Clinical trial NCT03061214
Conditions: Diabetes Diabetes Mellitus, Type 2
Sponsor: Novo Nordisk A/S
Start date: 2017-08-28; Completion date: 2019-04-15
Enrollment: 868 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This trial is conducted in Africa, Asia, Europe and South America. The aim of the trial is to compare the effect of once-weekly dosing of two dose levels of semaglutide versus sitagliptin 100 mg once-daily on glycaemic control after 30 weeks of treatment. Subjects will remain on their stable pre-trial metformin.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None arm 4: None
Interventions: intervention 1: Semaglutide 0.5 mg intervention 2: Semaglutide 1.0 mg intervention 3: Sitagliptin placebo intervention 4: Sitagliptin intervention 5: Semaglutide placebo 0.5 mg intervention 6: Semaglutide placebo 1.0 mg
Intervention descriptions: intervention 1: Up to 0.5 mg semaglutide injected subcutaneously (s.c., under the skin) once-weekly (OW) for 30 weeks intervention 2: Up to 1.0 mg semaglutide injected subcutaneously once-weekly for 30 weeks intervention 3: Sitagliptin placebo tablets taken once-daily for 30 weeks intervention 4: 100 mg sitagliptin tablets taken once-daily for 30 weeks intervention 5: Semaglutide placebo (0.5 mg) injected subcutaneously once-weekly for 30 weeks intervention 6: Semaglutide placebo (1.0 mg) injected subcutaneously once-weekly for 30 weeks

Protocol documents:
Prot_000.pdf: 
Cover Page for Protocol 
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT03061214  
Sponsor trial ID: 
NN9535-4114 
Official title of study: 
SUSTAINTM CHINA - Efficacy and safety of semaglutide 
once-weekly versus sitagliptin once-daily as add-on to 
metformin in subjects with type 2 diabetes 
Document date: 
22 August 2019 
 


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List of contents
Protocol - Version 1............................................................................................................................
Protocol - Version 2............................................................................................................................
Protocol - Version 3............................................................................................................................
Appendix A - Version 1......................................................................................................................
Appendix A - Version 2......................................................................................................................
Appendix A - Version 3......................................................................................................................
Appendix B - Version 1......................................................................................................................
Appendix B - Version 2......................................................................................................................
Appendix B - Version 3......................................................................................................................
Attachment I and II............................................................................................................................
Protocol amendment 1 - Global ........................................................................................................
Protocol amendment 2 - Global ........................................................................................................
Protocol amendment 3 - Global ........................................................................................................
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
Semaglutide s.c (Ozempic®)
Trial ID: NN9535-4114
Clinical Trial Report
Appendix 16.1.1
22 August 2019
1.0
Final
16.1.1 Protocol and protocol amendments
CONFIDENTIAL
 
 
 
 
 
Redacted protocol 
Includes redaction of personal identifiable information only. 
 
 
 
. 
 
 


Protocol
CONFIDENTIAL
Date:
14 April 2014
Novo Nordisk
Trial ID: NN9535-4114
Version:
1.0
UTN: U1111-1149-0432 
Status:
Final
EudraCT no.: NA
Page:
1 of 109
Protocol
Trial ID: NN9535-4114
SUSTAINTM CHINA
Efficacy and safety of semaglutide once-weekly versus
sitagliptin once-daily as add-on to metformin in subjects
with type 2 diabetes
A 30-week randomised, double-blind, double-dummy, active-controlled, 
parallel-group, multi-centre and multi-national trial
Trial phase: 3a
Protocol originator
ClinOps, Obesity, Liraglutide & Obesity
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:
14 April 2014
Novo Nordisk
Trial ID: NN9535-4114
Version:
1.0
UTN: U1111-1149-0432 
Status:
Final
EudraCT no.: NA
Page:
2 of 109
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 ................................................................................................................................................14
2.1
Flow chart explanatory descriptions............................................................................................17
3
Background information and rationale for the trial............................................................................18
3.1
Type 2 diabetes............................................................................................................................18
3.2
Glucagon-like peptide-1 ..............................................................................................................18
3.3
Semaglutide .................................................................................................................................19
3.3.1
Non-clinical data........................................................................................................19
3.3.1.1
Thyroid C-cell tumours in rodents ......................................................20
3.3.1.2
Teratogenicity in rats...........................................................................20
3.3.2
Clinical data...............................................................................................................20
3.3.2.1
Pharmacokinetics ................................................................................21
3.3.2.2
Efficacy ...............................................................................................21
3.3.2.3
Safety...................................................................................................22
3.4
Sitagliptin.....................................................................................................................................22
3.5
Risk and benefits assessment.......................................................................................................23
3.5.1
Semaglutide risks and precautions.............................................................................23
3.5.2
Sitagliptin risk and precautions..................................................................................24
3.5.3
Benefits......................................................................................................................24
3.5.4
Risk and benefit conclusion.......................................................................................25
3.6
Rationale for the trial...................................................................................................................25
4
Objectives and endpoints........................................................................................................................26
4.1
Objective......................................................................................................................................26
4.1.1
Primary objective.......................................................................................................26
4.1.2
Secondary objectives .................................................................................................26
4.2
Endpoints.....................................................................................................................................26
4.2.1
Primary endpoint........................................................................................................26
4.2.2
Secondary endpoints..................................................................................................26
4.2.2.1
Confirmatory secondary endpoint.......................................................26
4.2.2.2
Supportive secondary endpoints..........................................................26
5
Trial design..............................................................................................................................................28
5.1
Type of trial .................................................................................................................................28
5.2
Rationale for trial design..............................................................................................................29
5.3
Treatment of subjects...................................................................................................................30
5.3.1
Missed dose ...............................................................................................................31
5.3.2
Background medication.............................................................................................31
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Protocol
CONFIDENTIAL
Date:
14 April 2014
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Trial ID: NN9535-4114
Version:
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UTN: U1111-1149-0432 
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5.3.3
Treatment after end of trial........................................................................................31
5.4
Rationale for treatment ................................................................................................................32
6
Trial population.......................................................................................................................................33
6.1
Number of subjects......................................................................................................................33
6.2
Inclusion criteria ..........................................................................................................................33
6.3
Exclusion criteria.........................................................................................................................33
6.4
Rescue criteria..............................................................................................................................34
6.5
Withdrawal criteria ......................................................................................................................35
6.5.1
Discontinuation of trial product.................................................................................35
6.5.2
Withdrawal from trial ................................................................................................35
6.6
Subject replacement.....................................................................................................................36
6.7
Rationale for trial population.......................................................................................................36
7
Milestones ................................................................................................................................................37
8
Methods and assessments .......................................................................................................................38
8.1
Visit procedures...........................................................................................................................38
8.1.1
Screening visit 1 (V1)................................................................................................38
8.1.1.1
Screen failures.....................................................................................38
8.1.1.2
Re-screening........................................................................................39
8.1.2
Fasting visits ..............................................................................................................39
8.1.3
Randomisation V2 .....................................................................................................39
8.1.4
Visits..........................................................................................................................39
8.1.5
Missed visits and unscheduled visits .........................................................................40
8.1.6
End of treatment (V9/9A) and Follow-up (V10/10A) ...............................................40
8.1.6.1
Subjects completing the treatment period as per protocol...................40
8.1.6.2
Subjects who prematurely discontinue trial product ...........................40
8.1.7
Withdrawals...............................................................................................................41
8.1.8
Investigator’s assessment...........................................................................................41
8.2
Subject related information..........................................................................................................42
8.2.1
Demography ..............................................................................................................42
8.2.2
Diagnosis of diabetes.................................................................................................42
8.2.3
Diabetes treatment history .........................................................................................42
8.2.4
Diabetes complications..............................................................................................43
8.2.5
Concomitant illness and medical history...................................................................43
8.2.6
History of cardiovascular disease ..............................................................................43
8.2.7
History of gallbladder disease....................................................................................43
8.2.8
Smoking habits ..........................................................................................................44
8.2.9
Concomitant medication............................................................................................44
8.2.10
Fundoscopy/fundus photography...............................................................................44
8.2.11
Height ........................................................................................................................45
8.3
Assessments for efficacy .............................................................................................................45
8.3.1
Body weight...............................................................................................................45
8.3.2
Waist circumference ..................................................................................................45
8.3.3
BMI............................................................................................................................45
8.3.4
Systolic and diastolic blood pressure.........................................................................45
8.4
Assessments for safety.................................................................................................................46
8.4.1
Adverse events...........................................................................................................46
8.4.2
Hypoglycaemic episodes ...........................................................................................46
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Protocol
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Date:
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Trial ID: NN9535-4114
Version:
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8.4.3
Electrocardiogram......................................................................................................48
8.4.4
Physical examination.................................................................................................48
8.4.5
Pulse...........................................................................................................................48
8.5
Laboratory assessments ...............................................................................................................48
8.5.1
Laboratory assessments for efficacy..........................................................................49
8.5.1.1
Glucose metabolism............................................................................50
8.5.1.2
Biomarker............................................................................................50
8.5.1.3
Lipids (all fasting)...............................................................................50
8.5.1.4
Self measured plasma glucose (SMPG) 7 point profile ......................50
8.5.2
Laboratory assessments for safety .............................................................................51
8.5.2.1
Anti-semaglutide antibodies................................................................52
8.5.2.2
Biochemistry .......................................................................................52
8.5.2.3
Haematology .......................................................................................52
8.5.2.4
Calcitonin............................................................................................53
8.5.2.5
Pregnancy test .....................................................................................53
8.5.2.6
Urinalysis ............................................................................................53
8.6
Other assessments........................................................................................................................53
8.6.1
Patient reported Outcome questionnaires ..................................................................53
8.6.1.1
SF-36v2TM ...........................................................................................54
8.6.1.2
DTSQs.................................................................................................54
8.6.2
Subject diary ..............................................................................................................54
8.7
Subject compliance......................................................................................................................54
8.8
In case of specific safety issues ...................................................................................................55
8.8.1
Thyroidectomy...........................................................................................................55
8.8.1.1
Thyroidectomy pathology slides .........................................................55
8.8.1.2
Thyroid tissue sample collection in case of thyroidectomy ................55
8.8.1.3
Genetic testing in case of confirmed C-cell pathology .......................55
8.8.1.4
Assessments in case of suspicion of acute pancreatitis.......................56
8.8.1.5
Assessments in case of suspicion of severe hypersensitivity..............56
8.8.1.6
Assessments in case of suspicion of immune complex disease ..........56
9
Trial supplies ...........................................................................................................................................57
9.1
Trial products...............................................................................................................................57
9.2
Labelling......................................................................................................................................58
9.3
Storage.........................................................................................................................................58
9.4
Drug accountability and destruction............................................................................................59
9.5
Auxiliary supplies........................................................................................................................59
10 Interactive voice/web response system..................................................................................................60
11 Randomisation procedure and breaking of blinded codes..................................................................61
11.1
Breaking of blinded codes ...........................................................................................................61
12 Adverse events, and technical complaints and pregnancies................................................................62
12.1
Definitions ...................................................................................................................................62
12.2
Reporting of adverse events.........................................................................................................65
12.3
Follow-up of adverse events........................................................................................................68
12.4
Technical complaints and technical complaint samples ..............................................................69
12.4.1
Reporting of technical complaints .............................................................................69
12.4.2
Collection, storage and shipment of technical complaint samples ............................69
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Protocol
CONFIDENTIAL
Date:
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Trial ID: NN9535-4114
Version:
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UTN: U1111-1149-0432 
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EudraCT no.: NA
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12.5
Pregnancies..................................................................................................................................70
12.5.1
Pregnancies in female subjects ..................................................................................70
12.6
Precautions and/or overdose ........................................................................................................71
12.7
Committees related to safety........................................................................................................72
12.7.1
Novo Nordisk safety committee ................................................................................72
12.7.2
Event adjudication committee....................................................................................72
12.7.3
Calcitonin monitoring committee(CMC)...................................................................73
13 Case report forms....................................................................................................................................74
13.1
Corrections to case report forms..................................................................................................74
13.2
Case report form flow..................................................................................................................74
13.2.1
Electronic case report form flow................................................................................74
13.2.2
Paper case report form flow.......................................................................................75
14 Monitoring procedures...........................................................................................................................76
15 Data management....................................................................................................................................78
16 Computerised systems ............................................................................................................................79
17 Statistical considerations ........................................................................................................................80
17.1
Sample size calculation................................................................................................................81
17.2
Definition of analysis sets............................................................................................................82
17.3
Primary endpoint..........................................................................................................................82
17.4
Secondary endpoints....................................................................................................................85
17.4.1
Confirmatory secondary endpoints............................................................................85
17.4.2
Supportive secondary endpoints ................................................................................86
17.4.2.1
Efficacy endpoints...............................................................................86
17.4.2.2
Safety endpoints..................................................................................88
17.5
Health economics and/or patient reported outcomes...................................................................92
18 Ethics........................................................................................................................................................93
18.1
Informed consent .........................................................................................................................93
18.2
Data handling...............................................................................................................................94
18.3
Information to subject during trial...............................................................................................94
18.4
Premature termination of the trial and/or trial site.......................................................................95
19 Protocol compliance................................................................................................................................96
20 Audits and inspections............................................................................................................................97
21 Critical documents ..................................................................................................................................98
22 Responsibilities........................................................................................................................................99
23 Reports and publications......................................................................................................................100
23.1
Communication of results..........................................................................................................100
23.1.1
Authorship ...............................................................................................................101
23.1.2
Site-specific publication(s) by investigator(s) .........................................................101
23.2
Investigator access to data and review of results.......................................................................101
24 Retention of clinical trial documentation and human biospecimens................................................102
24.1
Retention of clinical trial documentation...................................................................................102
24.2
Retention of human biospecimens.............................................................................................102
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Protocol
CONFIDENTIAL
Date:
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Trial ID: NN9535-4114
Version:
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UTN: U1111-1149-0432 
Status:
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EudraCT no.: NA
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25 Institutional Review Boards/Independent Ethics Committees and regulatory authorities............104
26 Indemnity statement .............................................................................................................................105
27 References..............................................................................................................................................106
Appendix A: 
Medical events of special interest (MESI)
Appendix B:
Monitoring of calcitonin
Attachment I –
Global list of key staff and relevant departments and vendors
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Protocol
CONFIDENTIAL
Date:
14 April 2014
Novo Nordisk
Trial ID: NN9535-4114
Version:
1.0
UTN: U1111-1149-0432 
Status:
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EudraCT no.: NA
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Table of Figures   
Page
Figure 5–1
Trial design.............................................................................................................................28
Figure 12–1
Initial reporting of AEs...........................................................................................................67
Figure 17–1
ADA classification of hypoglycaemia....................................................................................91
Table of Tables
Page
Table 5–1
Treatment of subjects..............................................................................................................30
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
14 April 2014
Novo Nordisk
Trial ID: NN9535-4114
Version:
1.0
UTN: U1111-1149-0432 
Status:
Final
EudraCT no.: NA
Page:
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List of abbreviations
AACE
American Association of Clinical Endocrinologists
ADA
American Diabetes Association
AE
adverse event
BG
blood glucose
BMI
Body mass index
CMC
calcitonin monitoring committee
CRF
case report form
CRO
contract research organisation
CTR
clinical trial report
CVD
cardiovascular disease
DPP-4
dipeptidyl peptidase 4
DMC
data monitoring committee
DUN
dispensing unit number
DTSQs
Diabetes Treatment Satisfaction Questionnaire status
EAC
event adjudication committee
ECG
electrocardiogram
eCRF
electronic case report form
EE
ethinylestradiol
EFD
embryo-foetal development
eGFR
estimated glomerular filtration rate
FAS
full analysis set
FDAAA
Food and Drug Administration Amendment Act
FPFV
first patient first visit
FPG
fasting plasma glucose
FSFV
first subject first visit
GCP
Good Clinical Practice
GI
gastrointestinal
GIP
gastric inhibitory polypeptide
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
14 April 2014
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Trial ID: NN9535-4114
Version:
1.0
UTN: U1111-1149-0432 
Status:
Final
EudraCT no.: NA
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GLP-1
glucagon-like peptide-1
HbA1c
glycosylated haemoglobin
hCG
human chorionic gonadotrophin
HDL
high density lipoprotein
hsCRP
highly sensitive C-reactive protein
IB
Investigator’s Brochure
ICMJE
International Committee of Medical Journal Editors
IEC
independent ethics committee
IMP
investigational medicinal product
IRB
Institutional Review Board
IUD
intrauterine device 
IV/WRS
interactive voice/web response system
LDL
low density lipoprotein
LN
levonorgestrel
LPFV
last patient first visit
LPLV
last patient last visit
LSFV
last subject first visit
LSLV
last subject last visit
MACE
major adverse cardiovascular events
MAR
missing at random 
MCAR
missing completely at random 
MDRD
modification of diet in renal disease 
MEN2
multiple endocrine neoplasia syndrome type 2 
MESI
medical event of special interest
MMRM
mixed model for repeated measurements 
MTC
medullary thyroid carcinoma
NYHA
New York Heart Association
OAD
oral anti-diabetic drug
PG
plasma glucose
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Protocol
CONFIDENTIAL
Date:
14 April 2014
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Trial ID: NN9535-4114
Version:
1.0
UTN: U1111-1149-0432 
Status:
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EudraCT no.: NA
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PP
per protocol
PPG
postprandial glucose
PPND
pre- and postnatal development 
PRO
patient reported outcome
RA
receptor agonist
SAE
serious adverse event
SAP
statistical analysis plan
s.c.
subcutaneous
SD
standard deviation 
SDV
source data verification
SMBG
self-measured blood glucose
SMPG
self-measured plasma glucose
SUSAR
suspected unexpected serious adverse reaction
TMM
Trial Materials Manual
TEAE
treatment emergent adverse event
TVP
trial validation plan
UACR
urinary albumin to creatinine ratio 
UTN
universal trial number
V
visit
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Protocol
CONFIDENTIAL
Date:
14 April 2014
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Trial ID: NN9535-4114
Version:
1.0
UTN: U1111-1149-0432 
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EudraCT no.: NA
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1
Summary
Objectives and endpoints:
Primary objective
To compare the effect of once-weekly dosing of two dose levels of semaglutide versus sitagliptin 
100 mg once-daily on glycaemic control after 30 weeks of treatment
Primary endpoint
Change from baseline to week 30 in HbA1c
Secondary objectives
To compare the effects of once-weekly dosing of two dose levels of semaglutide versus sitagliptin
100 mg once-daily after 30 weeks of treatment on:
!
Inducing and maintaining weight loss
!
Other parameters of efficacy, safety and tolerability
Key secondary endpoint
Confirmatory secondary endpoint
!
Change from baseline to week 30 in body weight
Supportive secondary endpoints:
Change from baseline to week 30 in:
!
Fasting plasma glucose (FPG)
!
Systolic and diastolic blood pressure
!
Patient reported outcome (PRO) questionnaire: Diabetes Treatment Satisfaction 
Questionnaire status (DTSQs) score
Subjects who after 30 weeks treatment achieve (yes/no):
!
HbA1c ≤ 6.5% (48 mmol/mol) - American Association of Clinical Endocrinologists (AACE) 
target
Trial design:
This is a 30-week randomised, double-blind, double-dummy, active-controlled, multi-centre, multi-
national four-armed, parallel-group trial comparing semaglutide 0.5 mg and 1.0 mg once-weekly 
against sitagliptin 100 mg once-daily.
Subjects with type 2 diabetes inadequately controlled on metformin will be randomised in a 2:2:1:1 
manner to receive either:
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Protocol
CONFIDENTIAL
Date:
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Trial ID: NN9535-4114
Version:
1.0
UTN: U1111-1149-0432 
Status:
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EudraCT no.: NA
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!
semaglutide 0.5 mg once-weekly + sitagliptin placebo once-daily
!
semaglutide 1.0 mg once-weekly + sitagliptin placebo once-daily
!
sitagliptin 100 mg once-daily + semaglutide placebo (0.5) mg once-weekly
!
sitagliptin 100 mg once-daily + semaglutide placebo (1.0) mg once-weekly
Trial product will be add-on to subject’s stable pre-trial metformin. 
Key inclusion criteria:
!
Informed consent obtained before any trial-related activities. Trial-related activities are any 
procedures that are carried out as part of the trial, including activities to determine suitability 
for the trial
!
Male or female,  age ≥ 18 years at the time of signing informed consent
!
Subjects diagnosed with type 2 diabetes and on stable treatment in a period of 60 days prior 
to screening with metformin ≥ 1500 mg (or maximum tolerated dose ≥ 1000 mg). Stable is 
defined as unchanged medication and unchanged daily dose
!
HbA1c 7.0 – 10.5 % (53-91 mmol/mol) (both inclusive)
Key exclusion criteria: 
!
Female who is pregnant, breast-feeding or intends to become pregnant or is of childbearing 
potential not using an adequate contraceptive method throughout the trial including the 5 
week follow-up period (adequate contraceptive measure as required by local regulation or 
practice).
!
Any disorder which, in the opinion of the investigator, might jeopardise subject’s safety or 
compliance with the protocol
!
Treatment with glucose lowering agent(s) other than stated in the inclusion criteria in a 
period of 60 days before screening. An exception is short-term treatment (≤7 days in total) 
with insulin in connection with inter-current illness
!
History of chronic or idiopathic acute pancreatitis
!
Screening calcitonin value  ≥ 50 ng/L (pg/mL)
!
Personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine 
neoplasia syndrome type 2 (MEN 2)
!
Impaired renal function defined as estimated glomerular filtration rate (eGFR) < 60 
ml/min/1.73 m2 per modification of diet in renal disease (MDRM) formula (4 variable 
version)
!
Acute coronary or cerebrovascular event within 90 days before  randomisation
!
Heart failure, New York Heart Association (NYHA) class IV
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Protocol
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Date:
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Trial ID: NN9535-4114
Version:
1.0
UTN: U1111-1149-0432 
Status:
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EudraCT no.: NA
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Assessments:
Efficacy:
!
Glucose metabolism
!
Body measurements (body weight, body mass index (BMI) and waist circumference)
!
Systolic and diastolic blood pressure
!
Blood lipids
!
Patient reported outcome (PRO) questionnaires (SF-36v2TM and DTSQs)
Safety:
!
Adverse events and serious adverse events
!
Hypoglycaemic episodes
!
Biochemistry and haematology
!
Anti-semaglutide antibodies 
!
Physical examination (including electrocardiogram (ECG))
Trial products:
Novo Nordisk A/S will supply the following trial products:
!
Semaglutide 1.34 mg/mL, solution for injection, 1.5 mL pre-filled PDS290 pen-injector
!
Semaglutide placebo, solution for injection, 1.5 mL pre-filled PDS290 pen-injector
!
Sitagliptin (Januvia®) 100 mg tablets for oral administration
!
Sitagliptin placebo tablets for oral administration
CONFIDENTIAL


Protocol
UTN: U1111-1149-0432 
Date:
14 April 2014
Status:
Final
Novo Nordisk
Trial ID: NN9535-4114
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Version:
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2
Flow chart
Trial Periods
Screen
Rand
Treatment period
End of 
Treatment1
Follow Up1
End of 
Treatment 
premature 
discontinuation2
Follow Up
premature 
discontinuation2
Visit (V) or Phone (P) number
V1
V2
V3
P4
V5
V6
V7
V8
V9
V10
V9A
V10A
Time of visit
Weeks
-2
0
4
6
8
12
16
23
30
35
Visit window
Days
±7
±3
±3
±3
±3
±3
±3
±7
+7
SUBJECT RELATED INFO 
/ASSESSMENTS
Informed consent 18.1
x
In/exclusion criteria 6.2 and 6.3
x
x
Randomisation 8.1.3
x
Withdrawal criterion 6.5
x
x
x
x
x
x
x
X
Demography 8.2.1
x
Diagnosis of diabetes 8.2.2
x
Diabetes treatment history 8.2.3
x
Diabetes complications 8.2.4
x
Concomitant illness 8.2.5
x
Medical History 8.2.5
x
History of cardiovascular disease 8.2.6
x
History of 9 gallbladder disease 8.2.7
x
Smoking habits 8.2.8
x
Concomitant medication 8.2.9
x
x
x
x
x
x
x
x
x
x
X
x
Fundoscopy/fundus photography3 8.2.10
x
Height 8.2.11
x
EFFICACY
Body weight 8.3.1
x
x
x
x
x
x
x
X
Waist circumference 8.3.2
x
x
x
x
x
x
x
X
Systolic blood pressure, sitting 8.3.4
x
x
x
x
x
x
x
x
X


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Trial Periods
Screen
Rand
Treatment period
End of 
Treatment1
Follow Up1
End of 
Treatment 
premature 
discontinuation2
Follow Up
premature 
discontinuation2
Visit (V) or Phone (P) number
V1
V2
V3
P4
V5
V6
V7
V8
V9
V10
V9A
V10A
Time of visit
Weeks
-2
0
4
6
8
12
16
23
30
35
Visit window
Days
±7
±3
±3
±3
±3
±3
±3
±7
+7
Diastolic blood pressure, sitting 8.3.4
x
x
x
x
x
x
x
x
X
HbA1c 8.5.1.1
x
x
x
x
x
x
x
x
X
Fasting plasma glucose 8.5.1.1
x
x
x
x
x
x
x
X
Fasting insulin 8.5.1.1
x
x
x
X
Fasting proinsulin 8.5.1.1
x
x
x
X
Fasting C-peptide 8.5.1.1
x
x
x
X
Fasting glucagon 8.5.1.1
x
x
x
X
Lipids 8.5.1.3
x
x
x
X
hsCRP (highly sensitive CRP)8.5.1.2
x
x
x
X
SMPG 7 point profile 8.5.1.4
x
x
x
X
SAFETY
Adverse events 8.4.1
x
x
x
x
x
x
x
x
x
X
x
Hypoglycaemic episodes 8.4.2
x
x
x
x
x
x
x
x
x
X
x
ECG 8.4.3
x
x
x
X
x
Physical examination 8.4.4
x
x
X
Pulse, sitting 8.4.5
x
x
x
x
x
x
x
x
X
Anti-semaglutide antibodies4 8.5.2.1
x
x
x
x
X
x
Creatinine 8.5.2.2
x
x
x
x
x
x
x
X
Biochemistry 8.5.2.2
x
x
x
x
x
x
x
X
Haematology 8.5.2.3
x
x
x
x
x
x
x
X
Calcitonin 8.5.2.4
x
x
x
X
Pregnancy test5 8.5.2.5
x
x
x
x
x
x
x
x
x
X
x
Urinalysis 8.5.2.6
x
x
x
X
Urinalysis, Albumin : creatinine ratio 8.5.2.6
x
x
x
X


Protocol
UTN: U1111-1149-0432 
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Trial Periods
Screen
Rand
Treatment period
End of 
Treatment1
Follow Up1
End of 
Treatment 
premature 
discontinuation2
Follow Up
premature 
discontinuation2
Visit (V) or Phone (P) number
V1
V2
V3
P4
V5
V6
V7
V8
V9
V10
V9A
V10A
Time of visit
Weeks
-2
0
4
6
8
12
16
23
30
35
Visit window
Days
±7
±3
±3
±3
±3
±3
±3
±7
+7
OTHER ASSESSMENTS
PRO questionnaire: SF-36v2™8.6.1.1
x
x
X
PRO questionnaire: DTSQs 8.6.1.2
x
x
X
TRIAL MATERIAL
Drug accountability  9.4
x
x
x
X
IV/IWRS call 10
x
x
x
x
x
X
Dispensing visit 9.1
x
x
x
REMINDERS
Training in trial product, pen handling and 
dispense Direction for Use 9.1
x
x
x
End of trial  
x
Supply & instruction in BG meter use 8.5.1.4
x
Dispense and instruction in diary6 8.6.2
x
x
x
x
x
x
x
x
x6
X
x6
Attend visit fasting7 8.1.2
x
x
x
x
x
x
x
x8
X
x8
Dispense trial identity card 8.1.1
x


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2.1
Flow chart explanatory descriptions
Footer
Description
x1
V9 (End of Treatment) and V10 (Follow Up) are applicable for all randomised subjects. Subjects who have discontinued trial product prematurely should also 
attend V9 and V10 according to their initially scheduled week 30 and Week 35 visits.
x2
Subjects discontinuing trial product prematurely will be asked to attend two additional visits to undergo assessments: End of Treatment-premature 
discontinuation (V9A) and Follow Up -premature discontinuation (V10A). V9A should be scheduled at discontinuation of the trial product. V10A should be 
scheduled 5 weeks after discontinuation of trial product (+ 7 days visit window). 
x3
Fundoscopy/fundus photography performed within 90 days before visit 2 is acceptable if results are available for evaluation at the visit 2 and no deterioration 
in visual function since last assessment.
x4
Antibody sampling should preferably be done pre-dose. For fasting and non-fasting visit, where the injection takes place on the day of site visit, trial product 
must not be taken before blood sampling. 
For visit 9 and 10: Not applicable if taken at a premature discontinuation visit
x5
For women of child bearing potential: For all site visits a serum pregnancy test must be performed. Urine pregnancy test should be performed at any time 
during the trial if a menstrual period is missed, or as required by local law.
x6
At V10 and V10A collect diary only.
x7
Fasting is defined as having consumed only water since midnight. Glucose lowering agents and trial product cannot be taken until after blood sampling has 
been performed but other prescribed medication should be taken.
x8
For the follow-up visit (V10/V10A) attend fasting is defined as having consumed only water within the last 2 hours prior to the visit.
x9
pancreatitis and 


