Initial reporting and follow-up information must be reported within 14 calendar days of the 
investigator’s first knowledge of initial or follow-up information.
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2. Reporting of AE information
The investigator has to report AEs in connection with the pregnancy as well as in the foetus and 
newborn infant(s). The SAEs that must be reported include abnormal outcome, such as foetal 
death (including spontaneous abortion), and congenital anomalies (including those observed at 
gross examination or during autopsy of the foetus), as well as other pregnancy complications 
fulfilling the criteria of an SAE.
Forms and timelines for reporting AEs:
Non-serious AEs: 
–
AE forma within 14 calendar days of the investigator's first knowledge of the initial or 
follow-up information to the non-serious AE.
SAEs: 
–
AE forma within 24 hours of the investigator's first knowledge of the SAE.
–
Safety information form within 5 calendar days of the investigator's first knowledge of the 
SAE.
–
SAE follow-up information to the AE form and/or safety information form within 24 
hours of the investigator's first knowledge of the follow-up information.
a
It must be clearly stated in the AE diagnosis field on the AE form if the event occurred in 
the subject, foetus or newborn infant. If the AE occurred in the foetus or newborn infant, the 
AE can only be reported on paper AE and safety information form.
Any queries or follow-up requests from Novo Nordisk to non-serious AEs, SAEs and pregnancy 
forms must be responded to by the investigator within 14 calendar days from the date of receipt of 
the request, unless otherwise specified in the follow-up request.
12.6
Precautions and/or overdose
There are no specific antidotes to semaglutide. Treatment of an overdose should be symptomatic.
There is a potential risk of hypoglycaemia during dosing with semaglutide. The typical signs and 
symptoms of a non-severe hypoglycaemia include: hunger, slight headache, nausea, light-
headedness, palpitations and sweating. Symptoms of non-severe hypoglycaemia should be treated 
by ingestion of carbohydrates.
Severe hypoglycaemia resulting in loss of consciousness should be treated according to best 
available medical 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 
 mg of 
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oral semaglutide. The subject did not report any symptoms and treatment was continued without 
any change.
One case of accidental overdose has been reported in subjects treated with s.c. semaglutide once 
weekly. The subject inadvertently injected  mg of semaglutide instead of 0.4 mg, which 
corresponds to a 
-fold higher dose than the maximum dose included in that trial. After 
 hours 
the subject felt nauseated, vomited and had a headache. The subject was instructed to drink 
sufficient amounts of fluids. 
 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 Investigator’s Brochure for oral 
administration of semaglutide (NN9924), edition 624, and any updates hereof.
12.7
Committees related to safety
12.7.1
Novo Nordisk safety committee
Novo Nordisk will constitute an internal oral semaglutide safety committee to perform ongoing 
safety surveillance. The oral semaglutide safety committee may recommend unblinding of any data 
for further analysis, and in this case an independent ad hoc group will be established in order to 
maintain the blinding of the trial personnel.
12.7.2
Event adjudication committee
An independent external event adjudication committee (EAC) is established to perform validation 
of selected AEs according to pre-defined diagnostic criteria. The validation is based on review of 
pre-defined clinical data related to the specific AE. Pre-defined clinical data consist of copies of 
source documents collected and delivered by the investigational sites.
The EAC is composed of permanent members covering required medical specialities. EAC 
members must disclose any potential conflicts of interest and must be independent of Novo 
Nordisk.
The events are reviewed by the EAC in a blinded manner. The EAC will have no authorisations to 
impact on trial conduct, trial protocol or amendments.
The EAC works in accordance with written guidelines included in the EAC Charter describing in 
details the composition, tasks, responsibilities and work processes of the committee.
The events outlined in Table 12–2 have been selected for adjudication in order to obtain an external 
independent validation of the diagnosis. In addition, cardiovascular events are being adjudicated 
according to U.S. Food and Drug Administration (FDA) requirements48.
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The EAC will review copies in English (translated if necessary) of medical documentation received 
in the adjudication packages (e.g. x-ray, ECGs, ultrasound images, discharge summaries, pathology 
reports and death certificates). The investigator must provide medical documentation as soon as 
possible, when they receive the request from Novo Nordisk or the event adjudication vendor.
The AEs for adjudication are listed in Table 12–2:
Table 12–2
Adverse events for adjudication
Events
Description
Adjudication outcome
Death*
!
All-cause death
!
Cardiovascular death 
(including undetermined 
cause of death)
!
Non-Cardiovascular death
Acute Coronary Syndrome
Acute Coronary Syndrome conditions include: 
!
ST-elevation acute myocardial infarction 
(STEMI)
!
Non-ST elevation acute myocardial infarction 
(NSTEMI)
!
Silent myocardial infarction 
!
Unstable angina pectoris
!
Acute myocardial 
infarction (STEMI or 
NSTEMI), silent 
myocardial infarction 
!
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  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
!
Transient ischaemic 
attack
Heart failure requiring 
hospitalisation
!
Hospitalisation with a primary diagnosis of 
heart failure (new episode or worsening of 
existing heart failure)
!
Heart failure requiring 
hospitalisation
Acute pancreatitis
The diagnosis of acute pancreatitis requires two of 
the following three features:
!
Abdominal pain consistent with acute 
pancreatitis (acute onset of a persistent, 
severe, epigastric pain often radiating to the 
back)
!
Serum lipase activity (and/or amylase activity) 
at least three times greater than the UNL
!
Characteristic findings of acute pancreatitis on 
imaging
Acute pancreatitis
!
Mild
!
Moderately severe
!
Severe
Malignant neoplasm
Malignant neoplasms are defined as
!
neoplasms in which abnormal cells divide 
without control and can invade nearby tissues 
and/or spread to other parts of the body 
through the blood and lymph systems
!
Malignant neoplasm
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Events
Description
Adjudication outcome
Thyroid neoplasms are excluded in this event 
category
Thyroid disease, if malignant 
thyroid neoplasm or C-cell 
hyperplasia
Malignant thyroid neoplasms are defined as 
!
thyroid neoplasms in which abnormal cells 
divide without control and can invade nearby 
tissues and/or spread to other parts of the body 
through the blood and lymph systems
!
C-cell hyperplasia, defined as hyperplasia of 
the parafollicular C-cells of the thyroid gland
!
Malignant thyroid 
neoplasm
!
C-cell hyperplasia
Acute kidney injury
Acute kidney injury49 is defined as any of the 
following (not graded):
!
Increase in serum creatinine by ≥0.3 mg/dL 
(≥26.5 μmol/L) within 48 hours, or
!
Increase in serum creatinine to ≥1.5 times 
baseline, which is known or presumed to have 
occurred within the prior 7 days, or
!
Urine volume < 0.5 mL/kg/h for 6 hours
!
Acute kidney injury
Lactic acidosis
!
Lactic acidosis is characterized by increased 
blood lactate level in association with 
metabolic acidosis
!
Lactic acidosis
*Death is not a separate event, but an outcome
There are different processes for capturing events for adjudication:
!
Direct reporting by investigator:
–
All AEs need to be assessed by the investigator if any AE category is applicable. If the AE 
category selected is in scope for adjudication, the event specific adjudication form in the 
eCRF will be populated for sites to complete
–
AEs with fatal outcome
!
Screening: 
–
All AEs will be screened by Novo Nordisk for potential missed events for adjudication and 
if needed, the investigator will be asked to provide additional information such as an 
alternative aetiology, underlying cause(s) and/or clinical details.
–
All ECGs will be centrally read. If the central reading conclusion is suggestive of new 
myocardial infarction, the ECG adjudication form will be populated for sites to complete for 
all post-baseline ECGs.
!
EAC identified events:
–
The EAC can decide to have an AE adjudicated even if not initially reported as an event for 
adjudication by the investigator.
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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 the 
assessments made by the investigator. However, the adjudication made by the EAC, given its 
independent analysis of each event, will be attributed with greater importance of the two.
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13 Case report forms 
Novo Nordisk will provide a system for the eCRF. This system and support services to the system 
will be provided by an external supplier.
Ensure that all relevant questions are answered and that no empty data field exists. If a test or an 
assessment has not been done and will not be available, or if the question is irrelevant (e.g. is not 
applicable), indicate this according to the data entry instructions.
The following will be provided as paper CRFs:
!
Pregnancy forms
The following will be provided as paper CRFs to be used when access to the eCRF is revoked or if 
the eCRF is unavailable:
!
AE forms 
!
Safety information forms
!
Technical complaint forms (also to be used to report complaints that are not subject related (e.g. 
discovered at trial site before allocation)).
On the paper CRF forms print legibly, using a ballpoint pen. Ensure that all questions are answered 
and that no empty data blocks exist. Ensure that no information is recorded outside the data blocks. 
If a test/assessment has not been done and will not be available, indicate this by writing "ND" (not 
done) in the appropriate answer field in the CRF. If the question is irrelevant (e.g. is not applicable) 
indicate this by writing "NA" (not applicable) in the appropriate answer field. Further guidance can 
be obtained from the instructions in the CRF.
The investigator must ensure that all information is consistent with the source documentation. By 
electronically signing the case book in the eCRF, the investigator confirms that the information in 
the eCRF and related forms is complete and correct.
13.1
Corrections to case report forms 
Corrections to the eCRF data may be made by the investigator or the investigator's delegated staff. 
An audit trail will be maintained in the eCRF application containing as a minimum: the old and the 
new data, identification of the person entering the data, date and time of the entry and reason for the 
correction.
If corrections are made by the investigator's delegated staff after the date the investigator has signed 
the case book, the case book must be signed and dated again by the investigator.
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13.2
Case report form flow 
The investigator must ensure that data is recorded in the eCRF as soon as possible, preferably 
within 5 days after the visit. Once data has been entered, it will be available to Novo Nordisk for 
data verification and validation purposes.
At the end of the trial, the investigator must ensure that all remaining data have been entered into 
the eCRF no later than 3 days after LSLV at the site in order to ensure the planned lock of the 
database.
Site specific eCRF data (in an electronic readable format) will be provided to the trial site before 
access to the eCRF is revoked. This data must be retained at the trial site. When the final clinical 
trial report is available, the data will be archived by Novo Nordisk.
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14 Monitoring procedures
Monitoring will be conducted under a risk based approach.
During the course of the trial, the monitor will visit the trial site to ensure that the protocol is 
adhered to, that all issues have been recorded, to perform source data verification and to monitor 
drug accountability. The first monitoring visit will be performed as soon as possible after FSFV at 
the trial site and no later than 4 weeks after. The monitoring visit intervals will depend on the 
outcome of the remote monitoring of the eCRFs, the trial site's recruitment rate and the compliance 
of the trial site to the protocol and GCP, but will not exceed 12 weeks until LSLV at the trial site, 
for trial sites with active subjects (defined as subjects in screening, treatment or follow-up).
The monitor must be given direct access to all source documents (original documents, data and 
records). Direct access includes permission to examine, analyse, verify and reproduce any record(s) 
and report(s) that are important to the evaluation of the trial. If the electronic medical record does 
not have a visible audit trail, the investigator must provide the monitor with signed and dated 
printouts. In addition the relevant trial site staff should be available for discussions at monitoring 
visits and between monitoring visits (e.g. by telephone).
All data must be verifiable in source documentation other than the eCRF.
For all data recorded the source document must be defined in a source document agreement at each 
trial site. There must only be one source defined at any time for any data element.
Source data generated by the trial site can be corrected by another person than the person entering 
the source data if accepted by local regulations; any correction must be explained, signed and dated 
by the person making the correction.
The original of the completed diaries and/or PROs must not be removed from the trial site, unless 
they form part of the eCRF and a copy is kept at the site.
The monitor will ensure that the eCRFs are completed and that paper CRFs are collected.
The following data will be source data verified for screening failures:
!
Date for obtaining informed consent.
!
Reason for screening failure
Monitors will review the subject’s medical records and other source data (e.g. the diaries and PROs) 
to ensure consistency and/or identify omissions compared to the eCRF. If discrepancies are found, 
the investigator must be questioned about these.
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A follow-up letter (paper or electronic) will be sent to the investigator following each monitoring 
visit. This should address any action to be taken.
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15 Data management
Data management is the responsibility of Novo Nordisk. Data management may be delegated under 
an agreement of transfer of responsibilities to a Contract Research Organisation.
Appropriate measures, including encryption of data files containing person identifiable data, will be 
used to ensure confidentiality of subject data, when they are transmitted over open networks.
Data from central laboratories will be transferred electronically. In cases where data is transferred 
via non-secure electronic networks, data will be encrypted during transfer.
The subject and any biological material obtained from the subject will be identified by subject 
number and trial ID. Appropriate measures such as encryption or leaving out certain identifiers will 
be enforced to protect the identity of subjects in all presentations and publications as required by 
local, regional and national requirements.
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16 Computerised systems
Novo Nordisk will capture and process clinical data using computerised systems that are described 
in Novo Nordisk Standard Operating Procedures and IT architecture documentation. The use and 
control of these systems are documented.
Investigators working on the trial may use their own electronic systems to capture source data. 
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17 Statistical considerations
General considerations
If necessary, a statistical analysis plan 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 database lock.
The blinding of the randomised treatments will be maintained until the database has been released 
for statistical analysis.
Data from all sites will be analysed and reported together.
In statistical analyses where stratification is included, the three levels of antidiabetic background 
medication at screening (metformin, SU +/-metformin, basal insulin +/- metformin) and the two 
levels of renal function (eGFR 30 - 44 mL/min/1.73 m2 and eGFR 45 - 59 mL/min/1.73 m2 as per 
CKD-EPI) will be included based on the actual information collected through the eCRF. In case of 
missing eCRF information the information collected from the IWRS system will be used.
The latest available measurement, at or prior to the randomisation visit, will be used as the baseline 
measurement. If no measurement(s) have been obtained, at or prior to randomisation, the baseline 
value will be left missing.
Laboratory values below the lower limit of quantification (LLoQ) will be set to 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 oral semaglutide 14 mg vs. placebo with associated two-sided 95% confidence 
intervals and p-values corresponding to two-sided tests of no difference.