Protocol
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3
Background information and rationale for the trial
The trial will be conducted in compliance with this protocol, ICH GCP 1 and applicable regulatory 
requirements, and in accordance with the Declaration of Helsinki 2. 
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
Type 2 diabetes
Type 2 diabetes is a progressive metabolic disease primarily characterised by abnormal glucose 
metabolism. The pathogenesis is not fully understood but seems to be heterogeneous, involving 
environmental, lifestyle, and genetic factors leading to chronic hyperglycaemia caused by 
peripheral tissue insulin resistance, impaired insulin secretion due to abnormal beta-cell function 
and abnormal glucose metabolism in the liver 3.
Optimal glycaemic control is the treatment goal in subjects with type 2 diabetes, in order to prevent 
long-term complications associated with chronic hyperglycaemia 4,5. Despite the availability of 
several oral anti-diabetic drugs (OADs) and insulin, a significant proportion of subjects with type 2 
diabetes do not achieve the recommended blood glucose target levels 6-9.
In addition to the need for new effective and safe glucose lowering agents, it is important to 
establish the benefits of the available marketed glucose lowering agents in order to optimise the 
individual treatment in the best possible way.
3.2
Glucagon-like peptide-1
Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted from the L-cells in the small 
intestine. An incretin hormone is a gut-derived peptide with important physiological function in 
augmenting post-prandial insulin secretion in response to ingestion of a meal. GLP-1 has a glucose-
dependent stimulatory effect on insulin- and inhibitory effect on glucagon secretion from the 
pancreatic islets (i.e. when plasma glucose levels are above normal) 10,11. Both these effects are 
considered of importance for the glucose lowering effect of GLP-112 . Physiologically GLP-1 has a 
pronounced inhibitory effect on gastric emptying13. This effect seems to diminish upon chronic 
exposure to GLP-1 14,15. GLP-1 also lowers body weight due to a decreased energy intake induced 
by a lowered appetite 16.
Patients with diabetes have a decreased incretin effect 17-20). However, the insulinotropic action of 
GLP-1 and thus, the ability to lower blood glucose is preserved in subjects with type 2 diabetes 
when administered at supra physiological levels 21.
The mechanism of action makes GLP-1 a potent blood glucose lowering agent 22 and thus an 
attractive pharmacological tool for treatment of type 2 diabetes 23-25. However, the very short 
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elimination half-life (t½) of endogenous GLP-1 (t½ < 1.5 minutes after intravenous (iv) 
administration) due to rapid degradation by ubiquitous dipeptidyl peptidase (DPP-4) 26 makes 
endogenous GLP-1 an unattractive treatment option. Clinical trials have revealed that 24-hour 
infusion of endogenous GLP-1 would be necessary to achieve satisfactory glycaemic control. 
Therefore, to benefit from the potentials of GLP-1 in treatment of diabetes it has been necessary to 
develop GLP-1 receptor agonists with longer half-life. 
3.3
Semaglutide
Semaglutide is a potent human GLP-1 receptor agonist (RA) for once-weekly subcutaneous (s.c.) 
administration. It is structurally similar to liraglutide (Victoza®), a once-daily GLP-1 RA developed 
by Novo Nordisk and approved worldwide for the treatment of type 2 diabetes.
For the semaglutide molecule the principal mechanism of protraction is albumin binding facilitated
by a large fatty acid derived chemical moiety attached to the lysine in position 26. The specific
modifications in the molecule are: 1) a modification in position 8 (Alanine to 2-aminoisobutyric
acid) of the peptide backbone in order to further increase stability against DPP-4, and a change in
position 34 from a lysine to an arginine in order to only have one lysine in the sequence; 2) a large
hydrophilic linker between the lysine in position 26 and the gamma glutamate whereto the fatty acid
is attached; 3) a C18 fatty di-acid with a terminal acidic group. The latter two contribute to
increased albumin binding which results in decreased renal clearance. In addition to slowed
degradation in plasma and decreased renal clearance, delayed absorption from subcutis also
contributes to a prolonged half-life of approximately 160 hours making semaglutide suitable for
once-weekly s.c. administration.
In vitro receptor studies have shown that semaglutide is a potent and selective GLP-1 RA, and 
animal studies using non-diabetic rats, non-diabetic pigs and diabetic mice have shown lowering of 
blood glucose and inhibition of food intake.
3.3.1
Non-clinical data
The non-clinical programme for semaglutide was designed according to the ICH M3 27 guideline to 
support the clinical development. The standard non-clinical data package required to support phase 
3 clinical trials has been completed. In addition, 2-year carcinogenicity studies and a pre- and 
postnatal development toxicity study have been completed. 
Semaglutide is generally well tolerated with expected GLP-1 effects on food intake and body 
weight being dose limiting in mice, rats and cynomolgus monkeys. Two potential safety issues have 
been identified.
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3.3.1.1
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. Early C-cell changes were also 
identified in repeated dose toxicity studies with semaglutide in mice. However, this was not the case 
in other species including a 52-week repeat dose study in non-human primates at exposure levels up 
to 36-fold above the expected clinical exposure. The observed pattern of effects in mice and rats 
(thyroid C-cell proliferation preceded by increase in serum calcitonin) and lack of these effects in 
the non-human primate and in man suggest that the mechanism by which semaglutide acts on the 
thyroid C-cells in rodents is the same as has been demonstrated for other GLP-1 RAs, including 
liraglutide. The relevance for human subjects is unknown.
3.3.1.2
Teratogenicity in rats
Semaglutide has been concluded teratogenic in rats, with exposure at no observable adverse effect 
level (NOAEL) below expected human exposure. This effect is regarded to be caused by 
impairment of nutrient supply to the embryo across the inverted yolk sac with placental function 
which is specific to rats.
Non-human primates and humans do not depend on a yolk sac with placental function to supply 
nutrients to the embryo early in pregnancy. The effect on rat embryo-foetal development is 
therefore not likely to be relevant to humans. Preliminary and main embryo-foetal development 
(EFD) and pre- and postnatal development (PPND) studies with doses corresponding to 12-15 fold 
expected clinical exposure in cynomolgus monkeys have been finalised. In the main EFD study 
sporadic abnormalities were reported across all dose groups and in the PPND study a dose-
dependent increase in early pregnancy losses were observed. The findings observed across the three 
studies in cynomolgus monkeys are not indicative of a teratogenic potential of semaglutide in this 
species. The increase in early pregnancy losses is indicative of embryo-toxicity, which may be 
related to the maternal effect of semaglutide (marked body weight loss). A developmental toxicity 
NOAEL was determined at an exposure 1- to 2 fold the expected clinical exposure (1 mg/week). A 
risk for the developing human embryo or foetus cannot be definitely ruled out, but the absence of 
findings indicative of teratogenicity in the EFD and PPND studies in cynomolgus monkey decrease 
the level of concern.
A comprehensive review of results from the non-clinical studies can be found in Investigator’s 
Brochure, semaglutide (NN9535) (subcutaneous administration), Type 2 Diabetes and any updates 
hereof 28.
3.3.2
Clinical data
As of 09 January 2014, 5 clinical pharmacology trials (Trials 1820, 3679, 3633, 3616 and 3819) and 
1 phase 2 trial (Trial 1821) have been completed with semaglutide. Four trials are under 
reporting/on-going: Trial 4010, phase 1 bioequivalence, Trial 3744, phase 3 therapeutic 
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confirmatory trial to assess cardiovascular risk and long term safety, Trial 3626, phase 3 
confirmatory trial to assess parameters of efficacy and safety compared with sitagliptin and Trial 
3624, phase 3 confirmatory trial to assess parameters of efficacy and safety compared with 
exenatide extended release. In the completed trials 525 subjects have been exposed to semaglutide: 
164 healthy subjects (both single and multiple dosing), 313 subjects with T2DM (up to 12 weeks of 
treatment) and 48 subjects (four subjects had T2DM) with varying degrees of renal impairment 
(single dosing). In addition, 22 healthy subjects were exposed to semaglutide (s.c.) in the oral 
semaglutide administration project (Trials NN9924 3691 and NN9924 3692).
3.3.2.1
Pharmacokinetics
Results from one single dose trial (NN9535-3616) and from 1 multi-dose trial (NN9535-3819) 
based on the LC-MS/MS assay confirm that semaglutide has pharmacokinetic (PK) properties 
compatible with once-weekly administration, with a median time to maximum concentration (tmax) 
of 24-36 hours post dosing and an elimination half-life (t½) in the range of 166-184 hours (~7-8 
days). Overall, the PK properties of semaglutide appear similar in Caucasian and Japanese subjects, 
and also in healthy subjects and subjects with type 2 diabetes. In a trial with subjects with different 
degrees of renal impairment (NN9535-3616), data suggested that subjects with severe renal 
impairment had a slightly higher exposure compared to subjects with normal renal function. Area 
under curve (AUC0- ∞) increased by approximately 22% in subjects with severe renal impairment, 
whereas subjects with mild or moderate renal impairment and subjects on haemodialysis had 
exposure similar to subjects with normal renal function. No safety signals were identified in either 
of the renal groups, and tolerability profiles appeared similar across renal groups; thus, a dose-
reduction in subjects with severe renal impairment does not appear to be warranted. 
Interaction with oral contraceptives was assessed at semaglutide 1.0 mg steady-state exposures in 
postmenopausal women with type 2 diabetes (NN9535-3819). Steady-state exposures (AUC0-24h) 
of ethinylestradiol (EE) and levonorgestrel (LN) were slightly increased, with bioequivalence 
established for EE but not for LN; the increase was seen when oral contraceptives were co-
administered with semaglutide compared to oral contraceptives alone. Bioequivalence was 
demonstrated for Cmax of both EE and LN. These data indicate that semaglutide does not decrease 
the exposure of oral contraceptives, and suggest that no adjustments of oral contraceptive dose are 
warranted for women of childbearing potential using a low-dose oral contraceptive.
3.3.2.2
Efficacy
As of 06 April 2013, efficacy of semaglutide in the target population - subjects with type 2 diabetes 
has been investigated in one phase 2 dose range finding trial (NN9535-1821). The trial was a 12-
week, randomised, double-blind, placebo- and active-controlled trial in which 411 adults with type 
2 diabetes received once-weekly subcutaneous ( c) injection of 1 of 5 semaglutide dose levels (0.1-
1.6 mg) once-daily s.c. injection of open-label liraglutide (1.2 mg or 1.8 mg) or once-weekly 
placebo. 
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12 weeks of treatment, equivalent to 5-7 weeks in steady state on maintenance dose, provided 
statistically significant and clinically relevant improvement in glycaemic control for dose levels of 
0.2 mg and above. Changes in glycosylated haemoglobin (HbA1c) from baseline was up to -1.19 % 
(placebo adjusted estimated treatment difference). Dose-dependent improvements in fasting plasma 
glucose (FPG) and postprandial plasma glucose were also observed. The improvement in glycaemic 
control was accompanied by weight loss for semaglutide doses of 0.8 mg and above (placebo 
adjusted estimated treatment difference up to -3.64 kg).
3.3.2.3
Safety
From the clinical trials conducted so far the following safety observations have been made. 
Consistent with findings with other GLP-1 RAs, common adverse events (AEs) included nausea 
and vomiting; most of them were mild to moderate in intensity. Hypoglycaemia has occurred in 
subjects receiving semaglutide and these events have mainly been minor. An increase in heart rate 
has been observed in subjects exposed to semaglutide in line with the increase seen with other GLP-
1 analogous. The implications of this increase are unknown. As is the case with all protein based 
pharmaceuticals, subjects treated with semaglutide may develop immunogenic and allergic 
reactions. Few allergic reactions have been reported in connection with semaglutide. These have 
mainly been mild and transient however, more generalised reactions may occur, including urticaria, 
rash, pruritus and a single case of angioedema which have been observed. Injection site reactions 
have been infrequently reported. These have mainly been mild and transient in nature.
Please see Investigator’s Brochure, semaglutide (NN9535) (subcutaneous administration), Type 2 
Diabetes and any updates hereof 28.
3.4
Sitagliptin
Sitagliptin is an oral antihyperglycemic agent of the dipeptidyl peptidase-4 (DPP-4) inhibitor class 
suitable for once-daily oral administration. It was developed and marketed by Merck & Co as 
sitagliptin phosphate under the trade name Januvia®
Sitagliptin works by inhibition of the enzyme dipeptidyl peptidase 4 (DPP-4). This enzyme breaks 
down the incretin hormones GLP-1 and gastric inhibitory polypeptide (GIP). By preventing GLP-1 
and GIP inactivation, secretion of insulin is increased and release of glucagon is suppressed. The 
obvious advantage with a convenient route of administration is however counterbalanced by a 
significantly lower effect of the DPP-4 inhibitors on glycaemic control and body weight as 
compared to GLP-1 RAs. This has also been demonstrated for sitagliptin when compared to 
liraglutide (NN2211-1860).
Adverse reactions reported in >5% of patients treated with sitagliptin and more commonly than in 
patients treated with placebo are: upper respiratory tract infection, nasopharyngitis and headache. In 
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add-on to sulfonylurea and add-on to insulin studies, hypoglycaemia was also more commonly 
reported in patients treated with sitagliptin compared to placebo. (For more information see label 29)
3.5
Risk and benefits assessment
This assessment is based on the safety and efficacy data for semaglutide and sitagliptin presented 
above as well as potential risk identified as drug class effects.
3.5.1
Semaglutide risks and precautions
The nonclinical safety programme of semaglutide reveals no identified safety issues for humans 
based on conventional studies of safety pharmacology, repeat-dose toxicity or genotoxicity (see 
section 3.3.1). 
The human relevance of the proliferative C-cell changes found in rodents described in section 
3.3.1.1 is unknown, but data suggest that rodents are more sensitive to the mode of action for 
induction of C-cell tumours with GLP-1 analogues. However, as a precaution subjects with a family 
or personal history of multiple endocrine neoplasia type 2 (MEN2) or medullary thyroid carcinoma, 
and subjects with a screening calcitonin ≥50 ng/L will be excluded from trial. During the trial 
calcitonin will be measured on a regular basis and guidance for investigators of further evaluation 
and action on elevated plasma calcitonin concentrations will be carried out by an independent group 
of thyroid experts, the Calcitonin Monitoring Committee (CMC). This will ensure appropriate and 
consistent handling of elevated calcitonin levels across trials. 
Semaglutide has been concluded teratogenic in rats as described in section 3.3.1.2. The mechanism 
resulting in this effect is not considered relevant for humans. However as a risk for the developing 
foetus cannot be completely ruled out, subjects fulfilling the following exclusion criteria will be 
excluded: females of childbearing potential who are pregnant, breast-feeding or intend to become 
pregnant and females who are not using adequate contraceptive methods (adequate contraceptive 
measures as required by local law or practice) throughout the trial including the 5 week follow-up 
period.
Safety data from clinical trials are consistent with findings from other GLP-1 RAs. The most 
frequently reported AEs in the clinical trials with semaglutide thus far have been gastrointestinal 
(GI) disorders (nausea, vomiting, diarrhoea, dyspepsia and constipation). A new dose escalation 
regiment was tested in a phase 1 trial (NN9535-3819) in order to further improve GI tolerability. As 
the GI tolerability profile was substantially improved this regimen will be implemented in future
clinical trials with semaglutide.
As it is the case with all protein based pharmaceuticals subjects treated with semaglutide risk 
developing immunogenic and allergic reactions. These may include localised reactions or 
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generalised reactions including urticaria, rash or pruritus. Severe allergic reactions such as 
anaphylactic reactions could potentially also pose a risk for subjects treated with semaglutide.
As the mode of action of GLP-1 is glucose dependent10,11 the risk of development of 
hypoglycaemic event is low. However, hypoglycaemia has occurred in subjects receiving 
semaglutide and experience from the GLP-1 RA drugs class warrants special caution when 
semaglutide is combined with sulfonylureas.
Based on current knowledge about the GLP-1 RA drug class two potential risks have been found 
relevant. 
Firstly untoward effects of volume depletion including acute renal failure resulting from nausea, 
vomiting and dehydration have been observed in subjects treated with GLP-1 RAs. Semaglutide is 
not metabolised by the kidneys, and treatment has not been associated with impaired renal function 
in preclinical or clinical studies. However, as a precaution serum creatinine is measured regularly. 
Impaired renal function may increase the risk of metformin associated lactic acidosis when GLP-1 
RAs are co-administered with metformin. If semaglutide and metformin are co-administered, 
investigator should evaluate subjects with prolonged or severe nausea and vomiting, monitor serum 
creatinine, if clinically indicated and withhold metformin until resolution of the renal dysfunction.
Secondly acute pancreatitis, including reports of severe necrotising and haemorrhagic forms, has 
been associated with other GLP-1 RAs. However data from observational studies suggest an 
increased frequency of pancreatitis among diabetics and a relationship between pancreatitis and 
GLP-1 RAs can neither be established nor excluded30,31 . However, as a precaution subjects with a 
history of acute idiopathic or chronic pancreatitis will be excluded from clinical trials with 
semaglutide. Subjects will be monitored for elevated levels of amylase and lipase and be informed 
of the characteristic symptoms of acute pancreatitis.
3.5.2
Sitagliptin risk and precautions
Sitagliptin is generally considered to be well tolerated. The most commonly reported side effect is 
upper respiratory tract infection and headache. Some of the potential risk associated with GLP-1 
RA treatment has also been associated with treatment with the DPP-4 inhibitors as sitagliptin i.e. 
pancreatitis, acute renal impairment, hypersensitivity reactions and hypoglycaemia (US prescribing 
information32 and Chinese prescribing information33)
3.5.3
Benefits
In this trial subjects in all treatment arms will be treated within a regimen anticipated to be more 
efficacious than the treatment they receive at the time of randomisation into the trial. It is expected 
that subjects will benefit from the trial treatment with respect to optimised glycaemic control, a 
reduced risk of long-term diabetic complications and a potential weight loss. 
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Semaglutide has in a phase 2 trial (NN9535-1821) proven to have a clinically meaningful and dose-
dependent effect on HbA1c, FPG and weight. Doses ≥0.8 mg brought more subjects to target with 
regards to HbA1c and FPG and provided a greater weight loss than liraglutide 1.8 mg.
Sitagliptin has in phase 3 trials where sitagliptin has been given in combination with metformin 
proven to provide significant improvements in HbA1c and FPG34.
All subjects in this trial will receive active treatment and will receive trial drug and auxiliary free of 
charge.
Furthermore it is expected that all subjects participating in the trial will benefit from participation 
through close contact with the study site and close follow-up of their type 2 diabetes. Such careful 
medical examination will most likely result in an intensified management of their diabetes.
3.5.4
Risk and benefit conclusion
It is concluded that the potential benefits from participating in the trial outweigh the potential risks. 
The safety profile of semaglutide generated from the clinical and nonclinical development 
programme has not revealed any safety issues that would prohibit administration of once-weekly 
doses of 0.5 mg or 1.0 mg semaglutide in accordance with the planned clinical trial. Sitagliptin is 
already a marketed drug in the 100 mg dose and approved for the use in type 2 diabetic patients. It 
is concluded that the risk to the subjects in this trial is low and acceptable in view of the benefits a 
long-acting GLP-1 analogue would provide to subjects with type 2 diabetes. 
3.6
Rationale for the trial
The currently available treatment modalities for type 2 diabetes are still not satisfactory and there
is still a large proportion of patients not reaching the treatment targets despite a high level of
compliance with the treatment regimens. Furthermore, there is a segment of patients where either
compliance with once-daily treatment regimens is an issue resulting in sub-optimal glycaemic
control, or where there is a wish for a more convenient treatment regimen.
The rationale for this trial is to compare the efficacy of semaglutide versus sitagliptin in subjects 
with type-2 diabetes in terms of glycaemic control, weight loss and other efficacy parameters. 
Furthermore the trial is designed to address and compare safety, tolerability and patient satisfaction. 
This trial is designed to resemble the main trial NN9535-3626 (SUSTAINTM 2) in the global 
SUSTAINTM programme and will be conducted in China and several other countries . The study 
design is adjusted to fulfil the Chinese requirements.
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4
Objectives and endpoints
4.1
Objective
4.1.1
Primary objective
To compare the effect of once-weekly dosing of two dose levels of semaglutide versus sitagliptin 
100 mg once-daily on glycaemic control after 30 weeks of treatment
4.1.2
Secondary objectives
To compare the effects of once-weekly dosing of two dose levels of semaglutide versus sitagliptin
100 mg once-daily after 30 weeks of treatment on:
!
Inducing and maintaining weight loss
!
Other parameters of efficacy, safety and tolerability
4.2
Endpoints
4.2.1
Primary endpoint
!
Change from baseline to week 30 in HbA1c
4.2.2
Secondary endpoints
4.2.2.1
Confirmatory secondary endpoint
!
Change from baseline to week 30 in body weight
4.2.2.2
Supportive secondary endpoints
Supportive secondary efficacy endpoints
Change from baseline to week 30 in:
!
Fasting plasma glucose (FPG)*
!
Self-measured plasma glucose (SMPG), 7 point profile
o
Mean 7-point profile
o
Mean post-prandial increment (over all meals)
!
Insulin, C-peptide, glucagon, pro-insulin, pro-insulin/insulin ratio, homeostasis model
assessment of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) (all fasting)
!
Fasting blood lipids (total cholesterol, low density lipoprotein (LDL) cholesterol, very low 
density lipoprotein (VLDL) cholesterol, high density lipoprotein (HDL) cholesterol, 
triglycerides and free fatty acids
!
Body mass index (BMI)
!
Waist circumference
!
Systolic and diastolic blood pressure*
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!
Highly sensitive C-reactive protein (hsCRP)
!
Patient reported outcome (PRO) questionnaire: SF-36v2™ score
!
Patient reported outcome (PRO) questionnaire: Diabetes Treatment Satisfaction 
Questionnaire status (DTSQs) score*
Subjects who after 30 weeks treatment achieve (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*
!
Weight loss ≥ 5%
!
Weight loss ≥ 10%
!
HbA1c < 7.0% (53 mmol/mol) without severe or blood glucose (BG) confirmed symptomatic  
hypoglycaemia and no weight gain
Supportive secondary safety endpoints
!
Number of treatment emergent adverse events (TEAEs) during 30 weeks of treatment
!
Number of treatment emergent severe or BG confirmed symptomatic hypoglycaemic 
episodes during 30 weeks of treatment
!
Severe or BG confirmed symptomatic hypoglycaemic episodes during 30 weeks of 
treatment (yes/no)
Change from baseline to week 30 in:
!
Haematology
!
Biochemistry
!
Calcitonin
!
Urinalysis
!
Urinary albumin to creatinine ratio (UACR)
!
Pulse
!
Electrocardiogram (ECG) evaluation
!
Physical examination 
Occurrence of anti-semaglutide antibodies during 30 weeks of study duration (yes/no):
!
Anti-semaglutide antibodies with in vitro neutralising effect
!
Anti-semaglutide antibodies cross reacting with endogenous GLP-1
o
Cross reacting antibodies with in vitro neutralising effect to endogenous GLP-1
Antibody level during and after 30 weeks of treatment
*Key supportive secondary endpoint prospectively selected for posting on clinicaltrials.gov.
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5
Trial design
5.1
Type of trial
This is a 30-week randomised, double-blind, double-dummy, active-controlled, multi-centre, multi-
national trial, four-armed, parallel-group trial comparing semaglutide 0.5 mg and 1.0 mg once-
weekly against sitagliptin 100 mg once-daily.
Figure 5–1
Trial design
Subjects with type 2 diabetes inadequately controlled on metformin will be randomised in a 2:2:1:1 
manner to receive either:
!
semaglutide 0.5 mg once-weekly + sitagliptin placebo once-daily
!
semaglutide 1.0 mg once-weekly + sitagliptin placebo once-daily
!
sitagliptin 100 mg once-daily + semaglutide placebo (0.5) mg once-weekly
!
sitagliptin 100 mg once-daily + semaglutide placebo (1.0) mg once-weekly
The total trial duration for the individual subjects will be approximately 37 weeks. The trial 
includes a 2-week screening period followed by a 30-week randomised treatment period and a 5 
week follow-up period.
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A planned total of 1050 subjects will be randomised whereof approximately 792 subjects will be 
from China. Randomisation will be stratified by country.
5.2
Rationale for trial design
Parallel treatment groups and a randomised double-blind double dummy controlled design have 
been chosen in accordance with trial objectives and to avoid bias in the trial.
Treatment duration of 30 weeks is considered adequate in terms of assessing efficacy of 
semaglutide treatment versus sitagliptin treatment on change in HbA1c. Furthermore, 30 weeks is 
considered sufficient for addressing and comparing the safety, tolerability and patient satisfaction 
profiles.
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5.3
Treatment of subjects
Trial periods
Screening
Period 1
Period 2
Period 3
Follow-up
Alias for trial period
Screening
Dose escalation
Dose escalation/ 
Maintenance
Maintenance
Follow-up
Visits in each period
Visit 1-2
Visit 2-3 
Visit 3-5
Visit 5-9
Visit 9-10
Duration of each period
2 weeks
4 weeks
4 weeks
22 weeks
5 weeks
Treatment arm
N
!
Semaglutide 
0.5 mg
!
Sitagliptin 
placebo
350
Screening 
!
Semaglutide 
0.25 mg, 
1.34 mg/mL, 
190μL 
!
Sitagliptin 
placebo 
!
Semaglutide 
0.5 mg, 
1.34 mg/mL, 
370μL
!
Sitagliptin
placebo
!
Semaglutide
0.5 mg, 
1.34 mg/mL, 
370μL
!
Sitagliptin
placebo
Follow-up 
!
Semaglutide 
1.0 mg
!
Sitagliptin 
placebo
350
Screening 
!
Semaglutide 
0.25 mg, 
1.34 mg/mL, 
190μL 
!
Sitagliptin 
placebo
!
Semaglutide 
0.5 mg, 
1.34 mg/mL,  
370μL
!
Sitagliptin
placebo 
!
Semaglutide
1.0 mg, 
1.34 mg/mL, 
740μL
!
Sitagliptin
placebo 
Follow-up 
!
Sitagliptin 
!
Semaglutide 
placebo 
(0.5 mg)
175
Screening 
!
Sitagliptin 
100 mg
!
Semaglutide
placebo
0 mg, 
190μL 
!
Sitagliptin 
100 mg
!
Semaglutide
placebo
0 mg, 
370μL
!
Sitagliptin 
100 mg
!
Semaglutide
placebo
0 mg, 
370μL
Follow-up 
!
Sitagliptin
!
Semaglutide 
placebo
(1.0 mg)
175
Screening 
!
Sitagliptin 
100 mg
!
Semaglutide
placebo
0 mg, 
190μL 
!
Sitagliptin 
100 mg
!
Semaglutide
placebo
0 mg, 
370μL
!
Sitagliptin 
100 mg
!
Semaglutide
placebo
0 mg, 
740μL
Follow-up 
All on background medication of metformin  ≥ 1500 mg (or maximum tolerated dose ≥ 1000 mg) throughout the trial.
Table 5–1
Treatment of subjects
After randomisation subjects will follow a fixed dose escalation for semaglutide and semaglutide 
placebo. The maintenance dose of 0.5 mg will be reached after 4 doses (4 weeks) of 0.25 mg. The 
maintenance dose of 1.0 mg will be reached after 4 doses (4 weeks) of 0.25 mg, followed by 4 
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doses (4 weeks) of 0.5 mg. Doses must not be changed during the trial after the maintenance dose 
has been reached.
Semaglutide injections should be administered in the thigh, abdomen or upper arm, and should be
taken on the same day of the week during the trial. Both semaglutide and sitagliptin can be taken 
any time of day irrespective of meals.
If necessary, the trial product may be discontinued for safety reasons. In case trial product is 
discontinued, subjects will not be withdrawn from trial but should continue to follow scheduled 
visits to the extent possible (see section 6.5.1).
Trial product will be add-on in subjects failing on metformin monotherapy.
Subjects must not be prescribed other GLP-1 RA in the period between V9 and V10 or V9A and 
V10A.
5.3.1
Missed dose
If a semaglutide dose is missed, it should be administered as soon as noticed, provided the time to 
the next scheduled dose is at least 2 days (48 hours). If a dose is missed and the next scheduled dose 
is less than 2 days (48 hours) away, the subject should not administer a dose until the next 
scheduled dose. A missed dose should not affect the scheduled dosing day of the week.
5.3.2
Background medication
Subjects should upon inclusion continue pre-trial background medication throughout the entire trial. 
The background medication should be maintained at the stable, pre-trial dose and frequency during 
the whole treatment period unless rescue medication is needed (see section 6.4). 
Metformin is considered background medication (non-investigational medicinal product) and will 
not be provided by Novo Nordisk A/S (except for Brazil where Metformin will be provided by 
Novo Nordisk Farmacêutica do Brasil Ltda). Metformin should be used in accordance with standard 
of care in the individual country at the discretion of the investigator and the daily dose should be 
unchanged throughout the trial unless the rescue criteria is met. However the maximum approved 
dose in the individual country must not be exceeded. Treatment with metformin extended/slow 
release formulations is allowed.
5.3.3
Treatment after end of trial
When discontinuing trial products the subject should be switched to a suitable marketed product at 
the discretion of the investigator. (Brazil: After the study ending, if the investigator decides that the 
study medication is the best treatment option for the subject, the access to the study medication will 
be assured by the trial sponsor at no costs, according to the current regulations of Brazilian National 
Council of Health and Health Authority). 
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5.4
Rationale for treatment
Semaglutide has been developed for s.c. administration. The doses of 0.5 mg and 1.0 mg once-
weekly has been chosen based on careful evaluation to strike a satisfactory balance of efficacy and 
safety that would satisfy the majority of patients. Hence duration and the dose of the randomised 
treatments are considered adequate for obtaining meaningful information on efficacy and safety in 
accordance with the trial objectives. Subjects will enrol for a treatment period of 30 weeks in order 
to be able to evaluate full effect as well as durability of the primary and secondary endpoints as well 
as a reasonable safety assessment.
For further information please refer to Investigator’s Brochure, semaglutide (NN9535)
(subcutaneous administration), Type 2 Diabetes and any updates hereof28.
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6
Trial population
6.1
Number of subjects 
Planned number of subjects to be screened (i.e. documented informed consent): Up to 1750
Planned number of subjects to be randomised: 
1050
Expected number of subjects to complete the trial: 
840
Planned number of Chinese subjects to be randomised: 
792
Expected number of Chinese subjects to complete the trial: 
636
6.2
Inclusion criteria
For an eligible subject, all inclusion criteria must be answered "yes".
1. Informed consent obtained before any trial-related activities. Trial-related activities are any 
procedures that are carried out as part of the trial, including activities to determine suitability for 
the trial
2. Male or female, age ≥ 18 years at the time of signing informed consent
3. Subjects diagnosed with type 2 diabetes and on stable treatment in a period of 60 days prior to 
screening with metformin ≥ 1500 mg (or maximum tolerated dose ≥ 1000 mg). Stable is defined 
as unchanged medication and unchanged daily dose
4. HbA1c 7.0 – 10.5 % (53-91 mmol/mol) (both inclusive)
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 informed consent
3. Female who is pregnant, breast-feeding or intends to become pregnant or is of childbearing 
potential not using an adequate contraceptive method throughout the trial including the 5 week 
follow-up period (adequate contraceptive measure as required by local regulation or practice)
(China: Sterilization, intrauterine device (IUD), oral contraceptives or barrier methods). (Brazil: 
For women who expressly declare free of the risk of pregnancy, either by not engaging in sexual 
activity or by having sexual activity with no birth potential risk, use of contraceptive method 
will not be mandatory).
4. Receipt of any investigational medicinal product within 90 days before screening (Brazil, 
Participation in other trials within one year prior to screening visit (V1) unless there is a direct 
benefit to the research subject at the Investigator´s discretion)
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5. Any disorder which, in the opinion of the investigator, might jeopardise subject’s safety or 
compliance with the protocol
6. Treatment with glucose lowering agent(s) other than stated in the inclusion criteria in a period 
of 60 days before screening. An exception is short-term treatment (≤7 days in total) with insulin 
in connection with inter-current illness
7. Use of non-herbal Chinese medicine or other non-herbal local medicine with 
unknown/unspecified content. Herbal traditional Chinese medicine or other local herbal 
medicines may, at the Investigator’s discretion, be continued throughout the trial 
8. History of pancreatitis (acute or chronic)
9. Screening calcitonin value  ≥ 50 ng/L (pg/mL)
10. Personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine 
neoplasia syndrome type 2 (MEN 2)
11. Impaired renal function defined as eGFR < 60 ml/min/1.73 m2 per MDRD formula (4 variable 
version)
12. Acute coronary or cerebrovascular event within 90 days before  randomisation
13. Heart failure, New York Heart Association (NYHA) class IV
14. Known proliferative retinopathy or maculopathy requiring acute treatment according to the 
opinion of the  investigator
15. Diagnosis of malignant neoplasm in the previous 5 years (except basal cell skin cancer or 
squamous cell skin cancer)
16. Mental inability, unwillingness or language barrier precluding adequate understanding of or 
compliance with study procedures
6.4
Rescue criteria
If any of the fasting plasma glucose (FPG) values exceed the limits outlined below and no 
intercurrent cause of the hyperglycaemia can be identified the subject should be called for an 
unscheduled visit as soon as possible:
!
15.0 mmol/L (270 mg/dl) from week 0 to end of week 5
!
13.3 mmol/L (240 mg/dl) from week 6 to end of Week 11
!
11.1 mmol/L (200 mg/dl) from week 12 to end of trial
A confirmatory FPG should be obtained. If the confirmatory FPG exceeds the values described 
above the subject should be offered treatment intensification (rescue medication) at the discretion of 
the investigator and in accordance with ADA/European Association for the Study of Diabetes  
(preferably excluding GLP-1 RAs, DPP-4 inhibitors and amylin analogues). Rescue medication 
(intensification of existing background medication and/or initiation of new medication) and any 
changes hereto should be captured on the concomitant medication form in the eCRF. Rescue 
medication should be prescribed as add-on to randomized treatment unless contraindicated 
according to the local sitagliptin label. In this case trial medication should be discontinued before 
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initiation of rescue therapy. Subjects should continue to follow the protocol-specified visit schedule 
even if rescue treatment has been initiated.
6.5
Withdrawal criteria
6.5.1
Discontinuation of trial product
All efforts should be made to keep the subjects on trial product. However in case of a safety 
concern or unacceptable intolerability the trial product may be discontinued at the investigator’s 
discretion.
Trial product must be discontinued in case of: 
!
included in the trial in violation of any of the inclusion and/or exclusion criteria
!
Pregnancy
!
Intention to become pregnant
For procedure to be performed in case of discontinuation of trial product (see section 8.1.6.2). In 
case of suspicion of acute pancreatitis (see section 8.8.1.4).
Subjects discontinuing trial product prematurely should continue with the scheduled site contact. If 
necessary, in order to retain the subject in the trial, site visits can be replaced by phone contacts 
after discontinuation of trial product. As minimum these subjects should be asked to attend the
visits end of treatment (V9) and follow up (V10) at the time of the scheduled completion of the 
trial.
Subjects discontinuing trial product prematurely will be called in for an end of treatment –
premature discontinuation visit (V9A), as soon as possible after discontinuation of trial product, and 
for a follow-up - premature discontinuation visit (V10A) five weeks after last dose of trial product 
(see section 2 and 8.1.6.2).
Subjects discontinued from trial product should be prescribed alternative therapy at the 
investigator´s discretion. However subjects must not be prescribed other GLP-1 RA in the period 
between V9 and V10 or V9A and V10A.
6.5.2
Withdrawal from trial
The subject may withdraw at will at any time. Please see section 8.1.7 for procedure to be 
performed in case of subject withdrawal.
Subjects should stay in the trial irrespective of lack of adherence to randomised treatment, lack of 
adherence to visit schedule, missing assessments, trial product discontinuation due to AE (see 
section 6.5.1), unwillingness to cope with injection regimen, development of co-morbidities or 
clinical outcomes.
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A subject who agrees to provide information concerning morbidities which are relevant for the 
assessments of cardiovascular outcomes and/or other trial end-points at the planned end of the trial 
should not be considered withdrawn from the trial.
Subjects who consider withdrawing from the trial should as a minimum be encouraged to have 
procedures performed according to the end of treatment visit(V9) and the follow up visit(V10), 
please see 8.1.7.
Only subjects who decline any further contact with the site in relation to the trial, and hence do not 
agree to report information which is relevant for the assessments of cardiovascular outcomes and/or 
other trial end-points at the end of trial should be considered as withdrawn from the trial.
6.6
Subject replacement
Subjects who are withdrawn will not be replaced.
6.7
Rationale for trial population
This trial will be carried out in China and several other countries. The aim is to include a broad 
diabetes population, hence the limited number of exclusion criteria. Subjects with type 2 diabetes 
who are inadequately controlled on metformin monotherapy will be included in the trial. As 
sitagliptin is indicated as monotherapy or in combination with metformin in China, subjects on 
other OADs are not included.
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7
Milestones
Planned duration of recruitment period (i.e. FPFV– LPFV): 
26 weeks
End of trial is defined as last patient last visit.
Planned date for first patient first visit (FPFV): 
28-Apr-2016
Planned date for last patient first visit (LPFV): 
27-Oct-2016
Planned date for last patient last visit (LPLV): 
13-July-2017
To ensure that only the required number of subjects is randomised, screened subjects will be 
monitored closely via interactive voice response system/interactive web response system 
(IV/WRS).
A recruitment strategy will be developed in corporation with the participating countries to secure 
sufficient number of subjects from China and the other participating countries.
Recruitment will be monitored on an on-going basis by sponsor. Prior to FPFV all sites should have 
a recruitment strategy in place detailing how many subjects they can recruit within a certain period. 
If a site has not enrolled the number of subjects according to the recruitment strategy, the remaining 
subjects may be reallocated. 
The screening and randomisation rate will be followed closely via IV/WRS in order to estimate 
when to stop screening. All investigators will be notified immediately when the enrolment period 
comes to an end, after which no subjects must be screened, and the IV/WRS will be closed for 
further screening. All subjects included in the screening period by the time of IV/WRS closure and 
eligible for randomisation will be randomised.
Trial registration:
Information of the trial will be disclosed at clinicaltrials.gov, chinadrugtrials.org.cn and 
novonordisk-trials.com. According to the Novo Nordisk Code of Conduct for Clinical Trial 
Disclosure, it will also be disclosed according to other requirements such as those of the 
International Committee of Medical Journal Editors (ICMJE)35, the Food and Drug Administration 
Amendment Act (FDAAA) 36, European Commission Regulation for EudraCT 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).
The investigator must keep a subject screening log, a subject identification code list and a subject 
enrolment log. The subject screening log and subject enrolment log may be combined in one list
and may be generated from the IV/WRS.
In addition, the investigator must keep a log of staff and delegation of task(s) at site. Investigator 
must sign the log of staff and delegation of task(s) at site at the time of delegation of tasks.
8.1.1
Screening visit 1 (V1)
For procedures and assessments performed at screening, please see flow chart (see section 2).
The IV/WRS must be contacted to register the subject as screened (see section 10). Subject will be
assigned a unique number (lowest available number allocated to site) which is maintained
throughout the trial. It must be stated in the medical record that the subject is participating in the 
current trial. 
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. The subjects should be reminded to show the card to other health care providers, as 
applicable.
Once all data relating to screening V1 have been obtained, these must be reviewed by the 
investigator to ensure that the subject is eligible to continue the trial.
Ability and willingness to self-inject can be tested by administration of injection(s) with a test pen
(containing semaglutide placebo) for subjects who do not have prior experience with self-injection.
8.1.1.1
Screen failures
For screening failures the screening failure form 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 case report form eCRF. Follow-up of SAEs must be carried out 
according to section 12.
A screening failure session must be made in the IV/WRS. The case book must be signed in eCRF.
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8.1.1.2
Re-screening
Re-sampling or re-screening is NOT allowed if the subject has failed one of the inclucion or 
exclusion criteria related to laboratory parameters.
8.1.2
Fasting visits
The subjects should attend several visits in a fasting state (see section 2). Fasting is defined as 
having consumed only water since midnight. Glucose lowering agents and trial product cannot be 
taken until after blood sampling has been performed but other prescribed medication should be 
taken. An exception from this is the follow-up visit (V10) and follow-up premature discontinuation 
visit (V10A) where fasting is defined as having consumed only water within the last two hours prior 
to the visit. If the subject is not fasting as required, the subject should be called in for a new visit 
within the visit window to have the fasting procedures done. 
8.1.3
Randomisation V2
For procedures and assessments performed at randomisation (see section 2).
Visit 2 will take place two weeks (±7 days) after screening V1.
Eligible subjects will be randomised into one of four treatment arms. The IV/WRS will allocate the
dispensing unit number (DUN) of trial product to be dispensed to the subject.
Trial product will be dispensed to the subject by the site, hospital pharmacy or equivalent with
different intervals during the trial. Subject will be instructed in administration of sc injection of trial
product and the investigator must document that a direction for use (DFU) is given orally and/or in
writing at each dispensing visit. Date, time and dose of first administration of trial product will be
captured in the eCRF.
Please see section 9 for further information about the trial product.
8.1.4
Visits
For visit numbers, timing of site visits, phone contacts and visit windows during the trial period,
please refer to the flow chart (see section 2). Planned visits can be re-scheduled within the allowed 
visit window.
It is the responsibility of the investigator to ensure that all site visits and phone contacts occur 
according to the flow chart (2). 
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8.1.5
Missed visits and unscheduled visits
If a visit is missed and it is not possible to re-schedule, every effort should be made to ensure
information is collected at a telephone contact. Subjects will be invited for the next scheduled visit 
according to visit schedule.
If a subject is unable or unwilling to attend the subsequent visit(s) the investigator should aim to at 
least have the subject attending the end of treatment visit and follow-up visit as these two visits 
should be performed for all subjects regardless of compliance with the protocol and adherence to 
the treatment (see section 8.1.6). 
If a subject attends the clinic for a visit not described in the protocol, an unscheduled visit form 
must be completed. This only applies if assessments are done, hence not for the purpose of re-test of 
blood- or urine sampling, or re-supply of trial product. In case of re-supply a dispensing session 
should be made in the IV/WRS selecting additional medication. Re-scheduling of fasting visit 
samples is not considered as an unscheduled visit.
8.1.6
End of treatment (V9/9A) and Follow-up (V10/10A)
8.1.6.1
Subjects completing the treatment period as per protocol
An end of treatment visit (V9) should be scheduled when the subject has completed the treatment 
period as described per protocol and a follow-up visit (V10) should be performed at least 5 weeks 
after (+7 days visit window). Please see the flow chart for details (section 2).
The follow-up visit serves to collect AEs, technical complaints, hypoglycaemic episodes, ECG, 
concomitant medication and blood sampling for anti-semaglutide antibodies .
8.1.6.2
Subjects who prematurely discontinue trial product
For subjects who discontinue trial product prematurely the visit end of treatment – premature 
discontinuation (V9A) should be scheduled shortly after subject has discontinued trial product. The 
visit follow-up – premature discontinuation ( V10A) should be scheduled at least 5 weeks after
discontinuation of trial product (+7 days visit window). Please see the flow chart for details (section 
2).
Subjects discontinuing trial product prematurely should continue with the scheduled site contacts. If 
necessary, in order to retain the subject in the trial, site visits can be replaced by phone contacts 
after discontinuation of trial product. However, as a minimum these subjects will be called in for 
end of treatment (V9) and follow-up (V10) at the time of the scheduled completion of the trial.
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8.1.7
Withdrawals
If the subject fulfils the withdrawal criterion, the investigator must ask the subject to attend the End 
of Treatment visit (visit 9), as soon as possible, and the Follow Up visit (visit 10) at least 5 weeks 
after but not more than 6 weeks after, if possible.
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 site. The case book must be signed by the investigator in eCRF 
and a premature discontinuation of trial product session must be made in the IV/WRS (see section 
10). The case book must be signed by the investigator in the eCRF.
Although a subject is not obliged to give his/her reason(s) for withdrawing from a trial, the 
investigator must make a reasonable effort to ascertain the reason(s), while fully respecting the 
subject's rights. Where the reasons are obtained, the primary reason for not completing the trial
must be specified on the end-of-trial form in the CRF (see section 6.5).
Subjects who withdraw will be asked to allow the investigator to contact their family doctor at 
planned end of trial by having consented to this.
8.1.8
Investigator’s assessment
Review of diaries, patient reported outcomes (PROs), laboratory reports, ECGs, eye examination 
(fundoscopy/fundus photography), physical examination etc. must be documented either on the 
front page of the documents and/or in the subject's medical record. The signed 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? (No/Yes)
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For laboratory report values outside the reference range, the investigator must specify whether the 
value is clinically significant or clinically non-significant. All laboratory printouts must be signed 
and dated by the investigator on the day of evaluation. The signed laboratory report is retained at 
the site as source documentation.
In case of abnormal clinical 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 subjects medical record and record this in the concomitant illness form in the eCRF. At 
subsequent visits any clinically significant changes or new clinically significant findings must be 
reported as an AE according to section 12.
Investigator or site staff must review the diary to ensure that AEs, including overall change in 
health and concomitant medication are reported. 
If clarification of entries or discrepancies in the diary or patient reported outcomes (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.
8.2
Subject related information 
8.2.1
Demography
The following information must to be recorded in the subject’s medical record and will be 
transcribed into eCRF  at screening V1:
!
Date of birth(according to local regulation)
!
Sex
!
Race (according to local regulation)
!
Ethnicity (according to local regulation)
8.2.2
Diagnosis of diabetes
The following information must to be recorded in the subject’s medical record and will be 
transcribed into eCRF at screening V1:
!
Date of diagnosis of type 2 diabetes.
8.2.3
Diabetes treatment history
The following information must be recorded in the subject’s medical record and will be transcribed 
into eCRF at screening V1:
!
Current diabetes treatment
!
Dose of current diabetes treatment
!
Start date of current diabetes treatment
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8.2.4
Diabetes complications
The following information related to signs or symptoms of microvascular complications of diabetes 
must be recorded in the subject’s medical record and will be transcribed into eCRF at screening
V1:
!
Diabetic nephropathy 
!
Diabetic retinopathy 
!
Diabetic neuropathy
!
macroangiopathy including peripheral vascular disease
!
other complications where relevant
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.
8.2.5
Concomitant illness and medical history
A concomitant illness is any illness that is present at the start of the trial (V1).
Medical history is a medical event that the subject has experienced in the past. Only relevant 
medical history as judged by the investigator should be reported.
The information collected for concomitant illness and medical history should include diagnosis, 
date of onset and date of resolution or continuation, as applicable.
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.
Concomitant illness and medical history must be recorded in the subject’s medical record and will 
be transcribed into eCRF .
8.2.6
History of cardiovascular disease
Information related to history of cardiovascular disease (CVD) (i.e. heart failure incl. New York 
Heart Association class, hypertension or ischaemic stroke) or other risk factors for CVD must be 
recorded in the subjects medical record and will be transcribed into eCRF at screening V1. Please 
refer to Appendix A for detailed information of CVD.
8.2.7
History of gallbladder disease
Information related to gallbladder disease(. ie pancreatitis, gallstone disease, cholecystitis) must be 
recorded in the subjects medical record and will be transcribed into the eCRF at screening V1. 
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8.2.8
Smoking habits
Details of smoking habit must be recorded in the subject’s medical record at V1. Smoking is 
defined as smoking at least one cigarette, cigar or pipe daily. 
It must be recorded whether the subject is a smoker according to the following criteria:
!
Never smoked
!
Is a previous smoker
o
cessation date
o
average cigarettes per day
o
approximate years of smoking
!
Is a current smoker
o
average cigarettes per day
o
approximate years of smoking
8.2.9
Concomitant medication
A concomitant medication is any medication, other than the trial product, which is taken during 
the trial, including the screening and follow-up periods.
Details of any concomitant medication must be recorded in the eCRF at V1. Changes in 
concomitant medication, including rescue medication and anti-diabetic medication(s) prescribed at 
the end of the treatment (follow-up period), must be recorded at each visit as they occur. 
The information collected for each concomitant medication includes trade name or generic name, 
indication, start date and stop date or continuation and for anti-diabetic medication also total daily 
dose.
If a change is due to an AE, then this must be recorded and reported according to section 12. If the 
change influences the subject's eligibility to continue in the trial, the monitor must be informed.
8.2.10
Fundoscopy/fundus photography 
Fundoscopy/fundus photography will be performed as per flow chart by the investigator or 
according to local practise. Results of the fundoscopy/fundus photography will be interpreted by the 
investigator (see section 8.1.8). Dilation is not required.
If a fundoscopy/fundus photography has been performed within 90 days before 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.
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If the fundoscopy/fundus photography is performed before the subject has signed the informed 
consent form, it must be documented in the medical records that the reason for performing the 
procedure was not related to this trial.
8.2.11
Height
Height is measured without shoes in centimetres or inches and recorded in the eCRF to nearest ½ 
cm or 1/4 inch.
8.3
Assessments for efficacy
8.3.1
Body weight
Body weight must be measured in kilograms (kg) or pound(lb), with one decimal. The body weight 
should be measured  without shoes and only wearing light clothing.
The same scale should preferably be used throughout the trial.
8.3.2
Waist circumference
The waist circumference is defined as the minimal abdominal circumferences located midway 
between the lower rib margin and the iliac crest.
Three consecutive measurements of waist circumference should be performed and recorded in the 
eCRF. The waist circumference will be measured in cm to the nearest ½ cm using a non-stretchable 
measuring tape (measuring tapes will be provided to the sites).
The subject should be measured in a standing position with an empty bladder and wearing light 
clothing with accessible waist. The subject should be standing with arms down their side and feet 
together. 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.
8.3.3
BMI
BMI will be calculated by the eCRF using the equation as listed below:
BMI kg/m2 = Body weight (kg)/(Height (m) x Height (m)) or (kg/m2 = [lb/in2 x 703])
8.3.4
Systolic and diastolic blood pressure
The method for measuring systolic and diastolic blood pressure needs to follow the standard clinical 
practise at site, but as a minimum the following guidelines should be adhered to:
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!
Avoid caffeine, smoking and exercise at least 30 minutes prior to measuring the blood 
pressure
!
The blood pressure should be measured in a sitting position, with the legs uncrossed, the 
back and arms supported
!
Subjects should be sitting for five minutes before the measurement is taken
!
Subject or the observer should not talk during the measurement
It is recommended to use the same arm as used at V1 for subsequent measurements. 
8.4
Assessments for safety
The timing of the assessments for safety are outlined in the flow chart (see section 2).
8.4.1
Adverse events
AEs must be recorded at each visit in accordance with the procedures outlined in section 12.
Any clinically significant worsening from baseline of a previous finding must be reported as an AE.
8.4.2
Hypoglycaemic episodes
Blood glucose should always be measured and recorded when a hypoglycaemic episode is 
suspected. 
All plasma glucose values:
!
≤ 3.9 mmol/L (70 mg/dL) or
!
> 3.9 mmol/L (70 mg/dL) when they occur in conjunction with hypoglycaemic symptoms,
should be recorded by the subject in the diary. These must be transcribed into the eCRF 
(hypoglycaemic episode form) throughout the trial from V1 to V10/10A.
The record should include the following information:
!
Date and time of hypoglycaemic episode
!
The plasma glucose level before treating the episode (if available) 
!
Whether the episode was symptomatic
!
Whether the subject was able to treat him/herself, if No:
–
What treatment was administered by another person (oral carbohydrates, glucagon, IV 
glucose, other)
–
Where was the treatment administered (at home, paramedical care, emergency room, 
hospital, other)
–
What symptoms were associated with the hypoglycaemic episode (sweating, trembling, 
hunger, palpitations, confusion, drowsiness, speech difficulty, visual disturbances, odd 
behaviour, impaired balance, incoordination, headache, malaise, seizure, other)
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–
Was the subject unconscious/comatose
–
Did the symptoms alleviate after treatment
!
Type, date and time of last trial product and other antidiabetic drug(s) administrated prior to 
episode
–
Whether any of the above were related to a deviation from the prescribed dose of the 
antidiabetic drug(s)
!
Date and time of last main meal prior to episode
!
Whether the episode occurred in relation to exercise
The answer to the question: "Was subject able to treat him/herself?" must be answered "No" for an 
episode requiring assistance of another person to actively administer carbohydrate, glucagon, or 
take other corrective actions. 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 38 . 
Oral carbohydrates should not be given if the subject is unconscious.
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A hypoglycaemic episode form must be filled in for each hypoglycaemic episode. 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.
8.4.3
Electrocardiogram
12-lead electrocardiograms (ECG) will be performed locally by the investigator or delegated staff
during the trial (see section 2). The ECG print out must be interpreted, dated and signed by 
investigator as described in section 8.1.8. ECG printed is source documentation. 
Additional unscheduled ECG recordings can be performed at the investigator´s site at investigator´s 
discretion at other visits than the planned ECG visits.
8.4.4
Physical examination
A physical examination will be performed by the investigator according to local procedure (see 
section 2). A physical examination must include:
!
General appearance
!
Head, ears, eyes, nose, throat, neck
!
Thyroid glands
!
Respiratory system
!
Cardiovascular system
!
Gastrointestinalsystem including mouth
!
Musculoskeletal system
!
Central and peripheral nervous system
!
Skin
!
Lymph node palpation
8.4.5
Pulse
Pulse (beats per minute) should be recorded in the eCRF at site visits after resting for 5 minutes in a 
sitting position.
8.5
Laboratory assessments
For laboratory analysis of efficacy and safety parameters will be drawn during the 37 weeks of the 
trial. The laboratory analyses will be performed by a central laboratory except for anti-semaglutide 
antibodies and IgE antibodies where a special laboratory will be used. In the situation described in 
section (8.8.1.4) and (8.8.1.5) a local laboratory will be used. Laboratory samples comprise both 
urine and blood samples. 
Descriptions of assay methods, laboratory supplies and procedures for collecting, handling, storage 
and shipping of samples and information regarding who will perform the assessments will be 
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described in the laboratory manual provided by the central laboratory (for central and special 
laboratory details, see Attachment I).
Samples will be coded in order to keep subject identity anonymous.
Laboratory samples may be drawn at another day than on the day of the actual visit as long as it is 
within the visit window outlined 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 it is required for the sensitivity of the analysis,that 
the subject is fasting. 
Central laboratory will provide laboratory results to the investigator on an on-going basis and the 
investigator must reviewall laboratory results for signs of concomitant illness and AEs and report 
these according to section 12. An exception to this is that anti-semaglutide antibody result will not 
be available to the investigator during the trial. However these results will be provided to the 
investigator upon request after  the completion of the clinical trial report(CTR).
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 must be reported to the investigator.
All laboratory samples will be destroyed on an on-going basis after analysisand no later than CTR, 
except for samples taken for anti-semaglutide antibody samples, which will be kept until market 
authorisation approval or rejection of file.(Brazil, due to local regulation (Resolution 441/11 from 
National Council of Health), the laboratory samples for Braziliansubjects will be destroyed at the 
latest at the completion of the CTR, including samples for anti-semaglutide antibody analysis. No 
sample will be stored after the completion of CTR).
The investigator should ensure that the last samples are shipped to the central laboratory within 24 
hours after the last subject visit last at the site.
8.5.1
Laboratory assessments for efficacy
Blood samples be drawn according to flow chart (see section 2) and analysed at the central 
laboratory to determine levels of the following efficacy laboratory parameters:
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8.5.1.1
Glucose metabolism
!
HbA1c
!
Fasting plasma glucose
!
Fasting insulin
!
Fasting C-peptide
!
Fasting glucagon
!
Fasting pro-insulin
8.5.1.2
Biomarker
!
hsCRP
8.5.1.3
Lipids (all fasting)
!
Total cholesterol
!
LDL-cholesterol
!
VLDL-cholesterol
!
HDL-cholesterol
!
Triglycerides
!
Free fatty acids
8.5.1.4
Self measured plasma glucose (SMPG) 7 point profile
When using blood glucose meters the measurement is performed with capillary blood calibrated to 
plasma equivalent glucose values i.e. the measurement is performed on blood while the value is 
reported as plasma. It is important to be aware of this difference throughout the protocol. 
The subject will be instructed to perform a SMPG 7-point profile twice during the trial (see section 
2) on a day where the subject does not anticipate unusual strenuous exercise.
At screening V1 subjects will be provided with a blood glucose meter including lancets, plasma-
calibrated test strips and control solutions. Oral and written directions for use of the device 
including the performance of calibrations according to the manufacturer’s instructions will be 
provided to the subject. Sites should as necessary, repeat the directions for use to the subject at 
subsequent visits.
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. 
Subjects should be instructed in how to record the results of the SMBGs in the diaries. The record 
of each SMBG should include date and value. The record of each SMBG measurement should 
include date, time and value at the following seven time points: before and 90 minutes after the start 
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of breakfast, lunch, dinner, and at bedtime. All data from the diary must be transcribed into the 
eCRF during or following the contact.
8.5.2
Laboratory assessments for safety
Blood samples be drawn according to flow chart (see section 2) and analysed at the central 
laboratory to determine levels of the following safety laboratory parameters: anti-semaglutide
antibodies, biochemistry, haematology, calcitonin, pregnancy test and urinalysis.
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8.5.2.1
Anti-semaglutide antibodies
Blood samples will be drawn for measurement of serum antibodies to semaglutide at selected visits 
in randomised subjects. Positive anti-semaglutide antibody samples will be further characterised for 
cross reactivity to native GLP-1 (see section 2). Samples taken at follow-up which are positive for 
anti-semaglutide antibodies will be further characterised for in vitro neutralising effect towards 
semaglutide. In addition, samples taken at follow-up which are positive for cross-reactivity against 
native GLP-1 will be further analysed for in vitro neutralising effect towards native GLP-1.
Follow-up antibody (taken at the follow-up V10/10A) samples must be taken fasting (as a minimum 
by only having consumed water for at least two hours).
8.5.2.2
Biochemistry
!
Creatinine
!
Alanine aminotransferase (ALT)
!
Aspartate aminotransferase (AST)
!
Alkaline phosphatase
!
Sodium
!
Potassium
!
Albumin
!
Bilirubin (total)
!
Total protein
!
Urea
!
Creatine kinase
!
Calcium total
!
Calcium, albumin corrected (calcium, ionized)
!
Lipase
!
Amylase
8.5.2.3
Haematology
!
Haemoglobin
!
Haematocrit
!
Thrombocytes
!
Erythrocytes
!
Leucocytes
!
Differential count:
o
eosinophils
o
neutrophils
o
basophils
o
monocytes
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o
lymphocytes
8.5.2.4
Calcitonin
Blood samples for the measurement of calcitonin concentration will be drawn as per flow chart (see 
section 2). Calcitonin values ≥20 ng/L will be submitted to an independent committee of thyroid 
experts. The CMC will provide guidance to the investigator with regards to treatment and further 
investigations. It is recommended that screening failure subjects with a calcitonin value ≥10 ng/L 
are referred to a thyroid expert for further evaluation. For details please refer to Appendix B.
8.5.2.5
Pregnancy test
Females of childbearing potential will have a serum pregnancy test (beta-hCG) performed as 
specified in section 2 or as required by local law.
During the trial urine pregnancy tests must be performed at home for females of childbearing 
potential, if a menstrual period is missed or as required by local law.
Pregnancy testing will not be required (unless required by local law) for subjects who are 
postmenopausal (defined as women who have undergone a hysterectomy, bilateral oophorectomy or 
bilateral tubal ligation or for women above the age of 50, who have been without menstrual period 
for at least 1 year).
8.5.2.6
Urinalysis
The first morning urine sample will be taken during the trial (see section 2) and analysed at the 
central laboratory to determine levels of the following parameters:
!
Urinary albumin to creatinine ratio (UACR)
!
Urinalysis by urine dip-stick: erythrocytes, protein, glucose and ketones, pH
8.6
Other assessments
8.6.1
Patient reported Outcome questionnaires
The following PRO questionnaires will be used in this trial:
!
SF-36v2TM
!
DTSQs
The questionnaires should be completed by the subject as specified in the flow chart (see section 2), 
preferably before any other trial related activities. It takes approximately 10 minutes to complete 
each questionnaire. The assessment must be reviewed as described in section 8.1.8. All results from 
the PRO questionnaires must be transcribed into the eCRF.
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The PRO questionnaire will be used to assess subjects overall Health related Quality of Life and can 
also be used to estimate Quality Adjusted Life years (QALY) which is used in cost effectiveness 
calculations. 
8.6.1.1
SF-36v2TM
The SF-36v2™ questionnaire will be used to assess subjects overall Health related Quality of Life 
and can also be used to estimate QALY which is used in cost effectiveness calculations. This 
instrument contains 36 items and measures the individual overall health related quality of life on 8 
domains; physical functioning, role functioning, bodily pain, general health, vitality, social 
functioning, role emotional and mental health. 
8.6.1.2
DTSQs
The DTSQs questionnaire will be used to assess subject’s treatment satisfaction. This instrument 
contains 8 items and measures the treatment for your diabetes (including insulin, tablets and/or diet) 
in terms of convenience, flexibility and general feelings regarding treatment. 
8.6.2
Subject diary
The subject must be provided with paper diaries at all visits, except the follow-up visit (V10 and 
V10A). If a subject prematurely discontinues trial product, diaries should not be dispensed and 
filled out by the subjects after the follow-up – premature discontinuation visit. For these subjects all 
available data will be collected. 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, time, dose and injection site of first dose of trial product.
!
date, time and dose of last injection of trial product prior to each visit/phone contact
!
hypoglycaemic episodes
!
concomitant medication
!
AEs
!
SMPG 7-point profile
!
Urine pregnancy test for females of childbearing potential
The diaries should be collected at the visit described in the flow chart (see section 2). The 
recordings must be reviewed as described in section 8.1.8 and transcribed to the eCRF.
8.7
Subject compliance
Throughout the trial the investigator will remind the subjects to follow the trial procedures and 
requirements to ensure subject compliance. If a subject is found to be non-compliant, the 
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investigator will remind the subject of the importance of following the instructions given including 
taking the trial products as prescribed.
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 discovered to be non-compliant, the investigator must inform the subject of the 
importance of taking trial product as directed.
8.8
In case of specific safety issues
8.8.1
Thyroidectomy
Subjects scheduled for thyroidectomy (partial or total) will be asked to inform the investigator prior 
to their operation.
8.8.1.1
Thyroidectomy pathology slides
In addition to the examination of the thyroid tissue routinely made by the hospital pathology 
laboratory, the pathology slides of the thyroid tissue will be sent centrally for a second review by a 
pathologist with expertise in thyroid and C-cell pathology. The central pathologist will be blinded to 
both randomised treatment and the diagnosis from the hospital pathology laboratory. Both the 
hospital pathology report and the central pathology report will be reviewed by an independent event 
adjudication committee (EAC) (see section 12.7.2). Once the samples are re-examined they will be 
sent back to the hospital pathology laboratory.
The investigator will be informed of the results of central pathology report and if C-cell pathology 
is confirmed by the EAC, the CMC will provide guidance to the investigator with regards to 
treatment and further investigations.
8.8.1.2
Thyroid tissue sample collection in case of thyroidectomy
Prior to the thyroidectomy the subject will be asked to consent to have a sample of the removed 
thyroid tissue collected and stored in a tissue bank, if allowed by local law. If C-cell pathology is 
confirmed (i.e. hyperplastic or neoplastic thyroid C-cells) the sample will be tested for RET Y1062 
phosphorylation in the thyroid C-cells, if allowed by local law. The tissue sample will be destroyed 
after examination. (Brazil – All requirements of Resolution 340/04 must be followed. Otherwise 
genetic tests cannot be done for Brazilian patients).
8.8.1.3
Genetic testing in case of confirmed C-cell pathology
In addition, the subject will also be asked to consent to be tested (blood sample) to identify germline 
RET gene mutations associated with MEN2 syndrome. This RET gene mutation detection will only 
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be conducted if the EAC has confirmed c-cell abnormality (medullary carcinoma or C-cell 
hyperplasia). The genetic testing will only be performed if allowed by local law. 
The blood sample should be collected at the first visit to the clinic after the confirmation of C-cell 
pathology. The extraction of DNA will be performed by the central laboratorywhereas the 
identification of gene mutations will be performed by a specialised laboratory (for details please see 
Attachment I). The blood sample will be destroyed as soon as the genetic analysis is complete.
8.8.1.4
Assessments in case of suspicion of acute pancreatitis
In case of acute, severe persistent abdominal pain or other relevant symptoms leading to a 
suspicion of acute pancreatitis, the trial product should promptly be interrupted until pancreatitis is 
ruled out. Appropriate additional examinations must be performed, including local measurement of 
amylase and lipase. If acute pancreatitis is ruled out trial product should be re-initiated. Appropriate 
treatment and careful monitoring of the subject should be initiated if pancreatitis is confirmed (as a 
minimum 2 of 3): 
!
severe acute abdominal pain
!
amylase and/or lipase >3x upper normal range (UNR)
!
characteristic findings on relevant imaging eg computerised axial tomography
(CT)/magnetic resonance imaging (MRI)/ultrasound
Trial product should not be re-initiated but subject should remain in the trial. The event should be 
reported as a MESI and will undergo assessment by the EAC (see section 12.7.2).
8.8.1.5
Assessments in case of suspicion of severe hypersensitivity
If a severe immediate hypersensitivity reaction to the trial product is suspected, blood sampling for 
assessment of anti-semaglutide IgE antibodies and anti-semaglutide binding antibodies should be 
collected after a suitable washout period (minimum 5 weeks). In these cases, it is also 
recommended to test for tryptase (total and/or mature tryptase) within 3 hours of the reaction. In 
case a tryptase sample was collected within 3 hours of the event, a baseline tryptase sample should 
be taken at the same time as the IgE sample is obtained. Tryptase concentrations (if measured) as 
well as results of anti-semaglutide antibody and IgE-isotype anti-semaglutide antibodies will be 
collected by Novo Nordisk and included in the final MESI report (see section 12.1.
8.8.1.6
Assessments in case of suspicion of immune complex disease
If immune complex disease is suspected, blood sampling for central assessment of complement 
levels (C3 and C4) should be conducted and results should be included when reporting a MESI.
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9
Trial supplies
Trial supplies comprise trial products and auxiliary supplies. Additional details regarding trial 
supplies can be found in the Trial Materials Manual (TMM). 
Trial products must not be dispensed to any person not included in the trial. 
9.1
Trial products
The following trial products for subcutaneous injection will be provided by Novo Nordisk,
Denmark:
!
Semaglutide 1.34 mg/mL, solution for injection, 1.5 mL pre-filled PDS290 pen-injector
!
Semaglutide placebo, solution for injection, 1.5 mL pre-filled PDS290 pen-injector
The following trial products for oral administration will be provided by Novo Nordisk, Denmark:
!
Sitagliptin (Januvia®) 100 mg, tablet
!
Sitagliptin placebo, tablet
For both semaglutide and sitagliptin the placebo and active drug are identical with regard to 
appearance. 
Semaglutide both active drug and placebo are manufactured and supplied by Novo Nordisk, 
Denmark. Sitagliptin 100 mg and placebo is packed for use in clinical trials and supplied by Novo 
Nordisk, Denmark.
All trial products are considered investigational medicinal products (IMPs).
Other than trial product, test pens to ensure subject’s willingness and ability to self-inject will be 
supplied at the screening visit. The test pen contains semaglutide placebo, solution for injection, 1.5 
mL prefilled PDS290 pen-injector, the test pen is for single use only (using this test pen is optional).
Refer to the appropriate IB or local label for more detailed information regarding the listed trial 
products. 
Each site will be supplied with sufficient trial products for the trial on an on-going basis controlled 
by the IV/WRS and according to enrolment and randomisation with different intervals during the 
trial. Subject will be instructed in administration of trial product and the investigator must document 
that a DFU is given orally and in writing at each dispensing visit.
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9.2
Labelling
Labelling of the investigational medicinal products (IMPs) will be in accordance with Annex 1339, 
local law and trial requirements. Please refer to the TMM provided by Novo Nordisk for details 
regarding standard packages for the trial products.
9.3
Storage
Semaglutide preparations (both in-use and not in-use) must not be exposed to excessive heat or 
direct sunlight. Semaglutide preparations which have been frozen must not be used. Semaglutide 
must not be used, if it does not appear clear and colourless.
Trial product
Storage conditions
(not-in-use)
In-use conditions
Semaglutide 1.34 mg/mL and placebo
!
Store in a 
refrigerator (2°C 
to 8°C)
!
Do not freeze
!
Protect from 
light
!
Store below 30°C
!
Do not refrigerate
!
Do not freeze
!
Protect from light
!
Use within 1 
month*
Semaglutide placebo (test pen)
!
Store in a 
refrigerator (2°C 
to 8°C)
!
Do not freeze
!
Protect from 
light
For single use only
Sitagliptin 100 mg and placebo
!
Do not store 
above 30°C
!
Do not freeze
!
Do not 
refrigerate
!
Protect from 
light and 
humidity
Not applicable
* In-use time starts when first dose is taken.
The investigator must ensure the availability of proper storage conditions, record and evaluate the 
temperature. The investigator must inform Novo Nordisk (via the assigned monitor) immediately if 
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any trial product has been stored outside specified conditions (e.g. outside temperature range).
Fifteen minutes outside the indicated range is negligible, and should not be recorded as a deviation.
Trial products stored outside the temperature range are not to be used and must be stored separately 
within allowed temperature range until after evaluation of condition. Evaluation will be performed 
by Novo Nordisk. Trial products that have been stored improperly must not be dispensed to any 
subject before it has been re-evaluated and approved for further use by Novo Nordisk.
Returned trial products (unused, partly used or used including empty packaging material) must be 
stored separately from non-allocated trial products.
The temperatures during storage should be monitored by a calibrated and stationary system. A 
temperature log must be kept to document storage within the right temperature interval and storage 
facilities should be checked frequently. Investigator must take appropriate action to avoid 
recurrence of the detected temperature deviation.
9.4
Drug accountability and destruction
The trial products will be dispensed to each subject as required according to treatment group. The 
IV/WRS will allocate trial product to the subject at each dispensing visit, starting at the 
randomisation visit. The correct DUN(s) must be dispensed to the subject.
The investigator or delegated person is responsible for ensuring that:
!
Trial products are not dispensed to any person not included in the trial
!
Drug accountability is performed using the IV/WRS drug accountability module
!
Subjects are instructed to return all used, partly used and unused trial product including 
empty packaging material at each dispensing visit and at End of Treatment visit 
!
All returned trial products (used/partial used and unused including empty packaging 
material) is kept and stored separately from non-allocated trial products
Destruction of trial products will be done according to local law after accountability is finalised at 
site and reconciled by monitor. Destruction of trial products must be documented.
9.5
Auxiliary supplies
The following auxiliary supplies will be supplied by Novo Nordisk in accordance with the TMM:
!
Needles for pre-filled pen systems
!
Blood glucose meters, including lancets, plasma-calibrated test strips and control solutions
!
Directions for use for PDS290 pen-injector
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10
Interactive voice/web response system
A trial-specific IV/WRS will be set up which can be accessed at any time via the internet or 
telephone. Access to the IV/WRS must be restricted to and controlled by authorised persons. 
IV/WRS is used for: 
!
Screening
!
Screening failure
!
Randomisation
!
Medication arrival
!
Dispensing
!
Treatment discontinuation
!
Treatment completion
!
Drug accountability
!
Data change
IV/WRS user manuals will be provided to each trial site.
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11 Randomisation procedure and breaking of blinded codes
The trial is a double-blind trial. A randomisation session will be carried out for all subjects by using 
the IV/WRS. At the randomisation visit subjects meeting all inclusion/exclusion criteria will be 
randomised in a 2:2:1:1 manner to receive one of four parallel treatments groups:
!
Semaglutide 0.5 mg once-weekly + sitagliptin placebo once-daily
!
Semaglutide 1.0 mg once-weekly + sitagliptin placebo once-daily
!
Sitagliptin 100 mg once-daily + semaglutide placebo (0.5) mg once-weekly
!
Sitagliptin 100 mg once-daily + semaglutide placebo (1.0) mg once-weekly
Randomisation will be stratified by country.
11.1
Breaking of blinded codes
If the trial site needs to break the code, Novo Nordisk should if possible, be contacted before the 
code is broken. The IV/WRS 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 IV/WRS, 
record the reason, and sign and date the document.
If the code has been broken, the subject should be discontinued from trial product but be asked to 
continue in the trial (see section 8.1.6.2).
If the code has been broken the subject must be discontinued from trial product but be asked to 
continue in the trial. A treatment discontinuation session should be completed in IV/WRS. 
When the code is broken, the treatment allocation will be accessible to the investigator and the 
Novo Nordisk Global Safety department. If IV/WRS is not accessible at the time of code break 
monitor should be contacted and if monitor cannot get access the IV/WRS vendor helpdesk should 
be contacted.
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12 Adverse events, and technical complaints and pregnancies
12.1
Definitions
Adverse event 
An adverse event (AE) is any untoward medical occurrence in a subject administered a product, and 
which does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom or disease temporally associated with the use of a product, whether or not 
considered related to the product. 
An AE includes:
!
A clinically significant worsening of a concomitant illness.
!
A clinical laboratory adverse event (CLAE): a clinical laboratory abnormality which is 
clinically significant, ie an abnormality that suggests a disease and/or organ toxicity and is 
of a severity that requires active management. Active management includes active treatment 
or further investigations, for example change of medicine dose or more frequent follow-up 
due to the abnormality.
The following should not be reported as AEs:
!
Pre-existing conditions, including those found as a result of screening procedures (pre-
existing conditions should be reported as medical history or concomitant illness).
!
Pre-planned procedures unless the condition for which the procedure was planned has 
worsened from the first trial related activity after the subject has signed the informed 
consent.
!
Non-serious hypoglycaemia is an AE, but is reported on a hypoglycaemic episode form 
instead of on an AE form (see section 8.4.2).
The following three definitions are used when assessing an AE:
!
Severity assessment
–
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 assessment
The following terms are used when assessing the relationship between an AE and the relevant 
trial product(s): 
–
Probable - Good reason and sufficient documentation to assume a causal relationship.
–
Possible - A causal relationship is conceivable and cannot be dismissed.
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–
Unlikely - The event is most likely related to aetiology other than the trial product.
!
Final outcome of an AE
–
Recovered/resolved - The subject has fully recovered, or by medical or surgical 
treatment the condition has returned to the level observed at the first trial-related activity 
after the subject signed the informed consent.
–
Recovering/resolving - The condition is improving and the subject is expected to 
recover from the event. This term is only applicable if the subject has completed the trial 
or has died from another AE.
–
Recovered/resolved with sequelae - The subject has recovered from the condition, but 
with lasting effect due to a disease, injury, treatment or procedure. If a sequela meets an 
SAE criterion, the AE must be reported as an SAE.
–
Not recovered/not resolved - The condition of the subject has not improved and the 
symptoms are unchanged, or the outcome is not known.
–
Fatal - This term is only applicable if the subject died from a condition related to the 
reported AE. Outcomes of other reported AEs in a subject before he/she died should be 
assessed as "recovered/resolved", "recovering/resolving", "recovered/resolved with 
sequelae" or "not recovered/not resolved". An AE with fatal outcome must be reported 
as an SAE.
–
Unknown - This term is only applicable if the subject is lost to follow-up.
Serious adverse event
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. 
Suspicion of transmission of infectious agents via the trial product must always be 
considered an SAE.  
a.
The term "life threatening" in the definition of SAE refers to an event in which the subject was 
at risk of death at the time of the event. It does not refer to an event which hypothetically might 
have caused death if it was more severe.
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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
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 (eg following the 
event or clinical investigation the subject has significant, persistent or permanent change, 
impairment, damage or disruption in his/her body function or structure, physical activity and/or 
quality of life).
d. For example intensive treatment in an emergency room or at home of allergic bronchospasm, 
blood dyscrasiasis or convulsions that do not result in hospitalisation, or development of drug 
dependency or drug abuse.
Non-serious adverse event
A non-serious AE is any AE which does not fulfil the definition of an SAE.
Medical event of special interest
A medical event of special interest (MESI) is an event which, in the evaluation of safety, has a 
special focus. A MESI is an AE (SAE or non-serious AE) which fulfils one or more of the below 
defined MESI criteria.
1. Medication errors concerning trial products:
–
Administration of wrong drug.
–
Wrong route of administration, such as intramuscular instead of subcutaneous.
–
Administration of an overdose with the intention to cause harm (eg suicide attempt).
–
Accidental administration of a lower or higher dose than intended. That is a dose of
semaglutide 10% lower or higher than 1.0 mg week (± 24h) or of sitagliptin that is lower 
or higher than 100 mg/day; however the administered dose must deviate from the 
intended dose to an extend where clinical consequences for the trial subject were likely 
to happen as judged by the investigator, although not necessarily did happen.
2. Fatal events (if not covered by another MESI) (A)
3. Acute coronary syndrome (A)
–
Myocardial infarction
–
Hospitalisation for unstable angina
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4. Cerebrovascular event (stroke or transient ischaemic attack) (A)
5. Coronary revascularisation procedure (A)
6. Peripheral arterial revascularisation procedure
7. Heart failure requiring hospital admission (A)
8. Neoplasm (excluding thyroid neoplasm) (A)
9. Thyroid disease (including thyroid neoplasm) (A – if thyroid neoplasm or thyroidectomy)
10. Pancreatitis or clinical symptoms leading to suspicion of pancreatitis (A)
11. Immunogenicity events (allergic reactions, immune complex disease and anti-semaglutide 
antibody formation)
MESIs marked with an ‘(A)’ in the list above will undergo adjudication by an independent EAC 
(see section 12.7.2).
Any event confirmed or suspected to be a MESI must be reported as such. In case the sponsor 
identifies potentially missed MESIs through predefined review of available data, the investigator 
will be asked to reconsider if this is a MESI. However, MESIs should not be reported for screening 
failures.
For further information regarding definitions of MESIs and an overview of which events that should 
undergo adjudication, please refer to Appendix A.
Technical complaint
A technical complaint is any written, electronic, or oral communication that alleges product 
(medicine or device) defects. The technical complaint may be associated with an AE, but does not 
concern the AE itself.
Examples of technical complaints:
!
The physical or chemical appearance of trial products (eg discoloration, particles or 
contamination)
!
The packaging material (eg leakage, cracks, rubber membrane issues or errors in labelling 
text)
!
Problems related to devices (eg to the injection mechanism, dose setting mechanism, push 
button or interface between the pen and the needle)
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 (see section 2). The events must be recorded in the applicable 
CRF forms in a timely manner, see timelines below and Figure 12–1
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During each contact with the trial site staff, the subject must be asked about AEs and technical 
complaints, for example by asking: "Have you experienced any problems since the last contact?"
All AEs, either observed by the investigator or subject, must be reported by the investigator and 
evaluated. Novo Nordisk assessment of expectedness is performed according to the following 
reference documents
!
Investigator’s Brochure, semaglutide (NN9535) (subcutaneous administration), Type 2 
Diabetes and any updates hereof28
!
Sitagliptin (Januvia®): EU Summary of Product Characteristics (SmPC) 29, current version.
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. 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. 
MESIs, regardless of seriousness, must be reported using both the AE form and the safety 
information form and a MESI form. The MESI form is a form tailored to collect specific 
information related to the individual MESI.  
For MESIs qualifying for event adjudication, an event adjudication document collection form 
(adjudication form) will also have to be completed in the eCRF. The event adjudication document 
collection form is a check list of clinical data to be provided from the site. The investigator should 
provide relevant medical documentation within 4 weeks of event identification.
The AE form for a non-serious AE should be signed when the event is resolved or at the end of the 
trial.
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. 
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!
SAEs fulfilling the MESI criteria: In addition to above, the MESI form within 14 
calendar days of the investigator's first knowledge of the AE. 
!
Non-serious AE fulfilling the MESI criteria: The AE form, safety information form and 
MESI form within 14 calendar days of the investigator's first knowledge of the event.
!
Events for adjudication: The event adjudication document collection form must be 
completed within 14 calendar days. The investigator should provide the medical 
documentation within 4 weeks of event identification.
If the eCRF is unavailable, the concerned AE information must be reported on paper forms and sent 
to Novo Nordisk by fax, e-mail or courier within the same timelines as stated above. When the 
eCRF becomes available again, the investigator must re-enter the information on the appropriate 
forms in the eCRF. 
Contact details (fax, telephone, e-mail and address) are provided in the investigators trial file. 
Figure 12–1
Initial reporting of AEs
Reporting of trial product-related SUSARs by the sponsor:
Novo Nordisk will notify the investigator of trial product-related suspected unexpected serious 
adverse reactions (SUSARs) in accordance with local requirements and GCP 1 In addition, the 
investigator will be informed of any trial-related SAEs that may warrant a change in any trial 
procedure.
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In accordance with regulatory requirements, Novo Nordisk will inform the regulatory authorities, 
including European Medicines Agency(EMA), of trial product-related SUSARs. In addition, Novo 
Nordisk will inform the IRBs/IECs of trial product-related SUSARs in accordance with local 
requirement and GCP 1, unless locally this is an obligation of the investigator.
12.3
Follow-up of adverse events
The investigator must record follow-up information by updating 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 (eg 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.
!
Non-serious AE fulfilling the MESI criteria: Follow-up information on MESIs should 
only include new (eg corrections or additional) information and must be reported within 14 
calendar days of the investigator's first knowledge of the information. This is also the case 
for previously reported non-serious AEs which subsequently fulfil the MESI criteria. 
The investigator must ensure that the worst case severity and seriousness of an event is kept 
throughout the trial. A worsening of an unresolved AE must be reported as follow up with re-
assessment of severity and/or seriousness of the event.
Queries or follow-up requests from Novo Nordisk must be responded to within 14 calendar days
from the date of receipt of the request, unless otherwise specified in the follow-up request.
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12.4
Technical complaints and technical complaint samples
12.4.1
Reporting of technical complaints
All technical complaints and on any of the following products: 
!
Semaglutide 1.34 mg/mL solution for injection, 1.5 mL pre-filled PDS290 pen-injector
!
Semaglutide placebo, solution for injection, 1.5 mL pre-filled PDS290 pen-injector
!
Sitagliptin (Januvia®) 100 mg, tablet
!
Sitagliptin placebo, tablet
!
Needles for pre-filled pen systems
!
Semaglutide placebo, solution for injection, 1.5 mL pre-filled PDS290 pen-injector (test
pen)
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, SAEs, and/or
MESI.
Technical complaints must be reported on a separate technical complaint form for eachproduct 
listed. If the technical complaint involves more than one batch, code or lot number or more than one 
DUN, a technical complaint form for each batch, code or lot number or for each DUN must be 
completed.
The investigator must complete the technicalcomplaint form in the eCRF within the following 
timelines of the trial site obtaining knowledge of the technical complaint:
!
Technical complaint assessed as related to an SAE within 24 hours
!
All other technical complaints within 5 calendar days
If the eCRF is unavailable or when reporting a technical complaint that is not subject related, the 
information must be provided on a paper form by fax, e-mail or courier to Customer Complaint 
Center, Novo Nordisk, within the same timelines as stated above.
12.4.2
Collection, storage and shipment of technical complaint samples
The investigator must collect the technical complaint sample and notify the monitor within 5 
calendar daysof obtaining the sample at trial site. The monitor must coordinate the shipment to 
Customer Complaint Center, Novo Nordisk (the address is provided in Attachment I) and ensure 
that the sample is sent as soon as possible. A print or copy of the technical complaint form must be 
sent with the sample.
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The investigator must ensure that the technical complaint sample contains the batch or lot number 
and, if available, the DUN.
If the technical complaint sample is unobtainable, the investigator must specify on the technical 
complaint form why it is unobtainable. 
Storage of the technical complaint sample must be done in accordance with the conditions 
prescribed for the product. The shipment of the technical complaint sample should be done in 
accordance with the same conditions as for storage (see section 9). 
12.5
Pregnancies
12.5.1
Pregnancies in female subjects
Female subjects must be instructed to notify the investigator immediately if they become pregnant 
during the trial. The investigator must report any pregnancy in subjects who have received trial 
product(s).
The investigator must follow the pregnancy until the pregnancy outcome and the newborn infant is 
one month of age.
The investigator must report information about the pregnancy, pregnancy outcome, and health of 
the newborn infant(s), as well as AEs in connection with the pregnancy, and AEs in the foetus and 
newborn infant.
The following must be collected and reported by the investigator to Novo Nordisk  - electronically 
(eg 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 (ie 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: 
–
Paper AE form* within 14 calendar days of the investigator's first knowledge of the 
initial or follow-up information to the non-serious AE.
SAEs: 
–
Paper AE form* within 24 hours of the investigator's first knowledge of the SAE.
–
Paper 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.
*
It must be clearly stated in the AE diagnosis field on the AE form if the event occurred in 
the subject, foetus or newborn infant.
Any queries or follow-up requests from Novo Nordisk to non-serious AEs, SAEs and pregnancy 
forms must be responded to by the investigator within 14 calendar days from the date of receipt of 
the request, unless otherwise specified in the follow-up request.
12.6
Precautions and/or overdose
Semaglutide
Little experience of accidental overdose exists from the semaglutide clinical development 
programme. Events of nausea, vomiting and headache have been reported in connection with 
accidental administration of up to 4.0 mg semaglutide. No symptoms of hypoglycaemia have been 
reported in connection with overdose of semaglutide. In the event of overdose, appropriate 
supportive treatment should be initiated according to the subject’s clinical signs and symptoms. 
For other precautions, please see section 3.5.1.
Sitagliptin
During controlled clinical trials in healthy subjects, single doses of up to 800 mg sitagliptin were 
generally well tolerated. Minimal increases in QTc, not considered to be clinically relevant, were 
observed in one study at a dose of 800 mg sitagliptin. There is no experience with doses above 800 
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mg in clinical studies. In Phase I multiple-dose studies, there were no dose-related clinical adverse 
reactions observed with sitagliptin with doses of up to 600 mg per day for periods of up to 10 days 
and 400 mg per day for periods of up to 28 days.
In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., remove 
unabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining 
an electrocardiogram), and institute supportive therapy if required. Sitagliptin is modestly 
dialysable. In clinical studies, approximately 13.5 % of the dose was removed over a 3- to 4-hour 
hemodialysis session. Prolonged hemodialysis may be considered if clinically appropriate. It is not 
known if sitagliptin is dialysable by peritoneal dialysis. 
For other precautions, please see section 3.5.2.
12.7
Committees related to safety
12.7.1
Novo Nordisk safety committee
Novo Nordisk has constituted an internal semaglutide safety committee to perform ongoing safety 
surveillance. The semaglutide safety committee may recommend unblinding of any data for further 
analysis.
12.7.2
Event adjudication committee
An external event adjudication committee is established to perform qualitative or quantitative 
validation of selected AEs according to pre-defined diagnostic criteria. The validation is based on 
review of pre-defined clinical data related to the specific AE.
Adjudication will be completed based on a review of data collected from the sites. The provided 
data will be anonymised for subject identifiers. 
The events are reviewed by the event adjudication committee in an independent and blinded 
manner.
The EAC is composed of permanent members covering required medical specialities. EAC 
members must disclose potential conflicts of interest and must be independent of Novo Nordisk. 
The role of the EAC is solely to adjudicate events in a blinded manner. The EAC will have no 
authorisations to impact 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 will be adjudicated according to Food and Drug Administration (FDA) requirements.
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The EAC will review copies in English (translated if necessary) of medical documentation received 
in the adjudication package (for example X-ray, ECGs, ultrasound images, discharge summaries, 
pathology reports, and death certificates). The investigator should provide medical documentation 
within 4 weeks of event identification. The supplier of EAC can evaluate an event not initially 
reported as a MESI for adjudication to be adjudicated. In this case the investigator must provide 
medical documentation as soon as possible, when receiving a request from Novo Nordisk or the 
supplier.
The assessment made by the EAC will be included in the CTR as well as assessments made by the 
investigator. However, the adjudication made by an EAC, given its independence and in-depth 
analysis of each event, will be attributed with greater importance of the two. The outcomes of 
adjudication will be kept in the clinical trial database.
The following AEs will be adjudicated in this trial:
!
Fatal events (if not covered by another MESI)
!
Acute coronary syndrome
!
Cerebrovascular event (stroke or transient ischaemic attack)
!
Coronary Revascularisation Procedure
!
Heart failure requiring hospital admission
!
Neoplasms (excluding thyroid neoplasm)
!
Thyroid disease (including thyroid neoplasm or resulting in thyroidectomy)
!
Pancreatitis or clinical symptoms leading to suspicion of pancreatitis
Please see Appendix A for details.
Event adjudication will not be performed for AEs in screening failures.
AEs for adjudication must be reported according to section 12.2. In addition the specific event 
adjudication document collection form has to be completed within 14 days and all relevant pre-
defined documents has to be provided within 4 weeks of the investigator's first knowledge of the 
AE, according to instructions in the event adjudication site manual.
12.7.3
Calcitonin monitoring committee(CMC)
The CMC will provide recommendations to the investigators with regards to further investigation
and treatment of the individual subject (see Appendix B).
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13 Case report forms 
Novo Nordisk will provide a system for the electronic case report forms (eCRF). This system and 
support services to the system will be supplied by a vendor.
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 (eg is not 
applicable), indicate this according to the data entry instructions.
The following will be provided as paper CRFs:
!
Pregnancy forms
In addition paper AE forms and safety information forms will be provided. These must be used 
when access to the eCRF is revoked. 
The investigator must ensure that all information is consistent with the source documentation. By 
electronically signing the case book in the eCRF, the investigator confirms that the information in 
the eCRF and related forms is complete and correct.
13.1
Corrections to case report forms 
Corrections to the CRF data may be made by the investigator or the investigator's authorised staff. 
An audit trail will be maintained in the CRF application containing as a minimum: the old and the 
new data, identification of the person entering the data, date and time of the entry and reason for the 
correction.
If corrections are made by the investigator's authorised staff after the date the investigator has 
signed the case book, the case book must be signed and dated again by the investigator.
13.2
Case report form flow 
13.2.1
Electronic 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 trial the investigator must ensure that all remaining data have been entered into the 
eCRF no later than 3 days after the last subject’s last visit at the site in order to ensure the planned 
lock of the database.
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Site specific eCRF data (in an electronic readable format) will be provided to the investigator site 
after the trial database is released and access to update the trial data on the EDC application has 
been removed. This data will be retained by the site.
When the final CTR is available the data will be archived by Novo Nordisk.
13.2.2
Paper case report form flow
The pregnancy forms are paper based CRFs. 
Also, the SIF, technical complaint form, and AE form will be provided in paper but are only to be 
used if for any reason the eCRF is unavailable.
The investigator must ensure that data are recorded in these forms as soon as possible and ensure 
that Novo Nordisk receives these forms within the required timeline (see section 12).
Corrections to the data in the CRFs may only be made by drawing a straight line through the 
incorrect data and then writing the correct entry next to the data that were crossed out. Each 
correction must be initialled, dated and explained (if necessary) by the investigator or the 
investigator’s authorised staff.
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14 Monitoring procedures 
During the course of the trial, the monitor will visit the trial site to ensure that the protocol is 
adhered to, that all issues have been recorded, to perform source data verification and to monitor 
drug accountability. The first monitoring visit will be performed as soon as possible after FPFV or 
FSFV and no later than 4 weeks after. The monitoring visit intervals will depend on the outcome of 
the remote monitoring of the CRFs, the trial site's recruitment rate and the compliance of the trial 
site to the protocol and GCP, but will not exceed 8 weeks.
The intervals between monitoring visits can be shorter. Factors to be considered in this 
determination may include objective, endpoints, purpose, design, complexity, blinding, number of 
subjects and expected recruitment rate. 
The monitor must be given direct access to source documents (original documents, data and 
records). Direct access includes permission to examine, analyse, verify and reproduce any record(s) 
and report(s) that are important to the evaluation of the trial. If the electronic medical record does 
not have a visible audit trail, the investigator must provide the monitor with signed and dated 
printouts. In addition the relevant trial site staff should be available for discussions at monitoring 
visits and between monitoring visits (eg by telephone).
All data must be verifiable in source documentation other than the CRF.
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. Considering the 
electronic source data environment, it is accepted that the earliest practically retainable record 
should be considered as the location of the source data. Therefore transcription to the diary from the 
blood glucose meter is considered the source document for BG values.
Source data generated by the trial site can be corrected by another person than the person entering 
the source data, if accepted by local regulations; any correction must be explained, signed and dated 
by the person making the correction.
The original diaries and PROs are considered as source data and must not be removed from the trial 
site.
The monitor will ensure that the CRFs are completed on an on-going basis within the agreed 
timelines.
The monitor must ensure that all required eCRF forms for screening failures are completed, (e.g. 
screening failure form and the case book sign of (affirmation statement) is electronically signed by 
the investigator).
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Monitors must review the subject's medical records and other source data (eg the diaries and PROs) 
to ensure consistency and/or identify omissions compared to the CRF. If discrepancies are found, 
the investigator must be questioned about these.
When data has been source verified and all queries have been resolved the case book must be 
signed by the investigator in the eCRF
A follow-up letter (paper or electronic) will be sent to the investigator following each monitoring 
visit addressing 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 an external CRO. 
Appropriate measures, including encryption of data files containing person identifiable data, will be 
used to ensure confidentiality of subject data, when they are transmitted over open networks. 
Data from central laboratories will be transferred electronically from the laboratory performing the 
analyses. 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 identification number. 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
If necessary, a statistical analysis plan (SAP) may be written in addition to the protocol, including a 
more technical and detailed elaboration of the statistical analyses. The SAP will be finalised before 
database lock. 
Results from the statistical analysis will generally be presented by two-sided confidence intervals 
with a confidence level of 95%. Superiority will be formulated and tested as one-sided hypotheses 
at a 2.5% significance level. Non-inferiority between two treatments will be evaluated by 
comparing the upper limit of the associated two-sided 95% confidence interval for the difference 
with the pre-defined non-inferiority margin.
Handling of missing data
In the case of missing data no general imputation will be performed for the analyses, unless 
otherwise specified. If an assessment has been made both at screening and randomisation, the value 
from the randomisation visit will be used as the baseline value. If the value measured at the 
randomisation visit is missing and the assessment also has been made at screening, then the 
screening value will be used as the baseline value.
Laboratory values below the lower limit of quantification (LLOQ) will be set to ½ LLOQ.
The primary analysis model will be the mixed model for repeated measurements (MMRM), see 
section 17.3 for further details. One of the assumptions behind (MMRM) is that the missing data 
mechanism is missing at random (MAR). This means that given the observed data, the mechanism 
generating missing values is independent of the unobserved data that is the missing data. The 
MMRM and the negative binomial model both rely on the MAR assumption for generating 
unbiased estimates of treatment differences.
Based on previous semaglutide trials in subjects with type 2 diabetes, the withdrawal rate from 
randomised treatment is expected to be about 20%. The treatments in this trial should be effective, 
given the historical documentation, and this should minimise withdrawals due to ineffective 
therapy. The main reasons for withdrawal are expected to be AEs, ineffective therapy and non-
eligibility (subjects randomised although not fulfilling inclusion/exclusion criteria). Withdrawal due 
to non-eligibility can be regarded as missing completely at random (MCAR), i.e. it does not depend 
on the observed or missing data values. This category of missing data is not expected to introduce 
bias in the estimated treatment differences. Withdrawal due to lack of efficacy is expected to be 
reflected in the observed data obtained prior to the withdrawal from randomised treatment, and the 
corresponding missing data can therefore be assumed as MAR to some extent. Missing data due to 
AEs is expected to be similar between groups except for, potentially, a slightly higher incidence in 
the semaglutide treatment group due to gastrointestinal side effects. Together with potential 
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withdrawals due to the own will of the subject, the MAR assumption may be less adequate for this 
category of drop-outs.
Several different sensitivity analyses will be used to investigate whether the results from the 
MMRM approach are robust towards deviations from the assumption of MAR.
17.1
Sample size calculation
The primary objective is to compare the effect of two dose levels of semaglutide once-weekly 
treatment (0.5 mg or 1.0 mg) with sitagliptin 100 mg on the primary endpoint, change from baseline 
in HbA1c after 30 weeks of treatment. In the calculations determining the sample size it is presumed 
that in the analysis the two sitagliptin/semaglutide placebo groups will be pooled assuming no 
correlation between endpoints and placebo volume.
In total 1050 subjects will be randomised in a 2:2:1:1 manner. Assuming 20% of subjects 
discontinuing randomised treatment, and further taking the assumption that these subjects are 
excluded from the per protocol (PP) analysis set, 280 subjects in each group are expected to be 
included in the PP analysis set.
The sample size calculation is based on demonstrating HbA1c non-inferiority for semaglutide 0.5 
mg vs. sitagliptin 100 mg and HbA1c non-inferiority for semaglutide 1.0 mg vs. sitagliptin 100 mg.
The two hypothesis tests are assumed to be independent and for each of the hypothesis the power 
calculation is based on a t-statistic under the assumption of a one-sided test of size 2.5%. Using a 
non-inferiority margin of 0.3%, and assuming a true HbA1c difference (semaglutide minus 
sitagliptin) of 0% and a standard deviation (SD) of 1.1%, a total of 280 subjects per group in the PP 
analysis set will give 90% marginal power to conclude HbA1c non-inferiority for the comparison of 
a semaglutide dose vs. sitagliptin 100 mg.
Assuming the same HbA1c effect for the two dose levels of semaglutide, the overall power to 
demonstrate HbA1c non-inferiority for the two dose levels of semaglutide vs. sitagliptin will be at 
least 80%.
For change in body weight, the power calculation is based on the assumptions of a true difference of 
-1.5 kg and a SD of 4.0 kg. In addition, 50% efficacy retention is assumed for the anticipated 20% 
of subjects discontinuing randomised treatment giving an expected treatment difference of -1.35 kg, 
which is the number used in the power calculation. With the above assumptions, a total of 350 
subjects per group in the full analysis set (FAS) will give more than 99% marginal power to 
conclude superiority in body weight for the comparison of a semaglutide dose vs. sitagliptin 100 
mg.
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17.2
Definition of analysis sets
The following analysis sets are defined in accordance with the ICH-E9 guideline 40 .
Full Analysis Set (FAS): includes all randomised subjects who have received a dose and have any 
post randomisation data. The statistical evaluation of the FAS will follow the intention-to-treat 
(ITT) principle and subjects will contribute to the evaluation “as randomised”.
Per Protocol (PP) Analysis Set:
Includes all subjects in the FAS who fulfil the following criteria:
!
have not violated any inclusion criteria
!
have not fulfilled any exclusion criteria
!
have a non-missing HbA1c measurement at screening and /or randomisation
!
have at least 23 weeks actual treatment weeks of expose
!
have at least one non-missing HbA1c measurement after 23 actual weeks of expose
Subjects in the PP Analysis Set will contribute to the analysis “as treated”.
Safety Analysis Set (SAS): includes all subjects exposed to at least one dose of randomised 
semaglutide or stigliptin. Subjects in the SAS will contribute to the evaluation “as treated”.
Before data are locked for statistical analysis, a review of all data will take place. Any decision to 
exclude a subject or single observations from the statistical analysis is the joint responsibility of the 
members of the internal 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 CTR.
17.3
Primary endpoint
The primary endpoint is change from baseline in HbA1c after 30 weeks of treatment. In the analysis 
the two sitagliptin/semaglutide placebo groups will be pooled assuming no correlation between 
HbA1c change after 30 weeks and placebo volume.
The primary endpoint will be analysed by MMRM where all post baseline HbA1c measurements 
obtained at planned visits before discontinuation from randomised treatment or initiation of rescue 
treatment enter as the dependent variables, and visit, treatment, and country are included as fixed 
factors and baseline HbA1c as covariate. Furthermore, interaction terms of visit by treatment, visit 
by country and visit by baseline HbA1c will be included. An unstructured covariance matrix for 
HbA1c measurements within same subject will be employed. Regarding missing data this analysis 
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approach relies on the assumption that data are missing at random (MAR). At week 30 the 
estimated differences between each semaglutide dose level and sitagliptin and corresponding two 
sided p-values and 95% confidence intervals will be presented.
In order to preserve the overall type 1 error the conclusion of non-inferiority and superiority with 
treatment of each semaglutide dose versus sitagliptin after 30 weeks will be evaluated hierarchically 
according to the sequence below, and starting with the first. In this testing sequence it is necessary 
to fulfil the test criteria, which is to reject the corresponding null hypothesis in order to go to the 
next step. If the corresponding null hypothesis is not rejected, the testing will stop and no further 
conclusions will be drawn. 
The following ordering in the statistical test sequence will be used:
1. Non-inferiority in change in HbA1c for semaglutide 1.0 mg vs. sitagliptin
2. Non-inferiority in change in HbA1c for semaglutide 0.5 mg vs. sitagliptin
3. Superiority in change in HbA1c for semaglutide 1.0 mg vs. sitagliptin
4. Superiority in change in body weight for semaglutide 1.0 mg vs. sitagliptin
5. Superiority in change in body weight for semaglutide 0.5 mg vs. sitagliptin
6. Superiority in change in HbA1c for semaglutide 0.5 mg vs. sitagliptin
Non-inferiority will be concluded if the upper limit of the two-sided 95% confidence interval for the 
estimated difference in HbA1c between semaglutide and sitagliptin is less than 0.3%. Superiority for 
either change in HbA1c or change in body weight will be claimed if the upper limit of the two-sided 
95% confidence interval for the estimated difference is below 0% or 0 kg respectively.  
When establishing non-inferiority the analysis will be based on the full analysis set (FAS) and 
supplemented by an analysis with the per protocol population as supportive evidence. The FAS 
population will be used in the analysis when concluding superiority.
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Sensitivity analysis
To investigate the sensitivity of the main results, complimentary and separate analyses for primary 
endpoint and the confirmatory secondary endpoint will be performed, using the FAS only, except 
for HbA1c, where the PP analysis set will be used in a sensitivity analysis regarding the non-
inferiority evaluation. These analyses will investigate the sensitivity of the results due to the impact 
of missing values.
The primary analysis regarding non-inferiority of the primary endpoint change in HbA1c after 30 
weeks will also be performed separately based on the data in the PP analysis set only.
The primary endpoint and the secondary confirmatory endpoint will be evaluated in the following 
sensitivity analyses:
!
An analysis of covariance (ANCOVA) model will be analysed with imputation of missing 
values according to the last observation carried forward (LOCF) method. The model will 
include terms for treatment, country, and the corresponding baseline value as a covariate. 
The response variable will be the last available value obtained within the 30 weeks period of 
the trial
!
The MMRM will be analysed based on all data record after randomisation using also data 
from subjects who discontinued randomised treatment and /or initiated rescue treatment.
!
The MMRM will be analysed based on data only from subjects that completed the trial 
without receiving rescue treatment.
A pattern mixture model approach mimicking an ITT scenario where withdrawn subjects are 
assumed to be switched to a treatment inferior to the control treatment after withdrawal will be 
performed for evaluation of non-inferiority for the primary endpoint change in HbA1c at 30 weeks.
!
In the first step intermittent missing values 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 100 copies of the dataset will be generated.
!
In the second step, for each of the 100 copies of the dataset, an analysis of variance model 
with the same factors as the primary model, and baseline HbA1c and HbA1c at 4 weeks (V3) 
as covariate is fitted to the change in HbA1c from baseline to 8 weeks (V5) for the sitagliptin 
group only. The estimated parameters, and their variance, from this model are used to 
impute missing value at 8 weeks for subjects in all treatment groups, based on country and 
HbA1c at baseline and 4 weeks.  
!
In the third step, for each of the 100 copies of the dataset, missing HbA1c values at 12 
weeks (V6) are imputed in the same way as for 8 weeks. Now the imputation are based on 
an analysis of variance model with the same factors and the HbA1c values at baseline, 4 
weeks and 8 weeks as covariates, fitted to the control group.
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!
This stepwise procedure is then repeated sequentially over the available planned visits, 
adding one visit in each step until the last planned visit at 30 weeks (V9).
!
For each withdrawn subject in the investigational treatment group, a value of 0.3% (the non-
inferiority limit) is added to the change in HbA1c at 30 weeks.
!
For each of the complete data sets, the change from baseline to week 30 is analysed using an 
analysis of variance model with the same set of factors and the baseline HbA1c value as a 
covariate.
!
The estimates and standard deviations for the 100 data sets are pooled to one estimate and 
associated standard deviation using Rubin’s rule (page 255-257) 41 From these pooled 
estimates the confidence interval for the treatment differences and the associated p-value are 
calculated.
A pattern mixture model approach mimicking an ITT scenario where withdrawn subjects are 
assumed to be switched to the control treatment after withdrawal will be performed separately for 
the evaluation of superiority in the primary endpoint change in HbA1c and change in body weight at 
30 weeks. The same types of approach as used for the non-inferiority assessment in change in 
HbA1c will be employed, see above. However, the step where 0.3%, the non-inferiority limit, is 
added to the change in HbA1c at 30 weeks will not be performed in this sensitivity analysis.
Chinese/Korean subgroup analyses
A number of subgroup analyses by country will be performed with the aim to assess the treatment 
effect in the individual countries including China and Korea. They will be performed in a combined 
model using all data similar to the main analysis of the respective parameter but with an interaction 
between treatment and country.
17.4
Secondary endpoints
The planned secondary endpoints used to support the primary objective will be analysed as outlined 
in this section.
17.4.1
Confirmatory secondary endpoints
Weight loss
A confirmatory secondary variable is change in body weight after 30 weeks of treatment. This 
variable will be analysed in the same type of model as the primary endpoint although with baseline 
body weight as covariate.
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17.4.2
Supportive secondary endpoints
17.4.2.1
Efficacy endpoints
All efficacy endpoints in this section will be summarised and evaluated using the FAS.
Continuous variables
Change from baseline to week 30 in:
!
FPG
!
Insulin
!
C-peptide
!
glucagon
!
pro-insulin
!
pro-insulin/insulin ratio
!
HOMA-B
!
HOMA-IR
!
fasting blood lipids (total cholesterol, LDL-cholesterol, VLDL-cholesterol, HDL-
cholesterol, triglycerides and free fatty acids)
!
BMI
!
waist circumference
!
systolic and diastolic blood pressure
!
hsCRP
will all be analysed in the same type of model as the primary endpoint, but with the associated 
baseline value as a covariate.
Except for FPG, BMI, waist circumference, and blood pressure the values of the variables will be 
log transformed subject to analysis.
Beta-cell function
Beta-cell function (fasting HOMA-B and fasting HOMA-IR) will be calculated based on fasting 
insulin and FPG. The calculation will be done at the same time points as for fasting insulin and FPG 
samples (section 2).
The calculation of the fasting HOMA endpoints will be done as follows:
Fasting HOMA-B (%) = 20 x fasting insulin [μU/ml]/(FPG[mmol/l]-3.5)
Fasting HOMA-IR (%) = fasting insulin [μU/ml] x FPG [mmol/l]/22.5
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PRO outcomes
The PRO outcome endpoints:
!
PRO questionnaire outcome DTSQs (individual items and treatment satisfaction score (6 of 
the 8 items summed)), and
!
PRO questionnaire outcome SF-36v2TM
will be analysed separately with the same type of model as for the primary endpoint, that is, change 
from baseline to the end of  30 weeks of the randomised treatment. The baseline value of the 
corresponding endpoint will be used as covariate in the analysis model.
SMPG 7-point profile
Subjects will be asked to perform SMBG measurements before and 90 minutes after breakfast, 
lunch, dinner, and at bedtime.
The endpoints from the 7-point profiles that will be analysed at week 30 are:
!
Mean of the 7-point profile, defined as the area under the profile, calculated using the 
trapezoidal method, divided by the measurement time
!
Mean increment over all meals
The mean of the 7-point profile and the mean of the post prandial increments at week 30 will be 
analysed separately using the ANCOVA model. Factors in the model will be treatment and country. 
The corresponding endpoint obtained at baseline will be used as covariate.
Response in HbA1c and/or weight loss after 30 weeks
The secondary variables related to fixed response in HbA1c and/or weight loss at 30 weeks will be:
!
Responder in HbA1c after 30 weeks of treatment (yes/no) defined as HbA1c <7.0% (<53 
mmol/mol) – ADA target
!
Responder in HbA1c after 30 weeks of treatment (yes/no) defined as HbA1c ≤6.5% (48 
mmol/mol) – AACE target
!
Weight loss ≥5%
!
Weight loss ≥10%
!
HbA1c <7.0% (53 mmol/mol) without severe or confirmed symptomatic hypoglycaemia 
(plasma glucose ≤3.1 mmol/L) and no weight gain
All these variables will be analysed separately in the same type of logistic regression model. The 
model will include factors for treatment and country. For the two responder in HbA1c endpoints, 
baseline HbA1c will be included in the model as a covariate, whereas for the weight responder 
endpoint (≥5% and ≥10% weight loss), baseline weight will be included instead. For the composite 
endpoint (cf. last bullet), both baseline HbA1c and baseline weight will be included. 
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Missing response data at 30 weeks will be imputed from respectively the MMRM used for the 
primary analysis of HbA1c and the confirmatory secondary endpoint change in body weight at 30 
weeks. The results will be described by the odds ratio and the associated 95% confidence interval 
for the odds ratio.
17.4.2.2
Safety endpoints
The following secondary endpoints are used to support the safety objectives:
!
Number of treatment emergent AEs during 30 weeks of treatment
!
Number of  treatment emergent severe or BG confirmed symptomatic hypoglycaemic 
episodes during 30 weeks of treatment
!
Severe or BG confirmed symptomatic hypoglycaemic episodes during 30 weeks of 
treatment (yes/no)
Change in safety endpoints assessed from baseline to 30 weeks of treatment and/or follow up:
!
Haematology
!
Biochemistry
!
Calcitonin
!
Urinalysis
!
UACR
!
Pulse
!
ECG evaluation
!
Physical examination evaluation
Occurrence of semaglutide antibodies during 35 weeks of study duration (yes/no):
!
Anti-semaglutide antibodies
o
Anti-semaglutide antibodies with in vitro neutralising effect
o
Anti-semaglutide antibodies cross reacting with endogenous GLP-1