If no statistical analysis is specified, data will be presented using relevant summary statistics.
Primary and secondary estimands
Two estimands addressing different aspects of the trial objective will be defined; a primary de-facto 
(effectiveness) estimand and a secondary de-jure (efficacy) estimand:
!
Primary estimand
–
de-facto treatment difference (oral semaglutide versus placebo) at week 26 for all 
randomised subjects regardless of adherence to randomised treatment and initiation of 
rescue medication
The primary de-facto estimand assesses the expected glycaemic benefit in a future population that 
results from subjects initiating treatment with oral semaglutide including potential rescue 
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medication(s). Generalisation of this estimand depends among other things on the extent to which 
the use of rescue medication in this trial reflects clinical practice and the adherence to trial product 
administration in this trial reflects the behaviour of the target population. Accordingly, data 
collected regardless of discontinuation of trial product or initiation of rescue medication(s) will be 
used to draw inference.
!
Secondary estimand
–
de-jure treatment 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 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.
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(s), 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 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 20% of missing data 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. Whereas a higher proportion of subjects are 
expected to discontinue treatment due to AEs in the oral semaglutide arm. So overall the frequency 
of missing data is expected to be similar across treatment arms.
Descriptive summaries and graphical representation of extent, reason(s) for and pattern of missing 
data will be presented by treatment arm.
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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.
The sample size calculation is made to ensure a power of at least 90% for testing HbA1c superiority
of oral semaglutide vs. placebo out of the two pre-specified confirmatory hypotheses shown in 
Figure 17–1. The hierarchical testing procedure is used to control the overall type I error at a 
nominal two-sided 5% level. The statistical testing strategy is built on the principle that glycaemic 
effect will have to be established in terms of HbA1c superiority before testing for added benefits in 
terms of body weight superiority.
The sample size is calculated using the calcPower function in the R package, gMCP50, using 10000 
simulations. The two 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 
deviation (SD) 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).
Subjects are allowed to be on metformin and/or SU, basal insulin alone or metformin in 
combination with basal insulin as background medication; if they need rescue medication it is 
expected to have an effect on glycaemic control and the treatment effect compared to oral 
semaglutide will therefore be equalised. Furthermore 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 no effect in these subjects. The adjusted 
treatment effect for testing superiority is defined as:
!
Superiority
–
0.8×TE + 0.2×TE×0
Table 17–1
Assumptions for sample size calculation
Oral semaglutide 
vs. placebo
Treatment effect 
(TE)
Adjusted TE, 
superiority
Standard deviation
HbA1c (%-point)
-0.5
-0.4
1.1
Body weight (kg)
-2
-1.6
4
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With the above assumptions, allocating 162 subjects to each of the oral semaglutide and placebo 
arms provides at least 90% power to confirm HbA1c superiority of oral semaglutide vs. placebo. In 
total 2×162 = 324 subjects are planned to be randomised.
Calculated powers for individual hypotheses are presented in Table 17–2.
Table 17–2
Calculated powers for individual hypotheses
Statistical test
HbA1c superiority
Body weight superiority
Power (%)
91%
86%
Figure 17–1
Graphical illustration of the testing procedure
The overall significance level of α = 0.05 (two-sided) is initially allocated to the HbA1c superiority test of oral 
semaglutide vs. placebo. The local significance level (α-local) will be reallocated to the next body weight superiority 
hypothesis, if the HbA1c superiority hypothesis is confirmed. The sample size is based on the hypotheses in the dark 
box.
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. This 
will be referred to as contributing to the evaluation “as treated”.
 = 0
Body weight (%)
Superiority vs. placebo
HbA1c (%-point)
Superiority vs. placebo
 = 0.05
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Data selections and observation periods
Unless subjects withdraw their informed consent, data collection will continue for the full duration 
of the trial. The full duration of the trial is defined as up to and including:
!
the follow-up visit (V14) for subjects on trial product
!
the latest occurring visit of the end-of-treatment visit (V13) or the follow-up premature 
discontinuation visit (V14A), for subjects who have discontinued trial product prematurely.
Subjects and data to be used in an analysis will be selected in a two-step manner:
!
Firstly, subjects will be selected based on the specified analysis set
!
Secondly, data points on the selected subjects from the first step will be selected based on the 
specified observation period
Definition of the observation periods:
In-trial: This observation period represents the time period where subjects are considered to be in 
the trial, regardless of discontinuation of trial product or initiation of rescue medication. The in-trial 
observation period starts at randomisation (as registered in the IWRS) and ends at the date of:
!
the last direct subject-site contact, which is scheduled to take place 5 weeks after planned last 
dose of trial product at the follow-up visit
!
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, 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 (V14)
!
the follow-up prematurely discontinuation visit (V14A)
!
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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For efficacy and other safety assessments (laboratory assessments, physical examination and vital 
signs) the observation period ends at the last date on trial product +3 days. This will be used in 
order to ensure specificity to reversible effects of treatment.
On-treatment without rescue medication: This observation period is a subset of the on-treatment 
observation period, where subjects are considered treated with trial product, but have not initiated 
any rescue medications. Specifically it starts at date of first dose of trial product and the observation 
period ends at the first date of any of the following:
!
the last dose of trial product +3 days
!
initiation of rescue medication
The in-trial observation period will be the primary observation period when estimating the primary 
estimand. The on-treatment without rescue medication observation period will be the primary 
observation period when estimating the secondary estimand. The on-treatment observation period 
will be considered supportive for evaluating efficacy. Safety will be evaluated based on the in-trial 
and the on-treatment observation periods.
Data points collected outside an observation period will be treated as missing in the analysis. 
Baseline data will always be included in an observation period. For adjudicated events, the onset 
date will be the EAC adjudicated onset date.
Before data are locked for statistical analysis and the randomisation code is broken, a review of all 
data will take place. Any decision to exclude either a subject or single observations from the 
statistical analysis is the joint responsibility of the members of the Novo Nordisk study group. 
Exclusion of data from analyses will be used restrictively, and normally no data should be excluded 
from the FAS. The subjects or observations to be excluded, and the reasons for their exclusion must 
be documented and signed by those responsible before database lock. The subjects and observations 
excluded from analysis sets, and the reason for this, will be described in the clinical trial report.
Confirmatory hypotheses 
For the primary HbA1c endpoint and the secondary confirmatory body weight endpoint, the 
following one-sided hypotheses are planned to be tested for 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.
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Multiplicity and criteria for confirming hypotheses
The type I error for testing the two confirmatory hypotheses related to the HbA1c and body weight 
endpoints will be preserved in the strong sense at 5% (two-sided) using the hierarchical testing 
strategy as outlined in Figure 17–1.
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 the 5% two-sided significance level. This is equivalent to using a 
one-sided p-value (nominal α = 0.025) and a one-sided 2.5% overall significance level.
17.3
Primary endpoint
The primary endpoint is change from baseline to week 26 in HbA1c.
17.3.1
Primary analysis for the primary estimand
The primary estimand will be estimated based on the FAS using week 26 measurements from the 
in-trial observation period. The primary statistical analysis will be a pattern mixture model using 
multiple imputation to handle missing data assuming that the missing data mechanism is missing at 
random (MAR) within the groups used for imputation. Imputation of missing data at week 26 will 
be done within 4 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 two 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.
!
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 two 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 in HbA1c from baseline to week 
26 will be analysed using an ANCOVA with treatment, stratification factors, the interaction 
between the two stratification factors and region as categorical fixed effects and baseline HbA1c as 
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covariate. The results obtained from analysing the datasets will be combined using Rubin’s rule51 to 
draw inference.
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 (REML) will be used. The model will include all post 
baseline HbA1c measurements collected at scheduled visits up to and including week 26 as 
dependent variables. The independent effects included in the model will be treatment, stratification 
factors, the interaction between the two 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 sensitivity of the primary analysis results, complementary and separate analyses 
will be performed for the primary and secondary estimand. In line with European Medicines 
Agency recommendations52 and with a report from the US National Research Council53, 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 will be described that are 
not based on the pattern mixture model approach, see Section 17.3.3.2.
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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
!
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 AE(s) 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 
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to oral semaglutide. This sensitivity analysis is less conservative as compared to the first 
sensitivity analysis.
!
Tipping-point multiple imputation analysis: In this sensitivity analysis, missing data will first be 
imputed according to the primary analysis. Secondly, for the oral semaglutide treatment arm a 
penalty will be added to the imputed values at week 26. The approach is to gradually increase 
this penalty until a confirmed HbA1c conclusion from the primary analysis is changed. The 
specific value of the penalty that changes the conclusion will be used to evaluate the robustness 
of the primary analysis result.
17.3.3.2
Other sensitivity analyses
!
Last observation carried forward (LOCF) analysis: This sensitivity analysis will be based on 
the FAS using the on-treatment without rescue medication observation period. The change from 
baseline to week 26 in HbA1c will be analysed by a linear normal model (ANCOVA) with 
treatment, stratification factors, the interaction between the two 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 the sensitivity analyses inherent conservative nature, it will not be a 
requirement that all confirmatory hypotheses are consistently confirmed across the sensitivity 
analyses. Thus, no absolute success criteria will be pre-defined for each sensitivity analysis. The 
sensitivity results in totality will be used to substantiate the credibility of the trial results.
17.4
Secondary endpoints
17.4.1
Confirmatory secondary endpoints
Change from baseline to week 26 in body weight (kg) will be a confirmatory secondary endpoint.
The primary and secondary estimands will be estimated using the same approaches as described for 
the primary HbA1c endpoint. Body weight will only be tested for superiority. Baseline body weight 
will be used as a covariate instead of baseline HbA1c in both the 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 updated local two-sided significance level resulting from the closed testing
procedure in Figure 17–1. Sensitivity analyses similar to the ones pre-specified for testing 
superiority for the primary HbA1c endpoint will be made to evaluate the robustness of the body 
weight results.
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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 the supported secondary endpoints.
Continuous efficacy endpoints
Change from baseline to week 26 in:
!
Fasting plasma glucose (FPG)
!
Body weight (%)
!
Body mass index (BMI)
!
Waist circumference
!
Fasting lipid profile (total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density 
lipoprotein (HDL) cholesterol and triglycerides)
!
C-reactive protein (CRP)
BMI will be calculated based on body weight and height based on the formulae:
BMI kg/m2 = body weight (kg)/(height (m) x height (m)) or (kg/m2 = [lb/in2 x 703])
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 at week 26. This will result 
in imputation of missing data within 4 groups as described for the week 26 evaluation in Section
17.3.1.
For evaluation of the secondary estimand, the MMRM based primary analysis will include all 
scheduled post-baseline measurement up to and including week 26. From this model the estimated 
treatment differences (ratios) will be presented at week 26 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 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)
!
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%-point (10.9 mmol/mol) and weight loss ≥ 3%
The above eight binary endpoints will be analysed using a logistic regression model with treatment 
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 rule51.
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 
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treatment at the end-of-treatment visit and therefore might need addition of glucose-lowering 
medication during the follow-up period.
The endpoint will be described and compared for oral semaglutide versus placebo using likelihood 
ratio tests obtained from a Cox proportional hazards model with treatment, stratification factors, the 
interaction between the two stratification factors and region as categorical fixed effects and baseline 
HbA1c as a covariate. From this analysis the estimated Hazard ratios between oral semaglutide 
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 treatment-emergent adverse events (TEAEs) during exposure to trial product, 
assessed up to approximately 31 weeks
All AEs will be coded using the most recent version of the Medical Dictionary for Regulatory 
Activities (MedDRA) coding.
A TEAE 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.
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Other safety endpoints
Change from baseline to week 26 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. 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 in:
!
Haematology
!
Biochemistry (except for amylase and lipase)
!
eGFR as per CKD-EPI
!
Calcitonin
!
Urinalysis
!
Urinary albumin to creatinine ratio
!
Electrocardiogram (ECG) evaluation
!
Physical examination
Note that the urinary albumin to creatinine ratio is measured twice, so the mean will be used as 
endpoint.
Any occurrence of anti-semaglutide antibodies (yes/no) up to approximately 31 weeks:
!
Anti-semaglutide binding antibodies
!
Anti-semaglutide neutralising antibodies
!
Anti-semaglutide binding antibodies cross reacting with native GLP-1
!
Anti-semaglutide neutralising antibodies cross reacting with native GLP-1
Anti-semaglutide binding antibodies up to approximately 31 weeks: 
!
Anti-semaglutide binding antibody levels
The above safety endpoints will be summarised descriptively by treatment arm and visit. 
Categorical safety endpoints will be summarised as counts and relative frequencies. Calcitonin will 
also be presented by gender.
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Hypoglycaemia
!
Number of treatment-emergent severe or blood glucose-confirmed symptomatic hypoglycaemic 
episodes during exposure to trial product, assessed up to approximately 31 weeks
!
Treatment-emergent severe or blood glucose-confirmed symptomatic hypoglycaemic episodes 
during exposure to trial product, assessed up to approximately 31 weeks (yes/no)
Classification of hypoglycaemia:
Hypoglycaemic episodes will be summarised for the SAS and the on-treatment observation period 
only.
Treatment emergent: hypoglycaemic episodes will be defined as treatment-emergent if the onset of 
the episode occurs within the on-treatment observation period (see definition of observation periods 
in Section 17.2).
Nocturnal hypoglycaemic episodes: episodes occurring between 00:01 and 05.59 both inclusive.
Hypoglycaemic episodes are classified according to the Novo Nordisk classification of 
hypoglycaemia and the ADA classification of hypoglycaemia (see Figure 17–2).
Novo Nordisk classification of hypoglycaemia
In normal physiology, symptoms of hypoglycaemia occur below a plasma glucose level of 
3.1 mmol/L (56 mg/dL)54. Therefore, Novo Nordisk has included hypoglycaemia with plasma 
glucose (PG) levels below this cut-off point in the definition of blood glucose (BG) confirmed 
hypoglycaemia.
Novo Nordisk uses the following classification in addition to the ADA classification:
!