Cross reacting antibodies with in vitro neutralising effect to endogenous 
GLP-1
Anti-semaglutide antibody level during and after 30 weeks of treatment
All safety endpoints will be summarised and evaluated by descriptive statistics using the SAS.
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Adverse events
All AEs will be coded using the most recent version of the Medical Dictionary for regulatory 
Activities (MedDRA) coding. A treatment emergent adverse event (TEAE) is defined as an event 
that has onset date (or increase in severity) on or after the first day of exposure to randomised 
treatment and no later than the follow-up visit.
TEAEs will be summarised descriptively, whereas non-treatment emergent AE’s will be presented 
in listings. TEAE data will be displayed 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 1000 years (R).
Pulse
Pulse will be analysed separately with the same type of methods as for the primary endpoints but 
with the pulse value at baseline as a covariate.
Laboratory assessments
Amylase and lipase will be analysed separately with the same type of methods as for pulse with the 
corresponding baseline assessment as a covariate. The values will be log transformed in the 
analysis.
Calcitonin
Calcitonin will be displayed in terms of the number of subjects (N), the percentage of subjects (%) 
and the event rate per 1000 years of exposure (R). The following criteria are defined for tabulations:
Persistent (all post baseline measurements)
!
From <upper normal limit (UNL) to persistently ≥UNL
!
From <UNL to persistently ≥1.5 UNL
!
From <UNL to persistently ≥20 ng/L
!
From <UNL to persistently ≥50 ng/L
!
From <20 ng/L to persistently ≥20 ng/L
!
From <50 ng/L to persistently ≥50 ng/L
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Incidental (at least one post baseline measurements)
!
From <UNL to ≥UNL
!
From <UNL to ≥1.5 UNL
!
From <UNL to ≥20 ng/L
!
From <UNL to ≥50 ng/L
!
From <20 ng/L to ≥20 ng/L
!
From <50 ng/L to ≥50 ng/L
Summaries tables of calcitonin continuous measurements, will include number and percentage of 
observations < and ≥LLOQ, minimum, Q25, median, Q75 and maximum. Summaries will be 
presented for all subjects and by gender.
Classification of Hypoglycaemia 
Treatment emergent: hypoglycaemic episodes will be defined as treatment emergent if the onset of 
the episode occurs on or after the first day of trial product administration, and no later than the 
follow-up visit.
Nocturnal hypoglycaemic episodes: are episodes with time of onset between 00:01 and 05:59 both 
inclusive.
Hypoglycaemic episodes are classified according to the Novo Nordisk classification of 
hypoglycaemia and the ADA classification of hypoglycaemia (see Figure 17–1).
Novo Nordisk classification of hypoglycaemia
In normal physiology, symptoms of hypoglycaemia occur below a plasma glucose level of 3.1 
mmol/L (56 mg/dL) 42. Therefore, Novo Nordisk has included hypoglycaemia with plasma glucose 
levels below this cut-off point of hypoglycaemia.
In this trial Novo Nordisk use the following classification in addition to the ADA classification (see 
Figure 17–1):
!
Severe or BG confirmed symptomatic hypoglycaemia: An episode that is severe according 
to the ADA classification 38 or BG confirmed by a plasma glucose value <3.1 mmol/L (56 
mg/dL) with symptoms consistent with hypoglycaemia.
ADA classification of hypoglycaemia 38
!
Severe hypoglycaemia: An episode requiring assistance of another person to actively 
administer carbohydrate, glucagon, or take of other corrective actions. Plasma glucose 
concentration may not be available during an event, but neurological recovery following the 
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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).
Figure 17–1
ADA classification of hypoglycaemia
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Number of severe or BG confirmed symptomatic hypoglycaemic episodes
Data on treatment emergent hypoglycaemic episodes are 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 episodes rate per 100 years of exposure. Summaries of treatment 
emergent hypoglycaemic episodes will be presented as an overview including all episodes and 
episodes by severity.
The number of severe or BG confirmed symptomatic hypoglycaemic episodes during 30 weeks 
treatment will be analysed using a negative binomial regression model with a log-link function and 
the logarithm of the time period, from the randomisation and up to the time point in which an 
occurrence of a hypoglycaemic episode is considered treatment emergent as offset. The model will 
include factors for treatment, country as fixed factors and baseline HbA1c as covariate.
Number of nocturnal hypoglycaemic episodes
The number of nocturnal (00:01-05:59 am) severe or BG confirmed symptomatic hypoglycaemic 
episodes during 30 weeks of treatment will be analysed separately in the same type of model as the 
number of severe or BG confirmed symptomatic hypoglycaemic episodes during 30 weeks 
treatment.
Severe or BG confirmed symptomatic hypoglycaemic episodes (yes/no)
The binary endpoint indicating whether a subject has no treatment emergent severe or BG 
confirmed symptomatic hypoglycaemic episodes or at least one will be analysed using a logistic 
regression model with treatment, country as fixed factors and baseline HbA1c as covariate.
Nocturnal severe or BG confirmed symptomatic hypoglycaemic episodes (yes/no)
The binary endpoint indicating whether a subject has no treatment emergent nocturnal (00:01-05:59 
am) severe or BG confirmed symptomatic hypoglycaemic episodes or at least one will be analysed 
using the same type model as severe or BG confirmed symptomatic hypoglycaemic episodes during 
30 weeks treatment.
17.5
Health economics and/or patient reported outcomes
The PRO questionnaires, SF-36v2TM and DTSQs, will be used to evaluate the objective regarding 
Quality of Life, see section 17.4.2.1for the details of the corresponding statistical analysis.
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18 Ethics
The trial will be conducted in compliance with ICH GCP 1 and applicable regulatory requirements, 
and in accordance with the Declaration of Helsinki 2.
All subjects will be included after a thorough evaluation in regards to in- and exclusion criteria 
defined in order to ensure that subjects are eligible for trial treatment. Subjects will be treated 
within a regimen anticipated to be better than or equal to the treatment they receive at the time of 
entry into the trial. Subjects will have to spend some extra time, as additional assessments and visits 
to the clinic are required. It is the responsibility of the investigator to ensure the best possible care 
according to the principles outlined in Diabetes Care 2013 Standards of Medical Care in Diabetes 43, 
or any updates thereof.
It is concluded that the potential benefits from participating in the trial outweigh the potential risks. 
The safety profile of semaglutide generated from the clinical and nonclinical development 
programme has not revealed any safety issues that would prohibit administration of once weekly 
doses of 0.5 mg or 1.0 mg semaglutide in accordance with the planned clinical trial. It is concluded 
that the risk to the subjects in this trial is low and acceptable in view of the benefits a long-acting 
GLP-1 analogue would provide to people with type 2 diabetes (please see 3.5)
The trial products may be associated with AEs, but relevant precautions have been implemented in 
the design and planned conduct of the trial in order to minimise the risks and inconveniences of 
participation in the trial. These precautions include thorough information regarding the correct 
administration of the trial products and gradual dose adjustment. Furthermore, subjects are fully 
informed about possible AEs and inconveniences and will be instructed to contact the investigator 
in case of any concerns regarding the trial participation.
When treatment with trial products ends, the subject and investigator will decide on the best 
available treatment.
18.1
Informed consent 
In seeking and documenting informed consent, the investigator must comply with applicable 
regulatory requirement(s) and adhere to ICH GCP 1 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.
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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 task may 
be delegated by the investigator to a medically qualified person, in accordance with local 
requirements. The written informed consent must be signed and personally dated by the person who 
seeks the informed consent before any trial-related activity.
If information becomes available that may be relevant to the subject's willingness to continue 
participating in the trial, the investigator must inform the subject in a timely manner, and a revised 
written subject information must be provided and a new informed consent must be obtained.
In case a subject undergoes a thyroidectomy a separate informed consent will be obtained for 
collection of thyroid tissue sample and genetic testing (see section 8.8.1.2 and 8.8.1.3).
18.2
Data handling
If the subject is withdrawn from the trial or lost to follow up, then the subject's data will be handled 
as follows:
!
Data already collected and data collected at the end-of-trial visit will be retained by Novo 
Nordisk, entered into the database and used for the trial report. 
!
Safety events will be reported to Novo Nordisk and regulatory authorities according to 
local/national requirements.
If data is used, it will always be in accordance with local regulations and IRBs/IECs.
18.3
Information to subject during trial
The site will be offered a communication package to the subject during the conduct of the
trial. The package content is issued by Novo Nordisk. The communication package will
contain the letters intended for distribution to the subjects. The letters will be translated
and adjusted to local requirements and distributed to the subject by discretion of the
investigator. The subject may receive a “welcome to the trial letter” and a “thank for
your participation letter” at the end of the trial. Further the subject may receive trial
letters during the trial period.
All information to the subjects will be submitted to the health authorities and IECs/IRBs
for approval according to local regulations.
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18.4
Premature termination of the trial and/or trial site
Novo Nordisk, the investigator, the IRBs/IECs or a regulatory authority may decide to stop the trial, 
part of the trial or a trial site at any time, but agreement on procedures to be followed must be 
obtained.
If a trial is suspended or prematurely terminated, the investigator must inform the subjects promptly 
and ensure appropriate therapy and follow-up. The investigator and/or Novo Nordisk must also 
promptly inform the IRBs/IECs and provide a detailed written explanation. The relevant regulatory 
authorities must be informed.
If, after the termination of the trial, the risk/benefit analysis changes, the new evaluation must be 
provided to the IRBs/IECs in case it has an impact on the planned follow-up of subjects who have 
participated in the trial. If it has an impact, the actions needed to inform and protect the subjects 
should be described.
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19 Protocol compliance
Deviations from the protocol should be avoided.
If deviations do occur, the investigator must inform the monitor and the implications of the 
deviation must be reviewed and discussed.
Deviations must be documented and explained in a protocol deviation by stating the reason, date, 
and the action(s) taken. Some deviations, for which corrections are not possible, can be 
acknowledged and confirmed via edit checks in the eCRF or via listings from the clinical database. 
Documentation on protocol deviations must be kept in the investigator's trial file and Novo Nordisk 
trial master file.
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20 Audits and inspections
Any aspect of the clinical trial may be subject to audits conducted by Novo Nordisk or inspections 
from domestic or foreign regulatory authorities or from IRBs/IECs. Audits and inspections may 
take place during or after the trial. The investigator and the site staff as well as Novo Nordisk staff 
have an obligation to cooperate and assist in audits and inspections. This includes giving auditors 
and inspectors direct access to all source documents and other documents at the trial site relevant to 
the clinical trial. This includes permission to examine, analyse, verify and reproduce any record(s) 
and report(s) that are relevant to the evaluation of the trial.
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21
Critical documents
Before a trial site is allowed to start screening subjects, the following documents must be available 
to Novo Nordisk:
!
Regulatory approval and/or acknowledgement of notification as required 
!
Approval/favourable opinion from IRBs/IECs clearly identifying the documents reviewed as 
follows: protocol, any protocol amendments, subject information/informed consent form, 
any other written information to be provided to the subject and subject recruitment materials
!
List of IRB/IEC members and/or constitution
!
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 and local label for comparator
!
Signed and dated agreement on the final protocol
!
Signed and dated agreement on protocol amendment, if applicable
!
Financial agreement(s)
!
Source document agreement
!
Central laboratory certification and normal ranges
!
Insurance statement, if applicable
!
Signed and dated Investigator Agreement
!
Financial disclosure form from investigator and sub-investigator(s)
Novo Nordisk will analyse and report data from all sites together.
By signing the protocol, each investigator agrees to comply fully with ICH GCP 1, applicable 
regulatory requirements and the Declaration of Helsinki2. 
By signing the protocol, each investigator also agrees to allow Novo Nordisk making 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
All staff Novo Nordisk, site, Central Laboratories, CRO etc. must conduct the trial in compliance 
with ICH GCP 1, applicable regulatory requirements, and in accordance with the Declaration of 
Helsinki 2
The investigator is accountable for the conduct of the trial at his/her site. If any tasks are delegated, 
the investigator must maintain a list of appropriately qualified persons to whom he/she has 
delegated specified significant trial-related duties. The investigator must ensure that there is 
adequate training for all staff participating in the conduct of the trial. It is the investigator's 
responsibility to supervise the conduct of the trial and to protect the rights, safety, and well-being of 
the subjects.
A qualified physician, who is an investigator or a sub-investigator for the trial, must be responsible 
for all trial-related medical decisions.
The investigator must ensure adequate supervision of the conduct of the trial at the trial site. 
The investigator will follow instructions from Novo Nordisk when processing data.
The investigator is responsible for filing essential documents (ie those documents which 
individually and collectively permit evaluation of the conduct of a trial and the quality of the data 
produced) in the investigator's trial file. The documents should be kept in a secure locked facility, 
so no unauthorized persons can get access to the data. The subject identification code list must be 
kept securely and separate from the personal 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 (eg 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 Novo Nordisk for regulatory purposes and 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.
One principal investigator will be appointed to review and sign the clinical trial report (signatory 
investigator) on behalf of all participating investigators. The signatory investigator will be 
appointed based upon the criteria defined by the International Committee of Medical Journal 
Editors for research publications44. 
23.1
Communication of results
Novo Nordisk commits to communicating, and otherwise making available for public disclosure, 
results of trials regardless of outcome. Public disclosure includes publication of a paper in a 
scientific journal, abstract submission with a poster or oral presentation at a scientific meeting, or 
disclosure by other means.
The results of this trial will be subject to public disclosure on external web sites according to 
international and national regulations, as reflected in the Novo Nordisk Code of Conduct for 
Clinical Trial Disclosure.
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.
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.
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Where required by the journal, the principal 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 Editors 44 (sometimes referred to as the Vancouver 
Criteria).
At the end of the trial, one or more publications (abstracts, posters, manuscripts) will be prepared 
for submission to scientific congresses and peer-reviewed journals in collaboration between Novo 
Nordisk and investigator(s) appointed by Novo Nordisk. These investigator(s) must meet the 
ICMJE authorship criteria to be named authors on publications.
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 for publication of such primary 
policy will take place no later than 18 months after trial completion.
23.2
Investigator access to data and review of results
As owner of the trial database, Novo Nordisk has the discretion to determine who will have access 
to the database. 
Individual investigators will have their own research subjects' data, and will be provided with the 
randomisation code after results are available.
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24 Retention of clinical trial documentation and human biospecimens
24.1
Retention of clinical trial documentation
Subject's medical records must be kept for the maximum period permitted by the hospital, 
institution or private practice.
The investigator must agree to archive the documentation (this includes both electronic and paper-
based records) pertaining to the trial in an archive after completion or discontinuation of the trial if 
not otherwise notified. The investigator should not destroy any documents without prior permission 
from Novo Nordisk. If the investigator cannot archive the documents at the trial site, Novo Nordisk 
can refer the investigator to an independent archive provider that has a system in place to allow only 
the investigator to access the files.
The investigator must be able to access his/her trial documents without involving Novo Nordisk in 
any way. Site-specific CRFs and other subject data (in an electronic readable format or as paper 
copies or prints) will be provided to the investigator before access is revoked to the systems and/or 
electronic devices supplied by Novo Nordisk. These data must be retained by the trial site. If the 
Novo Nordisk provided data (eg the CD-ROM) is not readable during the entire storage period, the 
investigator can request a new copy. A copy of all data will be stored by Novo Nordisk.
Novo Nordisk will maintain Novo Nordisk documentation pertaining to the trial for as long as the 
product is on the market plus 20 years. 
The files from the investigator site/institution must be retained for 15 years after the completion of 
the trial, or longer if required by local regulations. The deletion process must ensure confidentiality 
of data and must be done in accordance with local regulatory requirements.
24.2
Retention of human biospecimens
Antibody samples may be stored until market authorisation in case Health Authorities requests 
further characterisation of the antibody response.(Brazil, due to local regulation, the laboratory 
samples for BR subjects will be destroyed at the latest at the completion of the CTR, including 
samples for anti-semaglutide antibody analysis. No sample will be stored after the completion of 
CTR).
Thyroid tissue samples will be stored in a tissue bank until testing for RET Y1062 phosphorylation 
in the thyroid-cells, if allowed by local law.
None of the data will be identified by name. Antibody samples and thyroid tissue will be identified 
only by a subject number, a visit number and a trial identification number. The trial staff is 
responsible for maintaining a code list which links to the subject number. The code list must be kept 
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for at least 15 years. The code list may be reviewed by Novo Nordisk staff including auditors or 
representatives from regulatory authorities, but no copies will be made of this list.
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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 sponsor, 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 risk/benefit 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's trial 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 local laws/acts/guidelines.
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27 References
1 ICH Harmonised Tripartite Guideline. International Conference on Harmonisation. 1996.
2 World Medical Association. Declaration of Helsinki. Ethical Principles for Medical Research 
Involving Human Subjects. 64th WMA General Assembly, Fortaleza. 1 Oct 2013.
3 DeFronzo RA. Pathogenesis of type 2 diabetes mellitus. Med Clin North Am 2004; 88(4):787-
835, ix.
4 UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with 
sulphonylureas or insulin compared with conventional treatment and risk of complications in 
patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352(9131):837-853.
5 The effect of intensive treatment of diabetes on the development and progression of long-term 
complications in insulin-dependent diabetes mellitus. The Diabetes Control and 
Complications Trial Research Group. N Engl J Med 1993; 329(14):977-986.
6 Chuang LM, Tsai ST, Huang BY, Tai TY, Diabcare A. The status of diabetes control in Asia--
a cross-sectional survey of 24 317 patients with diabetes mellitus in 1998. Diabetic medicine : 
a journal of the British Diabetic Association 2002; 19(12):978-985.
7 Liebl A, Mata M, Eschwege E,  AB. Evaluation of risk factors for development of 
complications in Type II diabetes in Europe. Diabetologia 2002; 45(7):S23-S28.
8 Ford ES, Li C, Little RR, Mokdad AH. Trends in A1C concentrations among U.S. adults with 
diagnosed diabetes from 1999 to 2004. Diabetes Care 2008; 31(1):102-104.
9 Harris MI, Eastman RC, Cowie CC, Flegal KM, Eberhardt MS. Racial and ethnic differences 
in glycemic control of adults with type 2 diabetes. Diabetes Care 1999; 22(3):403-408.
10 Holst JJ, Vilsbøll T, Deacon CF. The incretin system and its role in type 2 diabetes mellitus. 
Mol Cell Endocrinol 2009; 297:127-136.
11 Kieffer TJ, Habener JL. The glucagon-like peptides. Endocr Rev 1999; 20(6):876-913.
12 Hare KJ, Vilsbøll T, Asmar M, Deacon CF, Knop FK, Holst JJ. The Glucagonostatic and 
Insulinotropic Effects of Glucagon-Like Peptide 1 Contribute Equally to Its Glucose-
Lowering Action. Diabetes 2010; 59(7):1765-1770.
13 Nauck MA, Niedereichholz U, Ettler R, Holst JJ, Orskov C, Ritzel R et al. Glucagon-like 
peptide 1 inhibition of gastric emptying outweighs its insulinotropic effects in healthy 
humans. Am J Physiol 1997; 273(5 Pt 1):E981-E988.
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14 Flint A, Kapitza C, Hindsberger C, Zdravkovic M. The once-daily human glucagon-like 
peptide-1 (GLP-1) analog liraglutide improves postprandial glucose levels in type 2 diabetes 
patients. Adv Ther 2011; 28(3):213-226.
15 Kapitza C, Zdravkovic M, Hindsberger C, Flint A. The effect of the once-daily human 
glucagon-like peptide 1 analog liraglutide on the pharmacokinetics of acetaminophen. Adv 
Ther 2011; 28(8):650-660.
16 Flint A, Raben A, Astrup A, Holst JJ. Glucagon-like peptide 1 promotes satiety and 
suppresses energy intake in humans. J Clin Invest 1998; 101(3):515-520.
17 Bagger JI, Knop FK, Lund A, Vestergaard H, Holst JJ, Vilsboll T. Impaired regulation of the 
incretin effect in patients with type 2 diabetes. J Clin Endocrinol Metab 2011; 96(3):737-745.
18 Nauck M, Stockmann F, Ebert R, Creutzfeldt W. Reduced incretin effect in type 2 (non-
insulin-dependent) diabetes. Diabetologia 1986; 29(1):46-52.
19 Nauck MA, Vardarli I, Deacon CF, Holst JJ, Meier JJ. Secretion of glucagon-like peptide-1 
(GLP-1) in type 2 diabetes: what is up, what is down? Diabetologia 2011; 54:10-18.
20 Perley MJ, Kipnis DM. Plasma insulin responses to oral and intravenous glucose: studies in 
normal and diabetic subjects. J Clin Invest 1967; 46(12):1954-1962.
21 Højberg PV, Vilsbøll T, Rabøl R, Knop FK, Bache M, Krarup T et al. Four weeks of near-
normalisation of blood glucose improves the insulin response to glucagon-like peptide-1 and 
glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes. Diabetologia 
2009; 52:199-207.
22 Holst JJ. Enteroglucagon. Annu Rev Physiol 1997; 59:257-271.
23 Nauck MA, Kleine N, Orskov C, Holst JJ, Willms B, Creutzfeldt W. Normalization of fasting 
hyperglycaemia by exogenous glucagon-like peptide 1 (7-36 amide) in type 2 (non-insulin-
dependent) diabetic patients. Diabetologia 1993; 36(8):741-744.
24 Nauck MA. Incretin based therapies for type 2 diabetes mellitus: properties, functions, and 
clinical implications. Am J Med 2011; 124 (1 Suppl):S3-S18.
25 Toft-Nielsen MB, Madsbad S, Holst JJ. Determinants of the effectiveness of glucagon-like 
peptide-1 in type 2 diabetes. J Clin Endocrinol Metab 2001; 86(8):3853-3860.
26 Hansen L, Deacon CF, Orskov C, Holst JJ. Glucagon-like peptide-1-(7-36)amide is 
transformed to glucagon-like peptide-1-(9-36)amide by dipeptidyl peptidase IV in the 
capillaries supplying the L cells of the porcine intestine. Endocrinology 1999; 140(11):5356-
5363.
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27 ICH. ICH Harmonised Tripartite Guideline M3(R2): Guidance on nonclinical safety studies 
for the conduct of human clinical trials and marketing authorization for pharmaceuticals 
M3(R2).  11 Jun 2009. 
28 Investigators Brochure for s.c. Semaglutide (NN9535), Edition 8, 2013 or any updates hereof.
29 JANUVIA - European Summary of Product Characteristics. Merck Sharp & Dohme Limited. 
2014.
30 Yang L, He Z, Tang X, Liu J. Type 2 diabetes mellitus and the risk of acute pancreatitis: a 
meta-analysis. Eur J Gastroenterol Hepatol 2013; 25(2):225-231.
31 Wenten M, Gaebler JA, Hussein M, Pelletier EM, Smith DB, Girase P et al. Relative risk of 
acute pancreatitis in initiators of exenatide twice daily compared with other anti-diabetic 
medication: a follow-up study. Diabet Med 2012; 29(11):1412-1418.
32 JANUVIA - Labelling FDA. Merck & Co., Inc. 2013.
33 JANUVIA - Labelling CFDA. Merck Sharp & Dohme (Australia) Pty Limited. 2011.
34 Charbonnel B, Karasik A, Liu J, Wu M, Meininger G. Efficacy and safety of the dipeptidyl 
peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 
diabetes inadequately controlled with metformin alone. Diabetes Care 2006; 29(12):2638-
2643.
35 De Angelius C., Drazen JM, Frizelle FA, Haug C, Hoey J, Horton R et al. Clinical Trial 
Registration: A statement from the International Committee of Medical Journal Editors. N 
Engl J Med 2004; 351:1250-1251.
36 Food and Drug Administration Amendments Act of 2007. 11 Oct 2007.
37 European Commission Regulation for EudraCT. https://eudract.ema.europa.eu/ . 2011. 
38 Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L et al. Hypoglycemia and 
diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine 
Society. Diabetes Care 2013; 36(5):1384-1395.
39 European Union. The rules governing medicinal products in the European Union, Volume 4, 
Annex 13, manufacture of investigational products - Brussels. Feb 2010.
40 Phillips A, Haudiquet V. ICH E9 guideline 'Statistical principles for clinical trials': a case 
study. Stat Med 2003; 22(1):1-11.
41 Little RJA, Rubin DB. Statistical analysis with missing data. New York: John Wiley & Sons, 
1987.
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42 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):777-781.
43 American Diabetes Association. Standards of medical care in diabetes--2013. Diabetes Care 
2013; 36 Suppl 1:S11-66. doi: 10.2337/dc13-S011.:S11-S66.
44 International Committee of Medicinal Journal Editors. Uniform Requirements for Manuscripts 
submitted to Biomedical Journals. N Engl J Med 1997; 336:309-315.
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Protocol
Trial ID: NN9535-4114
SUSTAIN – CHINA MRCT
Efficacy and safety of semaglutide once-weekly versus
sitagliptin once-daily as add-on to metformin in subjects
with type 2 diabetes
A 30-week randomised, double-blind, double-dummy, active-controlled, 
parallel-group, multi-centre and multi-national trial
Trial phase: 3a
Protocol originator
Semaglutide Diabetes & Diabetes Outcomes
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 
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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 ................................................................................................................................................14
2.1
Flow chart explanatory descriptions............................................................................................17
3
Background information and rationale for the trial............................................................................18
3.1
Type 2 diabetes............................................................................................................................18
3.2
Glucagon-like peptide-1 ..............................................................................................................18
3.3
Semaglutide .................................................................................................................................18
3.3.1
Non-clinical data........................................................................................................19
3.3.1.1
Thyroid C-cell tumours in rodents ......................................................19
3.3.1.2
Embryo−foetal development toxicity..................................................19
3.3.2
Clinical data...............................................................................................................20
3.3.2.1
Pharmacokinetics ................................................................................20
3.3.2.2
Efficacy ...............................................................................................20
3.3.2.3
Safety...................................................................................................21
3.4
Sitagliptin.....................................................................................................................................22
3.5
Risk and benefits assessment.......................................................................................................22
3.5.1
Semaglutide risks and precautions.............................................................................22
3.5.2
Identified risks ...........................................................................................................23
3.5.3
Potential risks.............................................................................................................23
3.5.4
Other safety considerations........................................................................................25
3.5.5
Sitagliptin risk and precautions..................................................................................25
3.5.6
Benefits......................................................................................................................25
3.5.7
Risk and benefit conclusion.......................................................................................26
3.6
Rationale for the trial...................................................................................................................26
4
Objectives and endpoints........................................................................................................................28
4.1
Objective......................................................................................................................................28
4.1.1
Primary objective.......................................................................................................28
4.1.2
Secondary objectives .................................................................................................28
4.2
Endpoints.....................................................................................................................................28
4.2.1
Primary endpoint........................................................................................................28
4.2.2
Secondary endpoints..................................................................................................28
4.2.2.1
Confirmatory secondary endpoint.......................................................28
4.2.2.2
Supportive secondary endpoints..........................................................28
5
Trial design..............................................................................................................................................30
5.1
Type of trial .................................................................................................................................30
5.2
Rationale for trial design..............................................................................................................31
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5.3
Treatment of subjects...................................................................................................................32
5.3.1
Missed dose ...............................................................................................................33
5.3.2
Background medication.............................................................................................33
5.3.3
Treatment after end of trial........................................................................................33
5.4
Rationale for treatment ................................................................................................................34
6
Trial population.......................................................................................................................................35
6.1
Number of subjects......................................................................................................................35
6.2
Inclusion criteria ..........................................................................................................................35
6.3
Exclusion criteria.........................................................................................................................35
6.4
Rescue criteria..............................................................................................................................36
6.5
Withdrawal criteria ......................................................................................................................37
6.5.1
Discontinuation of trial product.................................................................................37
6.5.2
Withdrawal from trial ................................................................................................37
6.6
Subject replacement.....................................................................................................................38
6.7
Rationale for trial population.......................................................................................................38
7
Milestones ................................................................................................................................................39
8
Methods and assessments .......................................................................................................................40
8.1
Visit procedures...........................................................................................................................40
8.1.1
Screening visit 1 (V1)................................................................................................40
8.1.1.1
Screen failures.....................................................................................40
8.1.1.2
Re-screening........................................................................................41
8.1.2
Fasting visits ..............................................................................................................41
8.1.3
Randomisation V2 .....................................................................................................41
8.1.4
Visits..........................................................................................................................41
8.1.5
Missed visits and unscheduled visits .........................................................................41
8.1.6
End of treatment (V9/9A) and Follow-up (V10/10A) ...............................................42
8.1.6.1
Subjects completing the treatment period as per protocol...................42
8.1.6.2
Subjects who prematurely discontinue trial product ...........................42
8.1.7
Withdrawals...............................................................................................................42
8.1.8
Investigator’s assessment...........................................................................................43
8.2
Subject related information..........................................................................................................44
8.2.1
Demography ..............................................................................................................44
8.2.2
Diabetes history and diabetes complications.............................................................44
8.2.3
Concomitant illness and medical history...................................................................44
8.2.4
Concomitant medication............................................................................................45
8.2.5
Tobacco use ...............................................................................................................45
8.2.6
Childbearing potential................................................................................................46
8.2.7
Height ........................................................................................................................46
8.3
Assessments for efficacy .............................................................................................................46
8.3.1
Body weight...............................................................................................................46
8.3.2
Waist circumference ..................................................................................................46
8.3.3
BMI............................................................................................................................47
8.3.4
Systolic and diastolic blood pressure.........................................................................47
8.4
Assessments for safety.................................................................................................................48
8.4.1
Adverse events...........................................................................................................48
8.4.2
Medication error ........................................................................................................48
8.4.3
Adverse events requiring additional data collection..................................................48
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8.4.4
Hypoglycaemic episodes ...........................................................................................49
8.4.5
Electrocardiogram......................................................................................................51
8.4.6
Physical examination.................................................................................................51
8.4.7
Pulse...........................................................................................................................52
8.4.8
Eye examination ........................................................................................................52
8.5
Laboratory assessments ...............................................................................................................52
8.5.1
Laboratory assessments for efficacy..........................................................................53
8.5.1.1
Glucose metabolism............................................................................54
8.5.1.2
Biomarker............................................................................................54
8.5.1.3
Lipids (all fasting)...............................................................................54
8.5.1.4
Self measured plasma glucose (SMPG)..............................................54
8.5.1.5
7 point profile......................................................................................55
8.5.2
Laboratory assessments for safety .............................................................................55
8.5.2.1
Anti-semaglutide antibodies................................................................55
8.5.2.2
Biochemistry .......................................................................................56
8.5.2.3
Haematology .......................................................................................56
8.5.2.4
Calcitonin............................................................................................56
8.5.2.5
Pregnancy test .....................................................................................56
8.5.2.6
Urinalysis ............................................................................................57
8.6
Other assessments........................................................................................................................57
8.6.1
Patient reported Outcome questionnaires ..................................................................57
8.6.1.1
SF-36v2TM ...........................................................................................57
8.6.1.2
DTSQs.................................................................................................58
8.6.2
Subject diary ..............................................................................................................58
8.7
Subject compliance......................................................................................................................58
9
Trial supplies ...........................................................................................................................................59
9.1
Trial products...............................................................................................................................59
9.2
Labelling......................................................................................................................................60
9.3
Storage.........................................................................................................................................60
9.4
Drug accountability and destruction............................................................................................61
9.5
Auxiliary supplies........................................................................................................................61
10 Interactive web response system............................................................................................................62
11 Randomisation procedure and breaking of blinded codes..................................................................63
11.1
Breaking of blinded codes ...........................................................................................................63
12 Adverse events, and technical complaints and pregnancies................................................................64
12.1
Definitions ...................................................................................................................................64
12.1.1
Serious adverse event.................................................................................................65
12.1.2
Non-serious adverse event.........................................................................................66
12.1.3
Medication errors.......................................................................................................66
12.1.4
Adverse events requiring additional data collection..................................................67
12.1.5
Technical complaint...................................................................................................68
12.2
Reporting of adverse events.........................................................................................................68
12.3
Follow-up of adverse events........................................................................................................70
12.4
Technical complaints and technical complaint samples ..............................................................71
12.4.1
Reporting of technical complaints .............................................................................71
12.4.2
Collection, storage and shipment of technical complaint samples ............................72
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12.5
Pregnancies..................................................................................................................................72
12.5.1
Pregnancies in female subjects ..................................................................................72
12.6
Precautions and/or overdose ........................................................................................................74
12.7
Committees related to safety........................................................................................................75
12.7.1
Novo Nordisk safety committee ................................................................................75
12.7.2
Event adjudication committee....................................................................................75
13 Case report forms....................................................................................................................................78
13.1
Corrections to case report forms..................................................................................................78
13.2
Case report form flow..................................................................................................................78
13.2.1
Electronic case report form flow................................................................................78
13.2.2
Paper case report form flow.......................................................................................79
14 Monitoring procedures...........................................................................................................................80
15 Data management....................................................................................................................................82
16 Computerised systems ............................................................................................................................83
17 Statistical considerations ........................................................................................................................84
17.1
Sample size calculation................................................................................................................85
17.2
Definition of analysis sets............................................................................................................86
17.3
Primary endpoint..........................................................................................................................88
17.4
Secondary endpoints....................................................................................................................91
17.4.1
Confirmatory secondary endpoints............................................................................91
17.4.2
Supportive secondary endpoints ................................................................................92
17.4.2.1
Efficacy endpoints...............................................................................92
17.4.2.2
Safety endpoints..................................................................................94
17.5
Health economics and/or patient reported outcomes...................................................................99
18 Ethics......................................................................................................................................................100
18.1
Informed consent .......................................................................................................................100
18.2
Data handling.............................................................................................................................101
18.3
Information to subject during trial.............................................................................................101
18.4
Premature termination of the trial and/or trial site.....................................................................102
19 Protocol compliance..............................................................................................................................103
20 Audits and inspections..........................................................................................................................104
21 Critical documents ................................................................................................................................105
22 Responsibilities......................................................................................................................................106
23 Reports and publications......................................................................................................................107
23.1
Communication of results..........................................................................................................107
23.1.1
Authorship ...............................................................................................................108
23.1.2
Site-specific publication(s) by investigator(s) .........................................................108
23.2
Investigator access to data and review of results.......................................................................108
24 Retention of clinical trial documentation and human biospecimens................................................109
24.1
Retention of clinical trial documentation...................................................................................109
24.2
Retention of human biospecimens.............................................................................................109
25 Institutional Review Boards/Independent Ethics Committees and regulatory authorities............110
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 October 2016
Novo Nordisk
Trial ID: NN9535-4114
Version:
2.0
UTN: U1111-1149-0432 
Status:
Final
EudraCT no.: NA
Page:
6 of 115
26 Indemnity statement .............................................................................................................................111
27 References..............................................................................................................................................112
Appendix A: 
Monitoring of calcitonin
Appendix B:
Adverse events requiring additional data collection 
Attachment I:
Global list of key staff and relevant departments and vendors
Attachment II:
Country list of key staff and relevant departments 
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 October 2016
Novo Nordisk
Trial ID: NN9535-4114
Version:
2.0
UTN: U1111-1149-0432 
Status:
Final
EudraCT no.: NA
Page:
7 of 115
Table of Figures   
Page
Figure 5–1
Trial design.............................................................................................................................30
Figure 12–1
Reporting of AEs....................................................................................................................69
Figure 17–2
Novo Nordisk classification of hypoglycaemia......................................................................97
Figure 17–3
ADA classification of hypoglycaemia....................................................................................98
Table of Tables
Page
Table 5–1
Treatment of subjects..............................................................................................................32
Table 12–1
Adverse events requiring completion of specific event forms and/or are subject to event 
adjudication ............................................................................................................................67
Table 12–2
Adverse events for adjudication .............................................................................................76
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 October 2016
Novo Nordisk
Trial ID: NN9535-4114
Version:
2.0
UTN: U1111-1149-0432 
Status:
Final
EudraCT no.: NA
Page:
8 of 115
List of abbreviations
AACE
American Association of Clinical Endocrinologists
ADA
American Diabetes Association
AE
adverse event
BG
blood glucose
BMI
Body mass index
CRF
case report form
CRO
contract research organisation
CTR
clinical trial report
CVD
cardiovascular disease
DPP-4
dipeptidyl peptidase 4
DUN
dispensing unit number
DTSQs
Diabetes Treatment Satisfaction Questionnaire status
EAC
event adjudication committee
ECG
electrocardiogram
eCRF
electronic case report form
EE
ethinylestradiol
EFD
embryo-foetal development
eGFR
estimated glomerular filtration rate
FAS
full analysis set
FDAAA
Food and Drug Administration Amendment Act
FPFV
first patient first visit
FPG
fasting plasma glucose
FSFV
first subject first visit
GCP
Good Clinical Practice
GI
gastrointestinal
GIP
gastric inhibitory polypeptide
GLP-1
glucagon-like peptide-1
HbA1c
glycosylated haemoglobin
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 October 2016
Novo Nordisk
Trial ID: NN9535-4114
Version:
2.0
UTN: U1111-1149-0432 
Status:
Final
EudraCT no.: NA
Page:
9 of 115
hCG
human chorionic gonadotrophin
HDL
high density lipoprotein
hsCRP
highly sensitive C-reactive protein
IB
Investigator’s Brochure
ICMJE
International Committee of Medical Journal Editors
IEC
independent ethics committee
IMP
investigational medicinal product
IRB
Institutional Review Board
IUD
intrauterine device 
IWRS
interactive voice/web response system
LDL
low density lipoprotein
LN
levonorgestrel
LPFV
last patient first visit
LPLV
last patient last visit
LSFV
last subject first visit
LSLV
last subject last visit
MACE
major adverse cardiovascular events
MAR
missing at random 
MCAR
missing completely at random 
MDRD
modification of diet in renal disease 
MEN2
multiple endocrine neoplasia syndrome type 2 
MMRM
mixed model for repeated measurements 
MTC
medullary thyroid carcinoma
NYHA
New York Heart Association
OAD
oral anti-diabetic drug
PG
plasma glucose
PP
per protocol
PPG
postprandial glucose
PPND
pre- and postnatal development 
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 October 2016
Novo Nordisk
Trial ID: NN9535-4114
Version:
2.0
UTN: U1111-1149-0432 
Status:
Final
EudraCT no.: NA
Page:
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PRO
patient reported outcome
RA
receptor agonist
SAE
serious adverse event
SAP
statistical analysis plan
s.c.
subcutaneous
SD
standard deviation 
SDV
source data verification
SMBG
self-measured blood glucose
SMPG
self-measured plasma glucose
SU
sulphonylurea
SUSAR
suspected unexpected serious adverse reaction
TMM
Trial Materials Manual
TEAE
treatment emergent adverse event
TVP
trial validation plan
UACR
urinary albumin to creatinine ratio 
UTN
universal trial number
V
visit
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 October 2016
Novo Nordisk
Trial ID: NN9535-4114
Version:
2.0
UTN: U1111-1149-0432 
Status:
Final
EudraCT no.: NA
Page:
11 of 115
1
Summary
Objectives and endpoints:
Primary objective
To compare the effect of once-weekly dosing of two dose levels of semaglutide versus sitagliptin 
100 mg once-daily on glycaemic control after 30 weeks of treatment
Primary endpoint
Change from baseline to week 30 in HbA1c
Secondary objectives
To compare the effects of once-weekly dosing of two dose levels of semaglutide versus sitagliptin
100 mg once-daily after 30 weeks of treatment on:
!
Inducing and maintaining weight loss
!
Other parameters of efficacy, safety and tolerability
Key secondary endpoint
Confirmatory secondary endpoint
!
Change from baseline to week 30 in body weight
Supportive secondary endpoints:
Change from baseline to week 30 in:
!
Fasting plasma glucose (FPG)
!
Systolic and diastolic blood pressure
!
Patient reported outcome (PRO) questionnaire: Diabetes Treatment Satisfaction 
Questionnaire status (DTSQs) score
Subjects who after 30 weeks treatment achieve (yes/no):
!
HbA1c ≤ 6.5% (48 mmol/mol) - American Association of Clinical Endocrinologists (AACE) 
target
Trial design:
This is a 30-week randomised, double-blind, double-dummy, active-controlled, multi-centre, multi-
national four-armed, parallel-group trial comparing semaglutide 0.5 mg and 1.0 mg once-weekly 
against sitagliptin 100 mg once-daily.
Subjects with type 2 diabetes inadequately controlled on metformin will be randomised in a 2:2:1:1 
manner to receive either:
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 October 2016
Novo Nordisk
Trial ID: NN9535-4114
Version:
2.0
UTN: U1111-1149-0432 
Status:
Final
EudraCT no.: NA
Page:
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!
semaglutide 0.5 mg once-weekly + sitagliptin placebo once-daily
!
semaglutide 1.0 mg once-weekly + sitagliptin placebo once-daily
!
sitagliptin 100 mg once-daily + semaglutide placebo (0.5) mg once-weekly
!
sitagliptin 100 mg once-daily + semaglutide placebo (1.0) mg once-weekly
Trial product will be add-on to subject’s stable pre-trial metformin. 
Key inclusion criteria:
!
Informed consent obtained before any trial-related activities. Trial-related activities are any 
procedures that are carried out as part of the trial, including activities to determine suitability 
for the trial
!
Male or female,  age ≥ 18 years at the time of signing informed consent
!
Subjects diagnosed with type 2 diabetes and on stable treatment in a period of 60 days prior 
to screening with metformin ≥ 1500 mg (or maximum tolerated dose ≥ 1000 mg). Stable is 
defined as unchanged medication and unchanged daily dose
!
HbA1c 7.0 – 10.5 % (53-91 mmol/mol) (both inclusive)
Key exclusion criteria: 
!
Female who is pregnant, breast-feeding or intends to become pregnant or is of childbearing 
potential not using an adequate contraceptive method throughout the trial including the 5 
week follow-up period (adequate contraceptive measure as required by local regulation or 
practice).
!
Any disorder which, in the opinion of the investigator, might jeopardise subject’s safety or 
compliance with the protocol
!
Treatment with glucose lowering agent(s) other than stated in the inclusion criteria in a 
period of 60 days before screening. An exception is short-term treatment (≤7 days in total) 
with insulin in connection with inter-current illness
!
History of chronic or idiopathic acute pancreatitis
!
Screening calcitonin value  ≥ 50 ng/L (pg/mL)
!
Personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine 
neoplasia syndrome type 2 (MEN 2)
!
Impaired renal function defined as estimated glomerular filtration rate (eGFR) < 60 
ml/min/1.73 m2 per modification of diet in renal disease (MDRM) formula (4 variable 
version)
!
Acute coronary or cerebrovascular event within 90 days before  randomisation
!
Heart failure, New York Heart Association (NYHA) class IV
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 October 2016
Novo Nordisk
Trial ID: NN9535-4114
Version:
2.0
UTN: U1111-1149-0432 
Status:
Final
EudraCT no.: NA
Page:
13 of 115
Assessments:
Efficacy:
!
Glucose metabolism
!
Body measurements (body weight, body mass index (BMI) and waist circumference)
!
Systolic and diastolic blood pressure
!
Blood lipids
!
Patient reported outcome (PRO) questionnaires (SF-36v2TM and DTSQs)
Safety:
!
Adverse events and serious adverse events
!
Hypoglycaemic episodes
!
Biochemistry and haematology
!
Anti-semaglutide antibodies 
!
Physical examination (including electrocardiogram (ECG))
Trial products:
Novo Nordisk A/S will supply the following trial products:
!
Semaglutide 1.34 mg/mL, solution for injection, 1.5 mL pre-filled PDS290 pen-injector
!
Semaglutide placebo, solution for injection, 1.5 mL pre-filled PDS290 pen-injector
!
Sitagliptin (Januvia®) 100 mg tablets for oral administration
!
Sitagliptin placebo tablets for oral administration
CONFIDENTIAL