Severe or BG-confirmed symptomatic hypoglycaemia: An episode that is severe according to 
the ADA classification43 or BG-confirmed by a plasma glucose value < 3.1 mmol/L (56 mg/dL) 
with symptoms consistent with hypoglycaemia.
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ADA classification43 of hypoglycaemia
!
Severe hypoglycaemia: An episode requiring assistance of another person to actively administer 
carbohydrate, glucagon, or take other corrective actions. Plasma glucose concentrations may not 
be available during an event, but neurological recovery following the return of plasma glucose 
to normal is considered sufficient evidence that the event was induced by a low plasma glucose 
concentration.
!
Asymptomatic hypoglycaemia: An episode not accompanied by typical symptoms of 
hypoglycaemia, but with a measured plasma glucose concentration ≤3.9 mmol/L (70 mg/dL).
!
Documented symptomatic hypoglycaemia: An episode during which typical symptoms of 
hypoglycaemia are accompanied by a measured plasma glucose 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 plasma glucose 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 plasma glucose determination but that was presumably caused by a 
plasma glucose concentration ≤3.9 mmol/L (70 mg/dL).
Hypoglycaemic 
episode 
PG ≤ 3.9 mmol/L 
(70 mg/dL) 
or 
Alleviation of 
symptoms 
or
Seizure, coma or 
fatal 
SMPG
measurement
Asymptomatic 
hypoglycaemia
Documented 
symptomatic 
hypoglycaemia
Pseudo-
hypoglycaemia
Probable 
symptomatic 
hypoglycaemia
No
Yes
No measurement 
with symptoms
PG > 3.9 mmol/L 
(70 mg/dL)
with symptoms
PG ≤3.9 mmol/L 
(70 mg/dL)
with symptoms
PG ≤3.9 mmol/L 
(70 mg/dL)
without symptoms
No
Yes
Note: Glucose measurements are performed with capillary blood calibrated to plasma equivalent glucose values
PG: plasma glucose  SMPG: Self-measured plasma glucose  
Subject 
able to 
treat him/
herself
Severe 
hypoglycaemia
(ADA 2013)
Figure 17–2
ADA classification of hypoglycaemia
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Date:
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Version:
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Data on treatment-emergent hypoglycaemic episodes will be presented in terms of the number of 
subjects with at least one episode, the percentage of subjects with at least one episode (%), the total 
number of episodes and the episode rate per 100 patient years of observation time.
Analysis of severe or BG-confirmed symptomatic hypoglycaemic endpoints
The number of treatment-emergent severe or BG-confirmed symptomatic hypoglycaemic episodes 
will be evaluated for the on-treatment period using a negative binomial regression model with a log-
link function and the logarithm of the duration of the subject’s on-treatment observation period as 
offset. The model will include treatment, stratification factors, the interaction between the two 
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 two stratification factors and region 
as fixed factors and baseline HbA1c as covariate.
17.4.2.3
Pharmacokinetic endpoints
!
Semaglutide plasma concentrations for population PK analyses
!
SNAC plasma concentrations
The semaglutide plasma concentrations and SNAC 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.
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Date:
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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
Change from baseline to week 26 in:
!
Short Form (SF)-36v2™(acute version) health survey: Scores from the 8 domains and the 
physical component score  and mental component score summary scores
!
Diabetes Treatment Satisfaction Questionnaire – status version (DTSQs): Individual items and 
treatment satisfaction score (6 of the 8 items summed)
The PRO endpoints will be evaluated using the primary analysis for the primary estimand based on 
FAS using the in-trial observation period and using the primary analysis for the secondary estimand 
based on FAS using the on-treatment without rescue medication period. All of the above individual 
items and scores will be analysed separately as the other continuous efficacy endpoints.
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Date:
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Version:
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18 Ethics
18.1
Benefit-risk assessment of the trial
18.1.1
Risks and precautions
The nonclinical safety programme of oral semaglutide has not revealed any safety issues precluding 
use in humans.
The sections below describe the important identified and potential risks and precautions associated 
with oral semaglutide treatment. These are based on findings in nonclinical studies and clinical 
trials with oral semaglutide as well as other GLP-1 RAs. For each of these risks and precautions, 
mitigating actions have been implemented to minimise the risks for subjects enrolled in this trial.
Identified risks
Gastrointestinal adverse events
Consistent with findings with other GLP-1 RAs, the most frequently reported AEs in clinical trials 
with oral semaglutide have been gastrointestinal disorders (nausea, vomiting, diarrhoea, dyspepsia 
and constipation). Clinical trials have indicated that a low starting dose and gradual dose escalation 
mitigates the risk of gastrointestinal AEs. Consequently, a low starting dose and dose 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 Multiple Endocrine Neoplasia Type 2 or Medullary Thyroid Carcinoma will not be 
enrolled in the trial. During the trial, calcitonin will be measured on a regular basis, and the 
guidance for investigators on further evaluation and action on elevated calcitonin concentrations is 
included in appendix A.
Acute pancreatitis
Acute pancreatitis has been reported in subjects treated with GLP-1 RAs including oral 
semaglutide. As a precaution, subjects with a history of acute or chronic pancreatitis will not be 
enrolled in the trial. Also, subjects will be informed about the symptoms of acute pancreatitis and 
serum levels of lipase and amylase will be monitored throughout the trial.
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Pancreatic cancer
Patients with T2DM have an increased risk of certain types of cancer such as pancreatic cancer. 
There is currently no support from nonclinical studies or clinical trials or post-marketing data that 
GLP-1-based therapies increase the risk of pancreatic cancer. However, pancreatic cancer has been 
included as a separate potential risk due to the scientific debate surrounding a potential association 
to GLP-1-based therapies and the unknown long-term effects of stimulation of β-cells and 
suppression of α-cells. Pancreatic cancer has been classified as a potential class risk of GLP-1 RAs 
by the European Medicines Agency.
Allergic reactions
As in the case with all protein-based pharmaceuticals, treatment with oral semaglutide may evoke 
allergic reactions. These may include urticaria, rash, pruritus as well as anaphylactic reactions. As a 
precaution, subjects with known or suspected hypersensitivity to trial product(s) or related products 
will not be enrolled in the trial. In addition, subjects will be instructed to contact the site staff as 
soon as possible for further guidance if suspicion of a hypersensitivity reaction to the trial product 
occurs.
Hypoglycaemia
Based on current knowledge about the GLP-1 RA drug class, there is a risk of hypoglycaemic 
episodes. Hypoglycaemic episodes have mainly been observed when a GLP-1 RA is combined with 
SU or insulin. The risk for development of hypoglycaemia with oral semaglutide in combination 
with SU 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.
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Other safety considerations
Teratogenicity (embryo-foetal development toxicity)
Semaglutide caused embryo-foetal malformations in the rat through a GLP-1 receptor mediated 
effect on the inverted yolk sac placenta leading to impaired nutrient supply to the developing 
embryo. Primates do not have an inverted yolk sac placenta which makes this mechanism unlikely 
to be of relevance to humans. However, as a precaution, females who are pregnant, breast-feeding 
or intend to become pregnant or are of childbearing potential and not using an adequate 
contraceptive method will not be enrolled in the trial. In addition, pregnancy tests will be performed 
at all visits, including screening and follow-up and at any time during the trial if a menstrual period 
is missed, or as required by local law.
General precautions
All subjects will be included after a thorough evaluation with regards to in- and exclusion criteria
defined in order to ensure that subjects are eligible for trial treatment. 
There are also strict glyacemic rescue criteria in place to ensure acceptable glycaemic control 
during the trial. If rescue medication is required, it should be in accordance with ADA/European 
Association for the Study of Diabetes31, 32 (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 Diabetes.55
Further details with regards to safety of trial product are described in the current edition of the 
Investigator’s Brochure for oral semaglutide (NN9924)24, or any updates thereto.
18.1.2
Benefits
In this trial, subjects will be randomised in a 1:1 manner to either oral semaglutide or placebo as 
add on to their current background medication (metformin and/or SU, basal insulin alone or 
metformin in combination with basal insulin). Subjects will therefore, for the majority of the trial 
periode, be treated with a regime anticipated to be better than or equal to the treatment they received 
at the time of entry into the trial. Based on the results of the phase 2 dose finding trial, oral 
semaglutide is expected to provide clinically relevant improvements in glycaemic control and body 
weight in subjects with type 2 diabetes.
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.
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All subjects in this trial will receive trial products and auxiliary supplies free of charge.
18.1.3
Risk and benefit conclusion
The safety profile for oral semaglutide generated from the clinical and nonclinical development 
programme has not revealed any safety issues that would prohibit administration of oral 
semaglutide in accordance with the planned clinical trial. 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 will provide to subjects with T2DM.
18.2
Informed consent
In seeking and documenting informed consent, the investigator must comply with applicable 
regulatory requirements and adhere to ICH GCP1 and the requirements in the Declaration of 
Helsinki2.
Before any trial-related activity, the investigator must give the subject verbal and written 
information about the trial and the procedures involved in a form that the subject can read and 
understand.
The subjects must be fully informed of their rights and responsibilities while participating in the 
trial as well as possible disadvantages of being treated with the trial products.
The investigator must ensure the subject ample time to come to a decision whether or not to 
participate in the trial.
A voluntary, signed and personally dated informed consent must be obtained from the subject 
before any trial-related activity.
The responsibility for seeking informed consent must remain with the investigator, but the 
investigator may delegate the task to a medically qualified person, in accordance with local 
requirements. The written informed consent must be signed and personally dated by the person who 
seeks the informed consent before any trial-related activity.
If information becomes available that may be relevant to the subject’s willingness to continue 
participating in the trial, the investigator must inform the subject in a timely manner and a revised 
written subject information must be provided and a new informed consent must be obtained.
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In order to avoid missing data, the subjects will be informed about the importance of completing the 
trial also if the subjects discontinue from trial product.
18.3
Data handling
If the subject withdraws from the trial or is lost to follow-up, then the subject’s data will be handled 
as follows:
!
Data already collected and any data collected at the end-of-trial visit including follow-up visits
will be retained by Novo Nordisk, entered into the database and used for the clinical trial report.
!
Safety events will be reported to Novo Nordisk and regulatory authorities according to 
local/national requirements.
If data is used, it will always be in accordance with local regulations and IRBs/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 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 (NN9924), and any updates 
hereof
!
Signed and dated Agreement on Protocol
!
Signed and dated Agreement on Protocol Amendment, if applicable
!
Contract, signed by the investigator and/or appropriate parties on behalf of the investigator’s site 
and Novo Nordisk
!
Source document agreement
!
Central laboratory certification and normal ranges
!
Insurance statement, if applicable
!
Financial disclosure form from investigator and sub-investigator(s)
!
For US 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
Novo Nordisk will analyse and report data from all sites together if more than one site is involved in 
the trial.
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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 
investigators 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 Disclosure33.
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 and human biosamples
24.1
Retention of clinical trial documentation
Subject’s medical records must be kept for the maximum period permitted by the hospital, 
institution or private practice.
The investigator must agree to archive the documentation (this includes both electronic and paper-
based records) pertaining to the trial in an archive after completion or discontinuation of the trial if 
not otherwise notified. The investigator should not destroy any documents without prior permission 
from Novo Nordisk. If the investigator cannot archive the documents at the trial site, Novo Nordisk 
can refer the investigator to an independent archive provider that has a system in place to allow only 
the investigator to access the files.
The investigator must be able to access his/her trial documents without involving Novo Nordisk in 
any way. Site-specific CRFs and other subject data (in an electronic readable format or as paper 
copies or prints) will be provided to the investigator before access is revoked to the systems and/or 
electronic devices supplied by Novo Nordisk. These data must be retained by the trial site. If the 
provided data (e.g. the CD-ROM) is not readable during the entire storage period, the investigator 
can request a new copy. A copy of all data will be stored by Novo Nordisk.
Novo Nordisk will maintain Novo Nordisk documentation pertaining to the trial for at least 20 years 
after discontinuation of the marketing authorisation, termination of the trial or cancellation of the 
research project whichever is longest. 
The files from the trial site/institution must be retained for 15 years after end of trial as defined in 
Section 7, or longer if required by local regulations or Novo Nordisk. In any case trial files cannot 
be destroyed until the trial site/institution is notified by Novo Nordisk. The deletion process must 
ensure confidentiality of data and must be done in accordance with local regulatory requirements.
24.2
Retention of human biosamples
Antibody samples may be retained for later analysis for further characterisation of antibody 
responses towards drug if required by health authorities or for safety reasons.
The samples will be stored at a central bio-repository after end of trial and until marketing 
authorisation approval or until the research project terminates, but no longer than 15 years from end 
of trial after which they will be destroyed.
The subject’s identity will remain confidential and the antibody samples will be identified only by 
subject number, visit number and trial identification number. No direct identification of the subject 
will be stored together with the samples.
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Only Novo Nordisk staff and bio-repository personnel will have access to the stored antibody 
samples.
Subjects can contact the investigator if they wish to be informed about results derived from stored 
antibody samples obtained from their own body.
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25 Institutional Review Boards/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 Investigator´s 
Brochure, 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 Russia only: Federal law of 12 April 2010 No. 61-FZ ‘On Medicinal Drugs’ Circulation.
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27 References
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53.
National Academy of Sciences (NAS). The Prevention and Treatment of Missing Data in 
Clinical Trials. Washington D.C.: The National Academies Press. 2010.
54.
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.
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. 12/16/2014 
2014.
CONFIDENTIAL


Protocol - Appendix A
CONFIDENTIAL
Date:
06 April 2016
Novo Nordisk
Trial ID: NN9924-4234
Version:
1.0
UTN: U1111-1176-9230 
Status:
Final
EudraCT No.: 2015-005326-19
Page:
1 of 6
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:
06 April 2016
Novo Nordisk
Trial ID: NN9924-4234
Version:
1.0
UTN: U1111-1176-9230 
Status:
Final
EudraCT No.: 2015-005326-19
Page:
2 of 6
1
Background
Treatment with GLP-1 receptor agonists has shown to be associated with thyroid C-cell changes in 
rodents but not in non-human primates. The human relevance of this finding is unknown. However, 
based on the findings in rodents, monitoring of serum calcitonin (a sensitive biomarker for C-cell 
activation) is currently being performed in clinical trials with semaglutide.