Protocol
UTN: U1111-1149-0432 
Date:
28 October 2016
Status:
Final
Novo Nordisk
Trial ID: NN9535-4114
EudraCT no.: NA
Version:
2.0
Page:
14 of 115
2
Flow chart
Trial Periods
Screen
Rand
Treatment period
End of 
Treatment1
Follow Up1
End of 
Treatment 
premature 
discontinuation2
Follow Up
premature 
discontinuation2
Visit (V) or Phone (P) number
V1
V2
V3
P4
V5
V6
V7
V8
V9
V10
V9A
V10A
Time of visit
    Weeks
-2
0
4
6
8
12
16
23
30
35
Visit window
    Days
±7
±3
±3
±3
±3
±3
±3
±7
+7
SUBJECT RELATED INFO 
/ASSESSMENTS
Informed consent
18.1
x
In/exclusion criteria  
6.2,6.3
x
x
Randomisation 
8.1.3
x
Withdrawal criterion
6.5
x
x
x
x
x
x
x
x
Demography
8.2.1
x
Diabetes history and diabetes 
complications 
8.2.2
x
Concomitant illness and medical 
history
8.2.3
x
History of cardiovascular disease
8.2.3
x
History of gallbladder disease
8.2.3
x
Tobacco use
8.2.5
x
Concomitant medication
8.2.4
x
x
x
x
x
x
x
x
x
x
x
x
Height
8.2.7
x
EFFICACY
Body weight
8.3.1
x
x
x
x
x
x
x
x
Waist circumference 
8.3.2
x
x
x
x
x
x
x
x
BMI 
8.3.3
x
x
x
x
x
x
x
x
Systolic blood pressure, sitting
8.3.4
x
x
x
x
x
x
x
x
x
Diastolic blood pressure, sitting
8.3.4
x
x
x
x
x
x
x
x
x


Protocol
UTN: U1111-1149-0432 
Date:
28 October 2016
Status:
Final
Novo Nordisk
Trial ID: NN9535-4114
EudraCT no.: NA
Version:
2.0
Page:
15 of 115
Trial Periods
Screen
Rand
Treatment period
End of 
Treatment1
Follow Up1
End of 
Treatment 
premature 
discontinuation2
Follow Up
premature 
discontinuation2
Visit (V) or Phone (P) number
V1
V2
V3
P4
V5
V6
V7
V8
V9
V10
V9A
V10A
Time of visit
    Weeks
-2
0
4
6
8
12
16
23
30
35
Visit window
    Days
±7
±3
±3
±3
±3
±3
±3
±7
+7
HbA1c 
8.5.1.1
x
x
x
x
x
x
x
x
x
Fasting plasma glucose
8.5.1.1
x
x
x
x
x
x
x
x
Fasting insulin
8.5.1.1
x
x
x
x
Fasting proinsulin
8.5.1.1
x
x
x
x
Fasting C-peptide
8.5.1.1
x
x
x
x
Fasting glucagon
8.5.1.1
x
x
x
x
Lipids
8.5.1.3
x
x
x
x
hsCRP (highly sensitive CRP)
8.5.1.2
x
x
x
x
7 point profile  
8.5.1.4
x
x
x
x
SAFETY
Adverse events
8.4.1
x
x
x
x
x
x
x
x
x
x
x
Hypoglycaemic episodes
8.4.4
x
x
x
x
x
x
x
x
x
x
x
ECG
8.4.5
x
x
x
x
x
Physical examination
8.4.6
x
x
x
Pulse, sitting
8.4.7
x
x
x
x
x
x
x
x
x
Anti-semaglutide antibodies4
8.5.2.1
x
x
x
x
x
x
Creatinine
8.5.2.2
x
x
x
x
x
x
x
x
Biochemistry
8.5.2.2
x
x
x
x
x
x
x
x
Haematology
8.5.2.3
x
x
x
x
x
x
x
x
Calcitonin
8.5.2.4
x
x
x
x
Pregnancy test5
8.5.2.5
x
x
x
x
x
x
x
x
x
x
x
Urinalysis
8.5.2.6
x
x
x
x
Eye examination3
8.4.8
x
x
x
OTHER ASSESSMENTS


Protocol
UTN: U1111-1149-0432 
Date:
28 October 2016
Status:
Final
Novo Nordisk
Trial ID: NN9535-4114
EudraCT no.: NA
Version:
2.0
Page:
16 of 115
Trial Periods
Screen
Rand
Treatment period
End of 
Treatment1
Follow Up1
End of 
Treatment 
premature 
discontinuation2
Follow Up
premature 
discontinuation2
Visit (V) or Phone (P) number
V1
V2
V3
P4
V5
V6
V7
V8
V9
V10
V9A
V10A
Time of visit
    Weeks
-2
0
4
6
8
12
16
23
30
35
Visit window
    Days
±7
±3
±3
±3
±3
±3
±3
±7
+7
PRO questionnaires 
8.6.1
x
x
x
TRIAL MATERIAL
Drug accountability  
9.4
x
x
x
x
IWRS call
10
x
x
x
x
x
x
Dispensing visit
9.1
x
x
x
REMINDERS
Training in trial product, and pen 
handling
9.1
x
x
x
Hand-out Directions for Use (DFU)
9.5
x
End of treatment
8.1.6
x9
x9
End of trial  
8.1.6
x9
Hand-out and instruct in BG meter 
use
8.5.1.4
x
Hand-out and /or collect diary6 
8.6.2
x
x
x
x
x
x
x
x
x6
x
x6
Attend visit fasting7 
8.1.2
x
x
x
x
x
x
x
x8
x
x8
Hand-out ID card
8.1.1
x


Protocol
UTN: U1111-1149-0432 
Date:
28 October 2016
Status:
Final
Novo Nordisk
Trial ID: NN9535-4114
EudraCT no.: NA
Version:
2.0
Page:
17 of 115
2.1
Flow chart explanatory descriptions
Footer
Description
x1
V9 (End of Treatment) and V10 (Follow Up) are applicable for all randomised subjects. Subjects who have discontinued trial product prematurely should also 
attend V9 and V10 according to their initially scheduled week 30 and Week 35 visits.
x2
Subjects discontinuing trial product prematurely will be asked to attend two additional visits to undergo assessments: End of Treatment-premature 
discontinuation (V9A) and Follow Up -premature discontinuation (V10A). V9A should be scheduled at discontinuation of the trial product. V10A should be 
scheduled 5 weeks after discontinuation of trial product (+ 7 days visit window). 
x3
Fundus photography/dilated fundoscopy performed within 90 days before visit 2 is acceptable if results are available for evaluation at the visit 2 and no 
deterioration in visual function since last assessment.
x4
Antibody sampling should preferably be done pre-dose. For fasting and non-fasting visit, where the injection takes place on the day of site visit, trial product 
must not be taken before blood sampling. 
For visit 9 and 10: Not applicable if taken at a premature discontinuation visit
x5
For women of child bearing potential: For all site visits a serum pregnancy test must be performed. Urine pregnancy test should be performed at any time 
during the trial if a menstrual period is missed, or as required by local law.
x6
At V10 and V10A collect diary only.
x7
Fasting is defined as having consumed only water within the last 6 hours prior to the visit. Glucose lowering agents and trial product cannot be taken until 
after blood sampling has been performed but other prescribed medication should be taken.
x8
For the follow-up visit (V10/V10A) attend fasting is defined as having consumed only water within the last 2 hours prior to the visit.
x9
If premature discontinuation occurs, End of Treatment form must be filled-in when the discontinuation happens and End of Trial form at scheduled V10. If a 
subject completes both the treatment and the trial at scheduled time, the End of Treatment form must be filled at V9 and End of Trial form to be filled in at 
V10. In case of subject withdrawal, both End of Treatment form and End of Trial form must be filled-in at the time they withdraw from the trial. 