While there is general agreement on the clinical interpretation of substantially elevated calcitonin 
levels (greater than 100 ng/L) as likely indicative of C-cell neoplasia, the interpretation of values 
between upper normal range (5.0 and 8.4 ng/L for women and men, respectively) and 100 ng/L is 
less clear with regards to indication of disease.
There are several known confounding factors affecting calcitonin levels, e.g.:
!
renal dysfunction
!
smoking
!
autoimmune thyroiditis
!
several drug classes (e.g. proton pump inhibitors, beta-blockers, H2-blockers and 
glucocorticoids)
Physiology of C-cell activation in various clinical conditions and in different patient populations 
(i.e. with various co-morbidities) is poorly understood. There may be various clinical conditions not 
identified so far which mildly or moderately affect calcitonin secretion by C-cells.
CONFIDENTIAL


Protocol - Appendix A
CONFIDENTIAL
Date:
06 April 2016
Novo Nordisk
Trial ID: NN9924-4234
Version:
1.0
UTN: U1111-1176-9230 
Status:
Final
EudraCT No.: 2015-005326-19
Page:
3 of 6
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 
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.
CONFIDENTIAL


Protocol - Appendix A
CONFIDENTIAL
Date:
06 April 2016
Novo Nordisk
Trial ID: NN9924-4234
Version:
1.0
UTN: U1111-1176-9230 
Status:
Final
EudraCT No.: 2015-005326-19
Page:
4 of 6
Background: These values were found in 9 (0.15%) of a population of 5817 patients with thyroid 
nodular disease.1 All of these patients were diagnosed with medullary thyroid carcinoma 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 type 2 
and perform a genetic test for RET proto-oncogene mutation.
2.2
Calcitonin ≥ 50 and < 100 ng/L
Action: The subject should be referred to a thyroid specialist for further evaluation. The subject 
should remain in the trial and continuation on trial product should be based on the evaluation done 
by the thyroid specialist. 
Background: These values were found in 8 (0.14%) of the population of 5817 patients with thyroid 
nodular disease1. Two of these subjects were diagnosed with medullary thyroid carcinoma and two 
were diagnosed with C-cell hyperplasia, resulting in a positive predictive value of a C-cell anomaly 
of 50%.
Diagnostic evaluation should include: 
!
thyroid ultrasound examination 
!
if available and there are no contraindication, a pentagastrin stimulation test should be done. For 
subjects with positive pentagastrin stimulation test, surgery should be considered. 
!
if pentagastrin stimulation test is not available, thyroid ultrasound and fine needle aspiration 
biopsy may add important clinical information about the need for surgery.
2.3
Calcitonin ≥ 10 and < 50 ng/L
Action: The subject can continue in the trial on trial product. Continue sampling of calcitonin 
according to the protocol.
If the value is from the last sample taken in the trial, the subject should be referred to a thyroid 
specialist for further evaluation.
Background: Calcitonin values from 20-50 ng/L were found in up to 1% of subjects of the 
population of 5817 patients with thyroid nodular disease1. The predictive value of a C-cell anomaly 
CONFIDENTIAL


Protocol - Appendix A
CONFIDENTIAL
Date:
06 April 2016
Novo Nordisk
Trial ID: NN9924-4234
Version:
1.0
UTN: U1111-1176-9230 
Status:
Final
EudraCT No.: 2015-005326-19
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5 of 6
for this calcitonin level was 8.3%. However, the likelihood of having a medullary carcinoma >1 cm 
with calcitonin in this range is extremely low.
For calcitonin values between 10-20 ng/L Costante et al1 identified 216 (3.7%) patients. One patient 
out of the 216 had a subsequent basal (unstimulated) calcitonin of 33 ng/L and had C-cell 
hyperplasia at surgery. Two other studies used a cut-off of calcitonin > 10 ng/L to screen for C-cell 
disease, but they do not provide sufficient information on patients with basal calcitonin > 10 and < 
20 ng/L to allow conclusions.2, 3
CONFIDENTIAL


Protocol - Appendix A
CONFIDENTIAL
Date:
06 April 2016
Novo Nordisk
Trial ID: NN9924-4234
Version:
1.0
UTN: U1111-1176-9230 
Status:
Final
EudraCT No.: 2015-005326-19
Page:
6 of 6
3
References
1.
Costante G, Meringolo D, Durante C, Bianchi D, Nocera M, Tumino S, et al. Predictive 
value of serum calcitonin levels for preoperative diagnosis of medullary thyroid carcinoma 
in a cohort of 5817 consecutive patients with thyroid nodules. J Clin Endocrinol Metab. 
2007;92(2):450-5.
2.
Scheuba C, Kaserer K, Moritz A, Drosten R, Vierhapper H, Bieglmayer C, et al. Sporadic 
hypercalcitoninemia: clinical and therapeutic consequences. Endocr Relat Cancer. 
2009;16(1):243-53.
3.
Verga U, Ferrero S, Vicentini L, Brambilla T, Cirello V, Muzza M, et al. Histopathological 
and molecular studies in patients with goiter and hypercalcitoninemia: reactive or neoplastic 
C-cell hyperplasia? Endocr Relat Cancer. 2007;14(2):393-403.
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
06 April 2016
Novo Nordisk
Trial ID: NN9924-4234
Version:
1.0
UTN: U1111-1176-9230 
Status:
Final
EudraCT No.: 2015-005326-19
Page:
1 of 9
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:
06 April 2016
Novo Nordisk
Trial ID: NN9924-4234
Version:
1.0
UTN: U1111-1176-9230 
Status:
Final
EudraCT No.: 2015-005326-19
Page:
2 of 9
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 hospitalisation for unstable angina)
!
Cerebrovascular event (stroke or transient ischaemic attack)
!
Heart failure
!
Pancreatitis
!
Neoplasm (excluding thyroid neoplasm)
!
Thyroid disease (including thyroid neoplasm)
!
Renal event
!
Hypersensitivity reaction
!
Acute gallstone disease
!
Medication error (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.
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.
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
06 April 2016
Novo Nordisk
Trial ID: NN9924-4234
Version:
1.0
UTN: U1111-1176-9230 
Status:
Final
EudraCT No.: 2015-005326-19
Page:
3 of 9
1.1
Acute coronary syndrome
If an event of acute coronary syndrome (ranging from unstable angina pectoris to myocardial 
infarction) is observed during the trial, the following additional information must be reported if 
available:
!
Duration of symptoms
!
Changes in 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:
!
Signs and symptoms of pancreatitis
!
Specific laboratory test supporting a diagnosis of pancreatitis
!
Imaging performed and consistency with pancreatic disease
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
06 April 2016
Novo Nordisk
Trial ID: NN9924-4234
Version:
1.0
UTN: U1111-1176-9230 
Status:
Final
EudraCT No.: 2015-005326-19
Page:
4 of 9
!
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).
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
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
06 April 2016
Novo Nordisk
Trial ID: NN9924-4234
Version:
1.0
UTN: U1111-1176-9230 
Status:
Final
EudraCT No.: 2015-005326-19
Page:
5 of 9
!
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
!
Relevant immunological tests performed
!
Treatment given for the reaction
!
Previous history of similar reaction
!
Risk or confounding factors identified
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
06 April 2016
Novo Nordisk
Trial ID: NN9924-4234
Version:
1.0
UTN: U1111-1176-9230 
Status:
Final
EudraCT No.: 2015-005326-19
Page:
6 of 9
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:
!
Trial product(s) involved
!
Classification of medication error
!
Wrong drug(s) administered
!
Administration of an overdose
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
06 April 2016
Novo Nordisk
Trial ID: NN9924-4234
Version:
1.0
UTN: U1111-1176-9230 
Status:
Final
EudraCT No.: 2015-005326-19
Page:
7 of 9
!
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).
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
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
06 April 2016
Novo Nordisk
Trial ID: NN9924-4234
Version:
1.0
UTN: U1111-1176-9230 
Status:
Final
EudraCT No.: 2015-005326-19
Page:
8 of 9
!
Relevant laboratory test results
!
Diagnostic imaging performed
!
Possible cause(s) of the event
1.13.1
Assessments in case of increased levels of aminotransferases
Both events should prompt repeat testing (at central laboratory) including ALT, AST, alkaline 
phosphatase (ALP) and total bilirubin and discontinuation of trial product should be considered. 
Thereafter, repeat testing (at central laboratory) of ALT, AST, ALP and total bilirubin should be 
done regularly until the abnormalities return to normal or baseline state. Additional clinical 
information such as related symptoms, risk factors and contributing conditions (e.g. viral hepatitis, 
autoimmune hepatitis, alcoholic hepatitis, hepatobiliary or pancreatic disorders) should be gathered 
to seek a possible cause of the observed laboratory test abnormalities.
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
06 April 2016
Novo Nordisk
Trial ID: NN9924-4234
Version:
1.0
UTN: U1111-1176-9230 
Status:
Final
EudraCT No.: 2015-005326-19
Page:
9 of 9
2
References
1.
Banks PA, Freeman ML, Practice Parameters Committee of the American College of G. 
Practice guidelines in acute pancreatitis. Am J Gastroenterol. 2006;101(10):2379-400.
2.
Banks PA, Bollen TL, Dervenis C, Gooszen HG, Johnson CD, Sarr MG, et al. Classification 
of acute pancreatitis-2012: revision of the Atlanta classification and definitions by 
international consensus. Gut. 2013;62(1):102-11.
3.
U.S. Department of Health and Human Services, Food and Drug Administration. Guidance 
for Industry: Immunogenicity Assessment for Therapeutic Protein Products. August 2015.
CONFIDENTIAL


Global and country key Novo Nordisk staff
Attachments I and II (if applicable) to the protocol are located in the Trial Master File.
Content: Global key staff and Country key staff
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
Oral semaglutide
Trial ID: NN9924-4234
Clinical Trial Report
Appendix 16.1.1
13 December 2018
1.0
Final
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
10 June 2016
Novo Nordisk
Trial ID: NN9924-4234
Version:
1.0
UTN: U1111-1176-9230
Status:
Final
EudraCT No.: 2015-005326-19
Page:
1 of 4
Protocol Amendment
no 1-SE
to Protocol, final version 1.0
dated 06 April 2016
Trial ID: NN9924-4234
PIONEER 5 – renal impairment
Efficacy and safety of oral semaglutide versus placebo in subjects with
type 2 diabetes and moderate renal impairment
A 26-week randomised, double-blind, placebo-controlled trial
Trial phase: 3a
Applicable to Sweden
Amendment originator:
  
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol Amendment
CONFIDENTIAL
Date:
10 June 2016
Novo Nordisk
Trial ID: NN9924-4234
Version:
1.0
UTN: U1111-1176-9230
Status:
Final
EudraCT No.: 2015-005326-19
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
Section 6.3, exclusion criteria #3:..................................................................................................3
2.2
Section 8.2.5 Childbearing potential..............................................................................................3
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
10 June 2016
Novo Nordisk
Trial ID: NN9924-4234
Version:
1.0
UTN: U1111-1176-9230
Status:
Final
EudraCT No.: 2015-005326-19
Page:
3 of 4
1
Introduction including rationale for the protocol amendment
This local substantial amendment for Sweden implements the requirement for a changed definition 
on adequate contraceptive measures for patients participating in the trial in Sweden as requested by 
the Medical Products Agency (the MPA).
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
Section 6.3, exclusion criteria #3: 
The following text will be changed under exclusion criteria No 3:
For Sweden only: Adequate contraceptive measures are: oral (except low-dose gestagen 
(lynestrenol and norestisteron)), injectable, or implanted hormonal contraceptives, intrauterine 
device, intrauterine system (for example, progestin-releasing coil), vasectomised male (with 
appropriate postvasectomy documentation of the absence of sperm in the ejaculate).
is re-written according to the explicit request by the MPA to:
For Sweden only: Only highly effective methods of birth control are accepted (i.e. one that results 
in less than 1% per year failure rate when used consistently and correctly such as implants, 
injectables, combined (estrogen and progestogen containing) oral/intravaginal/transdermal 
contraceptives, progestogen-only oral/injectable/implantable contraceptives,  intrauterine device 
(IUD, IUS)), or sexual abstinence or vasectomised partner.
2.2
Section 8.2.5 Childbearing potential
The following text will be changed under For Sweden only:
For Sweden only: Adequate contraceptive measures are: oral (except low-dose gestagen 
(lynestrenol and norestisteron)), injectable, or implanted hormonal contraceptives, intrauterine 
device, intrauterine system (for example, progestin-releasing coil), vasectomised male (with 
appropriate postvasectomy documentation of the absence of sperm in the ejaculate).
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
10 June 2016
Novo Nordisk
Trial ID: NN9924-4234
Version:
1.0
UTN: U1111-1176-9230
Status:
Final
EudraCT No.: 2015-005326-19
Page:
4 of 4
is re-written according to the explicit request by the MPA to:
For Sweden only: Only highly effective methods of birth control are accepted (i.e. one that results 
in less than 1% per year failure rate when used consistently and correctly such as implants, 
injectables, combined (estrogen and progestogen containing) oral/intravaginal/transdermal 
contraceptives, progestogen-only oral/injectable/implantable contraceptives,  intrauterine device 
(IUD, IUS)), or sexual abstinence or vasectomised partner.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
14 November 2016
Novo Nordisk
Trial ID: NN9924-4234
Version:
1.0
UTN:U1111-1176-9230
Status:
Final
EudraCT No.:2015-005326-19
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Protocol Amendment
no 2
to Protocol, final version 1
dated 06 April 2016
Trial ID:NN9924-4234
PIONEER 5 – renal impairment
Efficacy and safety of oral semaglutide versus placebo in subjects with type 2 
diabetes and moderate renal impairment
A 26-week randomised, double-blind, placebo-controlled trial
Trial phase: 3a
Applicable to all countries 
Amendment originator:
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
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This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol Amendment
CONFIDENTIAL
Date:
14 November 2016
Novo Nordisk
Trial ID: NN9924-4234
Version:
1.0
UTN:U1111-1176-9230
Status:
Final
EudraCT No.:2015-005326-19
Page:
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Table of Contents   
Page
Table of Contents..............................................................................................................................................2
1
Introduction including rationale for the protocol amendment.............................................................3
1.1
Additional eye examinations and additional data collection on diabetic retinopathy....................3
1.2
Investigator’s responsibility in ensuring evaluation and management of certain risk factors 
and complications ..........................................................................................................................4
1.3
Clarification of the criteria for completion, withdrawal and lost to follow-up..............................4
1.4
Alignment of rescue medication not allowed ................................................................................4
1.5
Other minor adjustments, clarifications and correction of typographical errors............................4
1.5.1
Laboratory analysis......................................................................................................4
1.5.2
Adverse events for Adjudication .................................................................................5
1.5.3
Statistical considerations..............................................................................................5
2
Changes......................................................................................................................................................6
2.1
Section 2  Flow chart .....................................................................................................................6
2.2
Section 4.2.2.2  Supportive secondary endpoints ..........................................................................7
2.3
Section 6.6  Withdrawal from trial ................................................................................................7
2.4
Section 8.1.4  End-of-treatment (visit 13) and Follow-up (visit 14)..............................................7
2.5
Section 8.1.5  Premature discontinuation of trial product and follow-up (visit 13A and visit 
14A) ...............................................................................................................................................8
2.6
8.1.6.1  Lost to follow-up ..............................................................................................................9
2.7
8.4.1.2  Adverse events requiring additional data collection.........................................................9
2.8
Section 8.4.2  Physical examination ............................................................................................10
2.9
Section 8.4.4  Eye examination....................................................................................................10
2.10
Section 8.4.8   Anti-semaglutide antibodies ................................................................................10
2.11
Section 12.1.5  Adverse events requiring additional data collection...........................................10
2.12
Section 12.7.2  Event adjudication committee.............................................................................11
2.13
Section 17.2  Definition of analysis sets......................................................................................11
2.14
Section 17.3.1  Primary analysis for the primary estimand .........................................................12
2.15
Section 17.4.2.1  Efficacy endpoints ...........................................................................................12
2.16
Section 17.4.2.2 Safety endpoints................................................................................................13
2.17
Section 18.1 Benefit-risk assessment of the trial.........................................................................14
2.18
Section 27  References.................................................................................................................15
2.19
Reference numbers ......................................................................................................................15
2.20
Appendix B, section 1  Adverse events requiring additional data collection ..............................16
2.21
Appendix B, new section.............................................................................................................16
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
14 November 2016
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Trial ID: NN9924-4234
Version:
1.0
UTN:U1111-1176-9230
Status:
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EudraCT No.:2015-005326-19
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1
Introduction including rationale for the protocol amendment
This protocol amendment introduces:
1. Additional eye examinations and additional data collection on diabetic retinopathy 
2. 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. Alignment of rescue medication not allowed
5. Other minor corrections and clarifications
1.1
Additional eye examinations and additional data collection on diabetic retinopathy
Updated protocol Sections: 2, 4.2.2.2, 8.4.1.2, 8.4.4, 12.1.5, 17.4.2.2, 18.1 and Appendix B, section 
1, 1.14.
Transient worsening of diabetic retinopathy is a recognised complication in selected patients with 
diabetes after initiation of intensive antidiabetic treatment. Risk factors for these events include 
long-standing poor glycaemic control and presence of proliferative retinopathy, and initial large 
improvements in blood glucose may be an additional aggravating factor123. In a recently completed 
cardiovascular outcomes trial with s.c. semaglutide, results indicate an increased risk of events 
related to diabetic retinopathy in subjects treated with semaglutide compared to placebo4 . The 
majority of the related adverse events were moderate in severity and did not lead to premature 
discontinuation of trial product. 
, additional eye examinations 
have been implemented in all trials in the PIONEER program. Also, to further understand this  
safety signal, additional information will be collected  for all diabetic retinopathy events reported 
during the trial. The information will be collected not only from new subjects enrolled by the time 
of this amendment, but also from already enrolled subjects to the extent that the information is 
available. Furthermore, information to the investigators and subjects related to diabetic retinopathy 
has been added to the protocol (see Section 18) and the subject information. 
                                                
1 Dahl-Jørgensen K, Brinchmann-Hansen O, Hanssen KF, Sandvik L, Aagenaes O. Rapid tightening of blood glucose 
control leads to transient deterioration of retinopathy in insulin dependent diabetes mellitus: the Oslo study. Br Med J 
(Clin Res Ed). 1985;290(6471):811-5.
2 The Diabetes Control and Complications Trial Research Group. Early worsening of diabetic retinopathy in the 
Diabetes Control and Complications Trial. Arch Ophthalmol. 1998;116(7):874-86
3 Varadhan L, Humphreys T, Walker AB, Varughese GI. The impact of improved glycaemic control with GLP-1 
receptor agonist therapy on diabetic retinopathy. Diabetes Res Clin Pract. 2014;103(3):e37-9.
4 Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, et al. Liraglutide and Cardiovascular 
Outcomes in Type 2 Diabetes. N Engl J Med. 2016
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Protocol Amendment
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Date:
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Version:
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1.2
Investigator’s responsibility in ensuring evaluation and management of certain risk 
factors and complications
Updated protocol Section: 8.4.2 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.
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 subjects last planned visit. 
Only if contact is not regained at that time point can the subject be considered lost to follow up. 
Because this trial is not an outcome trial the terminology ‘health status’ is replaced with “relevant 
safety information” - the purpose of which is to follow up on any adverse events or pregnancy, and 
not to determine if a subject completes the trial or not.
1.4
Alignment of rescue medication not allowed
Updated protocol Section: 18.1.1.
The section 181.1 of the protocol has been updated as there was a discrepancy between the rescue 
medication which is not allowed are listed in 6.4 and in section 18 in order to avoid any mistakes in 
the use of rescue medication. The products which are not allowed as rescue medication are;
GLP-RAs, DPP-4 inhibitors and amylin analogues. 
1.5
Other minor adjustments, clarifications and correction of typographical errors
1.5.1
Laboratory analysis
Updated protocol Sections: 8.4.8 
The protocol currently specifies that the in vitro neutralising antibody assays will be performed by 
Novo Nordisk, however, it may be decided by Novo Nordisk that the laboratory currently 
responsible for antibody binding analysis (Celerion) will perform the assay. 
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Protocol Amendment
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1.5.2
Adverse events for Adjudication
Updated protocol Section: 12.7.2
Table 12-2 has been aligned with Table 12-1 reflecting that unstable angina pectoris (UAP) requires 
hospitalisation to qualify for Event Adjudication.
1.5.3
Statistical considerations
Updated protocol Sections: 17.2, 17.3.1 and 17.4.2.1
The eye examination category has been added to the list of assessments where the follow-up period 
is included in the “on-treatment” observation period. This is due to the inclusion of the fundus 
photography or dilated fundoscopy at the end of trial visit or within 5 weeks thereafter for subjects 
completing treatment.
For the pattern mixture model using multiple imputations, 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.
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Protocol Amendment
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Trial ID: NN9924-4234
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2
Changes
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through
2.1
Section 2 
Flow chart
…
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 V13 or within 5 weeks thereafter for subjects completing treatment
!
at V13A and within 5 weeks thereafter, and again within 5 weeks prior to V13 for 
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subjects who have prematurely discontinued from trial product
2.2
Section 4.2.2.2
Supportive secondary endpoints
…
Supportive secondary safety endpoints
…
Change from baseline to week 26 in:
!
Haematology
!
Biochemistry
!
Estimated glomerular filtration rate (eGFR) as per Chronic Kidney Disease Epidemiology 
Collaboration formula (CKD-EPI)
!
Calcitonin
!
Urinalysis
!
Urinary albumin to creatinine ratio
!
Pulse
!
Systolic blood pressure
!
Diastolic blood pressure
!
Electrocardiogram (ECG) evaluation
!
Physical examination
!
Eye examination category
2.3
Section 6.6 
Withdrawal from trial
The subject may withdraw consent at will at any time. The subject’s request to withdraw from the 
trial must always be respected.  Only subjects who withdraw consent should be considered as 
withdrawn from trial.  A subject who does not complete the trial is also considered withdrawn from 
the trial. Hence a subject is considered withdrawn if the following applies: 
!
Subject withdrew consent 
!
Subject was lost to follow up (only to be used if there was 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)
2.4
Section 8.1.4 
End-of-treatment (visit 13) and Follow-up (visit 14)
…
At V13 the subject should be reminded about the importance of attending the follow-up visit (V14). 
If the subject, nonetheless, does not attend V14, the site should make efforts to obtain contact with 
the subject within the visit window. 
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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 V14. (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 V14, 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.
2.5
Section 8.1.5 
Premature discontinuation of trial product and follow-up (visit 13A 
and visit 14A)
…
Subjects should continue with the originally scheduled site contacts after V14A and up to and 
including V13. If necessary, in order to retain the subject in the trial, site visits can be replaced by 
phone contacts after V14A. 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 V13 (end-of-treatment) as this 
visit should be performed for all subjects, if at all possible (except subjects who withdraw informed
consent, see Section 8.1.6).
Subjects, who only agree to attend or provide health status at the planned V13, should not be 
considered withdrawn from the trial. In case the subject cannot be reached (by clinic visit or phone 
contact) at the scheduled V13, 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 V13 (or V14A if it is scheduled 
after V13). The site should in due time prepare for establishing contact with the subject within the 
visit window of the scheduled V13, if the subject has agreed to attend this visit. 
In summary, subjects should stay in the trial irrespective of lack of adherence to randomised 
treatment, lack of adherence to visit schedule, missing assessments or trial product discontinuation 
for any reason. Only subjects who decline any further contact with the site in relation to the trial 
should be considered as having withdrawn consent from the trial (for withdrawal procedures see 
Section 8.1.6).
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Trial ID: NN9924-4234
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2.6
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: V14 for subjects who have completed treatment, whereas for subjects who have discontinued 
trial product prematurely the last visit is V13 (or V14A, if it is scheduled after V13). Only if contact 
with the subject is not regained by the end of the visit window of the last scheduled visit can the 
subject be considered lost to follow up (see Section 6.6). 
2.7
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 hospitalisation for unstable angina)
!
Cerebrovascular event (stroke or transient ischaemic attack)
!
Heart failure
!
Pancreatitis
!
Neoplasm (excluding thyroid neoplasm)
!
Thyroid disease (including thyroid neoplasm)
!
Renal event
!
Hypersensitivity reaction
!
Acute gallstone disease
!
Medication error
!
Lactic acidosis
!
Creatine kinase (CK) > 10 x UNL
!
Hepatic event defined as:
o
ALT or aspartate aminotransferase (AST) > 5 x UNL and total bilirubin ≤ 2 x UNL
o
ALT or AST > 3 x UNL and total bilirubin > 2 x 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 ALT or AST > 3x UNL and total bilirubin > 
2x 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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2.8
Section 8.4.2
Physical examination
A physical examination will be performed by the investigator according to local procedure (see 
Section 2 and Section 8.1.7). A physical examination must include:
!
General appearance
!
Head, ears, eyes, nose, throat, neck
!
Thyroid gland*
!
Respiratory system
!
Cardiovascular system
!
Gastrointestinal system including mouth
!
Musculoskeletal system
!
Central and peripheral nervous system
!
Skin
!
Lymph node palpation
*Please note that the diagnostic evaluation of thyroid nodules should be in accordance with the 
American Thyroid Association Management Guidelines or any updates hereof42 and adapted to 
local treatment guidelines if applicable.
2.9
Section 8.4.4 
Eye examination
Fundus photography or dilated fundoscopy will be performed as per flow chart (see Section 2) by 
the investigator or according to local practise. Fundoscopy requires pharmacological dilation of 
both pupils. Results of the fundus photography or dilated fundoscopy will be interpreted by the 
investigator (see Section 8.1.7).
…
2.10
Section 8.4.8 
Anti-semaglutide antibodies
…
Furthermore, samples drawn at randomisation may be used for calculations of the neutralising effect 
in the in vitro neutralising antibody assays. The in vitro neutralising assays will be performed by 
Novo Nordisk or the special laboratory responsible for binding antibody analysis.
…
2.11
Section 12.1.5 
Adverse events requiring additional data collection
…
Table 12-1 Adverse events requiring completion of specific event forms and/or are subject to 
event adjudication
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Note: Only shown is the event with updated event description, all other events are unchanged
Event
Specific
event form
Event
adjudication
Diabetic retinopathy and related complications
Yes
No
…
2.12
Section 12.7.2
Event adjudication committee
…
Table 12-2 Adverse events for adjudication
Note: Only shown is the event with updated event description, all other events are unchanged
Events
Description
Adjudication outcome
Acute Coronary Syndrome
Acute Coronary Syndrome conditions include: 
!
ST-elevation acute myocardial infarction 
(STEMI)
!
Non-ST elevation acute myocardial infarction 
(NSTEMI)
!
Silent myocardial infarction 
!
Unstable angina pectoris (UAP) requiring 
hospitalisation
!
Acute myocardial 
infarction (STEMI or 
NSTEMI), silent 
myocardial infarction 
!
Unstable angina pectoris 
requiring hospitalisation
…
2.13
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, 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 (V14)
!
the follow-up prematurely discontinuation visit (V14A)
!
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
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follow-up visit is +3 days.
…
2.14
Section 17.3.1 
Primary analysis for the primary estimand
…
Missing values for each group will be imputed as follows:
!
An analysis of covariance (ANCOVA) with region, stratification factors and the interaction 
between the two 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.
!
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 
interaction between the two 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 in HbA1c from baseline to 
week 26 will be analysed using an ANCOVA with treatment, stratification factors, the interaction 
between the two 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 rule52 to 
draw inference.