Protocol
CONFIDENTIAL
Date:
28 October 2016
Novo Nordisk
Trial ID: NN9535-4114
Version:
2.0
UTN: U1111-1149-0432 
Status:
Final
EudraCT no.: NA
Page:
18 of 115
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
Type 2 diabetes
Type 2 diabetes (T2D) is a progressive metabolic disease primarily characterised by abnormal 
glucose metabolism. The pathogenesis is not fully understood but seems to be 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 type 2 diabetes, in order to prevent 
long-term complications associated with chronic hyperglycaemia4,5. Despite the availability of 
several anti-diabetic drugs, a significant proportion of subjects with type 2 diabetes do not achieve 
the recommended blood glucose target levels6-9.
3.2
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 islets10, 11. Subjects
with T2D have a decreased response to GLP-112-15 . However, the insulinotropic action of GLP-1 
and thus, the ability to lower BG levels, is preserved when GLP-1 is administered at 
supraphysiological levels16. In addition, supraphysiological levels of GLP-1 induce reduction in 
body weight17. 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 regulation and food intake18, 19. 
Physiologically, GLP-1 also has a pronounced inhibitory effect on gastric emptying; however this 
effect seems to diminish upon chronic exposure17-19. These mechanisms of action make glucagon-
like peptide-1 receptor agonists (GLP-1 RAs) an attractive pharmacological treatment for T2D20-22.
Due to the very short half-life of <1.5 minutes after i.v. administration, native GLP-1 is not suitable 
for therapeutic use. To realise the full therapeutic potential of GLP-1, the pharmacokinetic and 
hence the pharmacodynamic effect needs to be protracted.
3.3
Semaglutide
Semaglutide is a potent human GLP-1 receptor agonist (RA) for once-weekly subcutaneous (s.c.) 
administration. It is structurally similar to liraglutide (Victoza®), a once-daily GLP-1 RA developed 
by Novo Nordisk and approved worldwide for the treatment of type 2 diabetes. The extended half-
life of the semaglutide molecule is primarily obtained due to binding to albumin, which is facilitated 
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 October 2016
Novo Nordisk
Trial ID: NN9535-4114
Version:
2.0
UTN: U1111-1149-0432 
Status:
Final
EudraCT no.: NA
Page:
19 of 115
by a large fatty acid derived chemical moiety attached to the lysine in position 26. The specific 
modifications in the molecule are: 1) a modification in position 8 (alanine to 2-aminoisobutyric 
acid) of the peptide backbone to increase stability against dipeptidyl peptidase-4 (DPP-4), and a 
change in position 34 from a lysine to an arginine to limit the options for acylation to the one 
remaining lysine in the sequence; 2) a large hydrophilic spacer between the lysine in position 26 
and the gamma glutamate whereto the fatty acid is attached; 3) a C18 fatty diacid with a terminal 
acidic group23, 24. The spacer and the fatty acid both contribute to increased albumin binding, which 
results in decreased renal clearance resulting in a prolonged half-life of approximately 1 week, 
making semaglutide suitable for once-weekly s.c. administration.
3.3.1
Non-clinical data
The non-clinical programme for semaglutide was designed according to the ICH M325 guideline to 
support the clinical development. The standard non-clinical data package required to support phase 
3 clinical trials has been completed. In addition, 2-year carcinogenicity studies and a pre- and 
postnatal development toxicity study have been completed. 
Semaglutide is generally well tolerated with expected GLP-1 effects on food intake and body 
weight being dose limiting in mice, rats and cynomolgus monkeys. Two potential safety issues have 
been identified.
3.3.1.1
Thyroid C-cell tumours in rodents
Thyroid C-cell neoplasia was seen in mice and rat 2-year carcinogenicity studies. Proliferative C
cell changes in rodents are a known effect following GLP-1 receptor activation by GLP-1 receptor
agonists. The finding in rodents is caused by a non-genotoxic, specific GLP-1 receptor-mediated
mechanism to which rodents are particularly sensitive. Recently published data have shown that the
GLP-1 receptor is not expressed in the normal human thyroid, and accordingly, the risk of GLP-1
receptor mediated C-cell changes in humans is considered to be low26.
3.3.1.2
Embryo−foetal development toxicity
Semaglutide adversely affected embryo−foetal development in the rat by a GLP-1 receptor
mediated impaired function of the inverted yolk sac placenta during a period of gestation when the
rat embryo is entirely dependent on the inverted yolk sac placenta for its nutrient supply. In
primates, the yolk sac does not invert to fully enclose the embryo, and it does not come in direct
contact with the uterine wall to form a placenta as in rodents. Accordingly, the mechanism by which 
semaglutide adversely affects embryo-foetal development in the rat, is not likely to be of relevance 
to humans. Studies in cynomolgus monkeys confirmed that maternal dosing of semaglutide does not 
affect embryo−foetal development in this species. However, the initial maternal body weight loss 
caused by the pharmacological effect of semaglutide coincided with increased early pregnancy loss 
in one of three studies. In cynomolgus monkeys, the overall developmental no observable adverse 
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
28 October 2016
Novo Nordisk
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effect level (NOAEL) was determined to be 0.015 mg/kg/3 days, which provides an exposure 
equivalent to the human exposure at 1.0 mg/week based on area under the curve (AUC).
A comprehensive review of results from the nonclinical studies can be found in the current edition 
of semaglutide (NN9535) investigator’s brochure (IB)27, or any updates hereof.
3.3.2
Clinical data
As of 1 August 2016, 16 clinical pharmacology trials (trials NN9535-1820, 3679, 3633, 3616, 3819,
4010, 3789, 3652, 3685, 3634, 3687, 3817,3818, 3684, 3651 and 3635), 1 phase 2 trial (NN9535-
1821) and 8 phase 3a trials (NN9535-3623, 3624, 3625,3626, 3627, 3744, 4091, 4092) have been
completed with semaglutide s.c. once-weekly. Clinical pharmacology trials were conducted in 
healthy subjects, in subjects with T2D, in subjects with obesity and in subjects with renal- and 
hepatic impairment. The phase 2 dose-finding trial was conducted in subjects with T2D. The 
semaglutide phase 3a programme evaluated the efficacy and safety of semaglutide in a broad T2D 
population and covered the continuum of T2D care. The programme evaluated mono- and 
combination therapy with anti-hyperglycaemic therapies and compared semaglutide with the most 
important comparators at the time of initiating the phase 3a programme. In addition, the phase 3a 
programme included a long-term (104-week) cardiovascular outcomes trial (trial 3744) in a T2D 
population at high risk of cardiovascular events.
3.3.2.1
Pharmacokinetics
The results from the completed clinical pharmacology trials confirm that semaglutide has PK
properties compatible with once-weekly administration, having a flat concentration profile over
time, with a median time to maximum concentration (tmax) of 1−3 days post-dosing and an
elimination half-life (t½) of approximately 1 week. The PK properties of semaglutide appear
comparable between healthy subjects, subjects with T2D and subjects with renal failure. Results 
from drug-interaction studies with warfarin, metformin, atorvastatin and digoxin indicate that no 
dose adjustment of the co-administered drugs is warranted when administered together with
semaglutide. In addition, semaglutide does not decrease the exposure of oral contraceptives and
hence, is not anticipated to decrease the effectiveness of oral contraceptives.
3.3.2.2
Efficacy
Based on results from the clinical pharmacology trials, semaglutide treatment reduced both fasting
and postprandial glucose compared to placebo, by improving multiple aspects of β-cell function and
by reducing both fasting and postprandial glucagon concentrations, all in a glucose dependent 
manner. The weight loss observed with semaglutide was primarily from fat tissue and was
considered to be explained by lowered appetite, both in the fasting and postprandial state, and
lowered energy intake. In addition, semaglutide improved control of eating and reduced food
cravings. Similar to other GLP-1 receptor agonists, semaglutide caused a minor delay of early
postprandial gastric emptying.
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Both as monotherapy and as combination therapy, semaglutide significantly reduced HbA1c and
body weight in all phase 3a trials when compared with the trial-specific comparator, including the
active comparators sitagliptin, exenatide ER and insulin glargine. In the 5 global phase 3a trials
(3623, 3624, 3625, 3626 and 3627), reductions in HbA1c and body weight of up to 1.85 %-point 
and 6.42 kg, respectively, were obtained with semaglutide 1.0 mg. Significantly more subjects with
semaglutide versus comparators reached the American Diabetes Association (ADA) and American
Association of Clinical Endocrinologists (AACE)-defined treatment target of an HbA1c <7% and
≤6.5%, respectively, and weight loss responses of ≥5% and ≥10%. The superior and clinically
relevant beneficial effects of semaglutide on glycaemic control as estimated by HbA1c were
substantiated by improvements in secondary glycaemia-related supportive endpoints28-31.
3.3.2.3
Safety
Data from the 5 global phase 3a clinical trials (NN9535-3623, 3624, 3625, 3626 and 3627) showed
that the safety and tolerability of semaglutide at doses up to 1.0 mg per week and administered for
up to 56 weeks of treatment were consistent with other GLP-1RAs. Commonly AEs included
nausea and vomiting, most of which were mild to moderate in severity. The escalation regimen
utilized was associated with good tolerability and low numbers of discontinuation due to AEs.
Accordingly, the most frequently reported AEs in subjects with T2D were gastrointestinal (e.g.,
nausea and vomiting), as were the most frequent AEs leading to premature treatment
discontinuation.
Hypoglycaemia occurred infrequently in subjects receiving semaglutide and the events were mainly
non-severe. Hypoglycaemic episodes have mainly been observed when semaglutide is combined
with sulphonylurea (SU) or insulin. 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
semaglutide. As with all protein based pharmaceuticals, subjects treated with semaglutide may
develop immunogenic and allergic reactions. However, only few subjects administered semaglutide 
experienced allergic reactions and injection site reactions. These have mainly been mild and 
transient of nature; however, more generalised reactions may occur.
The effect of semaglutide on major adverse cardiovascular events (MACE) was evaluated in a T2D 
population at high risk for CV events, in the cardiovascular outcome trial, SUSTAIN 6 (NN9535-
3744)32. SUSTAIN 6 trial achieved its primary objective by showing non-inferiority of once-weekly 
s.c. semaglutide versus placebo on cardiovascular outcomes; moreover, s.c. semaglutide statistically 
significantly reduced cardiovascular risk versus placebo32. In addition, results from the recently 
completed LEADER® trial (EX2211-3748) showed that treatment with the once daily liraglutide 
does not increase the risk of MACE as compared to placebo. In fact, treatment with liraglutide 
reduced the risk of the primary composite outcome consisting of death from cardiovascular causes, 
non-fatal myocardial infarction (MI) and non-fatal stroke by 13% versus placebo32. The overall 
safety profile of semaglutide in the SUSTAIN 6 trial (NN9535-3744) was consistent with previous 
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semaglutide clinical studies. However, in this trial, the diabetic retinopathy complications were 
reported more frequently in the semaglutide-treated subjects compared with placebo. 
Please see the current edition of semaglutide s.c. (NN9535) IB or any updates hereof for further 
details27.
3.4
Sitagliptin
Sitagliptin is an oral antihyperglycemic agent of the dipeptidyl peptidase-4 (DPP-4) inhibitor class 
suitable for once-daily oral administration. It was developed and marketed by Merck & Co as 
sitagliptin phosphate under the trade name Januvia®
Sitagliptin works by inhibition of the enzyme dipeptidyl peptidase 4 (DPP-4). This enzyme breaks 
down the incretin hormones GLP-1 and gastric inhibitory polypeptide (GIP). By preventing GLP-1 
and GIP inactivation, secretion of insulin is increased and release of glucagon is suppressed. The 
obvious advantage with a convenient route of administration is however counterbalanced by a 
significantly lower effect of the DPP-4 inhibitors on glycaemic control and body weight as 
compared to GLP-1 RAs. This has also been demonstrated for sitagliptin when compared to 
liraglutide33-35.
Adverse reactions reported in >5% of patients treated with sitagliptin and more commonly than in 
patients treated with placebo are: upper respiratory tract infection, nasopharyngitis and headache. In 
add-on to sulfonylurea and add-on to insulin studies, hypoglycaemia was also more commonly 
reported in patients treated with sitagliptin compared to placebo36.
3.5
Risk and benefits assessment
This assessment is based on the safety and efficacy data for semaglutide and sitagliptin presented 
above as well as potential risk identified as drug class effects.
3.5.1
Semaglutide risks and precautions
The nonclinical safety programme of 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 semaglutide treatment. These are based on findings in nonclinical studies and clinical trials
with 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.
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3.5.2
Identified risks
Gastrointestinal adverse events
Consistent with findings with other GLP-1 RAs, the most frequently reported AEs in clinical trials
with 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.
Diabetic retinopathy complications
A transient worsening of diabetic retinopathy is a recognised complication in selected patients with 
diabetes after initiation of intensive anti-diabetic treatment37. Risk factors for these events include 
long-standing poor glycaemic control and presence of proliferative retinopathy, and initial large 
improvements in BG may be an additional aggravating factor. Several studies have, however, 
documented long-term beneficial effects of intensive glycaemic treatment in reducing retinopathy 
progression38, 39 even in intensively treated patients who experienced early worsening40. In a 
cardiovascular outcomes trial with s.c. semaglutide, results indicate an increased risk of events 
related to diabetic retinopathy complications in subjects treated with semaglutide compared to 
placebo. As a precaution in this trial, all subjects are required to have a fundus photography or 
dilated fundoscopy performed before enrolment into the trial; moreover, subjects with proliferative 
retinopathy or maculopathy requiring acute treatment will be excluded. As part of good diabetes 
management the investigator is encouraged to ensure adequate monitoring and treatment of diabetic 
retinopathy in subjects enrolled into the trial41.
3.5.3
Potential risks
Medullary thyroid cancer
The human relevance of the proliferative C-cell changes found in rodents treated with GLP-1 RAs
is unknown, but data suggest that rodents are more sensitive to the mode of action of GLP-1 RAs
for induction of C-cell tumours. However, as a precaution, subjects with a family or personal
history of MEN 2 or MTC will not be enrolled in the trial. During the trial, calcitonin will be
measured on a regular basis, and the guidance for investigators on further evaluation and action on
elevated calcitonin concentrations is included in appendix A.
Acute pancreatitis
Acute pancreatitis has been reported in subjects treated with GLP-1 RAs including 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 T2D have an increased risk of certain types of cancer such as pancreatic cancer. There
is currently no support from nonclinical studies or clinical trials or post marketing data that GLP-1-
based therapies increase the risk of pancreatic cancer. However, pancreatic cancer has been
included as a separate potential risk due to the scientific debate surrounding a potential association
to GLP-1-based therapies and the unknown long-term effects of stimulation of β-cells and
suppression of α-cells. Pancreatic cancer has been classified as a potential class risk of GLP-1 RAs
by EMA.
Allergic reactions and injection site reaction
As in the case with all protein-based pharmaceuticals, treatment with semaglutide may evoke
allergic reactions. These may include localized injection site reactions or generalized reactions,
including urticaria, rash and 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 semaglutide is combined with
SU or insulin.
Acute renal impairment
In subjects treated with GLP-1 RAs, including semaglutide, gastrointestinal AEs such as nausea,
vomiting and diarrhoea may lead to significant dehydration and secondary acute renal impairment.
Subjects with gastrointestinal AEs are recommended to drink plenty of fluids to avoid volume
depletion. Also, serum creatinine and other markers of kidney function will be monitored
throughout the trial. SGLT-2 inhibitors, a background medication in this trial, have also been 
associated with volume depletion. It is recommended to monitor renal function and for signs and 
symptoms of fluid loss during therapy. Severe dehydration may be a risk factor for ketoacidosis.
Impaired renal function may increase the risk of metformin associated lactic acidosis when GLP-1
RAs are co-administered with metformin. 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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3.5.4
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 
according to flowchart in Section 2 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 in regards to in- and exclusion criteria 
defined in order to ensure that subjects are eligible for trial enrolment. There are also strict 
glycaemic rescue criteria in place to ensure acceptable glycaemic control during the trial (see 
Section 6.4). If rescue medication is required, it should be in accordance with ADA/European 
Association for the Study of Diabetes42, 43 (excluding GLP-1 RAs, DPP-4 inhibitors and amylin 
analogues).
It is the responsibility of the investigator to ensure the best possible care according to the principles 
outlined in Diabetes Care 2016 Standards of Medical Care in Diabetes44.
Further details with regards to safety of trial product are described in the current edition of the IB 
for semaglutide (NN9535)27, or any updates thereto.
3.5.5
Sitagliptin risk and precautions
Sitagliptin is generally considered to be well tolerated. The most commonly reported side effect is 
upper respiratory tract infection, nasopharyngitis and headache. Some of the potential risk 
associated with GLP-1 RA treatment has also been associated with treatment with the DPP-4
inhibitors as sitagliptin i.e. pancreatitis, acute renal impairment, hypersensitivity reactions and 
hypoglycaemia (US prescribing information45 and Chinese prescribing information46)
3.5.6
Benefits
In this trial subjects in all treatment arms will be treated within a regimen anticipated to be more 
efficacious than the treatment they receive at the time of randomisation into the trial. It is expected 
that subjects will benefit from the trial treatment with respect to optimised glycaemic control, a 
reduced risk of long-term diabetic complications and a potential weight loss. 
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Based on the results of the phase 3a trials, semaglutide is expected to provide clinically relevant 
improvements in glycaemic control and body weight in subjects with T2D.
Furthermore, data from two cardiovascular outcomes trials investigating treatment with GLP-1 RAs 
compared to placebo have indicated a beneficial effect of these drugs on cardiovascular outcomes 
when added to standard of care in subjects with T2D at high risk of cardiovascular events (see 
Section 3.3.2.3).
Sitagliptin has in phase 3 trials where sitagliptin has been given in combination with metformin 
proven to provide significant improvements in HbA1c and FPG47.
All subjects in this trial will receive active treatment and will receive trial drug and auxiliary free of 
charge.
Finally, it is expected that all subjects participating in the trial will benefit from participation
through close contact with the study site and close follow-up of their type 2 diabetes. Such careful 
medical examination will most likely result in an intensified management of their diabetes.
3.5.7
Risk and benefit conclusion
It is concluded that the potential benefits from participating in the trial outweigh the potential risks. 
The safety profile of semaglutide generated from the clinical and nonclinical development 
programme has not revealed any safety issues that would prohibit administration of once-weekly
doses of 0.5 mg or 1.0 mg semaglutide in accordance with the planned clinical trial. Sitagliptin is 
already a marketed drug in the 100 mg dose and approved for the use in type 2 diabetic patients. 
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 semaglutide will provide to subjects with T2D.
3.6
Rationale for the trial
The currently available treatment modalities for type 2 diabetes are still not satisfactory and there
is still a large proportion of patients not reaching the treatment targets. In the 5 global phase 3a 
trials (3623, 3624, 3625, 3626 and 3627), reductions in HbA1c and body weight with semaglutide 
was superior to sitagliptin, exenatide ER and insulin glargine demonstrating semaglutide as a highly 
efficacious treatment option.
The rationale for this trial is to compare the efficacy of semaglutide versus sitagliptin in subjects 
with type-2 diabetes in terms of glycaemic control, weight loss and other efficacy parameters. 
Furthermore the trial is designed to address and compare safety, tolerability and patient satisfaction. 
This trial is designed to resemble the main trial NN9535-3626 (SUSTAIN 2) in the global 
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SUSTAIN programme and will be conducted in China and several other countries. The study design 
is adjusted to fulfil the Chinese requirements.
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4
Objectives and endpoints
4.1
Objective
4.1.1
Primary objective
To compare the effect of once-weekly dosing of two dose levels of semaglutide versus sitagliptin 
100 mg once-daily on glycaemic control after 30 weeks of treatment
4.1.2
Secondary objectives
To compare the effects of once-weekly dosing of two dose levels of semaglutide versus sitagliptin
100 mg once-daily after 30 weeks of treatment on:
!
Inducing and maintaining weight loss
!
Other parameters of efficacy, safety and tolerability
4.2
Endpoints
4.2.1
Primary endpoint
!
Change from baseline to week 30 in HbA1c
4.2.2
Secondary endpoints
4.2.2.1
Confirmatory secondary endpoint
!
Change from baseline to week 30 in body weight
4.2.2.2
Supportive secondary endpoints
Supportive secondary efficacy endpoints
Change from baseline to week 30 in:
!
Fasting plasma glucose (FPG)*
!
Self-measured plasma glucose (SMPG), 7 point profile
o
Mean 7-point profile
o
Mean post-prandial increment (over all meals)
!
Insulin, C-peptide, glucagon, pro-insulin, pro-insulin/insulin ratio, homeostasis model
assessment of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) (all fasting)
!
Fasting blood lipids (total cholesterol, low density lipoprotein (LDL) cholesterol, very low 
density lipoprotein (VLDL) cholesterol, high density lipoprotein (HDL) cholesterol, 
triglycerides and free fatty acids
!
Body mass index (BMI)
!
Waist circumference
!
Systolic and diastolic blood pressure*
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!
Highly sensitive C-reactive protein (hsCRP)
!
Patient reported outcome (PRO) questionnaire: SF-36v2™ score
!
Patient reported outcome (PRO) questionnaire: Diabetes Treatment Satisfaction 
Questionnaire status (DTSQs) score*
Subjects who after 30 weeks treatment achieve (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*
!
Weight loss ≥ 5%
!
Weight loss ≥ 10%
!
HbA1c < 7.0% (53 mmol/mol) without severe or blood glucose (BG) confirmed symptomatic  
hypoglycaemia and no weight gain
Supportive secondary safety endpoints
!
Number of treatment emergent adverse events (TEAEs) during 30 weeks of treatment
!
Number of treatment emergent severe or BG confirmed symptomatic hypoglycaemic 
episodes during 30 weeks of treatment
!
Severe or BG confirmed symptomatic hypoglycaemic episodes during 30 weeks of 
treatment (yes/no)
Change from baseline to week 30 in:
!
Haematology
!
Biochemistry
!
Calcitonin
!
Urinalysis
!
Urinary albumin to creatinine ratio (UACR)
!
Pulse
!
Electrocardiogram (ECG) evaluation
!
Physical examination 
!
Eye examination
Occurrence of anti-semaglutide antibodies during 30 weeks of study duration (yes/no):
!
Anti-semaglutide antibodies with in vitro neutralising effect
!
Anti-semaglutide antibodies cross reacting with endogenous GLP-1
o
Cross reacting antibodies with in vitro neutralising effect to endogenous GLP-1
Antibody level during and after 30 weeks of treatment
*Key supportive secondary endpoint prospectively selected for posting on clinicaltrials.gov.
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5
Trial design
5.1
Type of trial
This is a 30-week randomised, double-blind, double-dummy, active-controlled, multi-centre, multi-
national trial, four-armed, parallel-group trial comparing semaglutide 0.5 mg and 1.0 mg once-
weekly against sitagliptin 100 mg once-daily.
Figure 5–1
Trial design
Subjects with type 2 diabetes inadequately controlled on metformin will be randomised in a 2:2:1:1 
manner to receive either:
!
semaglutide 0.5 mg once-weekly + sitagliptin placebo once-daily
!
semaglutide 1.0 mg once-weekly + sitagliptin placebo once-daily
!
sitagliptin 100 mg once-daily + semaglutide placebo (0.5) mg once-weekly
!
sitagliptin 100 mg once-daily + semaglutide placebo (1.0) mg once-weekly
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The total trial duration for the individual subjects will be approximately 37 weeks. The trial 
includes a 2-week screening period followed by a 30-week randomised treatment period and a 5 
week follow-up period.
A planned total of 1050 subjects will be randomised whereof approximately 792 subjects will be 
from China. Randomisation will be stratified by country.
5.2
Rationale for trial design
Parallel treatment groups and a randomised double-blind double dummy controlled design have 
been chosen in accordance with trial objectives and to avoid bias in the trial.
Treatment duration of 30 weeks is considered adequate in terms of assessing efficacy of 
semaglutide treatment versus sitagliptin treatment on change in HbA1c. Furthermore, 30 weeks is 
considered sufficient for addressing and comparing the safety, tolerability and patient satisfaction 
profiles.
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5.3
Treatment of subjects
Table 5–1
Treatment of subjects
Trial periods
Screening
Period 1
Period 2
Period 3
Follow-up
Alias for trial period
Screening
Dose escalation
Dose escalation/ 
Maintenance
Maintenance
Follow-up
Visits in each period
Visit 1-2
Visit 2-3 
Visit 3-5
Visit 5-9
Visit 9-10
Duration of each period
2 weeks
4 weeks
4 weeks
22 weeks
5 weeks
Treatment arm
N
!
Semaglutide 
0.5 mg
!
Sitagliptin 
placebo
350
Screening 
!
Semaglutide 
0.25 mg, 
1.34 mg/mL, 
190μL 
!
Sitagliptin 
placebo 
!
Semaglutide 
0.5 mg, 
1.34 mg/mL, 
370μL
!
Sitagliptin
placebo
!
Semaglutide
0.5 mg, 
1.34 mg/mL, 
370μL
!
Sitagliptin
placebo
Follow-up 
!
Semaglutide 
1.0 mg
!
Sitagliptin 
placebo
350
Screening 
!
Semaglutide 
0.25 mg, 
1.34 mg/mL, 
190μL 
!
Sitagliptin 
placebo
!
Semaglutide 
0.5 mg, 
1.34 mg/mL,  
370μL
!
Sitagliptin
placebo 
!
Semaglutide
1.0 mg, 
1.34 mg/mL, 
740μL
!
Sitagliptin
placebo 
Follow-up 
!
Sitagliptin 
!
Semaglutide 
placebo 
(0.5 mg)
175
Screening 
!
Sitagliptin 
100 mg
!
Semaglutide
placebo
0 mg, 
190μL 
!
Sitagliptin 
100 mg
!
Semaglutide
placebo
0 mg, 
370μL
!
Sitagliptin 
100 mg
!
Semaglutide
placebo
0 mg, 
370μL
Follow-up 
!
Sitagliptin
!
Semaglutide 
placebo
(1.0 mg)
175
Screening 
!
Sitagliptin 
100 mg
!
Semaglutide
placebo
0 mg, 
190μL 
!
Sitagliptin 
100 mg
!
Semaglutide
placebo
0 mg, 
370μL
!
Sitagliptin 
100 mg
!
Semaglutide
placebo
0 mg, 
740μL
Follow-up 
All on background medication of metformin  ≥ 1500 mg (or maximum tolerated dose ≥ 1000 mg) throughout the trial.
After randomisation subjects will follow a fixed dose escalation for semaglutide and semaglutide 
placebo. The maintenance dose of 0.5 mg will be reached after 4 doses (4 weeks) of 0.25 mg. The 
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maintenance dose of 1.0 mg will be reached after 4 doses (4 weeks) of 0.25 mg, followed by 4 
doses (4 weeks) of 0.5 mg. Doses must not be changed during the trial after the maintenance dose 
has been reached.
Semaglutide injections should be administered in the thigh, abdomen or upper arm, and should be
taken on the same day of the week during the trial. Both semaglutide and sitagliptin can be taken 
any time of day irrespective of meals.
If necessary, the trial product may be discontinued for safety reasons. In case trial product is 
discontinued, subjects will not be withdrawn from trial but should continue to follow scheduled 
visits to the extent possible (see section 6.5.1).
Trial product will be add-on in subjects failing on metformin monotherapy.
Subjects must not be prescribed other GLP-1 RA in the period between V9 and V10 or V9A and 
V10A.
5.3.1
Missed dose
If a semaglutide dose is missed, it should be administered as soon as noticed, provided the time to 
the next scheduled dose is at least 2 days (48 hours). If a dose is missed and the next scheduled dose 
is less than 2 days (48 hours) away, the subject should not administer a dose until the next 
scheduled dose. A missed dose should not affect the scheduled dosing day of the week.
5.3.2
Background medication
Subjects should upon inclusion continue pre-trial background medication throughout the entire trial. 
The background medication should be maintained at the stable, pre-trial dose and frequency during 
the whole treatment period unless rescue medication is needed (see section 6.4). 
Metformin is considered background medication (non-investigational medicinal product) and will 
not be provided by Novo Nordisk A/S (except for Brazil where Metformin will be provided by 
Novo Nordisk Farmacêutica do Brasil Ltda). Metformin should be used in accordance with standard 
of care in the individual country at the discretion of the investigator and the daily dose should be 
unchanged throughout the trial unless the rescue criteria are met. However the maximum approved 
dose in the individual country must not be exceeded. Treatment with metformin extended/slow 
release formulations is allowed.
5.3.3
Treatment after end of trial
When discontinuing trial products the subject should be switched to a suitable marketed product at 
the discretion of the investigator. 
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(Brazil: After the study ending, if the investigator decides that the study medication is the best 
treatment option for the subject, the access to the study medication will be assured by the trial 
sponsor at no costs, according to the current regulations of Brazilian National Council of Health and 
Health Authority). 
5.4
Rationale for treatment
Semaglutide has been developed for s.c. administration. The doses of 0.5 mg and 1.0 mg once-
weekly has been chosen based on careful evaluation to strike a satisfactory balance of efficacy and 
safety that would satisfy the majority of patients. Hence duration and the dose of the randomised 
treatments are considered adequate for obtaining meaningful information on efficacy and safety in 
accordance with the trial objectives. Subjects will enrol for a treatment period of 30 weeks in order 
to be able to evaluate full effect as well as durability of the primary and secondary endpoints as well 
as a reasonable safety assessment.
For further information please refer to Investigator’s Brochure, semaglutide (NN9535)
(subcutaneous administration), Type 2 Diabetes and any updates hereof27.
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6
Trial population
6.1
Number of subjects 
Planned number of subjects to be screened (i.e. documented informed consent): Up to 1750
Planned number of subjects to be randomised: 
1050
Expected number of subjects to complete the trial: 
840
Planned number of Chinese subjects to be randomised: 
792
Expected number of Chinese subjects to complete the trial: 
636
6.2
Inclusion criteria
For an eligible subject, all inclusion criteria must be answered "yes".
1. Informed consent obtained before any trial-related activities. Trial-related activities are any 
procedures that are carried out as part of the trial, including activities to determine suitability for 
the trial
2. Male or female, age ≥ 18 years at the time of signing informed consent
(For Korea: Male or female, age above or equal to 19 years at the time of signing informed 
consent.)
3. Subjects diagnosed with type 2 diabetes and on stable treatment in a period of 60 days prior to 
screening with metformin ≥ 1500 mg (or maximum tolerated dose ≥ 1000 mg). Stable is defined 
as unchanged medication and unchanged daily dose
4. HbA1c 7.0 – 10.5 % (53-91 mmol/mol) (both inclusive)
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 informed consent
3. Female who is pregnant, breast-feeding or intends to become pregnant or is of childbearing 
potential not using an adequate contraceptive method throughout the trial including the 5 week 
follow-up period (adequate contraceptive measure as required by local regulation or practice)
(China: Sterilization, intrauterine device (IUD), oral contraceptives or barrier methods).
(Brazil: For women who expressly declare free of the risk of pregnancy, either by not engaging 
in sexual activity or by having sexual activity with no birth potential risk, use of contraceptive 
method will not be mandatory).
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4. Receipt of any investigational medicinal product within 90 days before screening (Brazil:
Participation in other trials within one year prior to screening visit (V1) unless there is a direct 
benefit to the research subject at the Investigator´s discretion)
5. Any disorder which, in the opinion of the investigator, might jeopardise subject’s safety or 
compliance with the protocol
6. Treatment with glucose lowering agent(s) other than stated in the inclusion criteria in a period 
of 60 days before screening. An exception is short-term treatment (≤7 days in total) with insulin 
in connection with inter-current illness
7. Use of non-herbal Chinese medicine or other non-herbal local medicine with 
unknown/unspecified content. Herbal traditional Chinese medicine or other local herbal 
medicines may, at the Investigator’s discretion, be continued throughout the trial 
8. History of pancreatitis (acute or chronic)
9. Screening calcitonin value  ≥ 50 ng/L (pg/mL)
10. Personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine 
neoplasia syndrome type 2 (MEN 2)
11. Impaired renal function defined as eGFR < 60 ml/min/1.73 m2 per MDRD formula (4 variable 
version)
12. Acute coronary or cerebrovascular event within 90 days before  randomisation
13. Heart failure, New York Heart Association (NYHA) class IV
14. Proliferative retinopathy or maculopathy requiring acute treatment. Verified by fundus 
photography or dilated fundoscopy performed within the past 90 days prior to randomisation in 
accordance with the instructions in Section 8.4.8.
15. Diagnosis of malignant neoplasm in the previous 5 years (except basal cell skin cancer or 
squamous cell skin cancer)
16. Mental inability, unwillingness or language barrier precluding adequate understanding of or 
compliance with study procedures
6.4
Rescue criteria
If any of the fasting plasma glucose (FPG) values exceed the limits outlined below and no 
intercurrent cause of the hyperglycaemia can be identified the subject should be called for an 
unscheduled visit as soon as possible:
!
15.0 mmol/L (270 mg/dl) from week 0 to end of week 5
!
13.3 mmol/L (240 mg/dl) from week 6 to end of Week 11
!
11.1 mmol/L (200 mg/dl) from week 12 to end of trial
A confirmatory FPG should be obtained. If the confirmatory FPG exceeds the values described 
above the subject should be offered treatment intensification (rescue medication) at the discretion of 
the investigator and in accordance with ADA/European Association for the Study of Diabetes42, 43  
(excluding GLP-1 RAs, DPP-4 inhibitors and amylin analogues). Rescue medication 
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(intensification of existing background medication and/or initiation of new medication) and any 
changes hereto should be captured on the concomitant medication form in the eCRF. Rescue 
medication should be prescribed as add-on to randomized treatment unless contraindicated 
according to the local sitagliptin label. In this case trial medication should be discontinued before 
initiation of rescue therapy. Subjects should continue to follow the protocol-specified visit schedule 
even if rescue treatment has been initiated.
6.5
Withdrawal criteria
6.5.1
Discontinuation of trial product
All efforts should be made to keep the subjects on trial product. However in case of a safety 
concern or unacceptable intolerability the trial product may be discontinued at the investigator’s 
discretion.
Trial product must be discontinued in case of: 
!
Safety concern related to trial product or unacceptable intolerability
!
included in the trial in violation of any of the inclusion and/or exclusion criteria
!
Pregnancy
!
Intention to become pregnant
!
Simultaneous participation in another clinical trial of an approved or non-approved 
investigational medicinal product
!
Calcitonin ≥ 100 ng/L (see appendix A)
For procedures to be performed in case of discontinuation of trial product (see section 8.1.6.2). 
Subjects discontinuing trial product prematurely should continue with the scheduled site contact. 
Subjects discontinued from trial product should be prescribed alternative therapy at the 
investigator´s discretion. However subjects must not be prescribed other GLP-1 RA in the period 
between V9 and V10 or V9A and V10A.
6.5.2
Withdrawal from trial
The subject may withdraw 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. Please see section 8.1.7 for procedure to be performed in case of subject withdrawal.
Subjects should stay in the trial irrespective of lack of adherence to randomised treatment, lack of 
adherence to visit schedule, missing assessments, trial product discontinuation due to AE (see 
section 6.5.1), unwillingness to cope with injection regimen, development of co-morbidities or 
clinical outcomes.
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A subject who agrees to provide information concerning morbidities which are relevant for the 
assessments of cardiovascular outcomes and/or other trial end-points at the planned end of the trial 
should not be considered withdrawn from the trial.
Subjects who consider withdrawing from the trial should as a minimum be encouraged to have 
procedures performed according to the end of treatment visit (V9) and the follow up visit (V10), 
please see 8.1.7.
Only subjects who decline any further contact with the site in relation to the trial, and hence do not 
agree to report information which is relevant for the assessments of cardiovascular outcomes and/or 
other trial end-points at the end of trial should be considered as withdrawn from the trial.
6.6
Subject replacement
Subjects who are withdrawn will not be replaced.
6.7
Rationale for trial population
This trial will be carried out in China and several other countries. The aim is to include a broad 
diabetes population, hence the limited number of exclusion criteria. Subjects with type 2 diabetes 
who are inadequately controlled on metformin monotherapy will be included in the trial. As
sitagliptin is indicated as monotherapy or in combination with metformin in China, subjects on 
other oral anti-diabetic drugs (OADs) are not included.
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7
Milestones
Planned duration of recruitment period (i.e. FPFV– LPFV): 
26 weeks
End of trial is defined as last patient last visit.
Planned date for first patient first visit (FPFV): 
28-Aug-2017
Planned date for last patient first visit (LPFV): 
26-Feb-2018
Planned date for last patient last visit (LPLV): 
05-Nov-2018
To ensure that only the required number of subjects is randomised, screened subjects will be 
monitored closely via interactive voice response system/interactive web response system (IWRS).
A recruitment strategy will be developed in corporation with the participating countries to secure 
sufficient number of subjects from China and the other participating countries.
Recruitment will be monitored on an on-going basis by sponsor. Prior to FPFV all sites should have 
a recruitment strategy in place detailing how many subjects they can recruit within a certain period. 
If a site has not enrolled the number of subjects according to the recruitment strategy, the remaining 
subjects may be reallocated. 
The screening and randomisation rate will be followed closely via IWRS in order to estimate when 
to stop screening. All investigators will be notified immediately when the enrolment period comes 
to an end, after which no subjects must be screened, and the IWRS will be closed for further 
screening. All subjects included in the screening period by the time of IWRS closure and eligible 
for randomisation will be randomised.
Trial registration:
Information of the trial will be disclosed at clinicaltrials.gov, chinadrugtrials.org.cn and 
novonordisk-trials.com. According to the Novo Nordisk Code of Conduct for Clinical Trial 
Disclosure, it will also be disclosed according to other requirements such as those of the 
International Committee of Medical Journal Editors (ICMJE)48, the Food and Drug Administration 
Amendment Act (FDAAA) 49, European Commission Regulation for EudraCT50 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).
The investigator must keep a subject screening log, a subject identification code list and a subject 
enrolment log. The subject screening log and subject enrolment log may be combined in one list
and may be generated from the IWRS.
In addition, the investigator must keep a log of staff and delegation of task(s) at site. Investigator 
must sign the log of staff and delegation of task(s) at site at the time of delegation of tasks.
8.1.1
Screening visit 1 (V1)
For procedures and assessments performed at screening, please see flow chart (see section 2).
The IWRS must be contacted to register the subject as screened (see section 10). Subject will be
assigned a unique number (lowest available number allocated to site) which is maintained
throughout the trial. It must be stated in the medical record that the subject is participating in the 
current trial. 
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. The subjects should be reminded to show the card to other health care providers, as 
applicable.
Once all data relating to screening V1 have been obtained, these must be reviewed by the 
investigator to ensure that the subject is eligible to continue the trial.
8.1.1.1
Screen failures
For screening failures the screening failure form 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 case report form eCRF. Follow-up of SAEs must be carried out 
according to section 12.
A screening failure session must be made in the IWRS. The case book must be signed in eCRF.
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8.1.1.2
Re-screening
Re-sampling or re-screening is NOT allowed if the subject has failed one of the inclusion or 
exclusion criteria related to laboratory parameters.
8.1.2
Fasting visits
The subjects should attend several visits in a fasting state (see section 2). Fasting is defined as 
having consumed only water within the last 6 hours prior to the visit.. Glucose lowering agents and 
trial product cannot be taken until after blood sampling has been performed but other prescribed 
medication should be taken. An exception from this is the follow-up visit (V10) and follow-up 
premature discontinuation visit (V10A) where fasting is defined as having consumed only water 
within the last two hours prior to the visit. If the subject is not fasting as required, the subject must
be called in for a new visit within the visit window to have the fasting procedures done. 
8.1.3
Randomisation V2
For procedures and assessments performed at randomisation (see section 2).
Visit 2 will take place two weeks (±7 days) after screening V1.
Eligible subjects will be randomised into one of four treatment arms. The IWRS will allocate the
dispensing unit number (DUN) of trial product to be dispensed to the subject.
Trial product will be dispensed to the subject by the site, hospital pharmacy or equivalent with
different intervals during the trial. Subject will be instructed in administration of sc injection of trial
product and the investigator must document that a direction for use (DFU) is given orally and/or in
writing. Date, time and dose of first administration of trial product will be captured in the eCRF.
Please see section 9 for further information about the trial product.
8.1.4
Visits
For visit numbers, timing of site visits, phone contacts and visit windows during the trial period,
please refer to the flow chart (see section 2). Planned visits can be re-scheduled within the allowed 
visit window.
It is the responsibility of the investigator to ensure that all site visits and phone contacts occur 
according to the flow chart (2). 
8.1.5
Missed visits and unscheduled visits
If a visit is missed and it is not possible to re-schedule, every effort should be made to ensure
information is collected at a telephone contact. Subjects will be invited for the next scheduled visit 
according to visit schedule.
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If a subject is unable or unwilling to attend the subsequent visit(s) the investigator should aim to at 
least have the subject attending the end of treatment visit and follow-up visit as these two visits 
should be performed for all subjects regardless of compliance with the protocol and adherence to 
the treatment (see section 8.1.6). 
If a subject attends the clinic for a visit not described in the protocol, an unscheduled visit form 
must be completed. This only applies if assessments are done, hence not for the purpose of re-test of 
blood- or urine sampling, or re-supply of trial product. In case of re-supply a dispensing session 
should be made in the IWRS selecting additional medication. Re-scheduling of fasting visit samples 
is not considered as an unscheduled visit.
8.1.6
End of treatment (V9/9A) and Follow-up (V10/10A)
8.1.6.1
Subjects completing the treatment period as per protocol
An end of treatment visit (V9) should be scheduled when the subject has completed the treatment 
period as described per protocol and a follow-up visit (V10) should be performed at least 5 weeks 
after (+7 days visit window). Please see the flow chart for details (section 2).
The follow-up visit serves to collect AEs, technical complaints, hypoglycaemic episodes, ECG, 
concomitant medication and blood sampling for anti-semaglutide antibodies .
8.1.6.2
Subjects who prematurely discontinue trial product
For subjects who discontinue trial product prematurely the visit end of treatment – premature 
discontinuation (V9A) should be scheduled shortly after subject has discontinued trial product. The 
visit follow-up – premature discontinuation (V10A) should be scheduled at least 5 weeks after
discontinuation of trial product (+7 days visit window). Please see the flow chart for details (section 
2).
Subjects discontinuing trial product prematurely should continue with the scheduled site contacts. If 
necessary, in order to retain the subject in the trial, site visits can be replaced by phone contacts 
after discontinuation of trial product. However, as a minimum these subjects will be called in for 
end of treatment (V9) and follow-up (V10) at the time of the scheduled completion of the trial.
8.1.7
Withdrawals
Subjects who consider withdrawing from the trial should as a minimum be encouraged to have 
procedures performed according to the end of treatment visit (V9) as soon as possible and the 
follow up visit (V10) at least 5 weeks after but not more than 6 weeks after, if possible. If a subject 
has already prematurely discontinued from trial product and previously attended visit V9A and visit 
V10A, no further visits should be attended.
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The End of Treatment and 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 site. The case book must be signed by the 
investigator in eCRF and a premature discontinuation of trial product session must be made in the 
IWRS (see section 10).
Although a subject is not obliged to give his/her reason(s) for withdrawing from a trial, the 
investigator must make a reasonable effort to ascertain the reason(s), while fully respecting the 
subject's rights. Where the reasons are obtained, the primary reason for not completing the trial
must be specified on the end-of-trial form in the CRF (see section 6.5).
8.1.8
Investigator’s assessment
Review of diaries, patient reported outcomes (PROs), laboratory reports, ECGs, eye examination 
(fundus photography/dilated fundoscopy), physical examination etc. must be documented either on 
the front page of the documents and/or in the subject's medical record. The signed 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? (No/Yes)
For laboratory report values outside the reference range, the investigator must specify whether the 
value is clinically significant or clinically non-significant. All laboratory printouts must be signed 
and dated by the investigator on the day of evaluation. The signed laboratory report is retained at 
the site as source documentation.
In case of abnormal clinical 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 subjects’ medical record and record this in the concomitant illness form in the eCRF. At 
subsequent visits any clinically significant changes or new clinically significant findings must be 
reported as an AE according to section 12.
Investigator or site staff must review the diary to ensure that AEs, including overall change in 
health and concomitant medication are reported. 
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.
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8.2
Subject related information 
8.2.1
Demography
The following information must to be recorded in the subject’s medical record and will be 
transcribed into eCRF at screening V1:
!
Date of birth(according to local regulation)
!
Sex
!
Race (according to local regulation)
!
Ethnicity (according to local regulation)
8.2.2
Diabetes history and diabetes complications
Diabetes history and diabetes complications will be recorded at screening and consists of:
!
Date of diagnosis of type 2 diabetes
!
Information regarding diabetes complications including date of onset
o
Diabetic retinopathy
o
Diabetic neuropathy
o
Diabetic nephropathy
o
Macroangiopathy (including peripheral vascular disease)
8.2.3
Concomitant illness and medical history
A concomitant illness is any illness that is present at the start of the trial (V1).
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. Pre-existing conditions, including 
those found as a result of screening procedures performed at V1 and V2 should be reported as 
medical history or concomitant illness.
The information collected for concomitant illness and medical history should include diagnosis, 
date of onset and date of resolution or continuation, as applicable.
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.
Concomitant illness and medical history must be recorded in the subject’s medical record and will 
be transcribed into eCRF.
The following must be recorded in the eCRF on the disease specific forms only, i.e. not on the 
medical history/concomitant illness form:
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!
History of cardiovascular disease (CVD) (e.g. ischaemic heart disease, MI, heart failure incl. 
NYHA class, hypertension, stroke, peripheral arterial disease)
!
History of gallbladder disease (e.g. gallstone, cholecystitis, cholecystectomy)
It must be possible to verify the subject’s medical history in source documents such as subject’s 
medical record. If a subject is not from the investigators own practice; the investigator must make 
reasonable effort to obtain a copy of subject’s medical record from relevant party e.g. primary 
physician. The investigator must document any attempt to obtain external medical information by 
noting the date(s) when information was requested and who has been contacted.
8.2.4
Concomitant medication
A concomitant medication is any medication, other than the trial product, which is taken during 
the trial, including the screening and follow-up periods.
Details of any concomitant medication must be recorded at visit 1. Changes in concomitant 
medication, including antidiabetic treatment and rescue treatment, must be recorded at each visit as 
they occur. The eCRF should be updated accordingly.
The information collected for each concomitant medication includes trade name or generic name, 
indication, start date (only start year is applicable if more than one year) and stop date or 
continuation. Total daily dose is only applicable for antidiabetic medication.
If a change is due to an AE, then this must be reported according to Section12 . If the change 
influences the subject’s eligibility to continue in the trial, the monitor must be informed.
8.2.5
Tobacco use
Details of tobacco use must be recorded at V1. Smoking is defined as smoking at least one 
cigarette, cigar or pipe daily. The collected information should include whether or not the subject 
smokes or has smoked.
It must be recorded whether the subject is a smoker according to the following criteria:
!
Never smoked
!
Is a previous smoker
o
cessation date
o
average cigarettes per day
o
approximate years of smoking
!
Is a current smoker
o
average cigarettes per day
o
approximate years of smoking
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8.2.6
Childbearing potential  
It must be recorded in the eCRF whether female subjects are of childbearing potential. 
Pregnancy testing must be performed on female subjects of childbearing potential as described in 
Section 8.5.2.5. Female subjects of childbearing potential must be instructed to use adequate 
contraceptive methods throughout the trial and until 5 weeks after end of treatment. 
Female of non-childbearing potential is defined as:
!
Female who has undergone a hysterectomy, bilateral oophorectomy or bilateral tubal 
ligation or are postmenopausal (e.g. women above the age of 50, who have been without 
menstrual period for at least 1 year).
!
Other medical reasons preventing childbearing potential. 
For Brazil only: For women who expressly declare free of the risk of pregnancy, either by not 
engaging in sexual activity or by having sexual activity with no birth potential risk, use of 
contraceptive method will not be mandatory.
8.2.7
Height
Height is measured without shoes in centimetres or inches and recorded in the eCRF to nearest ½ 
cm or 1/4 inch.
8.3
Assessments for efficacy
8.3.1
Body weight
Body weight must be measured in kilograms (kg) or pound (lb), with one decimal. The body weight 
should be measured without shoes and only wearing light clothing.
The same scale should preferably be used throughout the trial.
8.3.2
Waist circumference
The waist circumference is defined as the minimal abdominal circumferences located midway 
between the lower rib margin and the iliac crest.
Three consecutive measurements of waist circumference should be performed and recorded in the 
eCRF. The waist circumference will be measured in cm to the nearest ½ cm using a non-stretchable 
measuring tape (measuring tapes will be provided to the sites).
The subject should be measured in a standing position with an empty bladder and wearing light 
clothing with accessible waist. The subject should be standing with arms down their side and feet 
together. The tape should touch the skin but not compress soft tissue and twists in the tape should 
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be avoided. The subject should be asked to breathe normally and the measurement should be taken 
when the subject is breathing out gently.
8.3.3
BMI
BMI will be calculated by the eCRF using the equation as listed below:
BMI kg/m2 = Body weight (kg)/(Height (m) x Height (m)) or (kg/m2 = [lb/in2 x 703])
8.3.4
Systolic and diastolic blood pressure
The method for measuring systolic and diastolic blood pressure needs to follow the standard clinical 
practise at site, but as a minimum the following guidelines should be adhered to:
!
Avoid caffeine, smoking and exercise at least 30 minutes prior to measuring the blood 
pressure
!
The blood pressure should be measured in a sitting position, with the legs uncrossed, the 
back and arms supported
!
Subjects should be sitting for five minutes before the measurement is taken
!
Subject or the observer should not talk during the measurement
It is recommended to use the same arm as used at V1 for subsequent measurements. 
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8.4
Assessments for safety
The timing of the assessments for safety are outlined in the flow chart (see section 2).
8.4.1
Adverse events
AEs must be recorded at each visit in accordance with the procedures outlined in section 12.
Any clinically significant worsening from baseline of a previous finding must be reported as an AE.
8.4.2
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:
!
Trial product(s) involved
!
Classification of medication error
!
Whether the subject experienced any hypoglycaemic episode and/or adverse event(s) as a result 
of the medication error
!
Suspected primary reason for the medication error
For definition of medication errors, see section 12.1.3
8.4.3
Adverse events requiring additional data collection
For the following AEs additional data collection is required and specific event forms must be 
completed 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
!
Hypersensitivity reaction
!
Neoplasm (excluding thyroid neoplasm)
!
Pancreatitis
!
Renal event
!
Thyroid disease (including thyroid neoplasm)
!
Hepatic event
!
Diabetic retinopathy
!
Laboratory outlier
See appendix B for details about the additional information to report. In case any of these events 
fulfil the criteria for a serious adverse event, please report accordingly, see Section 12.
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8.4.4
Hypoglycaemic episodes
Plasma glucose (PG) should always be measured and recorded when a hypoglycaemic episode is 
suspected.
All PG values:
!
≤ 3.9 mmol/L (70 mg/dL) or
!
3.9 mmol/L (70 mg/dL) occurring in conjunction with hypoglycaemic symptoms
should be reported in the diary according to the instructions below and section 8.6.2 throughout the
trial from V1 to V10/10A.
All information must be transcribed into the eCRF (hypoglycaemic episode form) throughout the
trial. For Novo Nordisk classification of hypoglycaemia, see Section 
Upon onset of a hypoglycaemic episode the subject is recommended to measure PG every 15 
minutes until the SMPG value is >3.9 mmol/L (70 mg/dL) and/or symptoms have been resolved in 
accordance to current guidelines51.
A SMPG value ≤ 3.9 mmol/L (70 mg/dL) or hypoglycaemic symptoms must be recorded in the 
diary at the hypoglycaemic episode form by the subject. Repeated SMPG measurements and/or 
symptoms will by default be considered as one hypoglycaemic episode until a succeeding SMPG 
value is > 3.9 mmol/L (70 mg/dL) and/or symptoms have been resolved. One hypoglycaemic 
episode form is to cover these measurements and/or symptoms.
In case of several low SMPG values within the hypoglycaemic episode, the lowest value is the one 
that will be reported as the SMPG value for the hypoglycaemic episode but the start time of the 
episode will remain as the time for the first SMPG value and/or symptom.
The record should include the following information:
!
Start date and time of the hypoglycaemic episode.
!
Stop date and time of the hypoglycaemic episode (stop time is the first time the PG value is 
>3.9 mmol/L (70 mg/dL) and/or symptoms have been resolved).
!
If a stop date and time is not reported, a hypoglycaemic episode will cover a period of 60 
minutes.
!
The PG level before treating the episode (if available) and any follow up measurements.
!
The lowest value measured during the hypoglycaemic episode will be reported as the PG 
value for the episode, the remaining values will be kept as source data in the diary.
!
Whether the episode was symptomatic (Yes/No).
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!
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 other anti-diabetic medications prior to 
the episode.
!
Date and time of last main meal (not including snacks) prior to the episode.
!
Whether the episode occurred in relation to physical activity.
!
Change in any concomitant illness
!
Any sign of fever and/or other acute disease.
!
Whether the subject was asleep when the episode occurred.
– If yes, whether the symptoms of the episode woke up the subject. The answer to the
question: "Was the subject able to treat him/herself?" must be answered "No" for an episode 
requiring assistance of another person to actively administer carbohydrate, glucagon, or take 
other corrective actions. PG concentrations may not be available during an event, but
neurological recovery following the return of PG to normal is considered sufficient evidence 
that the event was induced by a low PG concentration51. 
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), 
miscalculation of dose of antidiabetic medication, other factors not listed or unknown)
!
Did the subject experience seizure?
!
Was the subject unconscious/comatose?
!
Did the subject experience any of the following symptoms52 ?
– Autonomic: sweating, trembling, hunger or palpitations (rapid or irregular heart beat)
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– 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. The subject must be questioned whether any of the low values were severe, i.e. whether
the subject was able to self-treat or not. If the subject was not able to self-treat, it has to be reported
as a severe hypoglycaemic episode. 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 data53, 54. 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.
8.4.5
Electrocardiogram
12-lead electrocardiograms (ECG) will be performed locally by the investigator or delegated staff
during the trial (see section 2). The ECG print out must be interpreted, dated and signed by 
investigator as described in section 8.1.8. ECG printed is source documentation. 
Additional unscheduled ECG recordings can be performed at the investigator´s site at investigator´s 
discretion at other visits than the planned ECG visits.
8.4.6
Physical examination
A physical examination will be performed by the investigator according to local procedure (see 
section 2). A physical examination must include:
!
General appearance
!
Head, ears, eyes, nose, throat, neck
!
Thyroid glands
!
Respiratory system
!
Cardiovascular system
!
Gastrointestinalsystem including mouth
!
Musculoskeletal system
!
Central and peripheral nervous system
!
Skin
!
Lymph node palpation
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8.4.7
Pulse
Pulse (beats per minute) should be recorded in the eCRF at site visits after resting for 5 minutes in a 
sitting position.
8.4.8
Eye examination 
It is allowed to perform the baseline fundus photography or dilated fundoscopy between the 
screening visit and the randomisation visit.
Results of a fundus photography or dilated fundoscopy must be available and evaluated by the 
investigator before randomisation. If the subject had a fundus photography or dilated fundoscopy 
performed within 90 days prior to randomisation, the investigator may base their evaluation upon 
the results of that examination. However, the examination must be repeated before randomisation if 
the subject experienced worsening of visual function since the last examination. If the subject did 
not have a fundus photography or dilated fundoscopy performed within 90 days prior to 
randomisation, such examination must be performed by the investigator or other qualified health 
care professional prior to randomisation. If the applicable fundus photography or dilated 
fundoscopy was performed before the subject signed the informed consent form, it must be 
documented in the medical records that the reason for performing the examination was not related 
to this trial.
In addition, fundus photography /dilated fundoscopy must be performed at V9. In the case of 
premature discontinuation, the assessments must be performed both at V9A and at V9. The 
assessments at V9A and V9 can be performed in the period between V9A and V10A and between 
V9 and V10, respectively, but the results should be available no later than at V10A and V10, 
respectively. 
The investigator should indicate whether the outcome of the eye examination was normal or
abnormal, and, if abnormal, indicate whether clinically significant. Relevant findings as a result of 
this screening procedure must be recorded as diabetes history and diabetes complications or 
concomitant illness/medical history in accordance with Section 8.2.2 and 8.2.3 respectively.
8.5
Laboratory assessments
For laboratory analysis of efficacy and safety parameters will be drawn during the 37 weeks of the 
trial. The laboratory analyses will be performed by a central laboratory except for anti-semaglutide 
antibodies and IgE antibodies where a special laboratory will be used. In the situation of suspicion 
of acute pancreatitis or severe hypersensitivity described in appendix B, a local laboratory will be 
used. Laboratory samples comprise both urine and blood samples. 
Descriptions of assay methods, laboratory supplies and procedures for collecting, handling, storage 
and shipping of samples and information regarding who will perform the assessments will be 
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described in the laboratory manual provided by the central laboratory (for central and special 
laboratory details, see Attachment I).
Samples will be coded in order to keep subject identity anonymous.
Laboratory samples may be drawn at another day than on the day of the actual visit as long as it is 
within the visit window outlined 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 it is required for the sensitivity of the analysisthat
the subject is fasting. 
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 must be reported to the investigator.
For Brazil: All laboratory results will be communicated to the investigators.
Central laboratory will provide laboratory results to the investigator on an on-going basis and the 
investigator must reviewall laboratory results for signs of concomitant illness and AEs and report 
these according to section 12. An exception to this is that anti-semaglutide antibody result will not 
be available to the investigator during the trial. However these results will be provided to the 
investigator upon request after the completion of the clinical trial report(CTR).
All laboratory samples will be destroyed on an on-going basis after analysisand no later than CTR, 
except for samples taken for anti-semaglutide antibody samples, which will be kept until market 
authorisation approval or rejection of file.(For Brazil:the laboratory samples for Brazilian subjects 
will be destroyed at the latest at the completion of the CTR, including samples for anti-semaglutide 
antibody analysis. No sample will be stored after the completion of CTR).
The investigator should ensure that thelast samples are shipped to the central laboratory within 24 
hours after the last subject visit last at the site.
8.5.1
Laboratory assessments for efficacy
Blood samples must be drawn according to flow chart (see section 2) and analysed at the central 
laboratory to determine levels of the following efficacy laboratory parameters:
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8.5.1.1
Glucose metabolism
!
HbA1c
!
Fasting plasma glucose
!
Fasting insulin
!
Fasting C-peptide
!
Fasting glucagon
!
Fasting pro-insulin
8.5.1.2
Biomarker
!
hsCRP
8.5.1.3
Lipids (all fasting)
!
Total cholesterol
!
LDL-cholesterol
!
VLDL-cholesterol
!
HDL-cholesterol
!
Triglycerides
!
Free fatty acids
8.5.1.4
Self measured plasma glucose (SMPG)
At screening V1 subjects will be provided with a blood glucose meter including lancets, plasma-
calibrated test strips and control solutions. Oral and written directions for use of the device 
including the performance of calibrations according to the manufacturer’s instructions will be 
provided to the subject. Sites should, as necessary, repeat the directions for use to the subject at 
subsequent visits.
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. When using blood glucose meters the measurement is 
performed with capillary blood calibrated to plasma equivalent glucose values i.e. the measurement 
is performed on blood while the value is reported as plasma. It is important to be aware of this 
difference throughout the protocol. 
Only the blood glucose meter provided by Novo Nordisk should be used for the measurements 
required in the protocol.
Subjects should be instructed in how to record the results of the SMPG values in the diaries. The 
record of each SMPG value should include date, time and value. All data from the diary must be 
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transcribed into the eCRF during or following the contact. If obtained via phone and a discrepancy 
is later detected, 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.
8.5.1.5
7 point profile
The subject will be instructed to perform a SMPG 7-point profile, preferably within one week prior 
to the site visit according to the flow chart (see section 2) on a day where the subject does not 
anticipate unusual strenuous exercise.
Time points, including date and time, for the 7-point profile: 
!
before breakfast
!
90 min after start of breakfast
!
before lunch
!
90 min after start of lunch
!
before dinner
!
90 min after start of dinner
!
at bed time
8.5.2
Laboratory assessments for safety
Laboratory samples must be drawn according to flow chart (see section 2) and analysed at the 
central laboratory to determine levels of the following safety laboratory parameters:
8.5.2.1
Anti-semaglutide antibodies
Blood samples will be drawn for measurement of serum antibodies to semaglutide at selected visits 
in randomised subjects. Positive anti-semaglutide antibody samples will be further characterised for 
cross reactivity to native GLP-1 (see section 2). Samples taken at follow-up which are positive for 
anti-semaglutide antibodies will be further characterised for in vitro neutralising effect towards 
semaglutide. In addition, samples taken at follow-up which are positive for cross-reactivity against 
native GLP-1 will be further analysed for in vitro neutralising effect towards native GLP-1.
Follow-up antibody (taken at the follow-up V10/10A) samples must be taken fasting (as a minimum 
by only having consumed water for at least two hours).
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8.5.2.2
Biochemistry
!
Creatinine
!
Alanine aminotransferase (ALT)
!
Aspartate aminotransferase (AST)
!
Alkaline phosphatase
!
Sodium
!
Potassium
!
Albumin
!
Bilirubin (total)
!
Total protein
!
Urea
!
Creatine kinase
!
Calcium total
!
Calcium, albumin corrected (calcium, ionized)
!
Lipase
!
Amylase
8.5.2.3
Haematology
!
Haemoglobin
!
Haematocrit
!
Thrombocytes
!
Erythrocytes
!
Leucocytes
!
Differential count:
o
eosinophils
o
neutrophils
o
basophils
o
monocytes
o
lymphocytes
8.5.2.4
Calcitonin
Blood samples for the measurement of calcitonin concentration will be drawn as per flow chart (see 
section 2). In case any calcitonin value at any time of the trial is ≥10 ng/L, the algorithm in 
appendix A should be followed.
8.5.2.5
Pregnancy test
Females of childbearing potential will have a serum pregnancy test performed at all site visits (see 
Section 2). At visit 2, a urine pregnancy test must be performed prior to randomisation.
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In case a menstrual period is missed or if pregnancy is suspected at any time during the trial, a urine 
pregnancy test should be performed. The subject should be instructed not to dose trial product 
before pregnancy has been ruled out.
Pregnancy testing will not be required (unless required by local law) for women of non-childbearing 
potential, such as but not limited to women who have undergone a hysterectomy, bilateral 
oophorectomy, bilateral tubal ligation or are postmenopausal (e.g. women above the age of 50, who 
have been without menstrual period for at least 1 year).
8.5.2.6
Urinalysis
Subjects will be asked to bring the first morning urine during the trial (see section 2). The urine 
sample will be analysed at the central laboratory to determine levels of the following parameters:
!
Urinary albumin to creatinine ratio (UACR)
!
Urinalysis by urine dip-stick: erythrocytes, protein, glucose and ketones, pH
8.6
Other assessments
8.6.1
Patient reported Outcome questionnaires
The following PRO questionnaires will be used in this trial:
!
SF-36v2TM
!
DTSQs
The questionnaires should be completed by the subject as specified in the flow chart (see section 2), 
preferably before any other trial related activities. It takes approximately 10 minutes to complete 
each questionnaire. The assessment must be reviewed as described in section 8.1.8. All results from 
the PRO questionnaires must be transcribed into the eCRF.
The PRO questionnaire will be used to assess subjects overall Health related Quality of Life and can 
also be used to estimate Quality Adjusted Life years (QALY) which is used in cost effectiveness 
calculations. 
8.6.1.1
SF-36v2TM
The SF-36v2™ questionnaire will be used to assess subjects overall Health related Quality of Life 
and can also be used to estimate QALY which is used in cost effectiveness calculations. This 
instrument contains 36 items and measures the individual overall health related quality of life on 8 
domains; physical functioning, role functioning, bodily pain, general health, vitality, social 
functioning, role emotional and mental health. 
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8.6.1.2
DTSQs
The DTSQs questionnaire will be used to assess subject’s treatment satisfaction. This instrument 
contains 8 items and measures the treatment for your diabetes (including insulin, tablets and/or diet) 
in terms of convenience, flexibility and general feelings regarding treatment. 
8.6.2
Subject diary
The subject must be provided with paper diaries at all visits, except the follow-up visit (V10 and 
V10A). If a subject prematurely discontinues trial product, diaries should not be dispensed and 
filled out by the subjects after the follow-up – premature discontinuation visit. For these subjects all 
available data will be collected. 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, time and dose of first dose of trial products (injection and tablet)
!
date, time and dose of last injection of trial product prior to each visit/phone contact
!
hypoglycaemic episodes
!
concomitant medication
!
AEs
!
SMPG 7-point profile
!
Urine pregnancy test for females of childbearing potential
The diaries should be collected at the visit described in the flow chart (see section 2). The 
recordings must be reviewed as described in section 8.1.8 and transcribed to the eCRF.
8.7
Subject compliance
Throughout the trial the investigator will remind the subjects to follow the trial procedures and 
requirements to ensure subject compliance. 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.
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 discovered to be non-compliant, the investigator must inform the subject of the 
importance of taking trial product as directed.
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9
Trial supplies
Trial supplies comprise trial products and auxiliary supplies. Additional details regarding trial 
supplies can be found in the Trial Materials Manual (TMM). 
Trial products must not be dispensed to any person not included in the trial. 
9.1
Trial products
The following trial products for subcutaneous injection will be provided by Novo Nordisk,
Denmark:
!
Semaglutide 1.34 mg/mL, solution for injection, 1.5 mL pre-filled PDS290 pen-injector
!
Semaglutide placebo, solution for injection, 1.5 mL pre-filled PDS290 pen-injector
The following trial products for oral administration will be provided by Novo Nordisk, Denmark:
!
Sitagliptin (Januvia®) 100 mg, tablet
!
Sitagliptin placebo, tablet
For both semaglutide and sitagliptin the placebo and active drug are identical with regard to 
appearance. 
Semaglutide both active drug and placebo are manufactured and supplied by Novo Nordisk, 
Denmark. Sitagliptin 100 mg and placebo is packed for use in clinical trials and supplied by Novo 
Nordisk, Denmark.
All trial products are considered investigational medicinal products (IMPs).
Refer to the appropriate IB or local label for more detailed information regarding the listed trial 
products. 
Each site will be supplied with sufficient trial products for the trial on an on-going basis controlled 
by the IWRS and according to enrolment and randomisation with different intervals during the trial. 
Subject will be instructed in administration of trial product and the investigator must document that 
a DFU is given orally and in writing at randomisation visit.
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9.2
Labelling
Labelling of the investigational medicinal products (IMPs) will be in accordance with Annex 1355,  
local law and trial requirements. Please refer to the TMM provided by Novo Nordisk for details 
regarding standard packages for the trial products.
9.3
Storage
Semaglutide preparations (both in-use and not in-use) must not be exposed to excessive heat or 
direct sunlight. Semaglutide preparations which have been frozen must not be used. Semaglutide 
must not be used, if it does not appear clear and colourless.
Trial product
Storage conditions
(not-in-use)
In-use conditions
Semaglutide 1.34 mg/mL and placebo
!
Store in a 
refrigerator (2°C 
to 8°C)
!
Do not freeze
!
Protect from 
light
!
Store below 30°C
!
Do not refrigerate
!
Do not freeze
!
Protect from light
!
Use within 1 
month*
Sitagliptin 100 mg and placebo
!
Do not store 
above 30°C
!
Do not freeze
!
Do not 
refrigerate
!
Protect from 
light and 
humidity
Not applicable
* In-use time starts when first dose is taken.
The investigator must ensure the availability of proper storage conditions, record and evaluate the 
temperature. The investigator must inform Novo Nordisk (via the assigned monitor) immediately if 
any trial product has been stored outside specified conditions (e.g. outside temperature range).
Fifteen minutes outside the indicated range is negligible, and should not be recorded as a deviation.
Trial products stored outside the temperature range are not to be used and must be stored separately 
within allowed temperature range until after evaluation of condition. Evaluation will be performed 
by Novo Nordisk. Trial products that have been stored improperly must not be dispensed to any 
subject before it has been re-evaluated and approved for further use by Novo Nordisk.
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Returned trial products (unused, partly used or used including empty packaging material) must be 
stored separately from non-allocated trial products.
The temperatures during storage should be monitored by a calibrated and stationary system. A 
temperature log must be kept to document storage within the right temperature interval and storage 
facilities should be checked frequently. Investigator must take appropriate action to avoid 
recurrence of the detected temperature deviation.
9.4
Drug accountability and destruction
The trial products will be dispensed to each subject as required according to treatment group. The 
IWRS will allocate trial product to the subject at each dispensing visit, starting at the randomisation 
visit. The correct DUN(s) must be dispensed to the subject.
The investigator or delegated person is responsible for ensuring that:
!
Trial products are not dispensed to any person not included in the trial
!
Drug accountability is performed using the IWRS drug accountability module
!
Subjects are instructed to return all used, partly used and unused trial product including 
empty packaging material at each dispensing visit and at End of Treatment visit 
!
All returned trial products (used/partial used and unused including empty packaging 
material) is kept and stored separately from non-allocated trial products
Destruction of trial products will be done according to local law after accountability is finalised at 
site and reconciled by monitor. Destruction of trial products must be documented.
9.5
Auxiliary supplies
The following auxiliary supplies will be supplied by Novo Nordisk in accordance with the TMM:
!
Needles for pre-filled pen systems
!
Blood glucose meters, including lancets, plasma-calibrated test strips and control solutions
!
Directions for use for PDS290 pen-injector
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10
Interactive web response system
A trial-specific IWRS will be set up which can be accessed at any time via the internet or telephone. 
Access to the IWRS must be restricted to and controlled by authorised persons. 
IWRS is used for: 
!
Screening
!
Screening failure
!
Randomisation
!
Medication arrival
!
Dispensing
!
Treatment discontinuation
!
Treatment completion
!
Drug accountability
!
Data change
!
Dispensing verification (when barcode scanner is used)
IWRS user manuals will be provided to each trial site.
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11 Randomisation procedure and breaking of blinded codes
The trial is a double-blind trial. A randomisation session will be carried out for all subjects by using 
the IWRS. At the randomisation visit subjects meeting all inclusion/exclusion criteria will be 
randomised in a 2:2:1:1 manner to receive one of four parallel treatments groups:
!
Semaglutide 0.5 mg once-weekly + sitagliptin placebo once-daily
!
Semaglutide 1.0 mg once-weekly + sitagliptin placebo once-daily
!
Sitagliptin 100 mg once-daily + semaglutide placebo (0.5) mg once-weekly
!
Sitagliptin 100 mg once-daily + semaglutide placebo (1.0) mg once-weekly
Randomisation will be stratified by country.
11.1
Breaking of blinded codes
If the trial site needs to break the code, Novo Nordisk should if possible, be contacted before the 
code is broken. 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.
If the code has been broken the subject must be discontinued from trial product but be asked to 
continue in the trial (see section 8.1.6.2). A treatment discontinuation session should be completed 
in IWRS. 
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 
monitor should be contacted and if monitor cannot get access the IWRS vendor helpdesk should be 
contacted.
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12 Adverse events, and technical complaints and pregnancies
12.1
Definitions
Adverse event 
An adverse event (AE) is any untoward medical occurrence in a subject administered a product, and 
which does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom or disease temporally associated with the use of a product, whether or not 
considered related to the product. 
An AE includes:
!
A clinically significant worsening of a concomitant illness.
!
A clinical laboratory adverse event (CLAE): a clinical laboratory abnormality which is 
clinically significant, ie an abnormality that suggests a disease and/or organ toxicity and is 
of a severity that requires active management. Active management includes active treatment 
or further investigations, for example change of medicine dose or more frequent follow-up 
due to the abnormality.
The following should not be reported as AEs:
!
Pre-existing conditions, including those found as a result of screening procedures (pre-
existing conditions should be reported as medical history or concomitant illness).
!
Pre-planned procedures unless the condition for which the procedure was planned has 
worsened from the first trial related activity after the subject has signed the informed 
consent.
!
Non-serious hypoglycaemia is an AE, but is reported on a hypoglycaemic episode form 
instead of on an AE form (see section 8.4.4).
The following three definitions are used when assessing an AE:
!
Severity assessment
–
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 assessment
The following terms are used when assessing the relationship between an AE and the relevant 
trial product(s): 
–
Probable - Good reason and sufficient documentation to assume a causal relationship.
–
Possible - A causal relationship is conceivable and cannot be dismissed.
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–
Unlikely - The event is most likely related to aetiology other than the trial product.
!
Final outcome
–
Recovered/resolved - The subject has fully recovered, or by medical or surgical 
treatment the condition has returned to the level observed at the first trial-related activity 
after the subject signed the informed consent.
–
Recovering/resolving - The condition is improving and the subject is expected to 
recover from the event. This term is only applicable if the subject has completed the trial 
or has died from another AE.
–
Recovered/resolved with sequelae - The subject has recovered from the condition, but 
with lasting effect due to a disease, injury, treatment or procedure. If a sequela meets an 
SAE criterion, the AE must be reported as an SAE.
–
Not recovered/not resolved - The condition of the subject has not improved and the 
symptoms are unchanged, or the outcome is not known.
–
Fatal - This term is only applicable if the subject died from a condition related to the 
reported AE. Outcomes of other reported AEs in a subject before he/she died should be 
assessed as "recovered/resolved", "recovering/resolving", "recovered/resolved with 
sequelae" or "not recovered/not resolved". An AE with fatal outcome must be reported 
as an SAE.
–
Unknown - This term is only applicable if the subject is lost to follow-up.
12.1.1
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 (eg following the 
event or clinical investigation the subject has significant, persistent or permanent change, 
impairment, damage or disruption in his/her body function or structure, physical activity and/or 
quality of life).
d. For example intensive treatment in an emergency room or at home of allergic bronchospasm, 
blood dyscrasiasis or convulsions that do not result in hospitalisation, or development of drug 
dependency or drug abuse.
The following adverse events must always be reported as an SAE using the important medical event 
criterion if no other seriousness criteria are applicable:
!
suspicion of transmission of infectious agents via the trial product
!
risk of liver injury defined as ALT or AST >3 x UNL and total bilirubin >2 x UNL, where no 
alternative aetiology exists (Hy's law).
Additional assessments should be made for events meeting the criterion of Hy’s law as stated above 
(see appendix B).
12.1.2
Non-serious adverse event
A non-serious AE is any AE which does not fulfil the definition of an SAE.
12.1.3
Medication errors
Medication errors concerning trial products are defined as:
–
Administration of wrong drug. Note: Use of wrong DUN is not considered a medication 
error.
–
Wrong route of administration, such as intramuscular instead of subcutaneous.
–
Administration of an overdose with the intention to cause harm (eg suicide attempt)
misuse or abuse of trial product.
–
Accidental administration of a lower or higher dose than intended. The administered 
dose must deviate from the intended dose to an extend 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 8.4.2.
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12.1.4
Adverse events requiring additional data collection
AEs requiring additional data collection are AEs where the additional data will benefit the 
evaluation of the safety of the trial product.
In this trial the following AEs require the completion of specific event forms in the eCRF, see Table 
12–1
Table 12–1
Adverse events requiring completion of specific event forms and/or are subject 
to event adjudication
Event
Specific event form
Event adjudication
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)
Hypersensitivity reaction
Yes
No
Neoplasm (excluding thyroid neoplasm)
Yes
Yes (only if malignant)
Pancreatitis
Yes
Yes (only if acute pancreatitis)
Renal event
Yes
No
Thyroid disease (including thyroid neoplasm)
Yes
Yes (only if malignant thyroid 
neoplasm or C-cell hyperplasia)
Death
No
Yes
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
Diabetic retinopathy
Yes
No
Laboratory outlier
Yes
No
For details about specific event form, see appendix B
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12.1.5
Technical complaint
A technical complaint is any written, electronic, or oral communication that alleges product 
(medicine or device) defects. The technical complaint may be associated with an AE, but does not 
concern the AE itself.
Examples of technical complaints:
!
The physical or chemical appearance of trial products (eg discoloration, particles or 
contamination)
!
The packaging material including labelling 
!
Problems related to devices (eg to the injection mechanism, dose setting mechanism, push 
button or interface between the pen and the needle)
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 (see section 2). 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. 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. 
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.
Some events will undergo event adjudication by the Event Adjudication Committee (EAC), please 
refer to Section 12.7.2. For AEs qualifying for event adjudication, the 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.
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Timelines for initial reporting of AEs:
The investigator must complete the following forms in the eCRF within the specified timelines:
!
SAEs: The AE form within 24 hours and the safety information form within 5 calendar
days of the investigator's first knowledge of the SAE.
!
SAEs requiring reporting on a specific event form : In addition to above, the specific 
eventI form within 14 calendar days of the investigator's first knowledge of the AE. 
!
Events for adjudication: The event adjudication  form must be completed within 14 
calendar days of investigator’s first knowledge of the AE, see section 12.7.2. The 
investigator should 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-m ail or courier within the same timelines as stated above. When the 
eCRF becomes available again, the investigator must re-enter the information on the form into the 
eCRF. 
Contact details (fax, telephone, e-mail and address) are provided in the investigators trial master 
file. 
Figure 12–1
Reporting of AEs
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Novo Nordisk assessment of AE expectedness:
Novo Nordisk assessment of AE expectedness is performed according to the following reference
documents:
!
Semaglutide: NN9535 IB27 (subcutaneous administration), Type 2 diabetes, current version 
and any updates thereto
!
Sitagliptin (Januvia®): EU Summary of Product Characteristics (SmPC)56 current version.
Reporting of trial product-related SUSARs by the sponsor:
Novo Nordisk will notify the investigator of trial product-related suspected unexpected serious 
adverse reactions (SUSARs) in accordance with local requirements and ICH GCP1 In addition, the 
investigator will be informed of any trial-related SAEs that may warrant a change in any trial 
procedure. 
In accordance with regulatory requirements, Novo Nordisk will inform the regulatory authorities, 
including European Medicines Agency (EMA), of trial product-related SUSARs. In addition, Novo 
Nordisk will inform the 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
If an AE is considered to have a causal relationship with a Novo Nordisk marketed product used as 
concomitant medication in the trial, it is important that the suspected relationship is reported to 
Novo Nordisk, e.g. in the alternative aetiology section on the safety information form. Novo 
Nordisk may need to report this adverse event to relevant regulatory authorities.
12.3
Follow-up of adverse events
The investigator must record follow-up information by updating 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 (eg corrections or additional) 
information and must be reported within 24 hours of the investigator's first knowledge of the 
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information. This is also the case for previously non-serious AEs which subsequently become 
SAEs. 
!
Non-serious AEs: Non-serious AEs must be followed until the outcome of the event is
"recovering/resolving", "recovered/resolved" or "recovered/resolved with sequelae" or until
the end of the follow-up period stated in the protocol, whichever comes first, and until all
queries related to these AEs have been resolved. Cases of chronic conditions, cancer or AEs
ongoing at time of death (where death is due to another AE) may be closed with the
outcome "recovering/resolving" or "not recovered/not resolved". Cases can be closed with
the outcome of "recovering/resolving" when the subject has completed the follow-up period
and is expected by the investigator to recover.
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 
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 and on any of the following products: 
!
Semaglutide 1.34 mg/mL solution for injection, 1.5 mL pre-filled PDS290 pen-injector
!
Semaglutide placebo, solution for injection, 1.5 mL pre-filled PDS290 pen-injector
!
Sitagliptin (Januvia®) 100 mg, tablet
!
Sitagliptin placebo, tablet
!
Needles for pre-filled pen systems
which occur from the time of first usage of the product until the time of the last usage of the 
product, must be collected and reported to Customer Complaint Center, Novo Nordisk.
Contact details (fax, e-mail and address)are provided in Attachment I to the protocol.
The investigator must assess whether the technical complaint is related to any AEsand/orSAEs..
Technical complaints must be reported on a separate technical complaint form:
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!
One technical complaint form must be completed for each affected DUN
!
If DUN is not available, a technical complaint form for each code or lot number must be
completed
The investigator must complete the technical complaint form in the eCRF within the following 
timelines of the trial site obtaining knowledge of the technical complaint:
!
Technical complaint assessed as related to an SAE within 24 hours
!
All other technical complaints within 5 calendar days
If the eCRF is unavailable or when reporting a technical complaint that is not subject related, the 
information must be provided on a paper form by fax, e-mail or courier to Customer Complaint 
Center, Novo Nordisk, within the same timelines as stated above. When the eCRF becomes
available again, the investigator must enter the information on the technical complaint form in the 
eCRF.
12.4.2
Collection, storage and shipment of technical complaint samples
The investigator must collect the technical complaint sample and notify the monitor within 5 
calendar daysof obtaining the sample at trial site. The monitor must coordinate the shipment to 
Customer Complaint Center, Novo Nordisk (the address is provided in Attachment I) and ensure 
that the sample is sent as soon as possible. A print or copy of the technical complaint form must be 
sent with the sample.If several samples are returned in one shipment, the individual sample and the 
corresponding technical complaint form must be clearly separated.
The investigator must ensure that the technical complaint sample contains the batchor lot number 
and, if available, the DUN.All parts of the DUN should be returned.
If the technical complaint sample is unobtainable, the investigator must specify on the technical 
complaint form why it is unobtainable. 
Storage of the technical complaint sample must be done in accordance with the conditions 
prescribed for the product.
12.5
Pregnancies
12.5.1
Pregnancies in female subjects
Female subjects must be instructed to notify the investigator immediately if they become pregnant 
during the trial. The investigator must report any pregnancy in subjects who have received trial 
product(s).
The investigator must follow the pregnancy until the pregnancy outcome and the newborn infant is 
one month of age.
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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 
(eg 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 (ie congenital anomalies, foetal death including 
spontaneous abortion and/or any anomalies of the foetus observed at gross examination or 
during autopsy), and/or when a congenital anomaly is diagnosed within the first month, 
further information has to be reported for the female subject on maternal form 2. In addition, 
information from the male partner has to be reported on the paternal form, after an informed 
consent has been obtained from the male partner. 
Initial reporting and follow-up information must be reported within 14 calendar days of the 
investigator's first knowledge of initial or follow-up information.
2. Reporting of AE information
The investigator has to report AEs in connection with the pregnancy as well as in the foetus 
and newborn infant(s). The SAEs that must be reported include abnormal outcome, such as 
foetal death (including spontaneous abortion), and congenital anomalies (including those 
observed at gross examination or during autopsy of the foetus), as well as other pregnancy 
complications fulfilling the criteria of an SAE.
Forms and timelines for reporting AEs:
Non-serious AEs: 
–
AE form* within 14 calendar days of the investigator's first knowledge of the initial or 
follow-up information to the non-serious AE.
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SAEs: 
–
AE form* 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.
*
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
Semaglutide
Events of nausea, vomiting and headache have been reported in connection with accidental 
administration of up to 4.0 mg semaglutide. No symptoms of hypoglycaemia have been reported in 
connection with overdose of semaglutide. In the event of overdose, appropriate supportive treatment 
should be initiated according to the subject’s clinical signs and symptoms. 
For other precautions, please see section 3.5.1.
Sitagliptin
During controlled clinical trials in healthy subjects, single doses of up to 800 mg sitagliptin were 
generally well tolerated. Minimal increases in QTc, not considered to be clinically relevant, were 
observed in one study at a dose of 800 mg sitagliptin. There is no experience with doses above 800 
mg in clinical studies. In Phase I multiple-dose studies, there were no dose-related clinical adverse 
reactions observed with sitagliptin with doses of up to 600 mg per day for periods of up to 10 days 
and 400 mg per day for periods of up to 28 days.
In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., remove 
unabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining 
an electrocardiogram), and institute supportive therapy if required. Sitagliptin is modestly 
dialysable. In clinical studies, approximately 13.5 % of the dose was removed over a 3- to 4-hour 
hemodialysis session. Prolonged hemodialysis may be considered if clinically appropriate. It is not 
known if sitagliptin is dialysable by peritoneal dialysis. 
For other precautions, please see section 3.5.5.
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12.7
Committees related to safety
12.7.1
Novo Nordisk safety committee
Novo Nordisk has constituted an internal semaglutide safety committee to perform ongoing safety 
surveillance. The 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 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 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 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 section 12.1.4 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 Standardized Definitions57.
The EAC will review copies in English (translated if necessary) of medical documentation received 
in the adjudication package (for example X-ray, ECGs, ultrasound images, discharge summaries, 
pathology reports, and death certificates). The investigator must provide medical documentation as 
soon as possible, when receiving a request from Novo Nordisk or the event adjudication vendor.
The AEs for adjudication are listed in Table 12-2
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Table 12–2
Adverse events for adjudication
Events
Description
Adjudication outcome
Death*
!
All-cause death
!
Cardiovascular death 
(including 
undetermined cause of 
death)
!
Non-Cardiovascular 
death
Acute Coronary Syndrome
Acute Coronary Syndrome conditions include: 
!
ST-elevation acute myocardial infarction 
(STEMI)
!
Non-ST elevation acute myocardial infarction 
(NSTEMI)
!
Silent MI 
!
Unstable angina pectoris (UAP) requiring 
hospitalisation
!
Acute myocardial 
infarction (STEMI or 
NSTEMI), silent MI
!
Unstable angina 
pectoris requiring 
hospitalisation
Cerebrovascular events
!
Episode of focal or global neurological 
dysfunction caused by brain, spinal cord, or 
retinal vascular injury as a result of 
haemorrhage or infarction
!
Transient Ischaemic Attack (TIA) is defined 
as a transient episode (< 24 hours) of focal 
neurological dysfunction caused by brain, 
spinal cord, or retinal ischaemia, without acute 
infarction
!
Ischaemic stroke
!
Haemorrhagic stroke
!
Undetermined stroke
!
TIA
Heart failure requiring 
hospitalisation
!
Hospitalisation with a primary diagnosis of 
heart failure (new episode or worsening of 
existing heart failure)
!
Heart failure requiring 
hospitalisation
Acute pancreatitis
The diagnosis of acute pancreatitis requires two of the 
following three features:
!
Abdominal pain consistent with acute 
pancreatitis (acute onset of a persistent, 
severe, epigastric pain often radiating to the 
back)
!
Serum lipase activity (and/or amylase activity) 
at least three times greater than the upper limit 
of normal
!
Characteristic findings of acute pancreatitis on 
imaging
Acute pancreatitis
!
Mild
!
Moderate severe
!
Severe
Malignant neoplasm
Malignant neoplasms are defined as: 
!
Neoplasms in which abnormal cells divide 
without control and can invade nearby tissues 
and/or spread to other parts of the body 
through the blood and lymph systems
!
Thyroid neoplasms are excluded in this event 
category
!
Malignant neoplasm
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 
!
Malignant thyroid 
neoplasm
!
C-cell hyperplasia
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*Death is not a separate event, but an outcome
There are different processes for capturing events for adjudication:
!
Direct reporting by investigator:
- All AEs need to be assessed by the investigator if any AE category is applicable. If the AE 
category selected is in scope for adjudication, the event specific adjudication form will be 
populated for sites to complete
- AEs with fatal outcome
!
Screening:
- All AEs will be screened by NN for potential missed events for adjudication and if needed, 
the investigator will be asked to provide additional information such as an alternative 
aetiology, underlying cause(s) and/or clinical details.
!
EAC identified events:
- The EAC can decide to have an AE adjudicated even if not initially reported as an event 
for adjudication by the investigator.
Event adjudication will be performed for AEs in randomised subjects including AEs with an onset 
date during the screening period. Event adjudication will not be performed for AEs in screening 
failures.
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. The 
outcome of adjudication will be kept in the clinical trial database.
through the blood and lymph systems
!
C-cell hyperplasia, defined as hyperplasia of 
the parafollicular C-cells of the thyroid gland
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13 Case report forms 
Novo Nordisk will provide a system for the electronic case report forms (eCRF). This system and 
support services to the system will be supplied by a vendor.
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 (eg is not 
applicable), indicate this according to the data entry instructions.
The following will be provided as paper CRFs:
!
Pregnancy forms
In addition paper AE forms and safety information forms will be provided. These must be used 
when access to the eCRF is revoked. 
The investigator must ensure that all information is consistent with the source documentation. By 
electronically signing the case book in the eCRF, the investigator confirms that the information in 
the eCRF and related forms is complete and correct.
13.1
Corrections to case report forms 
Corrections to the CRF data may be made by the investigator or the investigator's authorised staff. 
An audit trail will be maintained in the CRF application containing as a minimum: the old and the 
new data, identification of the person entering the data, date and time of the entry and reason for the 
correction.
If corrections are made by the investigator's authorised staff after the date the investigator has 
signed the case book, the case book must be signed and dated again by the investigator.
13.2
Case report form flow 
13.2.1
Electronic 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 trial the investigator must ensure that all remaining data have been entered into the 
eCRF no later than 3 days after the last subject’s last visit 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 investigator site 
after the trial database is released and access to update the trial data on the EDC application has 
been removed. This data will be retained by the site.
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When the final CTR is available the data will be archived by Novo Nordisk.
13.2.2
Paper case report form flow
The pregnancy forms are paper based CRFs. 
Also, the SIF, technical complaint form, and AE form will be provided in paper but are only to be 
used if for any reason the eCRF is unavailable.
The investigator must ensure that data are recorded in these forms as soon as possible and ensure 
that Novo Nordisk receives these forms within the required timeline (see section 12).
Corrections to the data in the CRFs may only be made by drawing a straight line through the 
incorrect data and then writing the correct entry next to the data that were crossed out. Each 
correction must be initialled, dated and explained (if necessary) by the investigator or the 
investigator’s authorised staff.
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14 Monitoring procedures 
During the course of the trial, the monitor will visit the trial site to ensure that the protocol is 
adhered to, that all issues have been recorded, to perform source data verification and to monitor 
drug accountability. The first monitoring visit will be performed as soon as possible after FPFV or 
FSFV and no later than 4 weeks after. The monitoring visit intervals will depend on the outcome of 
the remote monitoring of the CRFs, the trial site's recruitment rate and the compliance of the trial 
site to the protocol and GCP, but will not exceed 12 weeks until LSLV at the trial site.
The intervals between monitoring visits can be shorter. Factors to be considered in this 
determination may include objective, endpoints, purpose, design, complexity, blinding, number of 
subjects and expected recruitment rate. 
The monitor must be given direct access to source documents (original documents, data and 
records). Direct access includes permission to examine, analyse, verify and reproduce any record(s) 
and report(s) that are important to the evaluation of the trial. If the electronic medical record does 
not have a visible audit trail, the investigator must provide the monitor with signed and dated 
printouts. In addition the relevant trial site staff should be available for discussions at monitoring 
visits and between monitoring visits (eg by telephone).
All data must be verifiable in source documentation other than the CRF.
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. Considering the 
electronic source data environment, it is accepted that the earliest practically retainable record 
should be considered as the location of the source data. Therefore transcription to the diary from the 
blood glucose meter is considered the source document for BG values.
Source data generated by the trial site can be corrected by another person than the person entering 
the source data, if accepted by local regulations; any correction must be explained, signed and dated 
by the person making the correction.
The original diaries and PROs are considered as source data and must not be removed from the trial 
site.
The monitor will ensure that the CRFs are completed on an on-going basis within the agreed 
timelines.
The monitor must ensure that all required eCRF forms for screening failures are completed, (e.g. 
screening failure form and the case book sign of (affirmation statement) is electronically signed by 
the investigator).
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Monitors must review the subject's medical records and other source data (eg the diaries and PROs) 
to ensure consistency and/or identify omissions compared to the CRF. If discrepancies are found, 
the investigator must be questioned about these.
When data has been source verified and all queries have been resolved the case book must be 
signed by the investigator in the eCRF.
A follow-up letter (paper or electronic) will be sent to the investigator following each monitoring 
visit addressing 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 an external CRO. 
Appropriate measures, including encryption of data files containing person identifiable data, will be 
used to ensure confidentiality of subject data, when they are transmitted over open networks. 
Data from central laboratories will be transferred electronically from the laboratory performing the 
analyses. 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 identification number. 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
If necessary, a statistical analysis plan (SAP) may be written in addition to the protocol, including a 
more technical and detailed elaboration of the statistical analyses. The SAP will be finalised before 
database lock. 
Results from the statistical analysis will generally be presented by two-sided confidence intervals 
with a confidence level of 95% and associated p-value. Superiority will be formulated and tested as 
one-sided hypotheses at a 2.5% significance level. Non-inferiority between two treatments will be 
evaluated by comparing the upper limit of the associated two-sided 95% confidence interval for the 
difference with the pre-defined non-inferiority margin.
Handling of missing data
In the case of missing data no general imputation will be performed for the analyses, unless 
otherwise specified. If an assessment has been made both at screening and randomisation, the value 
from the randomisation visit will be used as the baseline value. If the value measured at the 
randomisation visit is missing and the assessment also has been made at screening, then the 
screening value will be used as the baseline value.
Laboratory values below the lower limit of quantification (LLOQ) will be set to ½ LLOQ.
The primary analysis model will be the mixed model for repeated measurements (MMRM), see 
section 17.3 for further details. One of the assumptions behind (MMRM) is that the missing data 
mechanism is missing at random (MAR). This means that given the observed data, the mechanism 
generating missing values is independent of the unobserved data that is the missing data. The 
MMRM and the negative binomial model both rely on the MAR assumption for generating 
unbiased estimates of treatment differences.
Based on previous semaglutide trials in subjects with type 2 diabetes, the  treatment discontinuation 
rate from randomised treatment and trial withdrawal is expected to be about 20%. The treatments in 
this trial should be effective, given the historical documentation, and this should minimise treatment 
discontinuation due to ineffective therapy. The main reasons for treatment discontinuation are 
expected to be AEs, ineffective therapy and non-eligibility (subjects randomised although not 
fulfilling inclusion/exclusion criteria). Treatment discontination due to non-eligibility can be 
regarded as missing completely at random (MCAR), i.e. it does not depend on the observed or 
missing data values. This category of missing data is not expected to introduce bias in the estimated 
treatment differences. Treatment discontinuation due to lack of efficacy is expected to be reflected 
in the observed data obtained prior to the discontinuation from randomised treatment, and the 
corresponding missing data can therefore be assumed as MAR to some extent. Missing data due to 
AEs is expected to be similar between groups except for, potentially, a slightly higher incidence in 
the semaglutide treatment group due to gastrointestinal side effects. Together with potential 
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withdrawals from trial due to the own will of the subject, the MAR assumption may be less 
adequate for this category of drop-outs.
Several different sensitivity analyses will be used to investigate whether the results from the 
MMRM approach are robust towards deviations from the assumption of MAR.
17.1
Sample size calculation
The primary objective is to compare the effect of two dose levels of semaglutide once-weekly 
treatment (0.5 mg or 1.0 mg) with sitagliptin 100 mg on the primary endpoint, change from baseline 
in HbA1c after 30 weeks of treatment. In the calculations determining the sample size it is presumed 
that in the analysis the two sitagliptin/semaglutide placebo groups will be pooled assuming no 
correlation between endpoints and placebo volume.
In total 1050 subjects will be randomised in a 2:2:1:1 manner. Assuming 20% of subjects 
discontinuing randomised treatment, and further taking the assumption that these subjects are 
excluded from the per protocol (PP) analysis set, 280 subjects in each group are expected to be 
included in the PP analysis set.
The sample size calculation is based on demonstrating HbA1c non-inferiority for semaglutide 0.5 
mg vs. sitagliptin 100 mg and HbA1c non-inferiority for semaglutide 1.0 mg vs. sitagliptin 100 mg.
The two hypothesis tests are assumed to be independent and for each of the hypothesis the power 
calculation is based on a t-statistic under the assumption of a one-sided test of size 2.5%. Using a 
non-inferiority margin of 0.3%, and assuming a true HbA1c difference (semaglutide minus 
sitagliptin) of 0% and a standard deviation (SD) of 1.1%, a total of 280 subjects per group in the PP 
analysis set will give 90% marginal power to conclude HbA1c non-inferiority for the comparison of 
a semaglutide dose vs. sitagliptin 100 mg.
Assuming the same HbA1c effect for the two dose levels of semaglutide, the overall power to 
demonstrate HbA1c non-inferiority for the two dose levels of semaglutide vs. sitagliptin will be at 
least 80%.
For change in body weight, the power calculation is based on the assumptions of a true difference of 
-1.5 kg and a SD of 4.0 kg. In addition, 50% efficacy retention is assumed for the anticipated 20%
of subjects discontinuing randomised treatment giving an expected treatment difference of -1.35 kg, 
which is the number used in the power calculation. With the above assumptions, a total of 350 
subjects per group in the full analysis set (FAS) will give more than 99% marginal power to 
conclude superiority in body weight for the comparison of a semaglutide dose vs. sitagliptin 100 
mg.
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17.2
Definition of analysis sets
The following analysis sets are defined in accordance with the ICH-E9 guideline58 .
Full Analysis Set (FAS): includes all randomised subjects.  Subjects in the FAS will contribute to 
the evaluation “as randomised”.
Per Protocol (PP) Analysis Set:
Includes all subjects in the FAS who fulfil the following criteria:
!
have not violated any inclusion criteria
!
have not fulfilled any exclusion criteria
!
have a non-missing HbA1c measurement at screening and /or randomisation
!
have at least 23 weeks actual treatment weeks of expose
!
have at least one non-missing HbA1c measurement after 23 actual weeks of expoures
Subjects in the PP Analysis Set will contribute to the analysis “as treated”.
Safety Analysis Set (SAS): includes all subjects exposed to at least one dose of trial product.
Subjects in the SAS will contribute to the evaluation based on the trial product received for the 
majority of the period they were on treatment. This will be referred to as contributing to the 
evaluation “as treated”.
Before data are locked for statistical analysis, a review of all data will take place. Any decision to 
exclude a subject or single observations from the statistical analysis is the joint responsibility of the 
members of the internal 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 CTR.
Data selections and observation periods
Subjects and data to be used in an analysis will be selected in a two-step manner.
!
Firstly, subjects will be selected based on the specified analysis set
!
Secondly, data points on the selected subjects from first step will be selected based on the 
specified observation period 
Definition of the observation periods:
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In-trial: This observation period represents the time period where subjects are considered to be in 
the trial after randomisation, regardless of discontinuation of trial product or initiation of rescue 
medication. The in-trial observation period starts at randomisation (as registered in IWRS) and ends 
at the date of: 
!
The last direct subject-site contact, which is scheduled to take place 5 weeks after planned 
last dose of trial product at a follow-up visit 
!
Withdrawal for subjects who withdraw their informed consent
!
The last subject-investigator contact as defined by the investigator for subjects who are lost 
to follow-up
!
Death for subjects who dies before any of the above
For subjects not randomised but exposed to trial product the in-trial periods starts at the date of first 
dose of trial product
On-treatment: This observation period represents the time period where subjects are considered 
treated with trial product. The observation period is a sub-set 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 according to the flow chart. For adjudicated events, ECG’s and 
AEs including hypoglycaemic episodes, the observation period ends at the first date of any of the 
following: 
!
the follow-up visit (V10)
!
the follow-up prematurely discontinuation visit (V10A)
!
the last date on trial product + 42 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 subcutaneous semaglutide. The visit window for 
the follow-up visit is + 7 days, which is the reason for the 42 days specified in the bullet above. 
Hence, for those assessments this period reflects the period in which subjects are exposed.
For efficacy and other safety assessments (laboratory assessments, physical examination and vital 
signs) the observation period ends at the last date on trial product + 7 days in accordance with trial 
flow chart and assessment times. This ascertainment window corresponds to the dosing interval and 
will be used to avoid attenuation of a potential treatment effect on endpoints for which the effect is 
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reversible shortly after treatment discontinuation. Hence, for those assessments this period reflects 
the period in which subjects are treated.
On-treatment without rescue medication: This observation period is a sub-set 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 +7 days
!
initiation of rescue medication
The ’on-treatment without rescue medication’ observation period will be the primary observation 
period for efficacy evaluations. The in-trial observation period will be considered supportive for 
efficacy evaluation. Safety will be evaluated based on the in-trial and the on-treatment observation 
periods unless otherwise specified.
For subjects who have no post-baseline scheduled assessments available in the on-treatment without 
rescue period, the baseline value will be carried forward to the first scheduled visit for the 
associated endpoint to ensure that all randomised subjects will contribute to the statistical analysis. 
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.
17.3
Primary endpoint
The primary endpoint is change from baseline in HbA1c after 30 weeks of treatment. In the analysis 
the two sitagliptin/semaglutide placebo groups will be pooled assuming no correlation between 
HbA1c change after 30 weeks and placebo volume.
The primary endpoint will be based on FAS using data from the ‘on-treatment without rescue 
medication’ observation period in a Mixed Model for Repeated Measures (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 30 data as dependent 
variables. The independent effects included in the model will be treatment and country as fixed 
effects and baseline response as covariate, all nested within visit. An unstructured covariance matrix 
will be employed for measurements within the same subjects, assuming that measurements across 
subjects are independent. Regarding missing data this analysis approach relies on the assumption 
that data are missing at random (MAR). From this mode, the two by dose level estimated treatment 
differences between s.c.semaglutide versus sitagliptin at week 30 will be presented together with 
associated two-sided 95% confidence intervals and unadjusted two sided p-values (nominal 
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alpha=0.05) for testing non-inferiority and superiority. In order to preserve the overall type 1 error 
the conclusion of non-inferiority and superiority with treatment of each semaglutide dose versus 
sitagliptin after 30 weeks will be evaluated hierarchically according to the sequence below, and 
starting with the first. In this testing sequence it is necessary to fulfil the test criteria, which is to 
reject the corresponding null hypothesis in order to go to the next step. If the corresponding null 
hypothesis is not rejected, the testing will stop and no further conclusions will be drawn. 
The following ordering in the statistical test sequence will be used:
1. Non-inferiority in change in HbA1c for semaglutide 1.0 mg vs. sitagliptin
2. Non-inferiority in change in HbA1c for semaglutide 0.5 mg vs. sitagliptin
3. Superiority in change in HbA1c for semaglutide 1.0 mg vs. sitagliptin
4. Superiority in change in body weight for semaglutide 1.0 mg vs. sitagliptin
5. Superiority in change in body weight for semaglutide 0.5 mg vs. sitagliptin
6. Superiority in change in HbA1c for semaglutide 0.5 mg vs. sitagliptin
Non-inferiority will be concluded if the upper limit of the two-sided 95% confidence interval for the 
estimated difference in HbA1c between semaglutide and sitagliptin is less than 0.3%. Superiority for 
either change in HbA1c or change in body weight will be claimed if the upper limit of the two-sided 
95% confidence interval for the estimated difference is below 0% or 0 kg respectively.  
When establishing non-inferiority the analysis will be based on the full analysis set (FAS) and 
supplemented by an analysis with the per protocol population using the data from the ‘on treatment 
without rescue medication’ observation period as supportive evidence. The FAS population will be 
used in the analysis when concluding superiority.
Sensitivity analysis
To investigate the sensitivity of the main results, complimentary and separate analyses for primary 
endpoint and the confirmatory secondary endpoint will be performed, using the FAS only, except 
for HbA1c, where the PP analysis set will be used in a sensitivity analysis regarding the non-
inferiority evaluation. These analyses will investigate the sensitivity of the results due to the impact 
of missing values.
The primary analysis regarding non-inferiority of the primary endpoint change in HbA1c after 30 
weeks will also be performed separately based on the data in the PP analysis set only.
The primary endpoint and the secondary confirmatory endpoint will be evaluated in the following 
sensitivity analyses:
!
An analysis of covariance (ANCOVA) model will be analysed with imputation of missing 
values according to the last observation carried forward (LOCF) method. based on the FAS 
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using the data  from the ‘on-treatment without rescue medication’ observation period. The 
model will include terms for treatment, country, and the corresponding baseline value as a 
covariate. The response variable will be the last available value obtained within the 30 
weeks period of the trial
!
The MMRM will be analysed based on all data from the ‘in-trial’ observation period The 
MMRM will be analysed based on data only from subjects that completed the trial without 
receiving rescue treatment.
A pattern mixture model based on the FAS using the ‘on-treatment without rescue medication’ 
observation period approach mimicking an ITT scenario where withdrawn subjects are assumed to 
be switched to a treatment inferior to the control treatment after treatment discontinuation will be 
performed for evaluation of non-inferiority for the primary endpoint change in HbA1c at 30 weeks.
!
In the first step intermittent missing values 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 500 copies of the dataset will be generated.
!
In the second step, for each of the 500 copies of the dataset, an analysis of variance model 
with the same factors as the primary model, and baseline HbA1c and HbA1c at 4 weeks (V3) 
as covariate is fitted to the change in HbA1c from baseline to 8 weeks (V5) for the sitagliptin 
group only. The estimated parameters, and their variance, from this model are used to 
impute missing value at 8 weeks for subjects in all treatment groups, based on country and 
HbA1c at baseline and 4 weeks.  
!
In the third step, for each of the 500 copies of the dataset, missing HbA1c values at 12 
weeks (V6) are imputed in the same way as for 8 weeks. Now the imputation are based on 
an analysis of variance model with the same factors and the HbA1c values at baseline, 4 
weeks and 8 weeks as covariates, fitted to the control group.
!
This stepwise procedure is then repeated sequentially over the available planned visits, 
adding one visit in each step until the last planned visit at 30 weeks (V9).
!
For each withdrawn subject in the investigational treatment group, a value of 0.3% (the non-
inferiority limit) is added to the change in HbA1c at 30 weeks.
!
For each of the complete data sets, the change from baseline to week 30 is analysed using an 
analysis of variance model with the same set of factors and the baseline HbA1c value as a 
covariate.
!
The estimates and standard deviations for the 500 data sets are pooled to one estimate and 
associated standard deviation using Rubin’s rule (page 255-257)59 From these pooled 
estimates the confidence interval for the treatment differences and the associated p-value are 
calculated.
A pattern mixture model approach mimicking an ITT scenario where withdrawn subjects are 
assumed to be switched to the control treatment after treatment discontinuation will be performed 
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separately for the evaluation of superiority in the primary endpoint change in HbA1c and change in 
body weight at 30 weeks. The same types of approach as used for the non-inferiority assessment in 
change in HbA1c will be employed, see above. However, the step where 0.3%, the non-inferiority 
limit, is added to the change in HbA1c at 30 weeks will not be performed in this sensitivity analysis.
Chinese/Korean subgroup analyses
A number of subgroup analyses by country will be performed with the aim to assess the treatment 
effect in the individual countries including China and Korea. They will be performed in a combined 
model using all data similar to the main analysis of the respective parameter but with an interaction 
between treatment and country.
17.4
Secondary endpoints
The planned secondary endpoints used to support the primary objective will be analysed as outlined 
in this section.
17.4.1
Confirmatory secondary endpoints
Weight loss
A confirmatory secondary variable is change in body weight after 30 weeks of treatment. This 
variable will be analysed in the same type of model as the primary endpoint although with baseline 
body weight as covariate.
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17.4.2
Supportive secondary endpoints
17.4.2.1
Efficacy endpoints
All efficacy endpoints in this section will be summarised and evaluated using the FAS.
Continuous variables
Change from baseline to week 30 in:
!
FPG
!
Insulin
!
C-peptide
!
glucagon
!
pro-insulin
!
pro-insulin/insulin ratio
!
HOMA-B
!
HOMA-IR
!
fasting blood lipids (total cholesterol, LDL-cholesterol, VLDL-cholesterol, HDL-
cholesterol, triglycerides and free fatty acids)
!
BMI
!
waist circumference
!
systolic and diastolic blood pressure
!
hsCRP
will all be analysed based on the same data and type of model as the primary endpoint, but with the 
associated baseline value as a covariate.
Except for FPG, BMI, waist circumference, and blood pressure the values of the variables will be 
log transformed subject to analysis.
Beta-cell function
Beta-cell function (fasting HOMA-B and fasting HOMA-IR) will be calculated based on fasting 
insulin and FPG. The calculation will be done at the same time points as for fasting insulin and FPG 
samples (section 2).
The calculation of the fasting HOMA endpoints will be done as follows:
Fasting HOMA-B (%) = 20 x fasting insulin [μU/ml]/(FPG[mmol/l]-3.5)
Fasting HOMA-IR (%) = fasting insulin [μU/ml] x FPG [mmol/l]/22.5
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PRO outcomes
The PRO outcome endpoints:
!
PRO questionnaire outcome DTSQs (individual items and treatment satisfaction score (6 of 
the 8 items summed)), and
!
PRO questionnaire outcome SF-36v2TM short Form health survey: Total scores(physical 
component and mental component) and scores from the 8 domains
will be analysed separately using the ANCOVA model based on the data from the on-treatment
without rescue medication observation period. Factors in the model will be treatment and country.
The baseline value of the corresponding endpoint will be used as covariate in the analysis model.
7-point profile
Subjects will be asked to perform SMPG measurements see section 8.5.1.5.
The endpoints from the 7-point profiles that will be analysed at week 30 are:
!
Mean of the 7-point profile, defined as the area under the profile, calculated using the 
trapezoidal method, divided by the measurement time
!
Mean increment over all meals
The mean of the 7-point profile and the mean of the post prandial increments at week 30 will be 
analysed separately with the same data and type of methods as primary endpoint but with the 
corresponding baseline assessment as a covariate.
Response in HbA1c and/or weight loss after 30 weeks
The secondary variables related to fixed response in HbA1c and/or weight loss at 30 weeks will be:
!
Responder in HbA1c after 30 weeks of treatment (yes/no) defined as HbA1c <7.0% (<53 
mmol/mol) – ADA target
!
Responder in HbA1c after 30 weeks of treatment (yes/no) defined as HbA1c ≤6.5% (48 
mmol/mol) – AACE target
!
Weight loss ≥5%
!
Weight loss ≥10%
!
HbA1c <7.0% (53 mmol/mol) without severe or confirmed symptomatic hypoglycaemia 
(plasma glucose ≤3.1 mmol/L) and no weight gain
All these variables will be analysed based on the ‘on-treatment without rescue medication’ 
observation period separately in the same type of logistic regression model. The model will include 
factors for treatment and country. For the two responder in HbA1c endpoints, baseline HbA1c will be 
included in the model as a covariate, whereas for the weight responder endpoint (≥5% and ≥10% 
weight loss), baseline weight will be included instead. For the composite endpoint (cf. last bullet), 
both baseline HbA1c and baseline weight will be included. 
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Missing response data at 30 weeks will be imputed from respectively the MMRM used for the 
primary analysis of HbA1c and the confirmatory secondary endpoint change in body weight at 30 
weeks. The results will be described by the odds ratio and the associated 95% confidence interval 
for the odds ratio.
17.4.2.2
Safety endpoints
The safety endpoints will be evaluated based on SAS using both the on-treatment observation 
period and the in-trial observation period unless otherwise stated. 
The following secondary endpoints are used to support the safety objectives:
!
Number of treatment emergent AEs during 30 weeks of treatment
!
Number of  treatment emergent severe or BG confirmed symptomatic hypoglycaemic 
episodes during 30 weeks of treatment
!
Severe or BG confirmed symptomatic hypoglycaemic episodes during 30 weeks of 
treatment (yes/no)
Change in safety endpoints assessed from baseline to 30 weeks of treatment and/or follow up:
!
Haematology
!
Biochemistry
!
Calcitonin
!
Urinalysis
!
UACR
!
Pulse
!
ECG evaluation
!
Physical examination evaluation
!
Eye examination
Occurrence of semaglutide antibodies during 35 weeks of study duration (yes/no):
!
Anti-semaglutide antibodies
o
Anti-semaglutide antibodies with in vitro neutralising effect
o
Anti-semaglutide antibodies cross reacting with endogenous GLP-1