2.15
Section 17.4.2.1
Efficacy endpoints
…
Binary efficacy endpoints
…
The above eight binary endpoints will be analysed using a logistic regression model with treatment, 
stratification factors, the interaction between the two 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 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.
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!
Each of the created complete data set will be analysed with the logistic model and inference 
will be drawn using Rubin’s rule52.
2.16
Section 17.4.2.2
Safety endpoints
…
Other safety endpoints
…
Change from baseline to week 26 in:
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!
Haematology
!
Biochemistry (except for amylase and lipase)
!
eGFR as per CKD-EPI
!
Calcitonin
!
Urinalysis
!
Urinary albumin to creatinine ratio
!
Electrocardiogram (ECG) evaluation
!
Physical examination 
!
Eye examination category 
Note that the urinary albumin to creatinine ratio is measured twice, so the mean will be used as 
endpoint.
2.17
Section 18.1
Benefit-risk assessment of the trial
…
18.1.1 Risks and precautions
…
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 treatment56,57,58. 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 progression59,60 even in intensively treated patients who experienced early 
worsening57. 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 
placebo61. 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 trial62. 
…
General precautions
…
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 Diabetes31.32 (excluding GLP-1 RAs, DPP-4 inhibitors, and amylin 
analogues and SGLT-2 inhibitors).
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It is the responsibility of the investigator to ensure the best possible care of the subject. This 
includes adequate glycaemic control, appropriate risk factor modification such as optimal 
treatment of hypertension, dyslipidaemia and other cardiovascular risk factors, as well as regular 
monitoring and treatment of diabetic kidney disease and diabetic retinopathy according to the 
principles outlined in (Diabetes Care 2016 Standards of Medical Care in Diabetes)62.
2.18
Section 27
References
42. 
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.
56.
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.
57.
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.
58.
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.
59.
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.
60.
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.
61. 
Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, et al. 
Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016.
62.
American Diabetes Association. Standards of medical care in diabetes - 2016. Diabetes 
Care. 2016;39 (Suppl. 1):S1-S109.
2.19
Reference numbers
Will change throughout the updated protocol when new reference numbers are introduced.
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2.20
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 hospitalisation for unstable angina)
!
Cerebrovascular event (stroke or transient ischaemic attack)
!
Heart failure
!
Pancreatitis
!
Neoplasm (excluding thyroid neoplasm)
!
Thyroid disease (including thyroid neoplasm)
!
Renal event
!
Hypersensitivity reaction
!
Acute gallstone disease
!
Medication error (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
!
Diabetic retinopathy and related complications
…
2.21
Appendix B, new section 
1.14 Diabetic retinopathy and related complications
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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 
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SAP_001.pdf: 
Cover Page for Statistical Analysis Plan  
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT02827708 
Sponsor trial ID: 
NN9924-4234 
Official title of study: 
Efficacy and Safety of Oral Semaglutide Versus Placebo in 
Subjects with Type 2 Diabetes and Moderate Renal Impairment 
Document date: 
13-December-2018 
 


Link
Link
List of contents
Statistical analysis plan......................................................................................................................
Pre-defined MedDRA search – list of preferred terms...................................................................
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Status:
Oral semaglutide
Trial ID: NN9924-4234
Clinical Trial Report
Appendix 16.1.9
13 December 2018
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Final
16.1.9 Documentation of statistical methods
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Statistical Analysis Plan
Trial ID: NN9924-4234
PIONEER 5 –Renal impairment
Efficacy and safety of oral semaglutide versus placebo in 
subjects with type 2 diabetes and moderate renal 
impairment
Trial phase: Phase 3a
Authors:
Name:          
 & 
Department:
 
This confidential document is the property of Novo Nordisk. No unpublished information contained herein 
may be disclosed without prior written approval from Novo Nordisk. Access to this document must be 
restricted to relevant parties.
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disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
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Statistical Analysis Plan
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EudraCT No.: 2015-005326-19
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Table of contents 
Page
Table of contents.........................................................................................................................................2
Table of figures ...........................................................................................................................................3
Table of tables.............................................................................................................................................3
List of Abbreviations ..................................................................................................................................4
1
Introduction .........................................................................................................................................6
1.1
Trial information.......................................................................................................................6
1.1.1
Primary Objective ........................................................................................................6
1.1.2
Secondary Objectives ...................................................................................................6
1.1.3
Trial Design .................................................................................................................6
1.2
Scope of the Statistical Analysis Plan ........................................................................................6
2
Statistical considerations .....................................................................................................................8
2.1
General considerations ..............................................................................................................8
2.2
Primary and secondary estimands..............................................................................................8
2.3
Missing data considerations at week 26 .....................................................................................9
2.4
Sample size calculation ...........................................................................................................10
2.5
Definition of analysis sets........................................................................................................12
2.6
Data selections and observation periods...................................................................................12
2.7
Confirmatory hypotheses.........................................................................................................14
2.8
Multiplicity and criteria for confirming hypotheses..................................................................14
2.9
Primary endpoint.....................................................................................................................14
2.9.1
Primary analysis for the primary estimand..................................................................14
2.9.2
Primary analysis for the secondary estimand...............................................................15
2.9.3
Sensitivity analyses ....................................................................................................16
2.9.3.1
Sensitivity analyses for the primary estimand .............................................16
2.9.3.2
Sensitivity analyses for the secondary estimand..........................................16
2.9.3.3
Pattern mixture models...............................................................................17
Assessment of sensitivity analyses..............................................................................17
2.10
Secondary endpoints ...............................................................................................................17
2.10.1
Confirmatory secondary endpoints .............................................................................18
2.10.2
Supportive secondary endpoints .................................................................................18
2.10.2.1
Efficacy endpoints......................................................................................18
2.10.2.2
Safety endpoints and safety assessments.....................................................22
2.10.2.3
Pharmacokinetic endpoints .........................................................................26
2.11
Interim Analysis......................................................................................................................26
2.12
Pharmacokinetic and/or pharmacodynamic modelling .............................................................26
2.13
Patient reported outcomes .......................................................................................................26
2.13.1
SF-36v2® (acute version) health survey ......................................................................27
2.13.2
Diabetes Treatment Satisfaction Questionnaire – status version (DTSQs) ...................29
2.13.3
Responder analyses ....................................................................................................30
3
Changes to the statistical analyses planned in the protocol..............................................................31
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4
References ..........................................................................................................................................33
Table of figures 
Page
Figure 2-1
Graphical illustration of the testing procedure..........................................................................11
Figure 2-2
ADA classification of hypoglycaemia .....................................................................................25
Table of tables 
Page
Table 2-1 
Assumptions used in the sample size calculation .....................................................................11
Table 2-2
Calculated powers for individual hypotheses ...........................................................................11
Table 2-3
Overview of domains for SF-36v2® (acute version)................................................................27
Table 2-4
Responder thresholds for SF-36v2 (acute version)...............................................................28
Table 2-5
Overview of items in DTSQs questionnaire.............................................................................29
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List of Abbreviations
AACE 
American Association of Clinical Endocrinologists
ADA 
American Diabetes Association
AE
Adverse Event
ANOVA
Analysis of Variance
BG 
Blood Glucose
BMI
Body Mass Index
CDF
Cumulative Distribution Function
CI
Confidence Interval
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CoEQ
Control of Eating Questionnaire
CRF
Case Report Form
CRP 
C-reactive Protein
CTR
Clinical Trial Report
DTR-QoL
Diabetes Therapy-Related Quality of Life
DTSQs
Diabetes Treatment Satisfaction Questionnaire status
eCRF
Electronic Case Report Form
eGFR
Estimated Glomerular Filtration Rate
EAC 
Event Adjudication Committee
ECG 
Electrocardiogram
EoT
End-of-Text
FAS 
Full Analysis Set
FPG 
Fasting Plasma Glucose
GLP-1 
Glucagon-like Peptide-1
HRQoL
Health-Related Quality of Life
IWQOL-Lite-CT
Impact of Weight on Quality of Life – Lite Clinical Trials version
IWRS
Interactive Web Response System
LLoQ
Lower Limit of Quantification
LOCF
Last Observation Carried Forward
MAR
Missing at Random
MCS
Mental Component Score
MedDRA
Medical Dictionary for Regulatory Activities
MID
Minimally Important Difference
MMRM 
Mixed Model for Repeated Measurements
MNAR
Missing Not at Random
PCS
Physical Component Score
PD
Pharmacodynamics
PGI-C
Patient Global Impression of Change
PGI-S
Patient Global Impression of Status
PK
Pharmacokinetics
PP
Per Protocol
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PRO 
Patient Reported Outcomes
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SAS
safety analysis set
SD
Standard Deviation
SE
Standard Error
SF-36v2 (acute version)
Short Form 36 version 2.0 Health Survey (acute version)
TEAE 
treatment-emergent adverse events
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1
Introduction
1.1
Trial information
This is a 26-week, randomised, double-blind, placebo-controlled, parallel-group, multicentre,
multinational trial with 2 arms comparing the efficacy and safety of oral semaglutide with placebo
in subjects with type 2 diabetes mellitus and moderate renal impairment.
1.1.1
Primary Objective
To compare the effect of once-daily dosing of 14 mg oral semaglutide versus placebo, both in 
combination with metformin and/or sulfonylurea, basal insulin alone or metformin in combination 
with basal insulin on glycaemic control in subjects with type 2 diabetes mellitus and moderate renal 
impairment (metformin alone, SU alone or in combination with metformin, basal insulin alone or in 
combination with metformin).
1.1.2
Secondary Objectives
To compare the effect of once-daily dosing of 14 mg oral semaglutide versus placebo, both in
combination with metformin and/or sulfonylurea, basal insulin alone or metformin in combination
with basal insulin on body weight in subjects with type 2 diabetes mellitus and moderate renal
impairment.
To compare the safety and tolerability of once-daily dosing of 14 mg oral semaglutide versus 
placebo, both in combination with metformin and/or sulfonylurea, basal insulin alone or metformin 
in combination with basal insulin in subjects with type 2 diabetes mellitus and moderate renal 
impairment.
1.1.3
Trial Design
Subjects will be randomised in a 1:1 manner to receive either a dose of 14 mg oral semaglutide or 
placebo once daily. The total trial duration for the individual subject will be approximately 33 
weeks. The trial includes a 2-week screening period, followed by a 26-week randomised treatment 
period and a follow-up period of 5 weeks. 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 NN9924-4234 “Efficacy and 
safety of oral semaglutide versus placebo in subjects with type 2 diabetes and moderate renal 
impairment”, version 2.0 (14 November 2016), and includes more detailed procedures for executing 
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the statistical analyses of the primary and secondary endpoints. Statistical analyses and a number of 
clarifications additional to those specified in the trial protocol are pre-specified with this SAP. All 
changes to the statistical analyses planned in the trial protocol are documented in Section 3.
Novo Nordisk will be responsible for the statistical analyses and reporting.
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2
Statistical considerations
2.1
General considerations
The blinding of the randomised treatments will be maintained until the database has been released 
for statistical analysis.
Data from all sites will be analysed and reported together.
In statistical analyses where stratification is included, the three levels of antidiabetic background 
medication at screening (metformin, SU +/-metformin, basal insulin +/- metformin) and the two 
levels of renal function (eGFR 30 - 44 mL/min/1.73 m2 and eGFR 45 - 59 mL/min/1.73 m2 as per
CKD-EPI) 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 details of the region variables included in statistical analyses were not specified in protocol. 
The regions are: Europe (Denmark, Finland, Israel, Poland, Russian Fed., Sweden, United 
Kingdom) and North America (United States).
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 oral semaglutide 14 mg vs. placebo with associated two-sided 95% confidence 
intervals and p-values corresponding to two-sided tests of no difference.
If no statistical analysis is specified, data will be presented using relevant summary statistics.
2.2
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 – ‘Treatment policy’
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–
de-facto 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 adherence to trial product
administration in this trial reflects the behaviour of the target population. Accordingly, data
collected regardless of discontinuation of trial product or initiation of rescue medication(s) will be
used to draw inference.
!
Secondary estimand – ‘Hypothetical’
–
de-jure 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 will be pre-defined for the remaining secondary endpoints addressing 
the secondary objective. 
2.3
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(s), 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 missing data is expected to be higher
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(20%) since data collected after discontinuation of trial product or initiation of rescue medication(s)
will be set to missing. The 20% of missing data is based on the 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. Whereas a higher proportion of subjects are
expected to discontinue treatment due to AEs in the oral semaglutide arm. So overall the frequency
of missing data is expected to be similar across treatment arms.
Descriptive summaries and graphical representation of extent, reason(s) for and pattern of missing
data will be presented by treatment arm.
2.4
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.
The sample size calculation is made to ensure a power of at least 90% for testing HbA1c superiority 
of oral semaglutide vs. placebo out of the two pre-specified confirmatory hypotheses shown in 
Figure 2-1. The hierarchical testing procedure is used to control the overall type I error at a nominal 
two-sided 5% level. The statistical testing strategy1 is built on the principle that glycaemic effect 
will have to be established in terms of HbA1c superiority before testing for added benefits in terms 
of body weight superiority.
The sample size is calculated using the calcPower function in the R package, gMCP2, using 10000 
simulations. The two 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 
deviation (SD) 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).
Subjects are allowed to be on metformin alone, SU alone or in combination with metformin, basal 
insulin alone or in combination with metformin as background medication; if they need rescue 
medication it is expected to have an effect on glycaemic control and the treatment effect compared 
to oral semaglutide will therefore be equalised. Furthermore a conservative approach for handling 
of missing data will be performed. An adjustment in treatment effect will be implemented for the 
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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 no effect in these subjects. The adjusted 
treatment effect for testing superiority is defined as: 0.8×TE + 0.2×TE×0
Table 2-1
Assumptions used in the sample size calculation
Oral semaglutide 
vs. placebo
Treatment effect
(TE)
Adjusted TE,
superiority
Standard deviation
HbA1c(%-point)
-0.5
-0.4
1.1
Body weight (kg)
-2
-1.6
4
With the above assumptions, allocating 162 subjects to each of the oral semaglutide and placebo 
arms provides at least 90% power to confirm HbA1c superiority of oral semaglutide vs. placebo. In 
total 2×162 = 324 subjects are planned to be randomised. Calculated powers for individual 
hypotheses are presented in Table 2-2.
Table 2-2
Calculated powers for individual hypotheses
Statistical test
HbA1c superiority
Body weight superiority
Power (%)
91%
86%
Figure 2-1
Graphical illustration of the testing procedure
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The overall significance level of α = 0.05 (two-sided) is initially allocated to the HbA1c superiority 
test of oral semaglutide vs. placebo. The local significance level (α-local) will be reallocated to the 
next body weight superiority hypothesis, if the HbA1c superiority hypothesis is confirmed. The 
sample size is based on the hypotheses in the dark box.
2.5
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.  This 
will be referred to as contributing to the evaluation “as treated”.
2.6
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 (V14) for subjects on trial product
!
the latest occurring visit of the end-of-treatment visit (V13) or the follow-up premature 
discontinuation visit (V14A), for subjects who have discontinued trial product prematurely.
Subjects and data to be used in an analysis will be selected in a two-step manner:
!
Firstly, subjects will be selected based on the specified analysis set
!
Secondly, data points on the selected subjects from the first step will be selected based on 
the specified observation period
Definition of the observation periods:
In-trial: This observation period represents the time period where subjects are considered to be in 
the trial, regardless of discontinuation of trial product or initiation of rescue medication. The in-trial 
observation period starts at randomisation (as registered in the IWRS) and ends at the date of:
!
the last direct subject-site contact, which is scheduled to take place 5 weeks after planned 
last dose of trial product at the follow-up visit
!
withdrawal for subjects who withdraw their informed consent
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!
the last subject-investigator contact as defined by the investigator for subjects who are lost 
to follow-up
!
death for subjects who die 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, 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 (V14)
!
the follow-up premature discontinuation visit (V14A)
!
the last date on trial product +38 days
!
the end-date for the in-trial observation period
The follow-up visit is scheduled to take place 5 weeks after the last date on trial product
corresponding to approximately five half-lives of oral semaglutide. The visit window for the
follow-up visit is +3 days.
For efficacy and other safety assessments (laboratory assessments, physical examination and vital
signs) the observation period ends at the last date on trial product +3 days. This will be used in 
order to ensure specificity to reversible effects of treatment.
On-treatment without rescue medication: This observation period is a subset of the on-treatment 
observation period, where subjects are considered treated with trial product, but have not initiated 
any rescue medications. Specifically it starts at date of first dose of trial product and the observation 
period ends at the first date of any of the following:
!
the last dose of trial product +3 days
!
initiation of rescue medication
The in-trial observation period will be the primary observation period when estimating the primary 
estimand. The on-treatment without rescue medication observation period will be the primary 
observation period when estimating the secondary estimand. The on-treatment observation period 
will be considered supportive for evaluating efficacy. Safety will be evaluated based on the in-trial 
and the on-treatment observation periods.
Data points collected outside an observation period will be treated as missing in the analysis.
Baseline data will always be included in an observation period. For adjudicated events, the onset 
date will be the EAC adjudicated onset date.
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Before data are locked for statistical analysis and the randomisation code is broken, a review of all 
data will take place. Any decision to exclude either a subject or single observations from the 
statistical analysis is the joint responsibility of the members of the Novo Nordisk study group.
Exclusion of data from analyses will be used restrictively, and normally no data should be excluded 
from the FAS. The subjects or observations to be excluded, and the reasons for their exclusion must 
be documented and signed by those responsible before database lock. The subjects and observations 
excluded from analysis sets, and the reason for this, will be described in the clinical trial report.
2.7
Confirmatory hypotheses
For the primary HbA1c endpoint and the secondary confirmatory body weight endpoint, the 
following one-sided hypotheses are planned to be tested for 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.
2.8
Multiplicity and criteria for confirming hypotheses
The type I error for testing the two confirmatory hypotheses related to the HbA1c and body weight 
endpoints will be preserved in the strong sense at 5% (two-sided) using the hierarchical testing 
strategy as outlined in Figure 2-1.
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 the 5% two-sided significance level. This is equivalent to using a 
one-sided p-value (nominal α = 0.025) and a one-sided 2.5% overall significance level.
2.9
Primary endpoint
The primary endpoint is change from baseline to week 26 in HbA1c.
2.9.1
Primary analysis for the primary estimand
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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 4 groups of subjects defined by randomised treatment arm, and whether subjects at 
week 26; (i) have discontinued treatment or initiated rescue medication or (ii) are still on treatment 
and have not initiated rescue medication. It is hereby assumed that the likely values of what the 
missing data would have been if available are best described by information from subjects who at 
week 26 are similar in terms of randomised treatment arm and treatment adherence/rescue 
medication status.
Missing values for each group will be imputed as follows:
!
An analysis of covariance (ANCOVA) with stratification 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.
!
The estimated parameters for location and dispersion will be used to impute 1000 values for 
each subject with missing week 26 data based on the two stratification factors and baseline 
HbA1c. 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 in HbA1c from baseline to week
26 will be analysed using an ANCOVA with treatment, region, stratification factors and the 
interaction between the two stratification factors as categorical fixed effects and baseline 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 difference between oral semaglutide and placebo 
together with associated two-sided 95% confidence interval and unadjusted two-sided p-value for 
testing no difference from zero will be presented.
2.9.2
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 (REML) will be used. The model will include all post 
baseline HbA1c measurements collected at scheduled visits up to and including week 26 as 
dependent variables. The independent effects included in the model will be treatment, stratification 
factors, the interaction between the two stratification factors and region as categorical fixed effects 
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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.
For subjects who do not have post-baseline assessments for planned visits available in the on-
treatment without rescue medication period, the baseline value will be carried forward to the first 
planned visit, if this falls within 8 weeks, to ensure that all randomised subjects will contribute to 
the statistical analysis.
2.9.3
Sensitivity analyses
To investigate the sensitivity of the primary analysis results, complementary and separate analyses 
will be performed for the primary and secondary estimand. In line with European Medicines 
Agency recommendations5 and with a report from the US National Research Council6, 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 imputations. 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. 
2.9.3.1
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
2.9.3.2
Sensitivity analyses for the secondary estimand
The estimation of the secondary estimand will be repeated using the following sensitivity analysis:
!
A tipping-point multiple imputation analysis based on FAS using the on-treatment without 
rescue medication observation period
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2.9.3.3
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 AE(s) 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. This sensitivity analysis is less conservative as 
compared to the first sensitivity analysis.
!
Tipping-point multiple imputation analysis: In this sensitivity analysis, missing data will 
first be imputed according to the primary analysis. Secondly, for the oral semaglutide 
treatment arm a penalty will be added to the imputed values at week 26. The approach is to 
gradually increase this penalty until a confirmed HbA1c conclusion from the primary 
analysis is changed. The specific value of the penalty that changes the conclusion will be 
used to evaluate the robustness of the primary analysis result.
Assessment of sensitivity analyses
The results from the sensitivity analyses will be collectively used to interpret the robustness of the 
trial results for HbA1c. Due to the sensitivity analyses inherent conservative nature, it will not be a 
requirement that all confirmatory hypotheses are consistently confirmed across the sensitivity 
analyses. Thus, no absolute success criteria will be pre-defined for each sensitivity analysis. The 
sensitivity results in totality will be used to substantiate the credibility of the trial results.
2.10
Secondary endpoints
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2.10.1
Confirmatory secondary endpoints
Change from baseline to week 26 in body weight (kg) will be a confirmatory secondary endpoint.
The primary and secondary estimands will be estimated using the same approaches as described for
the primary HbA1c endpoint. Body weight will only be tested for superiority. Baseline body weight
will be used as a covariate instead of baseline HbA1c in both the 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 updated local two-sided significance level resulting from the closed testing
procedure in Figure 2-1. Sensitivity analyses similar to the ones pre-specified for testing superiority 
for the primary HbA1cendpoint will be made to evaluate the robustness of the body weight results.
2.10.2
Supportive secondary endpoints
2.10.2.1
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 the supportive secondary endpoints.
Continuous efficacy endpoints
Change from baseline to week 26 in:
!
Fasting plasma glucose (FPG)
!
Body weight (%)
!
Body mass index (BMI)
!
Waist circumference
!
Fasting lipid profile (total cholesterol, low-density lipoprotein (LDL) cholesterol, high-
density lipoprotein (HDL) cholesterol and triglycerides)
!
C-reactive protein (CRP)
BMI will be calculated based on body weight and height based on the formulae:
      BMI kg/m2 = body weight (kg)/(height (m) x height (m)) or (kg/m2 = [lb/in2 x 703])
The above continuous endpoints will be analysed separately using similar model approaches as for 
the primary endpoint with the associated baseline response as a covariate. Fasting lipid profile 
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endpoints and C-reactive protein endpoint 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 at week 26. This will result 
in imputation of missing data within 4 groups as described for the week 26 evaluation in Section 
2.9.1.
For evaluation of the secondary estimand, the MMRM based primary analysis will include all 
scheduled post-baseline measurement up to and including week 26. From this model the estimated 
treatment differences (ratios) will be presented at week 26 with 95% confidence intervals and two-
sided p-values for test of no difference. The baseline value will be carried forward to the first 
planned visit, if this falls within 8 weeks.
Binary efficacy endpoints
If a subject after week 26 achieves (yes/no):
!
HbA1c < 7.0% (53 mmol/mol) (ADA) target
!
HbA1c ≤ 6.5% (48 mmol/mol) (AACE) target
!
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%-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 or BG-confirmed 
symptomatic hypoglycaemia as data collected regardless of discontinuation of trial product or 
initiation of rescue medication(s) is used. The above six endpoints will be evaluated after week 26.
The above six binary endpoints will be analysed using a logistic regression model with treatment,
stratification factors, the interaction between the two 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). 
Missing data for the above six binary endpoints will be accounted for using multiple imputation 
techniques. For the treatment policy estimand the binary endpoints will be calculated as 
dichotomisations of the 1000 multiple imputations underlying the primary MI analysis. For the 
hypothetical estimand the model will be implemented using a sequential imputation approach 
assuming MAR. The imputation will be done as described below:
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!
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 dataset will be generated.
!
A sequential regression approach for imputing monotone missing values at planned visits 
will be implemented starting with the first visit after baseline and sequentially continuing to 
the planned end of treatment visit. For each treatment group an analysis of covariance model 
will be used to impute missing values at each planned visit. The model will include 
stratification factors as categorical effects and baseline and post-baseline values prior to the 
visit in question as covariate.
The binary endpoints will be derived as dichotomisations of the 1000 multiple imputations from the 
sequential imputation.
For both estimands, each of the 1000 datasets 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, 
baseline body weight for body weight endpoints and both baseline HbA1c and baseline body weight 
for the composite binary endpoints that comprise both parameters). The results will be combined 
using Rubin’s rule to draw inference.
Only observed data within the corresponding observation period will be included for the ‘without 
hypoglycaemia’ component of the composite endpoint. Because the number of hypoglycaemic 
episodes is expected to be very low in this trial, the observed data is considered sufficient when 
addressing both estimands.
Time to event 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 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.
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1.
New anti-diabetic medication: Anti-diabetic medication (4th-level ATC code) that is initiated 
at or after randomisation and is new compared to the anti-diabetic background medication at 
randomisation (see above) and with a dosing duration of more than 21 days 
2.
Intensification of anti-diabetic medication: A more than 20% increase in the dose of anti-
diabetic medication at or 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 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) 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 supporting 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 another anti-diabetic treatment is therefore also considered an event and 
withdrawn subjects or subject lost to follow-up will be considered as having an event (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 supporting the hypothetical estimand is addressed for the FAS using the on-treatment 
without rescue medication observation period. Time from first dose of trial product to initiation of 
rescue medication will be analysed using the same model as described above. The endpoint aims to 
address a lack of effect of treatment with trial product. Only initiation of rescue 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 
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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.
2.10.2.2
Safety endpoints and safety assessments
The safety endpoints and safety assessments 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 and assessments 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 31 weeks
All AEs will be coded using the most recent version of the Medical Dictionary for Regulatory 
Activities (MedDRA) coding.
A TEAE is defined as an AE with onset in the on-treatment observation period (see definition of 
observation periods in Section 2.6).
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 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. Results will be presented at 
week 26. Amylase and lipase endpoints will be log-transformed prior to analysis with the associated 
log-transformed baseline value as a covariate.
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Change from baseline to week 26 in:
!
Urinalysis
!
Urinary albumin to creatinine ratio
!
Electrocardiogram (ECG) evaluation
!
Physical examination
!
Eye examination category
Note that the urinary albumin to creatinine ratio is measured twice, so the mean will be used as
endpoint.
Any occurrence of anti-semaglutide antibodies (yes/no) up to approximately 31 weeks:
!
Anti-semaglutide binding antibodies
!
Anti-semaglutide neutralising antibodies
!
Anti-semaglutide binding antibodies cross reacting with native GLP-1
!
Anti-semaglutide neutralising antibodies cross reacting with native GLP-1
Anti-semaglutide binding antibodies up to approximately 31 weeks:
!
Anti-semaglutide binding antibody levels
Other safety assessments
!
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 and assessments will be summarised as counts and relative 
frequencies. Calcitonin will also be presented by gender.
Hypoglycaemia endpoints
!
Number of treatment-emergent severe or blood glucose-confirmed symptomatic 
hypoglycaemic episodes during exposure to trial product, assessed up to approximately 31 
weeks
!
Treatment-emergent severe or blood glucose-confirmed symptomatic hypoglycaemic 
episodes during exposure to trial product, assessed up to approximately 31 weeks (yes/no)
Classification of hypoglycaemia
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Hypoglycaemic episodes will be summarised for the SAS and the on-treatment observation period 
only.