Cross reacting antibodies with in vitro neutralising effect to endogenous 
GLP-1
Anti-semaglutide antibody level during and after 30 weeks of treatment
All safety endpoints will be summarised and evaluated by descriptive statistics using the SAS.
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Adverse events
The following endpoint related to adverse events is used to support the safety objective;
!
Number of treatment emergent adverse events (TEAEs)
A treatment-emergent AE is an event that has onset date (or increase in severity) during the on-
treatment observation period. These will therefore be referred to as ‘on-treatment AEs’ hereafter. 
On-treatment adverse events are summarised descriptively 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 years (R). These summaries are replicated by outputs including all 
‘in-trial’ adverse events (i.e., adverse events with onset date [or increase in severity] during the ‘in-
trial’ observation period). Adverse events with onset after the end of the ‘in-trial’ observation 
period will be reported in a listing. The development over time in gastrointestinal AEs will be 
presented graphically.
The most frequent adverse events will be defined as preferred terms (PTs) that are experienced by at 
least 5% of the subjects in any of the treatment arms. 
All AEs will be coded using the most recent version of the Medical Dictionary for Regulatory 
Activities (MedDRA) coding.
Pulse
Pulse will be analysed separately using an analysis similar to the primary analysis of the primary 
endpoint. However this analysis will be based on FAS using the data from the on-treatment 
observation period but with the pulse value at baseline as a covariate.
Laboratory assessments
Amylase and lipase will be analysed separately with the same type of methods as for pulse with the 
corresponding baseline assessment as a covariate. The values will be log transformed in the 
analysis.
Calcitonin
Calcitonin will be displayed in terms of the number of subjects (N), the percentage of subjects (%) 
and the event rate per 1000 years of exposure (R). The following criteria are defined for tabulations:
Persistent (all post baseline measurements)
!
From <upper normal limit (UNL) to persistently ≥UNL
!
From <UNL to persistently ≥1.5 UNL
!
From <UNL to persistently ≥20 ng/L
!
From <UNL to persistently ≥50 ng/L
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!
From <20 ng/L to persistently ≥20 ng/L
!
From <50 ng/L to persistently ≥50 ng/L
Incidental (at least one post baseline measurements)
!
From <UNL to ≥UNL
!
From <UNL to ≥1.5 UNL
!
From <UNL to ≥20 ng/L
!
From <UNL to ≥50 ng/L
!
From <20 ng/L to ≥20 ng/L
!
From <50 ng/L to ≥50 ng/L
Summaries tables of calcitonin continuous measurements, will include number and percentage of 
observations < and ≥LLOQ, minimum, Q25, median, Q75 and maximum. Summaries will be 
presented for all subjects and by gender.
Classification of Hypoglycaemia 
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: are episodes with time of onset 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)60. Therefore, Novo Nordisk has included hypoglycaemia with plasma glucose 
levels below this cut-off point of hypoglycaemia.
In this trial Novo Nordisk use the following classification in addition to the ADA classification (see 
Figure 17–1):
!
Severe or BG confirmed symptomatic hypoglycaemia: An episode that is severe according 
to the ADA classification51 or BG confirmed by a plasma glucose value <3.1 mmol/L (56 
mg/dL) with symptoms consistent with hypoglycaemia.
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Hypoglycaemic
episode
PG ≤ 3.9 mmol/L 
(70 mg/dL) 
or 
Alleviation of 
symptoms 
or
Seizure, coma or 
fatal 
SMPG
measurement
PG < 3.1 mmol/L
(56 mg/dL)
with symptoms
PG < 3.1 mmol/L
(56 mg/dL)
without
symptoms
Symptomatic BG 
confirmed 
hypoglycaemia
Asymptomatic BG 
confirmed 
hypoglycaemia
Yes
No
Severe or 
BG confirmed 
symptomatic 
hypoglycaemia
BG confirmed 
hypoglycaemia
Severe or BG 
confirmed 
hypoglycaemia
Note: Glucose measurements are performed with capillary blood calibrated to plasma equivalent glucose values
BG: blood glucose  PG: plasma glucose  SMPG: Self-measured plasma glucose  
Subject 
able to 
treat him/
herself
Severe 
hypoglycaemia
(ADA 2013)
Figure 17–1
Novo Nordisk classification of hypoglycaemia
ADA classification of hypoglycaemia51
!
Severe hypoglycaemia: An episode requiring assistance of another person to actively 
administer carbohydrate, glucagon, or take of other corrective actions. Plasma glucose 
concentration 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).
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Hypoglycaemic 
episode 
PG ≤ 3.9 mmol/L 
(70 mg/dL) 
or 
Alleviation of 
symptoms 
or
Seizure, coma or 
fatal 
SMPG
measurement
Asymptomatic 
hypoglycaemia
Documented 
symptomatic 
hypoglycaemia
Pseudo-
hypoglycaemia
Probable 
symptomatic 
hypoglycaemia
No
Yes
No measurement 
with symptoms
PG > 3.9 mmol/L 
(70 mg/dL)
with symptoms
PG ≤3.9 mmol/L 
(70 mg/dL)
with symptoms
PG ≤3.9 mmol/L 
(70 mg/dL)
without symptoms
No
Yes
Note: Glucose measurements are performed with capillary blood calibrated to plasma equivalent glucose values
PG: plasma glucose  SMPG: Self-measured plasma glucose  
Subject 
able to 
treat him/
herself
Severe 
hypoglycaemia
(ADA 2013)
Figure 17–2
ADA classification of hypoglycaemia
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Number of severe or BG confirmed symptomatic hypoglycaemic episodes
Data on treatment emergent hypoglycaemic episodes are 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 episodes rate per 100 years of exposure. Summaries of treatment 
emergent hypoglycaemic episodes will be presented as an overview including all episodes and 
episodes by severity.
The number of severe or BG confirmed symptomatic hypoglycaemic episodes during 30 weeks 
treatment will be analysed using a negative binomial regression model with a log-link function and 
the logarithm of the time period, from the randomisation and up to the time point in which an 
occurrence of a hypoglycaemic episode is considered treatment emergent as offset assuming MAR. 
The model will include factors for treatment, country as fixed factors and baseline HbA1c as 
covariate. The SAS will be used for the analysis.
Number of nocturnal hypoglycaemic episodes
The number of nocturnal (00:01-05:59 am) severe or BG confirmed symptomatic hypoglycaemic 
episodes during 30 weeks of treatment will be analysed separately in the same type of model as the 
number of severe or BG confirmed symptomatic hypoglycaemic episodes during 30 weeks 
treatment.
Severe or BG confirmed symptomatic hypoglycaemic episodes (yes/no)
The binary endpoint indicating whether a subject has no treatment emergent severe or BG 
confirmed symptomatic hypoglycaemic episodes or at least one will be analysed using a logistic 
regression model with treatment, country as fixed factors and baseline HbA1c as covariate.
Nocturnal severe or BG confirmed symptomatic hypoglycaemic episodes (yes/no)
The binary endpoint indicating whether a subject has no treatment emergent nocturnal (00:01-05:59 
am) severe or BG confirmed symptomatic hypoglycaemic episodes or at least one will be analysed 
using the same type model as severe or BG confirmed symptomatic hypoglycaemic episodes during 
30 weeks treatment.
17.5
Health economics and/or patient reported outcomes
The PRO questionnaires, SF-36v2TM and DTSQs, will be used to evaluate the objective regarding 
Quality of Life, see section 17.4.2.1for the details of the corresponding statistical analysis.
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18 Ethics
The trial will be conducted in compliance with ICH GCP1 and applicable regulatory requirements, 
and in accordance with the Declaration of Helsinki2.
All subjects will be included after a thorough evaluation in regards to in- and exclusion criteria 
defined in order to ensure that subjects are eligible for trial treatment. Subjects will be treated 
within a regimen anticipated to be better than or equal to the treatment they receive at the time of 
entry into the trial. Subjects will have to spend some extra time, as additional assessments and visits 
to the clinic are required. It is the responsibility of the investigator to ensure the best possible care 
according to the principles outlined in Diabetes Care 2013 Standards of Medical Care in Diabetes61, 
or any updates thereof.
It is concluded that the potential benefits from participating in the trial outweigh the potential risks. 
The safety profile of semaglutide generated from the clinical and nonclinical development 
programme has not revealed any safety issues that would prohibit administration of once weekly 
doses of 0.5 mg or 1.0 mg semaglutide in accordance with the planned clinical trial. It is concluded 
that the risk to the subjects in this trial is low and acceptable in view of the benefits a long-acting 
GLP-1 analogue would provide to people with type 2 diabetes (please see 3.5)
The trial products may be associated with AEs, but relevant precautions have been implemented in 
the design and planned conduct of the trial in order to minimise the risks and inconveniences of 
participation in the trial. These precautions include thorough information regarding the correct 
administration of the trial products and gradual dose adjustment. Furthermore, subjects are fully 
informed about possible AEs and inconveniences and will be instructed to contact the investigator 
in case of any concerns regarding the trial participation.
When treatment with trial products ends, the subject and investigator will decide on the best 
available treatment.
18.1
Informed consent 
In seeking and documenting informed consent, the investigator must comply with applicable 
regulatory requirement(s) and adhere to ICH GCP1 and the requirements in the Declaration of 
Helsinki2.
Before any trial-related activity, the investigator must give the subject verbal and written 
information about the trial and the procedures involved in a form that the subject can read and 
understand. 
The subjects must be fully informed of their rights and responsibilities while participating in the 
trial as well as possible disadvantages of being treated with the trial products.
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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 task may 
be delegated by the investigator 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.
18.2
Data handling
If the subject is withdrawn from the trial or lost to follow up, then the subject's data will be handled 
as follows:
!
Data already collected and data collected at the end-of-trial visit will be retained by Novo 
Nordisk, entered into the database and used for the trial report. 
!
Safety events will be reported to Novo Nordisk and regulatory authorities according to 
local/national requirements.
If data is used, it will always be in accordance with local regulations and IRBs/IECs.
18.3
Information to subject during trial
The site will be offered a communication package to the subject during the conduct of the
trial. The package content is issued by Novo Nordisk. The communication package will
contain the letters intended for distribution to the subjects. The letters will be translated
and adjusted to local requirements and distributed to the subject by discretion of the
investigator. The subject may receive a “welcome to the trial letter” and a “thank for
your participation letter” at the end of the trial. Further the subject may receive trial
letters during the trial period.
All information to the subjects will be submitted to the health authorities and IECs/IRBs
for approval according to local regulations.
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18.4
Premature termination of the trial and/or trial site
Novo Nordisk, the investigator, the IRBs/IECs or a regulatory authority may decide to stop the trial, 
part of the trial or a trial site at any time, but agreement on procedures to be followed must be 
obtained.
If a trial is suspended or prematurely terminated, the investigator must inform the subjects promptly 
and ensure appropriate therapy and follow-up. The investigator and/or Novo Nordisk must also 
promptly inform the IRBs/IECs and provide a detailed written explanation. The relevant regulatory 
authorities must be informed.
If, after the termination of the trial, the risk/benefit analysis changes, the new evaluation must be 
provided to the IRBs/IECs in case it has an impact on the planned follow-up of subjects who have 
participated in the trial. If it has an impact, the actions needed to inform and protect the subjects 
should be described.
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19 Protocol compliance
Deviations from the protocol should be avoided.
If deviations do occur, the investigator must inform the monitor and the implications of the 
deviation must be reviewed and discussed.
Deviations must be documented and explained in a protocol deviation by stating the reason, date, 
and the action(s) taken. Some deviations, for which corrections are not possible, can be 
acknowledged and confirmed via edit checks in the eCRF or via listings from the clinical database. 
Documentation on protocol deviations must be kept in the investigator's trial file and Novo Nordisk 
trial master file.
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20 Audits and inspections
Any aspect of the clinical trial may be subject to audits conducted by Novo Nordisk or inspections 
from domestic or foreign regulatory authorities or from IRBs/IECs. Audits and inspections may 
take place during or after the trial. The investigator and the site staff as well as Novo Nordisk staff 
have an obligation to cooperate and assist in audits and inspections. This includes giving auditors 
and inspectors direct access to all source documents and other documents at the trial site relevant to 
the clinical trial. This includes permission to examine, analyse, verify and reproduce any record(s) 
and report(s) that are relevant to the evaluation of the trial.
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21
Critical documents
Before a trial site is allowed to start screening subjects, the following documents must be available 
to Novo Nordisk:
!
Regulatory approval and/or acknowledgement of notification as required 
!
Approval/favourable opinion from IRBs/IECs clearly identifying the documents reviewed as 
follows: protocol, any protocol amendments, subject information/informed consent form, 
any other written information to be provided to the subject and subject recruitment materials
!
List of IRB/IEC members and/or constitution
!
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 and local label for comparator
!
Signed and dated agreement on the final protocol
!
Signed and dated agreement on protocol amendment, if applicable
!
Financial agreement(s)
!
Source document agreement
!
Central laboratory certification and normal ranges
!
Insurance statement, if applicable
!
Signed and dated Investigator Agreement
!
Financial disclosure form from investigator and sub-investigator(s)
Novo Nordisk will analyse and report data from all sites together.
By signing the protocol, each investigator agrees to comply fully with ICH GCP1, applicable 
regulatory requirements and the Declaration of Helsinki2. 
By signing the protocol, each investigator also agrees to allow Novo Nordisk making 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
All staff Novo Nordisk, site, Central Laboratories, CRO etc. must conduct the trial in compliance 
with ICH GCP1, applicable regulatory requirements, and in accordance with the Declaration of 
Helsinki2.
The investigator is accountable for the conduct of the trial at his/her site. If any tasks are delegated, 
the investigator must maintain a list of appropriately qualified persons to whom he/she has 
delegated specified significant trial-related duties. The investigator must ensure that there is 
adequate training for all staff participating in the conduct of the trial. It is the investigator's 
responsibility to supervise the conduct of the trial and to protect the rights, safety, and well-being of 
the subjects.
A qualified physician, who is an investigator or a sub-investigator for the trial, must be responsible 
for all trial-related medical decisions.
The investigator must ensure adequate supervision of the conduct of the trial at the trial site. 
The investigator will follow instructions from Novo Nordisk when processing data.
The investigator is responsible for filing essential documents (ie those documents which 
individually and collectively permit evaluation of the conduct of a trial and the quality of the data 
produced) in the investigator's trial file. The documents should be kept in a secure locked facility, 
so no unauthorized persons can get access to the data. The subject identification code list must be 
kept securely and separate from the personal 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 (eg 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 Novo Nordisk for regulatory purposes and 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.
One principal investigator will be appointed to review and sign the clinical trial report (signatory 
investigator) on behalf of all participating investigators. The signatory investigator will be 
appointed based upon the criteria defined by the International Committee of Medical Journal 
Editors for research publications62. 
23.1
Communication of results
Novo Nordisk commits to communicating, and otherwise making available for public disclosure, 
results of trials regardless of outcome. Public disclosure includes publication of a paper in a 
scientific journal, abstract submission with a poster or oral presentation at a scientific meeting, or 
disclosure by other means.
The results of this trial will be subject to public disclosure on external web sites according to 
international and national regulations, as reflected in the Novo Nordisk Code of Conduct for 
Clinical Trial Disclosure.
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.
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.
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Where required by the journal, the principal 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 Editors62 (sometimes referred to as the Vancouver 
Criteria).
At the end of the trial, one or more publications (abstracts, posters, manuscripts) will be prepared 
for submission to scientific congresses and peer-reviewed journals in collaboration between Novo 
Nordisk and investigator(s) appointed by Novo Nordisk. These investigator(s) must meet the 
ICMJE authorship criteria to be named authors on publications.
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 for publication of such primary 
policy will take place no later than 18 months after trial completion.
23.2
Investigator access to data and review of results
As owner of the trial database, Novo Nordisk has the discretion to determine who will have access 
to the database. 
Individual investigators will have their own research subjects' data, and will be provided with the 
randomisation code after results are available.
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24 Retention of clinical trial documentation and human biospecimens
24.1
Retention of clinical trial documentation
Subject's medical records must be kept for the maximum period permitted by the hospital, 
institution or private practice.
The investigator must agree to archive the documentation (this includes both electronic and paper-
based records) pertaining to the trial in an archive after completion or discontinuation of the trial if 
not otherwise notified. The investigator should not destroy any documents without prior permission 
from Novo Nordisk. If the investigator cannot archive the documents at the trial site, Novo Nordisk 
can refer the investigator to an independent archive provider that has a system in place to allow only 
the investigator to access the files.
The investigator must be able to access his/her trial documents without involving Novo Nordisk in 
any way. Site-specific CRFs and other subject data (in an electronic readable format or as paper 
copies or prints) will be provided to the investigator before access is revoked to the systems and/or 
electronic devices supplied by Novo Nordisk. These data must be retained by the trial site. If the 
Novo Nordisk provided data (eg the CD-ROM) is not readable during the entire storage period, the 
investigator can request a new copy. A copy of all data will be stored by Novo Nordisk.
Novo Nordisk will maintain Novo Nordisk documentation pertaining to the trial for as long as the 
product is on the market plus 20 years. 
The files from the investigator site/institution must be retained for 15 years after the completion of 
the trial, or longer if required by local regulations. The deletion process must ensure confidentiality 
of data and must be done in accordance with local regulatory requirements.
24.2
Retention of human biospecimens
Antibody samples may be stored until market authorisation in case Health Authorities requests 
further characterisation of the antibody response.
(For Brazil: the laboratory samples for BR subjects will be destroyed at the latest at the completion 
of the CTR, including samples for anti-semaglutide antibody analysis. No sample will be stored 
after the completion of CTR).
None of the data will be identified by name. Antibody samples and thyroid tissue will be identified 
only by a subject number, a visit number and a trial identification number. The trial staff is 
responsible for maintaining a code list which links to the subject number. The code list must be kept 
for at least 15 years. The code list may be reviewed by Novo Nordisk staff including auditors or 
representatives from regulatory authorities, but no copies will be made of this list.
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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 sponsor, 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 risk/benefit 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's trial 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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Trial ID: NN9535-4114
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EudraCT no.: NA
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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 local laws/acts/guidelines.
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Trial ID: NN9535-4114
Version:
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EudraCT no.: NA
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27 References
1.
International Conference on Harmonisation. ICH Harmonised Tripartite Guideline for Good 
Cinical Practice. Geneva, Switzerland. 5/1/1996 1996.
2.
World Medical Association. WMA Declaration of Helsinki - Ethical Principles for Medical 
Research Involving Human Subjects. Last amended by the 64th WMA General Assembly, 
Fortaleza, Brazil. October 2013.
3.
DeFronzo RA. Pathogenesis of type 2 diabetes mellitus. Med Clin North Am. 
2004;88(4):787-835, ix.
4.
UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with 
sulphonylureas or insulin compared with conventional treatment and risk of complications 
in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352(9131):837-53.
5.
The effect of intensive treatment of diabetes on the development and progression of long-
term complications in insulin-dependent diabetes mellitus. The Diabetes Control and 
Complications Trial Research Group. N Engl J Med. 1993;329(14):977-86.
6.
Chuang LM, Tsai ST, Huang BY, Tai TY, Diabcare-Asia Study Group. The status of 
diabetes control in Asia--a cross-sectional survey of 24 317 patients with diabetes mellitus 
in 1998. Diabet Med. 2002;19(12):978-85.
7.
Liebl A, Mata M, Eschwege E, Board ODEA. Evaluation of risk factors for development of 
complications in Type II diabetes in Europe. Diabetologia. 2002;45(7):S23-8.
8.
Ford ES, Li C, Little RR, Mokdad AH. Trends in A1C concentrations among U.S. adults 
with diagnosed diabetes from 1999 to 2004. Diabetes Care. 2008;31(1):102-4.
9.
Harris MI, Eastman RC, Cowie CC, Flegal KM, Eberhardt MS. Racial and ethnic 
differences in glycemic control of adults with type 2 diabetes. Diabetes Care. 
1999;22(3):403-8.
10.
Holst JJ, Vilsboll T, Deacon CF. The incretin system and its role in type 2 diabetes mellitus. 
Mol Cell Endocrinol. 2009;297(1-2):127-36.
11.
Kieffer TJ, Habener JF. The glucagon-like peptides. Endocr Rev. 1999;20(6):876-913.
12.
Bagger JI, Knop FK, Lund A, Vestergaard H, Holst JJ, Vilsboll T. Impaired regulation of 
the incretin effect in patients with type 2 diabetes. J Clin Endocrinol Metab. 2011;96(3):737-
45.
13.
Nauck M, Stockmann F, Ebert R, Creutzfeldt W. Reduced incretin effect in type 2 (non-
insulin-dependent) diabetes. Diabetologia. 1986;29(1):46-52.
14.
Nauck MA, Vardarli I, Deacon CF, Holst JJ, Meier JJ. Secretion of glucagon-like peptide-1 
(GLP-1) in type 2 diabetes: what is up, what is down? Diabetologia. 2011;54:10-8.
15.
Perley MJ, Kipnis DM. Plasma insulin responses to oral and intravenous glucose: studies in 
normal and diabetic sujbjects. J Clin Invest. 1967;46(12):1954-62.
16.
Hojberg PV, Vilsboll T, Rabol R, Knop FK, Bache M, Krarup T, et al. Four weeks of near-
normalisation of blood glucose improves the insulin response to glucagon-like peptide-1 and 
glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes. Diabetologia. 
2009;52(2):199-207.
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Date:
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Trial ID: NN9535-4114
Version:
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UTN: U1111-1149-0432 
Status:
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EudraCT no.: NA
Page:
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17.
Meier JJ. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. 
Nat Rev Endocrinol. 2012;8(12):728-42.
18.
Flint A, Raben A, Astrup A, Holst JJ. Glucagon-like peptide 1 promotes satiety and 
suppresses energy intake in humans. J Clin Invest. 1998;101(3):515-20.
19.
Nauck MA, Niedereichholz U, Ettler R, Holst JJ, Orskov C, Ritzel R, et al. Glucagon-like 
peptide 1 inhibition of gastric emptying outweighs its insulinotropic effects in healthy 
humans. Am J Physiol. 1997;273(5 Pt 1):E981-8.
20.
Nauck MA, Kleine N, Orskov C, Holst JJ, Willms B, Creutzfeldt W. Normalization of 
fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7-36 amide) in type 2 (non-
insulin-dependent) diabetic patients. Diabetologia. 1993;36(8):741-4.
21.
Nauck MA. Incretin-based therapies for type 2 diabetes mellitus: properties, functions, and 
clinical implications. Am J Med. 2011;124(1 Suppl):S3-18.
22.
Toft-Nielsen MB, Damholt MB, Madsbad S, Hilsted LM, Hughes TE, Michelsen BK, et al. 
Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic 
patients. J Clin Endocrinol Metab. 2001;86(8):3717-23.
23.
Nauck MA, Petrie JR, Sesti G, Mannucci E, Courrèges, J.P., et al. A Phase 2, Randomized, 
Dose-Finding Study of the Novel Once-Weekly Human GLP-1 Analog, Semaglutide, 
Compared With Placebo and Open-Label Liraglutide in Patients With Type 2 Diabetes. 
Diabetes Care. 2016;39(2):231-41.
24.
Lau J, Bloch P, Schäffer L, Pettersson I, Spetzler J, Kofoed J, et al. Discovery of the Once-
Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide. J Med Chem. 
2015;58(18):7370-80.
25.
ICH Harmonised Tripartite Guideline. Guidance on non-clinical safety studies for the 
conduct of human clinical trials and marketing authorization for pharmaceuticals M3(R2). 
2009.
26.
Waser B, Blank A, Karamitopoulou E, Perren A, Reubi JC. Glucagon-like-peptide-1 
receptor expression in normal and diseased human thyroid and pancreas. Mod Pathol. 
2015;28(3):391-402.
27.
Investigator's Brochure for s.c. Semaglutide (NN9535), Edition 11 or any updates hereof. 
2016.
28.
Sorli C HS, Tsoukas G, Unger J, Derving Karsbol J, Hansen T, Bain S. Efficacy and safety 
of once-weekly semaglutide monotherapy versus placebo in subjects with type 2 diabetes 
(SUSTAIN 1).  ENDO 2016 - 98th Annual Meeting of the Endocrine Society2016.
29.
Ahmann A CM, Charpentier G, Dotta F, Henkel E, Lingvay I, Gaarsdal Holst A, Chang D, 
Aroda V. Efficacy and Safety of Once-weekly Semaglutide vs Exenatide ER After 56 
Weeks in Subjects With Type 2 Diabetes (SUSTAIN 3). Diabetes. 2016.
30.
Ahrén B CL, Kumar H, Sargin M, Derving Karsbøl J, Jacobsen SH, Chow F. Efficacy and 
Safety of Once-weekly Semaglutide vs Sitagliptin as add-on to Metformin and/or 
Thiazolidinediones After 56 Weeks in Subjects With Type 2 Diabetes (SUSTAIN 2). 
Diabetes. 2016.
31.
Aroda V BS, Cariou B, Piletic M, Rose L, Axelsen MB, Everton R, de Vries JH. Efficacy 
and safety of once-weekly semaglutide vs once-daily insulin glargine in insulin-naïve 
subjects with type 2 diabetes (SUSTAIN 4). Endocrine practice. 2016.
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Date:
28 October 2016
Novo Nordisk
Trial ID: NN9535-4114
Version:
2.0
UTN: U1111-1149-0432 
Status:
Final
EudraCT no.: NA
Page:
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32.
Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, et al. Semaglutide and 
Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2016.
33.
Bailey T TR, Tinahones FJ, Rao P, Tsoukas GM, Thomsen AB,, Kaltoft MS aMM. Efficacy 
and safety of switching from sitagliptin to liraglutide in subjects with type 2 diabetes
(LIRA-SWITCH™): a randomized, double-blind, double-dummy, active-controlled 26-week trial. 
Diabetes, Obesity and Metabolim2016.
34.
Zang L, Liu Y, Geng J, Luo Y, Bian F, Lv X, et al. Efficacy and safety of liraglutide versus 
sitagliptin, both in combination with metformin, in Chinese patients with type 2 diabetes: a 
26-week, open-label, randomized, active comparator clinical trial. Diabetes Obes Metab. 
2016;18(8):803-11.
35.
Pratley R, Nauck M, Bailey T, Montanya E, Cuddihy R, Filetti S, et al. One year of 
liraglutide treatment offers sustained and more effective glycaemic control and weight 
reduction compared with sitagliptin, both in combination with metformin, in patients with 
type 2 diabetes: a randomised, parallel-group, open-label trial. International Journal of 
Clinical Practice. 2011;65(4):397-407.
36.
Limited MSD. JANUVIA – Labelling FDA. 4/27/2015 2015.
37.
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.
38.
Effect of intensive blood-glucose control with metformin on complications in overweight 
patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) 
Group. Lancet. 1998;352(9131):854-65.
39.
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.
40.
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.
41.
American Diabetes Association. Standards of medical care in diabetes - 2016. Diabetes 
Care. 2016;39 (Suppl. 1):S1-S109.
42.
Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. 
Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position 
statement of the American Diabetes Association (ADA) and the European Association for 
the Study of Diabetes (EASD). Diabetes Care. 2012;35(6):1364-79.
43.
Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. 
Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position 
statement of the American Diabetes Association (ADA) and the European Association for 
the Study of Diabetes (EASD). Diabetologia. 2012;55(6):1577-96.
44.
Standards of Medical Care in Diabetes-2016: Summary of Revisions. Diabetes Care. 
2016;39 Suppl 1:S4-5.
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Protocol
CONFIDENTIAL
Date:
28 October 2016
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Trial ID: NN9535-4114
Version:
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UTN: U1111-1149-0432 
Status:
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EudraCT no.: NA
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45.
Merck & Co. I. JANUVIA - Labelling FDA. 2013 2013.
46.
Limited MSDAP. JANUVIA - Labelling CFDA. 2011 2011.
47.
Charbonnel B, Karasik A, Liu J, Wu M, Meininger G, Sitagliptin Study G. Efficacy and 
safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy 
in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes 
Care. 2006;29(12):2638-43.
48.
De Angelis C, Drazen JM, Frizelle FA, Haug C, Hoey J, Horton R, et al. Clinical trial 
registration: a statement from the International Committee of Medical Journal Editors. N 
Engl J Med. 2004;351(12):1250-1.
49.
U.S. Department of Health and Human Services, Food and Drug Administration. Food and 
Drug Administration Amendments Act of 2007. 27 September 2007.
50.
European Commission Regulation for EudraCT. 2011 2011.
51.
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.
52.
McAulay V, Deary IJ, Frier BM. Symptoms of hypoglycaemia in people with diabetes. 
Diabet Med. 2001;18(9):690-705.
53.
U.S. Department of Health and Human Services, Food and Drug Administration. Guidance 
for Industry. Patient-Reported Outcome Measures: Use in Medical Product Development to 
Support Labeling Claims. December 2009.
54.
Stull DE, Leidy NK, Parasuraman B, Chassany O. Optimal recall periods for patient-
reported outcomes: challenges and potential solutions. Curr Med Res Opin. 2009;25(4):929-
42.
55.
European Commission. The Rules Governing Medicinal Products in the European Union, 
Volume 4, Annex 13, Investigational Medicinal Products (ENTR/F/2/AM/an D[2010] 
3374). 03 Feb 2010.
56.
Limited MSD. JANUVIA - European Summary of Product Characteristics Annex 1. 
5/26/2015 2015.
57.
Hicks KA, Hung HMJ, Mahaffey KW, Mehran R, Nissen SE, Strockbridge NL, et al. 
Standardized Definitions for Cardiovascular and Stroke End Point Events in Clinical Trials 
(Draft). 20 Aug 2014.
58.
Phillips A, Haudiquet V. ICH E9 guideline 'Statistical principles for clinical trials': a case 
study. Stat Med. 2003;22(1):1-11; discussion 3-7.
59.
Little RJA, Rubin DB. Statistical analysis with missing data: New York: John Wiley & 
Sons. 1987.
60.
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.
61.
American Diabetes Association. Standards of medical care in diabetes (2013). Diabetes 
Care. 2013;36 Suppl 1:S11-66.
62.
International Committee of Medicinal Journal Editors. Uniform Requirements for 
Manuscripts submitted to Biomedical Journals.: N Engl J Med; 1997 1997. p. 309-15.
CONFIDENTIAL