Treatment emergent: hypoglycaemic episodes will be defined as treatment-emergent if the onset of 
the episode occurs within the on-treatment observation period (see definition of observation periods 
in Section 17.2 in the Protocol).
Nocturnal hypoglycaemic episodes: episodes occurring between 00:01 and 05.59 both inclusive.
Hypoglycaemic episodes are classified according to the Novo Nordisk classification of 
hypoglycaemia and the ADA classification of hypoglycaemia (see Figure 2-2).
Novo Nordisk classification of hypoglycaemia
In normal physiology, symptoms of hypoglycaemia occur below a plasma glucose level of 3.1 
mmol/L (56 mg/dL)7. Therefore, Novo Nordisk has included hypoglycaemia with plasma glucose 
(PG) levels below this cut-off point in the definition of blood glucose (BG) confirmed 
hypoglycaemia.
Novo Nordisk uses the following classification in addition to the ADA classification:
!
Severe or BG-confirmed symptomatic hypoglycaemia: An episode that is severe according 
to the ADA classification8 or BG-confirmed by a plasma glucose value < 3.1 mmol/L (56 
mg/dL) with symptoms consistent with hypoglycaemia.
ADA classification8 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.
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!
Probable symptomatic hypoglycaemia: An episode during which symptoms of 
hypoglycaemia are not accompanied by a PG determination but that was presumably caused 
by a PG concentration ≤ 3.9 mmol/L (70 mg/dL).
Hypoglycaemic 
episode 
PG ≤ 3.9 mmol/L 
(70 mg/dL) 
or 
Alleviation of 
symptoms 
or
Seizure, coma or 
fatal 
SMPG
measurement
Asymptomatic 
hypoglycaemia
Documented 
symptomatic 
hypoglycaemia
Pseudo-
hypoglycaemia
Probable 
symptomatic 
hypoglycaemia
No
Yes
No measurement 
with symptoms
PG > 3.9 mmol/L 
(70 mg/dL)
with symptoms
PG ≤3.9 mmol/L 
(70 mg/dL)
with symptoms
PG ≤3.9 mmol/L 
(70 mg/dL)
without symptoms
No
Yes
Note: Glucose measurements are performed with capillary blood calibrated to plasma equivalent glucose values
PG: plasma glucose  SMPG: Self-measured plasma glucose  
Subject 
able to 
treat him/
herself
Severe 
hypoglycaemia
(ADA 2013)
Figure 2-2
ADA classification of hypoglycaemia
Data on treatment-emergent hypoglycaemic episodes will be presented in terms of the number of 
subjects with at least one episode, the percentage of subjects with at least one episode (%), the total 
number of episodes and the episode rate per 100 patient years of observation time.
Analysis of severe or BG-confirmed symptomatic hypoglycaemic endpoints
The number of treatment-emergent severe or BG-confirmed symptomatic hypoglycaemic episodes 
will be evaluated for the on-treatment period using a negative binomial regression model with a log -
link function and the logarithm of the duration of the subject’s on-treatment observation period as 
offset. The model will include treatment, stratification factors and the interaction between the two 
stratification factors and region as fixed factors and baseline HbA1c as covariate. The linear 
predictor of the model will be reduced if deemed necessary.
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 
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model with treatment, stratification factors, the interaction between the two stratification factors and 
region as fixed factors and baseline HbA1c as covariate. The linear predictor of the model will be 
reduced if deemed necessary.
2.10.2.3
Pharmacokinetic endpoints
! Semaglutide plasma concentrations for population PK analysis
! SNAC plasma concentrations 
The semaglutide plasma concentrations and SNAC 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 2.12.
2.11
Interim Analysis
No interim analyses or other analyses of unblinded data will be performed before the database is 
locked.
2.12
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 (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 clinical trial 
report.
2.13
Patient reported outcomes
Change from baseline to week 26 in:
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!
SF-36v2™ ® (acute version) health survey: Scores from the 8 domains and summaries of the
physical component score and the mental component score
!
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 patient reported outcomes (PRO) questionnaires 
used in the trial is provided in the following sections.
No multiplicity adjustments will be done for the PRO questionnaires.
2.13.1
SF-36v2® (acute version) health survey
The SF-36v2® Health Survey (SF-36v2) (acute version) instrument is a commonly used generic 
instrument measuring health-related quality of life (HRQoL)/general health status across disease 
areas including diabetes. The SF-36v2 is a PRO questionnaire for adults with a 1-week recall period 
contains 36 items.
A total of 35 items measure eight domains of functional health and well-being as well as two 
component summary scores: physical functioning (10 items), role limitation due to physical health 
problems (4 items), bodily pain (2 items), general health perceptions (5 items), vitality (4 items), 
social functioning (2 items), role limitations due to emotional problems (3 items) and general 
mental health (5 items), mental component summary (MCS) score, physical component summary 
(PCS) score. There is an additional single item giving information on health cha nge over the past 
week.
Domain scores
Norm-based scores (NBS) will be derived using the QualityMetric Health Outcomes™ Scoring 
Software1 including the 2009 US general population norm. The most recent version of the 
QualityMetric Health Outcomes™ Scoring Software available at time of licensing was used for the 
specific trial (version 4.5 for PIONEER 5). 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 CRF) is not 
included in any score. 
Table 2-3
Overview of domains for SF-36v2® (acute version)
Domain
Items numbers of items 
included in domain
Comment
Physical Functioning (PF)
Items 3a-j
Role Limitations Due to Physical Health (Role-Physical; RP)
Items 4a-d
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Domain
Items numbers of items 
included in domain
Comment
Bodily Pain (BP)
Items 7, 8
Both item scores reversed 
General Health Perceptions (General Health; GH)
Items 1, 11a-d
Item scores 1, 11b and 11d reversed
Vitality (VT)
Items 9a, 9e, 9g, 9i
Item scores 9a and 9e reversed 
Social Functioning (SF)
Items 6, 10
Item score 6 reversed 
Role Limitations Due To Emotional Problems (Role-
Emotional; RE)
Items 5a-c
Mental Health (MH)
Items 9b, 9c, 9d, 9f, 9h
Item scores 9d and 9h reversed 
Physical component summary (PCS)
NA
The PCS score is a weighted average of 
the 8 domain scores. 
Mental component summary (MCS)
NA
The MCS score is also a weighted 
average of the 8 domain scores. 
Weights differ from PCS to MCS. 
Missing data at instrument level will be handled using the Maximum Data Recovery method: The 
method applies a value to a domain item rendered missing if at least one of the items in that domain 
has valid data. A domain score is considered missing if all item values in the domain are missing. 
PCS and MCS are calculated when at least seven of the eight domains have valid data, either actual 
or estimated. However, to calculate PCS, the PF domain must be one of the seven domains having 
valid data. Also, to calculate MCS, the MH domain must be one of the seven domains having valid 
data.
The domains will be evaluated using the primary analysis for the treatment policy estimand for the 
CTR. The domains will be evaluated using the primary analysis for the hypothetical estimand in a 
report separate from the CTR.
Responder threshold values
The responder threshold values, in terms of T-score points for change from baseline are defined in 
Table 2-44.
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 
2.13.3.
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2.13.2
Diabetes Treatment Satisfaction Questionnaire – status version (DTSQs)
The DTSQs questionnaire will be used to assess subject’s treatment satisfaction. This questionnaire 
contains 8 items that measures the treatment satisfaction for subjects’ diabetes treatment in terms of 
convenience, flexibility and general feelings regarding treatment (see Table 2-5).
Table 2-5
Overview of items in DTSQs questionnaire
Item 
No.
Item text 
Response scale
1
How satisfied are you with your current treatment?
6 = very satisfied, 5, 4, 3, 2, 1, 0 = very 
dissatisfied
2
How often have you felt that your blood sugars have been 
unacceptably high recently?
6 = most of the time, 5, 4, 3, 2, 1, 0 = none of 
the time
3
How often have you felt that your blood sugars have been 
unacceptably low recently?
6 = most of the time, 5, 4, 3, 2, 1, 0 = none of 
the time
4
How convenient have you been finding your treatment to be 
recently?
6 = very convenient, 5, 4, 3, 2, 1, 0 = very 
inconvenient
5
How flexible have you been finding your treatment to be recently?
6 = very flexible, 5, 4, 3, 2, 1, 0 = very 
inflexible
6
How satisfied are you with your understanding of your diabetes?
6 = very satisfied, 5, 4, 3, 2, 1, 0 = very 
dissatisfied
7
Would you recommend this form of treatment to someone else with 
your kind of diabetes?
6 = Yes, I would definitely recommend the 
treatment, 5, 4, 3, 2, 1, 0 = No, I would 
definitely not recommend the treatment
8
How satisfied would you be to continue with your present form of 
treatment?
6 = very satisfied, 5, 4, 3, 2, 1, 0 = very 
dissatisfied
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 blood glucose levels being “none of the 
time” unacceptably high (item 2) or low (item 3). If data are missing for an item, the item score is 
treated as missing. No reversal of item scores will be done.
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. 
Scoring algorithm:
!
Step 1: Sum the existing item scores (i.e. either 5 or 6 item scores)
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!
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 2.13.3.
2.13.3
Responder analyses
Responder analyses will be reported in a report separate from the CTR for SF-36v2® and DTSQs. 
These additional analyses were not in scope during the development process of the protocols for the 
NN9924 phase 3a programme. 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 
domain.
For descriptive statistics the following subject responder categorisation is applied for all relevant 
time points and domains:
!
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 effect 
endpoints (Section 2.10.2.1). 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 NN9924-4234. However, 
clarifications, more detailed descriptions of endpoints and analyses are provided in this SAP. The 
changes from the protocol of NN9924-4234 are summarised below:
!
Section 2.1: It has been specified which countries belong to which regions.
!
Section 2.2: The primary and secondary estimand has changed name from de-facto and de-
jure to treatment policy and hypothetical, respectively.
!
Section 2.9.1: The set of fixed effects used in the pattern mixture multiple imputation model 
has been reduced to stratification factors only. The actual distribution over the full design of 
region, stratification factors and the interaction between the two stratification factors is too 
sparse to fit the imputation model.
!
Section 2.9.2: For the MMRM analyses, it is specified that for subjects who do not have 
post-baseline assessments for planned visits available in the on-treatment without rescue 
medication period, the baseline value will be carried forward to the first planned visit, if the 
first planned visit do not fall later than 8 weeks after randomisation, to ensure that all 
randomised subjects will contribute to the statistical analyses. 
!
Section 2.9.3: The amount of sensitivity analyses has reduced for the trial. The tipping point 
analysis has been kept for both the primary and the secondary estimand as an approach for 
performing a sensitivity analysis under the missing not at random (MNAR) assumption. In 
other words, the tipping point approach is like a progressive stress-testing to assess how 
severe departures from missing at random (MAR) must be in order to overturn conclusions 
from the primary analysis. This sensitivity analysis is considered sufficient t o stress-test the 
secondary estimand, thus the three MI sensitivity analyses of the secondary estimand have 
been omitted in section 2.9.3.2.  In addition to the tipping point analysis, two sensitivity 
analyses for primary estimand has been kept, to get a better understanding of the primary 
results.
!
The LOCF sensitivity analysis specified in the trial protocol (section 17.3.3.2) has been 
omitted. It is judged not to add additional value to the evaluation of the effect. This is 
because it seems unrealistic that data from a subject with missing data would have been 
stable from the point of dropout to trial completion.
!
Section 2.10.2.1: The following binary endpoints will not be included in the analysis:
–
HbA1c reduction ≥ 1%-point (10.9 mmol/mol)
–
Weight loss ≥3%
autonomously but as components of the composite endpoint
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–
HbA1c reduction ≥ 1%-point (10.9 mmol/mol) and weight loss ≥ 3% .
!
Section 2.10.2.1: For the binary efficacy endpoints, it has been specified with more details 
how missing data in the analyses for the hypothetical estimand will be imputed using a 
sequential imputation approach assuming MAR.
!
Section 2.10.2.1: It is specified that the CRP endpoints will be log-transformed prior to 
analysis.
!
Section 2.10.2.1: A clarification of the ‘without hypoglycaemia’ component in composite 
binary endpoints has been added. The specification on how to analyse the binary component 
‘without hypoglycaemia’ in the composite endpoint ‘HbA1c <7% (53 mmol/mol) without 
hypoglycaemia (severe or BG-confirmed symptomatic hypoglycaemia) and no weight gain’ 
has not been described in the statistical section in the protocol. The specification is therefore 
included.
!
Section 2.10.2.1: The definitions of rescue medication and additional antidiabetic 
medication used for the time-to-event endpoints were added along with discussion on 
additional antidiabetic medication. Furthermore, the accompanying statistical analyses have 
been further clarified.
!
Section 2.10.2.2: It has been specified that all safety laboratory results (except amylase and 
lipase) are safety assessments and not safety endpoints as written in the trial protocol.
!
Section 2.13: Additional details regarding the patient reported outcomes (SF-36v2 acute 
version and DTSQs) are provided.
!
Section 2.13: The primary analysis for the primary estimand of SF-36v2(acute version) and 
for both estimands of DTSQs will be reported in the CTR. The primary analysis for the 
secondary estimand of SF-36v2 (acute version) will be presented in a report separate from
and after finalisation of the CTR.
!
Section 2.13.3: The responder analyses of both PROs (SF-36v2 (acute version) and DTSQs)
will be presented in a report separate from and after finalisation of the CTR.
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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 RJA, Rubin DB. Statistical analysis with missing data: New York: John Wiley & Sons. 
1987.
4.
Maruish ME, (Ed.). User's manual for the SF-36v2 Health Survey (3rd ed.). Lincoln, RI: 
QualityMetric Incorporated. 2011.
5.
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.
6.
National Academy of Sciences (NAS). The Prevention and Treatment of Missing Data in 
Clinical Trials. Washington D.C.: The National Academies Press. 2010.
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.
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 Documentation of statistical methods, Version 1.0, dated 13-December-2018 
Overview of deleted pages 
Pages 
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Title 
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Pre-defined MedDRA search – list of preferred terms