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Date:
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Novo Nordisk
Trial ID: NN9535-4114
Version:
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UTN: U1111-1149-0432 
Status:
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EudraCT no.: NA
Page:
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Protocol
Trial ID: NN9535-4114
SUSTAIN – CHINA MRCT
Efficacy and safety of semaglutide once-weekly versus
sitagliptin once-daily as add-on to metformin in subjects
with type 2 diabetes
A 30-week randomised, double-blind, double-dummy, active-controlled, 
parallel-group, multi-centre and multi-national trial
Trial phase: 3a
Protocol originator
Semaglutide Diabetes & Diabetes Outcomes
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:
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Trial ID: NN9535-4114
Version:
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UTN: U1111-1149-0432 
Status:
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EudraCT no.: NA
Page:
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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 ................................................................................................................................................14
2.1
Flow chart explanatory descriptions............................................................................................17
3
Background information and rationale for the trial............................................................................18
3.1
Type 2 diabetes............................................................................................................................18
3.2
Glucagon-like peptide-1 ..............................................................................................................18
3.3
Semaglutide .................................................................................................................................18
3.3.1
Non-clinical data........................................................................................................19
3.3.1.1
Thyroid C-cell tumours in rodents ......................................................19
3.3.1.2
Embryo−foetal development toxicity..................................................19
3.3.2
Clinical data...............................................................................................................20
3.3.2.1
Pharmacokinetics ................................................................................20
3.3.2.2
Efficacy ...............................................................................................20
3.3.2.3
Safety...................................................................................................21
3.4
Sitagliptin.....................................................................................................................................22
3.5
Risk and benefits assessment.......................................................................................................22
3.5.1
Semaglutide risks and precautions.............................................................................22
3.5.2
Identified risks ...........................................................................................................23
3.5.3
Potential risks.............................................................................................................23
3.5.4
Other safety considerations........................................................................................25
3.5.5
Sitagliptin risk and precautions..................................................................................25
3.5.6
Benefits......................................................................................................................25
3.5.7
Risk and benefit conclusion.......................................................................................26
3.6
Rationale for the trial...................................................................................................................26
4
Objectives and endpoints........................................................................................................................28
4.1
Objective......................................................................................................................................28
4.1.1
Primary objective.......................................................................................................28
4.1.2
Secondary objectives .................................................................................................28
4.2
Endpoints.....................................................................................................................................28
4.2.1
Primary endpoint........................................................................................................28
4.2.2
Secondary endpoints..................................................................................................28
4.2.2.1
Confirmatory secondary endpoint.......................................................28
4.2.2.2
Supportive secondary endpoints..........................................................28
5
Trial design..............................................................................................................................................30
5.1
Type of trial .................................................................................................................................30
5.2
Rationale for trial design..............................................................................................................31
5.3
Treatment of subjects...................................................................................................................32
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5.3.1
Missed dose ...............................................................................................................33
5.3.2
Background medication.............................................................................................33
5.3.3
Treatment after end of trial........................................................................................33
5.4
Rationale for treatment ................................................................................................................34
6
Trial population.......................................................................................................................................35
6.1
Number of subjects......................................................................................................................35
6.2
Inclusion criteria ..........................................................................................................................35
6.3
Exclusion criteria.........................................................................................................................35
6.4
Rescue criteria..............................................................................................................................36
6.5
Withdrawal criteria ......................................................................................................................37
6.5.1
Discontinuation of trial product.................................................................................37
6.5.2
Withdrawal from trial ................................................................................................37
6.6
Subject replacement.....................................................................................................................38
6.7
Rationale for trial population.......................................................................................................38
7
Milestones ................................................................................................................................................39
8
Methods and assessments .......................................................................................................................40
8.1
Visit procedures...........................................................................................................................40
8.1.1
Screening visit 1 (V1)................................................................................................40
8.1.1.1
Screen failures.....................................................................................40
8.1.1.2
Re-screening........................................................................................41
8.1.2
Fasting visits ..............................................................................................................41
8.1.3
Randomisation V2 .....................................................................................................41
8.1.4
Visits..........................................................................................................................41
8.1.5
Missed visits and unscheduled visits .........................................................................41
8.1.6
End of treatment (V9/9A) and Follow-up (V10/10A) ...............................................42
8.1.6.1
Subjects completing the treatment period as per protocol...................42
8.1.6.2
Subjects who prematurely discontinue trial product ...........................42
8.1.7
Withdrawals...............................................................................................................42
8.1.8
Investigator’s assessment...........................................................................................43
8.2
Subject related information..........................................................................................................44
8.2.1
Demography ..............................................................................................................44
8.2.2
Diabetes history and diabetes complications.............................................................44
8.2.3
Concomitant illness and medical history...................................................................44
8.2.4
Concomitant medication............................................................................................45
8.2.5
Tobacco use ...............................................................................................................45
8.2.6
Childbearing potential................................................................................................46
8.2.7
Height ........................................................................................................................46
8.3
Assessments for efficacy .............................................................................................................46
8.3.1
Body weight...............................................................................................................46
8.3.2
Waist circumference ..................................................................................................46
8.3.3
BMI............................................................................................................................47
8.3.4
Systolic and diastolic blood pressure.........................................................................47
8.4
Assessments for safety.................................................................................................................48
8.4.1
Adverse events...........................................................................................................48
8.4.2
Medication error ........................................................................................................48
8.4.3
Adverse events requiring additional data collection..................................................48
8.4.4
Hypoglycaemic episodes ...........................................................................................49
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
09 December 2016
Novo Nordisk
Trial ID: NN9535-4114
Version:
3.0
UTN: U1111-1149-0432 
Status:
Final
EudraCT no.: NA
Page:
4 of 115
8.4.5
Electrocardiogram......................................................................................................51
8.4.6
Physical examination.................................................................................................51
8.4.7
Pulse...........................................................................................................................52
8.4.8
Eye examination ........................................................................................................52
8.5
Laboratory assessments ...............................................................................................................52
8.5.1
Laboratory assessments for efficacy..........................................................................53
8.5.1.1
Glucose metabolism............................................................................54
8.5.1.2
Biomarker............................................................................................54
8.5.1.3
Lipids (all fasting)...............................................................................54
8.5.1.4
Self measured plasma glucose (SMPG)..............................................54
8.5.1.5
7 point profile......................................................................................55
8.5.2
Laboratory assessments for safety .............................................................................55
8.5.2.1
Anti-semaglutide antibodies................................................................55
8.5.2.2
Biochemistry .......................................................................................56
8.5.2.3
Haematology .......................................................................................56
8.5.2.4
Calcitonin............................................................................................56
8.5.2.5
Pregnancy test .....................................................................................56
8.5.2.6
Urinalysis ............................................................................................57
8.6
Other assessments........................................................................................................................57
8.6.1
Patient reported Outcome questionnaires ..................................................................57
8.6.1.1
SF-36v2TM ...........................................................................................57
8.6.1.2
DTSQs.................................................................................................58
8.6.2
Subject diary ..............................................................................................................58
8.7
Subject compliance......................................................................................................................58
9
Trial supplies ...........................................................................................................................................59
9.1
Trial products...............................................................................................................................59
9.2
Labelling......................................................................................................................................60
9.3
Storage.........................................................................................................................................60
9.4
Drug accountability and destruction............................................................................................61
9.5
Auxiliary supplies........................................................................................................................61
10 Interactive web response system............................................................................................................62
11 Randomisation procedure and breaking of blinded codes..................................................................63
11.1
Breaking of blinded codes ...........................................................................................................63
12 Adverse events, and technical complaints and pregnancies................................................................64
12.1
Definitions ...................................................................................................................................64
12.1.1
Serious adverse event.................................................................................................65
12.1.2
Non-serious adverse event.........................................................................................66
12.1.3
Medication errors.......................................................................................................66
12.1.4
Adverse events requiring additional data collection..................................................67
12.1.5
Technical complaint...................................................................................................68
12.2
Reporting of adverse events.........................................................................................................68
12.3
Follow-up of adverse events........................................................................................................70
12.4
Technical complaints and technical complaint samples ..............................................................71
12.4.1
Reporting of technical complaints .............................................................................71
12.4.2
Collection, storage and shipment of technical complaint samples ............................72
12.5
Pregnancies..................................................................................................................................72
12.5.1
Pregnancies in female subjects ..................................................................................72
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
09 December 2016
Novo Nordisk
Trial ID: NN9535-4114
Version:
3.0
UTN: U1111-1149-0432 
Status:
Final
EudraCT no.: NA
Page:
5 of 115
12.6
Precautions and/or overdose ........................................................................................................74
12.7
Committees related to safety........................................................................................................75
12.7.1
Novo Nordisk safety committee ................................................................................75
12.7.2
Event adjudication committee....................................................................................75
13 Case report forms....................................................................................................................................78
13.1
Corrections to case report forms..................................................................................................78
13.2
Case report form flow..................................................................................................................78
13.2.1
Electronic case report form flow................................................................................78
13.2.2
Paper case report form flow.......................................................................................79
14 Monitoring procedures...........................................................................................................................80
15 Data management....................................................................................................................................82
16 Computerised systems ............................................................................................................................83
17 Statistical considerations ........................................................................................................................84
17.1
Sample size calculation................................................................................................................85
17.2
Definition of analysis sets............................................................................................................86
17.3
Primary endpoint..........................................................................................................................88
17.4
Secondary endpoints....................................................................................................................91
17.4.1
Confirmatory secondary endpoints............................................................................91
17.4.2
Supportive secondary endpoints ................................................................................92
17.4.2.1
Efficacy endpoints...............................................................................92
17.4.2.2
Safety endpoints..................................................................................94
17.5
Health economics and/or patient reported outcomes...................................................................99
18 Ethics......................................................................................................................................................100
18.1
Informed consent .......................................................................................................................100
18.2
Data handling.............................................................................................................................101
18.3
Information to subject during trial.............................................................................................101
18.4
Premature termination of the trial and/or trial site.....................................................................102
19 Protocol compliance..............................................................................................................................103
20 Audits and inspections..........................................................................................................................104
21 Critical documents ................................................................................................................................105
22 Responsibilities......................................................................................................................................106
23 Reports and publications......................................................................................................................107
23.1
Communication of results..........................................................................................................107
23.1.1
Authorship ...............................................................................................................108
23.1.2
Site-specific publication(s) by investigator(s) .........................................................108
23.2
Investigator access to data and review of results.......................................................................108
24 Retention of clinical trial documentation and human biospecimens................................................109
24.1
Retention of clinical trial documentation...................................................................................109
24.2
Retention of human biospecimens.............................................................................................109
25 Institutional Review Boards/Independent Ethics Committees and regulatory authorities............110
26 Indemnity statement .............................................................................................................................111
27 References..............................................................................................................................................112
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
09 December 2016
Novo Nordisk
Trial ID: NN9535-4114
Version:
3.0
UTN: U1111-1149-0432 
Status:
Final
EudraCT no.: NA
Page:
6 of 115
Appendix A: 
Monitoring of calcitonin
Appendix B:
Adverse events requiring additional data collection 
Attachment I:
Global list of key staff and relevant departments and vendors
Attachment II:
Country list of key staff and relevant departments 
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
09 December 2016
Novo Nordisk
Trial ID: NN9535-4114
Version:
3.0
UTN: U1111-1149-0432 
Status:
Final
EudraCT no.: NA
Page:
7 of 115
Table of Figures
Page
Figure 5–1
Trial design.............................................................................................................................30
Figure 12–1
Reporting of AEs....................................................................................................................69
Figure 17–1
Novo Nordisk classification of hypoglycaemia......................................................................97
Figure 17–2
ADA classification of hypoglycaemia....................................................................................98
Table of Tables
Page
Table 5–1
Treatment of subjects..............................................................................................................32
Table 12–1
Adverse events requiring completion of specific event forms and/or are subject to event 
adjudication ............................................................................................................................67
Table 12–2
Adverse events for adjudication .............................................................................................76
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
09 December 2016
Novo Nordisk
Trial ID: NN9535-4114
Version:
3.0
UTN: U1111-1149-0432 
Status:
Final
EudraCT no.: NA
Page:
8 of 115
List of abbreviations
AACE
American Association of Clinical Endocrinologists
ADA
American Diabetes Association
AE
adverse event
BG
blood glucose
BMI
Body mass index
CRF
case report form
CRO
contract research organisation
CTR
clinical trial report
CVD
cardiovascular disease
DPP-4
dipeptidyl peptidase 4
DUN
dispensing unit number
DTSQs
Diabetes Treatment Satisfaction Questionnaire status
EAC
event adjudication committee
ECG
electrocardiogram
eCRF
electronic case report form
EE
ethinylestradiol
EFD
embryo-foetal development
eGFR
estimated glomerular filtration rate
FAS
full analysis set
FDAAA
Food and Drug Administration Amendment Act
FPFV
first patient first visit
FPG
fasting plasma glucose
FSFV
first subject first visit
GCP
Good Clinical Practice
GI
gastrointestinal
GIP
gastric inhibitory polypeptide
GLP-1
glucagon-like peptide-1
HbA1c
glycosylated haemoglobin
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
09 December 2016
Novo Nordisk
Trial ID: NN9535-4114
Version:
3.0
UTN: U1111-1149-0432 
Status:
Final
EudraCT no.: NA
Page:
9 of 115
hCG
human chorionic gonadotrophin
HDL
high density lipoprotein
hsCRP
highly sensitive C-reactive protein
IB
Investigator’s Brochure
ICMJE
International Committee of Medical Journal Editors
IEC
independent ethics committee
IMP
investigational medicinal product
IRB
Institutional Review Board
IUD
intrauterine device 
IWRS
interactive voice/web response system
LDL
low density lipoprotein
LN
levonorgestrel
LPFV
last patient first visit
LPLV
last patient last visit
LSFV
last subject first visit
LSLV
last subject last visit
MACE
major adverse cardiovascular events
MAR
missing at random 
MCAR
missing completely at random 
MDRD
modification of diet in renal disease 
MEN2
multiple endocrine neoplasia syndrome type 2 
MMRM
mixed model for repeated measurements 
MTC
medullary thyroid carcinoma
NYHA
New York Heart Association
OAD
oral anti-diabetic drug
PG
plasma glucose
PP
per protocol
PPG
postprandial glucose
PPND
pre- and postnatal development 
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
09 December 2016
Novo Nordisk
Trial ID: NN9535-4114
Version:
3.0
UTN: U1111-1149-0432 
Status:
Final
EudraCT no.: NA
Page:
10 of 115
PRO
patient reported outcome
RA
receptor agonist
SAE
serious adverse event
SAP
statistical analysis plan
s.c.
subcutaneous
SD
standard deviation 
SDV
source data verification
SMBG
self-measured blood glucose
SMPG
self-measured plasma glucose
SU
sulphonylurea
SUSAR
suspected unexpected serious adverse reaction
TMM
Trial Materials Manual
TEAE
treatment emergent adverse event
TVP
trial validation plan
UACR
urinary albumin to creatinine ratio 
UTN
universal trial number
V
visit
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
09 December 2016
Novo Nordisk
Trial ID: NN9535-4114
Version:
3.0
UTN: U1111-1149-0432 
Status:
Final
EudraCT no.: NA
Page:
11 of 115
1
Summary
Objectives and endpoints:
Primary objective
To compare the effect of once-weekly dosing of two dose levels of semaglutide versus sitagliptin 
100 mg once-daily on glycaemic control after 30 weeks of treatment
Primary endpoint
Change from baseline to week 30 in HbA1c
Secondary objectives
To compare the effects of once-weekly dosing of two dose levels of semaglutide versus sitagliptin
100 mg once-daily after 30 weeks of treatment on:
!
Inducing and maintaining weight loss
!
Other parameters of efficacy, safety and tolerability
Key secondary endpoint
Confirmatory secondary endpoint
!
Change from baseline to week 30 in body weight
Supportive secondary endpoints:
Change from baseline to week 30 in:
!
Fasting plasma glucose (FPG)
!
Systolic and diastolic blood pressure
!
Patient reported outcome (PRO) questionnaire: Diabetes Treatment Satisfaction
Questionnaire status (DTSQs) score
Subjects who after 30 weeks treatment achieve (yes/no):
!
HbA1c ≤ 6.5% (48 mmol/mol) - American Association of Clinical Endocrinologists (AACE)
target
Trial design:
This is a 30-week randomised, double-blind, double-dummy, active-controlled, multi-centre, multi-
national four-armed, parallel-group trial comparing semaglutide 0.5 mg and 1.0 mg once-weekly 
against sitagliptin 100 mg once-daily.
Subjects with type 2 diabetes inadequately controlled on metformin will be randomised in a 2:2:1:1 
manner to receive either:
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
09 December 2016
Novo Nordisk
Trial ID: NN9535-4114
Version:
3.0
UTN: U1111-1149-0432 
Status:
Final
EudraCT no.: NA
Page:
12 of 115
!
semaglutide 0.5 mg once-weekly + sitagliptin placebo once-daily
!
semaglutide 1.0 mg once-weekly + sitagliptin placebo once-daily
!
sitagliptin 100 mg once-daily + semaglutide placebo (0.5) mg once-weekly
!
sitagliptin 100 mg once-daily + semaglutide placebo (1.0) mg once-weekly
Trial product will be add-on to subject’s stable pre-trial metformin. 
Key inclusion criteria:
!
Informed consent obtained before any trial-related activities. Trial-related activities are any
procedures that are carried out as part of the trial, including activities to determine suitability
for the trial
!
Male or female,  age ≥ 18 years at the time of signing informed consent
!
Subjects diagnosed with type 2 diabetes and on stable treatment in a period of 60 days prior
to screening with metformin ≥ 1500 mg (or maximum tolerated dose ≥ 1000 mg). Stable is
defined as unchanged medication and unchanged daily dose
!
HbA1c 7.0 – 10.5 % (53-91 mmol/mol) (both inclusive)
Key exclusion criteria: 
!
Female who is pregnant, breast-feeding or intends to become pregnant or is of childbearing
potential not using an adequate contraceptive method throughout the trial including the 5
week follow-up period (adequate contraceptive measure as required by local regulation or
practice).
!
Any disorder which, in the opinion of the investigator, might jeopardise subject’s safety or
compliance with the protocol
!
Treatment with glucose lowering agent(s) other than stated in the inclusion criteria in a
period of 60 days before screening. An exception is short-term treatment (≤7 days in total)
with insulin in connection with inter-current illness
!
History of chronic or idiopathic acute pancreatitis
!
Screening calcitonin value  ≥ 50 ng/L (pg/mL)
!
Personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine
neoplasia syndrome type 2 (MEN 2)
!
Impaired renal function defined as estimated glomerular filtration rate (eGFR) < 60
ml/min/1.73 m2 per modification of diet in renal disease (MDRD) formula (4 variable
version)
!
Acute coronary or cerebrovascular event within 90 days before  randomisation
!
Heart failure, New York Heart Association (NYHA) class IV
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
09 December 2016
Novo Nordisk
Trial ID: NN9535-4114
Version:
3.0
UTN: U1111-1149-0432 
Status:
Final
EudraCT no.: NA
Page:
13 of 115
Assessments:
Efficacy:
!
Glucose metabolism
!
Body measurements (body weight, body mass index (BMI) and waist circumference)
!
Systolic and diastolic blood pressure
!
Blood lipids
!
Patient reported outcome (PRO) questionnaires (SF-36v2TM and DTSQs)
Safety:
!
Adverse events and serious adverse events
!
Hypoglycaemic episodes
!
Biochemistry and haematology
!
Anti-semaglutide antibodies
!
Physical examination (including electrocardiogram (ECG))
Trial products:
Novo Nordisk A/S will supply the following trial products:
!
Semaglutide 1.34 mg/mL, solution for injection, 1.5 mL pre-filled PDS290 pen-injector
!
Semaglutide placebo, solution for injection, 1.5 mL pre-filled PDS290 pen-injector
!
Sitagliptin (Januvia®) 100 mg tablets for oral administration
!
Sitagliptin placebo tablets for oral administration
CONFIDENTIAL


Protocol
UTN: U1111-1149-0432 
Date:
09 December 2016
Status:
Final
Novo Nordisk
Trial ID: NN9535-4114
EudraCT no.: NA
Version:
3.0
Page:
14 of 115
2
Flow chart
Trial Periods
Screen
Rand
Treatment period
End of 
Treatment1
Follow Up1
End of 
Treatment 
premature 
discontinuation2
Follow Up
premature 
discontinuation2
Visit (V) or Phone (P) number
V1
V2
V3
P4
V5
V6
V7
V8
V9
V10
V9A
V10A
Time of visit
    Weeks
-2
0
4
6
8
12
16
23
30
35
Visit window
    Days
±7
±3
±3
±3
±3
±3
±3
±7
+7
SUBJECT RELATED INFO 
/ASSESSMENTS
Informed consent
18.1
x
In/exclusion criteria  
6.2,6.3
x
x
Randomisation 
8.1.3
x
Withdrawal criterion
6.5
x
x
x
x
x
x
x
x
Demography
8.2.1
x
Diabetes history and 
diabetes complications 
8.2.2
x
Concomitant illness and 
medical history
8.2.3
x
History of cardiovascular 
disease
8.2.3
x
History of gallbladder 
disease
8.2.3
x
Tobacco use
8.2.5
x
Concomitant medication
8.2.4
x
x
x
x
x
x
x
x
x
x
x
x
Height
8.2.7
x
EFFICACY
Body weight
8.3.1
x
x
x
x
x
x
x
x
Waist circumference 
8.3.2
x
x
x
x
x
x
x
x
BMI 
8.3.3
x
x
x
x
x
x
x
x
Systolic blood pressure, 
sitting
8.3.4
x
x
x
x
x
x
x
x
x


Protocol
UTN: U1111-1149-0432 
Date:
09 December 2016
Status:
Final
Novo Nordisk
Trial ID: NN9535-4114
EudraCT no.: NA
Version:
3.0
Page:
15 of 115
Trial Periods
Screen
Rand
Treatment period
End of 
Treatment1
Follow Up1
End of 
Treatment 
premature 
discontinuation2
Follow Up
premature 
discontinuation2
Visit (V) or Phone (P) number
V1
V2
V3
P4
V5
V6
V7
V8
V9
V10
V9A
V10A
Time of visit
    Weeks
-2
0
4
6
8
12
16
23
30
35
Visit window
    Days
±7
±3
±3
±3
±3
±3
±3
±7
+7
Diastolic blood pressure, 
sitting
8.3.4
x
x
x
x
x
x
x
x
x
HbA1c 
8.5.1.1
x
x
x
x
x
x
x
x
x
Fasting plasma glucose
8.5.1.1
x
x
x
x
x
x
x
x
Fasting insulin
8.5.1.1
x
x
x
x
Fasting proinsulin
8.5.1.1
x
x
x
x
Fasting C-peptide
8.5.1.1
x
x
x
x
Fasting glucagon
8.5.1.1
x
x
x
x
Lipids
8.5.1.3
x
x
x
x
hsCRP (highly sensitive 
CRP)
8.5.1.2
x
x
x
x
7 point profile  
8.5.1.4
x
x
x
x
SAFETY
Adverse events
8.4.1
x
x
x
x
x
x
x
x
x
x
x
Hypoglycaemic episodes
8.4.4
x
x
x
x
x
x
x
x
x
x
x
ECG
8.4.5
x
x
x
x
x
Physical examination
8.4.6
x
x
x
Pulse, sitting
8.4.7
x
x
x
x
x
x
x
x
x
Anti-semaglutide antibodies4
8.5.2.1
x
x
x
x
x
x
Creatinine
8.5.2.2
x
x
x
x
x
x
x
x
Biochemistry
8.5.2.2
x
x
x
x
x
x
x
x
Haematology
8.5.2.3
x
x
x
x
x
x
x
x
Calcitonin
8.5.2.4
x
x
x
x
Pregnancy test5
8.5.2.5
x
x
x
x
x
x
x
x
x
x
x
Urinalysis
8.5.2.6
x
x
x
x


Protocol
UTN: U1111-1149-0432 
Date:
09 December 2016
Status:
Final
Novo Nordisk
Trial ID: NN9535-4114
EudraCT no.: NA
Version:
3.0
Page:
16 of 115
Trial Periods
Screen
Rand
Treatment period
End of 
Treatment1
Follow Up1
End of 
Treatment 
premature 
discontinuation2
Follow Up
premature 
discontinuation2
Visit (V) or Phone (P) number
V1
V2
V3
P4
V5
V6
V7
V8
V9
V10
V9A
V10A
Time of visit
    Weeks
-2
0
4
6
8
12
16
23
30
35
Visit window
    Days
±7
±3
±3
±3
±3
±3
±3
±7
+7
Eye examination3
8.4.8
x
x
x
OTHER ASSESSMENTS
PRO questionnaires 
8.6.1
x
x
x
TRIAL MATERIAL
Drug accountability  
9.4
x
x
x
x
IWRS call
10
x
x
x
x
x
x
Dispensing visit
9.1
x
x
x
REMINDERS
Training in trial product, and 
pen handling
9.1
x
x
x
Hand-out Directions for Use 
(DFU)
9.5
x
End of treatment
8.1.6
x9
x9
End of trial  
8.1.6
x9
Hand-out and instruct in BG 
meter use
8.5.1.4
x
Hand-out and /or collect
diary6 
8.6.2
x
x
x
x
x
x
x
x
x6
x
x6
Attend visit fasting7 
8.1.2
x
x
x
x
x
x
x
x8
x
x8
Hand-out ID card
8.1.1
x


Protocol
UTN: U1111-1149-0432 
Date:
09 December 2016
Status:
Final
Novo Nordisk
Trial ID: NN9535-4114
EudraCT no.: NA
Version:
3.0
Page:
17 of 115
2.1
Flow chart explanatory descriptions
Footer
Description
x1
V9 (End of Treatment) and V10 (Follow Up) are applicable for all randomised subjects. Subjects who have discontinued trial product prematurely should 
also attend V9 and V10 according to their initially scheduled week 30 and Week 35 visits.
x2
Subjects discontinuing trial product prematurely will be asked to attend two additional visits to undergo assessments: End of Treatment-premature 
discontinuation (V9A) and Follow Up -premature discontinuation (V10A). V9A should be scheduled at discontinuation of the trial product. V10A should be 
scheduled 5 weeks after discontinuation of trial product (+ 7 days visit window). 
x3
Fundus photography/dilated fundoscopy performed within 90 days before visit 2 is acceptable if results are available for evaluation at the visit 2 and no 
deterioration in visual function since last assessment.
x4
Antibody sampling should preferably be done pre-dose. For fasting and non-fasting visit, where the injection takes place on the day of site visit, trial product 
must not be taken before blood sampling. 
For visit 9 and 10: Not applicable if taken at a premature discontinuation visit
x5
For women of child bearing potential: For all site visits a serum pregnancy test must be performed. Urine pregnancy test should be performed at any time 
during the trial if a menstrual period is missed, or as required by local law.
x6
At V10 and V10A collect diary only.
x7
Fasting is defined as having consumed only water within the last 6 hours prior to the visit. Glucose lowering agents and trial product cannot be taken until 
after blood sampling has been performed but other prescribed medication should be taken.
x8
For the follow-up visit (V10/V10A) attend fasting is defined as having consumed only water within the last 2 hours prior to the visit.
x9
If premature discontinuation occurs, End of Treatment form must be filled-in when the discontinuation happens and End of Trial form at scheduled V10. If a 
subject completes both the treatment and the trial at scheduled time, the End of Treatment form must be filled at V9 and End of Trial form to be filled in at 
V10. In case of subject withdrawal, both End of Treatment form and End of Trial form must be filled-in at the time they withdraw from the trial. 


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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
Type 2 diabetes
Type 2 diabetes (T2D) is a progressive metabolic disease primarily characterised by abnormal 
glucose metabolism. The pathogenesis is not fully understood but seems to be 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 type 2 diabetes, in order to prevent 
long-term complications associated with chronic hyperglycaemia4,5. Despite the availability of 
several anti-diabetic drugs, a significant proportion of subjects with type 2 diabetes do not achieve 
the recommended blood glucose target levels6-9.
3.2
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 islets10, 11. Subjects
with T2D have a decreased response to GLP-112-15. However, the insulinotropic action of GLP-1 
andthus, the ability to lower BG levels, is preserved when GLP-1 is administered at 
supraphysiologicallevels16. In addition, supraphysiological levels of GLP-1 induce reduction in 
body weight17. 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 regulationand food intake18, 19. 
Physiologically, GLP-1 also has a pronouncedinhibitory effect on gastric emptying; however this 
effect seems to diminish upon chronicexposure17-19. These mechanisms of action make glucagon-
like peptide-1 receptor agonists (GLP-1RAs) an attractive pharmacological treatment for T2D20-22.
Due to the very short half-life of <1.5 minutes after i.v. administration, native GLP-1 is not suitable 
for therapeutic use. To realise the full therapeutic potential of GLP-1, the pharmacokinetic and 
hence the pharmacodynamic effect needs to be protracted.
3.3
Semaglutide
Semaglutide is a potent human GLP-1 receptor agonist (RA) for once-weekly subcutaneous (s.c.) 
administration. It is structurally similar to liraglutide (Victoza®), a once-daily GLP-1 RA developed 
by Novo Nordisk and approved worldwide for the treatment of type 2 diabetes. The extended half-
life of the semaglutide molecule is primarily obtained due to binding to albumin, which is facilitated 
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by a large fatty acid derived chemical moiety attached to the lysine inposition 26. The specific 
modifications in the molecule are: 1) a modification in position 8 (alanineto 2-aminoisobutyric 
acid) of the peptide backbone to increase stability against dipeptidylpeptidase-4 (DPP-4), and a 
change in position 34 from a lysine to an arginine to limit the optionsfor acylation to the one 
remaining lysine in the sequence; 2) a large hydrophilic spacer between thelysine in position 26 
and the gamma glutamate whereto the fatty acid is attached; 3) a C18 fatty diacidwith a terminal 
acidic group23, 24. The spacer and the fatty acid both contribute to increasedalbumin binding, which 
results in decreased renal clearance resulting in a prolonged half-life ofapproximately 1 week, 
making semaglutide suitable for once-weekly s.c. administration.
3.3.1
Non-clinical data
The non-clinical programme for semaglutide was designed according to the ICH M325guideline to 
support the clinical development. The standard non-clinical data package required to support phase 
3 clinical trials has been completed. In addition, 2-year carcinogenicity studies and a pre-and 
postnataldevelopment toxicity study have been completed. 
Semaglutide is generally well tolerated with expected GLP-1 effects on food intake and body 
weight being dose limiting in mice, rats and cynomolgus monkeys. Two potential safety issues have 
been identified.
3.3.1.1
Thyroid C-cell tumours in rodents
Thyroid C-cell neoplasia was seen in mice and rat 2-year carcinogenicity studies. Proliferative C
cellchanges in rodents are a known effect following GLP-1 receptor activation by GLP-1 receptor
agonists. The finding in rodents is caused by a non-genotoxic, specific GLP-1 receptor-mediated
mechanism to which rodents are particularly sensitive. Recently published data have shown that the
GLP-1 receptor is not expressed in the normal human thyroid, and accordingly, the risk of GLP-1
receptor mediated C-cell changes in humans is considered to be low26.
3.3.1.2
Embryo−foetal development toxicity
Semaglutide adversely affected embryo−foetal development in the rat by a GLP-1 receptor
mediated impaired function of the inverted yolk sac placenta during a period of gestation when the
rat embryo is entirely dependent on the inverted yolk sac placenta for its nutrient supply. In
primates, the yolk sac does not invert to fully enclose the embryo, and it does not come in direct
contact with the uterine wall to form a placenta as in rodents. Accordingly, the mechanism by which 
semaglutide adversely affects embryo-foetal development in the rat, is not likely to be of relevance 
to humans. Studies in cynomolgus monkeys confirmed that maternal dosing of semaglutide does not 
affect embryo−foetal development in this species. However, the initial maternal body weight loss 
caused by the pharmacological effect of semaglutide coincided with increased early pregnancy loss 
in one of three studies. In cynomolgus monkeys, the overall developmental no observable adverse 
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effect level (NOAEL) was determined to be 0.015 mg/kg/3days, which provides an exposure 
equivalent to the human exposure at 1.0 mg/week based on areaunder the curve (AUC).
A comprehensive review of results from the nonclinical studies can be found in the current edition 
of semaglutide (NN9535) investigator’s brochure (IB)27, or any updates hereof.
3.3.2
Clinical data
As of 1 August 2016, 16 clinical pharmacology trials (trials NN9535-1820, 3679, 3633, 3616, 3819,
4010, 3789, 3652, 3685, 3634, 3687, 3817,3818, 3684, 3651 and 3635), 1 phase 2 trial (NN9535-
1821) and 8 phase 3a trials (NN9535-3623, 3624, 3625,3626, 3627, 3744, 4091, 4092) have been
completed with semaglutide s.c. once-weekly. Clinical pharmacology trials were conducted in 
healthy subjects, in subjects with T2D, in subjects with obesity and in subjects with renal- and 
hepatic impairment. The phase 2 dose-finding trial was conducted in subjects with T2D. The 
semaglutide phase 3a programme evaluated the efficacy and safety of semaglutide in a broad T2D 
population and covered the continuum of T2D care. The programme evaluated mono- and 
combination therapy with anti-hyperglycaemic therapies and compared semaglutide with the most 
important comparators at the time of initiating the phase 3a programme. In addition, the phase 3a 
programme included a long-term (104-week) cardiovascular outcomes trial (trial 3744) in a T2D 
population at high risk of cardiovascular events.
3.3.2.1
Pharmacokinetics
The results from the completed clinical pharmacology trials confirm that semaglutide has PK
properties compatible with once-weekly administration, having a flat concentration profile over
time, with a median time to maximum concentration (tmax) of 1−3 days post-dosing and an
elimination half-life (t½) of approximately 1 week. The PK properties of semaglutide appear
comparable between healthy subjects, subjects with T2D and subjects with renal failure. Results 
from drug-interaction studies with warfarin, metformin, atorvastatin and digoxin indicate that no 
dose adjustment of the co-administered drugs is warranted when administered together with
semaglutide. In addition, semaglutide does not decrease the exposure of oral contraceptives and
hence, is not anticipated to decrease the effectiveness of oral contraceptives.
3.3.2.2
Efficacy
Based on results from the clinical pharmacology trials, semaglutide treatment reduced both fasting
and postprandial glucose compared to placebo, by improving multiple aspects of β-cell function and
by reducing both fasting and postprandial glucagon concentrations, all in a glucose dependent 
manner. The weight loss observed with semaglutide was primarily from fat tissue and was
considered to be explained by lowered appetite, both in the fasting and postprandial state, and
lowered energy intake. In addition, semaglutide improved control of eating and reduced food
cravings. Similar to other GLP-1 receptor agonists, semaglutide caused a minor delay of early
postprandial gastric emptying.
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Both as monotherapy and as combination therapy, semaglutide significantly reduced HbA1c and
body weight in all phase 3a trials when compared with the trial-specific comparator, including the
active comparators sitagliptin, exenatide ER and insulin glargine. In the 5 global phase 3a trials
(3623, 3624, 3625, 3626 and 3627), reductions in HbA1c and body weight of up to 1.85 %-point 
and6.42 kg, respectively, were obtained with semaglutide 1.0 mg. Significantly more subjects with
semaglutide versus comparators reached the American Diabetes Association (ADA) and American
Association of Clinical Endocrinologists (AACE)-defined treatment target of an HbA1c <7% and
≤6.5%, respectively, and weight loss responses of ≥5% and ≥10%. The superior and clinically
relevant beneficial effects of semaglutide on glycaemic control as estimated by HbA1c were
substantiated by improvements in secondary glycaemia-related supportive endpoints28-31.
3.3.2.3
Safety
Data from the 5 global phase 3a clinical trials (NN9535-3623, 3624, 3625, 3626 and 3627) showed
that the safety and tolerability of semaglutide at doses up to 1.0 mg per week and administered for
up to 56 weeks of treatment were consistent with other GLP-1RAs. Commonly AEs included
nausea and vomiting, most of which were mild to moderate in severity. The escalation regimen
utilized was associated with good tolerability and low numbers of discontinuation due to AEs.
Accordingly, the most frequently reported AEs in subjects with T2D were gastrointestinal (e.g.,
nausea and vomiting), as were the most frequent AEs leading to premature treatment
discontinuation.
Hypoglycaemia occurred infrequently in subjects receiving semaglutide and the events were mainly
non-severe. Hypoglycaemic episodes have mainlybeen observed when semaglutide is combined
with sulphonylurea (SU) or insulin. 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
semaglutide. As with all protein based pharmaceuticals, subjects treated with semaglutide may
develop immunogenic and allergic reactions. However, only few subjects administered semaglutide 
experienced allergic reactions and injection site reactions. These have mainly beenmildand 
transient of nature; however, more generalised reactions may occur.
The effect of semaglutide on major adverse cardiovascular events (MACE) was evaluated in a T2D 
population at high risk for CV events, in the cardiovascular outcome trial, SUSTAIN6 
(NN9535-3744)32. SUSTAIN 6 trial achieved its primary objective by showingnon-inferiority of 
once-weekly s.c. semaglutide versus placebo on cardiovascular outcomes; moreover,s.c. 
semaglutide statisticallysignificantly reduced cardiovascular risk versus placebo32. In addition, 
results from the recentlycompleted LEADER® trial (EX2211-3748) showed that treatment with the 
once daily liraglutidedoes not increase the risk of MACE as compared to placebo. In fact, treatment 
with liraglutidereduced the risk of the primary composite outcome consisting of death from 
cardiovascular causes,non-fatal myocardial infarction (MI) and non-fatal stroke by 13% versus 
placebo32.The overallsafety profile of semaglutide in the SUSTAIN 6 trial (NN9535-3744) was 
consistent with previous
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semaglutide clinical studies. However, in this trial, the diabetic retinopathy complications were 
reported more frequently in the semaglutide-treated subjects compared with placebo. 
Please see the current edition of semaglutide s.c. (NN9535) IB orany updates hereof for further 
details27.
3.4
Sitagliptin
Sitagliptin is an oral antihyperglycemic agent of the dipeptidyl peptidase-4 (DPP-4) inhibitor class 
suitable for once-daily oral administration. It was developed and marketed by Merck & Co as 
sitagliptin phosphate under the trade name Januvia®
Sitagliptin works by inhibition of the enzyme dipeptidyl peptidase 4 (DPP-4). This enzyme breaks 
down the incretin hormones GLP-1 and gastric inhibitory polypeptide (GIP). By preventing GLP-1 
and GIP inactivation, secretion of insulin is increased and release of glucagon is suppressed. The 
obvious advantage with a convenient route of administration is however counterbalanced by a 
significantly lower effect of the DPP-4 inhibitors on glycaemic control and body weight as 
compared to GLP-1 RAs. This has also been demonstrated for sitagliptin when compared to 
liraglutide33-35.
Adverse reactions reported in >5% of patients treated with sitagliptin and more commonly than in 
patients treated with placebo are: upper respiratory tract infection, nasopharyngitis and headache. In 
add-on to sulfonylurea and add-on to insulin studies, hypoglycaemiawas also more commonly 
reported in patients treated with sitagliptin compared to placebo36.
3.5
Risk and benefits assessment
This assessment is based on the safety and efficacy data for semaglutide and sitagliptin presented 
above as well as potential risk identified as drug class effects.
3.5.1
Semaglutide risks and precautions
The nonclinical safety programme of 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 semaglutide treatment. These are based on findings in nonclinical studies and clinical trials
with 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.
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3.5.2
Identified risks
Gastrointestinal adverse events
Consistent with findings with other GLP-1 RAs, the most frequently reported AEs in clinical trials
with 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.
Diabetic retinopathycomplications
A transient worsening of diabetic retinopathy is a recognised complication in selected patients with 
diabetes after initiation of intensive anti-diabetic treatment37. Risk factors for these events include 
long-standing poor glycaemic control and presence of proliferativeretinopathy, and initial large 
improvements in BG may be an additional aggravating factor.Several studies have, however, 
documented long-term beneficial effects of intensive glycaemic treatment in reducing retinopathy 
progression38, 39even in intensively treated patients who experienced early worsening40. In a 
cardiovascular outcomes trial with s.c. semaglutide, results indicate an increased risk of events 
related to diabetic retinopathycomplicationsin subjects treated with semaglutide compared to 
placebo. As aprecaution in this trial, all subjects are required to have a fundus photography or 
dilated fundoscopy performe d 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 trial41.
3.5.3
Potential risks
Medullary thyroid cancer
The human relevance of the proliferative C-cell changes found in rodents treated with GLP-1 RAs
is unknown, but data suggest that rodents are more sensitive to the mode of action of GLP-1 RAs
for induction of C-cell tumours. However, as a precaution, subjects with a family or personal
history of MEN 2 or MTC will not be enrolled in the trial. During the trial, calcitonin will be
measured on a regular basis, and the guidance for investigators on further evaluation and action on
elevated calcitonin concentrations is included in appendix A.
Acute pancreatitis
Acute pancreatitis has been reported in subjects treated with GLP-1 RAs including 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 T2D have an increased risk of certain types of cancer such as pancreatic cancer. There
is currently no support from nonclinical studies or clinical trials or post marketing data that GLP-1-
based therapies increase the risk of pancreatic cancer. However, pancreatic cancer has been
included as a separate potential risk due to the scientific debate surrounding a potential association
to GLP-1-based therapies and the unknown long-term effects of stimulation of β-cells and
suppression of α-cells. Pancreatic cancer has been classified as a potential class risk of GLP-1 RAs
by EMA.
Allergic reactions and injection site reaction
As in the case with all protein-based pharmaceuticals, treatment with semaglutide may evoke
allergic reactions. These may include localized injection site reactions or generalized reactions,
including urticaria, rash and 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 semaglutide is combined with
SU or insulin.
Acute renal impairment
In subjects treated with GLP-1 RAs, including semaglutide, gastrointestinal AEs such as nausea,
vomiting and diarrhoea may lead to significant dehydration and secondary acute renal impairment.
Subjects with gastrointestinal AEs are recommended to drink plenty of fluids to avoid volume
depletion. Also, serum creatinine and other markers of kidney function will be monitored
throughout the trial. SGLT-2 inhibitors, a background medication in this trial, have also been 
associated with volume depletion. It is recommended to monitor renal function and for signs and 
symptoms of fluid loss during therapy. Severe dehydration may be a risk factor for ketoacidosis.
Impaired renal function may increase the risk of metformin associated lactic acidosis when GLP-1
RAs are co-administered with metformin. 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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3.5.4
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 
according to flowchart in Section 2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 in regards to in-and exclusion criteria 
defined in order to ensure that subjects are eligible for trial enrolment. There are also strict 
glycaemic rescue criteria in place to ensure acceptable glycaemic control during the trial (see 
Section 6.4). If rescue medication is required, it should be inaccordance with ADA/European 
Associationfor the Study of Diabetes42, 43(excluding GLP-1 RAs, DPP-4 inhibitors and amylin 
analogues).
It is the responsibility of the investigator to ensure the best possible care according to the principles 
outlined in Diabetes Care 2016 Standards of Medical Care in Diabetes44.
Further details with regards to safety of trial product are described in the current edition of the IB 
for semaglutide (NN9535)27, or any updates thereto.
3.5.5
Sitagliptin risk and precautions
Sitagliptinis generally considered to be well tolerated. The most commonly reported side effect is 
upper respiratory tract infection, nasopharyngitisand headache. Some of the potential risk 
associated with GLP-1 RAtreatment has also been associated with treatment with the DPP-4 
inhibitors as sitagliptin i.e. pancreatitis, acute renal impairment, hypersensitivity reactions and 
hypoglycaemia (US prescribing information45and Chinese prescribing information46)
3.5.6
Benefits
In this trial subjects in all treatment arms will be treated within a regimen anticipated to be more 
efficacious than the treatment they receive at the time of randomisation into the trial. It is expected 
that subjects will benefit from the trial treatment with respect to optimised glycaemic control, a 
reduced risk of long-term diabetic complications and a potential weight loss. 
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Based on the results of the phase 3a trials, semaglutide is expected to provide clinically relevant 
improvements in glycaemic control and body weight in subjects with T2D.
Furthermore,data from two cardiovascular outcomes trials investigating treatment with GLP-1 RAs 
compared to placebo have indicated a beneficial effect of these drugs on cardiovascular outcomes 
when added to standard of care in subjects with T2D at high risk of cardiovascular events (see 
Section 3.3.2.3).
Sitagliptin has in phase 3 trials where sitagliptin hasbeen given in combination with metformin 
proven to provide significant improvements in HbA1cand FPG47.
All subjects in this trial will receive active treatment and will receive trial drug and auxiliary free of 
charge.
Finally, it is expected that all subjects participating in the trial will benefit from participation 
through close contact with the study site and close follow-up of their type 2 diabetes. Such careful 
medical examination will most likely result in an intensified management of their diabetes.
3.5.7
Risk and benefit conclusion
It is concluded that the potential benefits from participating in the trial outweigh the potential risks. 
The safety profile of semaglutide generated from the clinical and nonclinical development 
programme has not revealed any safety issues that would prohibit administration of once-weekly 
doses of 0.5 mg or 1.0 mg semaglutide in accordance with the planned clinical trial. Sitagliptin is 
already a marketed drug in the 100 mg dose and approved for the use in type 2 diabetic patients. 
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 semaglutide will provide to subjects with T2D.
3.6
Rationale for the trial
The currently available treatment modalities for type 2 diabetes are still not satisfactory and there
is still a large proportion of patients not reaching the treatment targets. In the 5 global phase 3a 
trials (3623, 3624, 3625, 3626 and 3627), reductions in HbA1c and body weight with semaglutide 
was superior to sitagliptin, exenatide ER and insulin glargine demonstrating semaglutide as a highly 
efficacious treatment option.
The rationale for this trial is to compare the efficacy of semaglutide versus sitagliptin in subjects 
with type-2 diabetes in terms of glycaemic control, weight loss and other efficacy parameters. 
Furthermore the trial is designed to address and compare safety, tolerability and patient satisfaction. 
This trial is designed to resemble the main trial NN9535-3626 (SUSTAIN 2) in the global 
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SUSTAIN programme and will be conducted in China and several other countries. The study design 
is adjusted to fulfil the Chinese requirements.
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4
Objectives and endpoints
4.1
Objective
4.1.1
Primary objective
To compare the effect of once-weekly dosing of two dose levels of semaglutide versus sitagliptin 
100 mg once-daily on glycaemic control after 30 weeks of treatment
4.1.2
Secondary objectives
To compare the effects of once-weekly dosing of two dose levels of semaglutide versus sitagliptin
100 mg once-daily after 30 weeks of treatment on:
!
Inducing and maintaining weight loss
!
Other parameters of efficacy, safety and tolerability
4.2
Endpoints
4.2.1
Primary endpoint
!
Change from baseline to week 30 in HbA1c
4.2.2
Secondary endpoints
4.2.2.1
Confirmatory secondary endpoint
!
Change from baseline to week 30 in body weight
4.2.2.2
Supportive secondary endpoints
Supportive secondary efficacy endpoints
Change from baseline to week 30 in:
!
Fasting plasma glucose (FPG)*
!
Self-measured plasma glucose (SMPG), 7 point profile
o
Mean 7-point profile
o
Mean post-prandial increment (over all meals)
!
Insulin, C-peptide, glucagon, pro-insulin, pro-insulin/insulin ratio, homeostasis model
assessment of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) (all fasting)
!
Fasting blood lipids (total cholesterol, low density lipoprotein (LDL) cholesterol, very low
density lipoprotein (VLDL) cholesterol, high density lipoprotein (HDL) cholesterol,
triglycerides and free fatty acids
!
Body mass index (BMI)
!
Waist circumference
!
Systolic and diastolic blood pressure*
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!
Highly sensitive C-reactive protein (hsCRP)
!
Patient reported outcome (PRO) questionnaire: SF-36v2™ score
!
Patient reported outcome (PRO) questionnaire: Diabetes Treatment Satisfaction
Questionnaire status (DTSQs) score*
Subjects who after 30 weeks treatment achieve (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*
!
Weight loss ≥ 5%
!
Weight loss ≥ 10%
!
HbA1c < 7.0% (53 mmol/mol) without severe or blood glucose (BG) confirmed symptomatic
hypoglycaemia and no weight gain
Supportive secondary safety endpoints
!
Number of treatment emergent adverse events (TEAEs) during 30 weeks of treatment
!
Number of treatment emergent severe or BG confirmed symptomatic hypoglycaemic
episodes during 30 weeks of treatment
!
Severe or BG confirmed symptomatic hypoglycaemic episodes during 30 weeks of
treatment (yes/no)
Change from baseline to week 30 in:
!
Haematology
!
Biochemistry
!
Calcitonin
!
Urinalysis
!
Urinary albumin to creatinine ratio (UACR)
!
Pulse
!
Electrocardiogram (ECG) evaluation
!
Physical examination
!
Eye examination
Occurrence of anti-semaglutide antibodies during 30 weeks of study duration (yes/no):
!
Anti-semaglutide antibodies with in vitro neutralising effect
!
Anti-semaglutide antibodies cross reacting with endogenous GLP-1
o
Cross reacting antibodies with in vitro neutralising effect to endogenous GLP-1
Antibody level during and after 30 weeks of treatment
*Key supportive secondary endpoint prospectively selected for posting on clinicaltrials.gov.
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5
Trial design
5.1
Type of trial
This is a 30-week randomised, double-blind, double-dummy, active-controlled, multi-centre, multi-
national trial, four-armed, parallel-group trial comparing semaglutide 0.5 mg and 1.0 mg once-
weekly against sitagliptin 100 mg once-daily.
Figure 5–1
Trial design
Subjects with type 2 diabetes inadequately controlled on metformin will be randomised in a 2:2:1:1 
manner to receive either:
!
semaglutide 0.5 mg once-weekly + sitagliptin placebo once-daily
!
semaglutide 1.0 mg once-weekly + sitagliptin placebo once-daily
!
sitagliptin 100 mg once-daily + semaglutide placebo (0.5) mg once-weekly
!
sitagliptin 100 mg once-daily + semaglutide placebo (1.0) mg once-weekly
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The total trial duration for the individual subjects will be approximately 37 weeks. The trial 
includes a 2-week screening period followed by a 30-week randomised treatment period and a 5 
week follow-up period.
A planned total of 1050 subjects will be randomised whereof approximately 792 subjects will be 
from China. Randomisation will be stratified by country.
5.2
Rationale for trial design
Parallel treatment groups and a randomised double-blind double dummy controlled design have 
been chosen in accordance with trial objectives and to avoid bias in the trial.
Treatment duration of 30 weeks is considered adequate in terms of assessing efficacy of 
semaglutide treatment versus sitagliptin treatment on change in HbA1c. Furthermore, 30 weeks is 
considered sufficient for addressing and comparing the safety, tolerability and patient satisfaction 
profiles.
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5.3
Treatment of subjects
Table 5–1
Treatment of subjects
Trial periods
Screening
Period 1
Period 2
Period 3
Follow-up
Alias for trial period
Screening
Dose escalation
Dose escalation/ 
Maintenance
Maintenance
Follow-up
Visits in each period
Visit 1-2
Visit 2-3 
Visit 3-5
Visit 5-9
Visit 9-10
Duration of each period
2 weeks
4 weeks
4 weeks
22 weeks
5 weeks
Treatment arm
N
!
Semaglutide
0.5 mg
!
Sitagliptin
placebo
350
Screening 
!
Semaglutide
0.25 mg,
1.34 mg/mL,
190μL
!
Sitagliptin
placebo
!
Semaglutide
0.5 mg,
1.34 mg/mL,
370μL
!
Sitagliptin
placebo
!
Semaglutide
0.5 mg,
1.34 mg/mL,
370μL
!
Sitagliptin
placebo
Follow-up 
!
Semaglutide
1.0 mg
!
Sitagliptin
placebo
350
Screening 
!
Semaglutide
0.25 mg,
1.34 mg/mL,
190μL
!
Sitagliptin
placebo
!
Semaglutide
0.5 mg,
1.34 mg/mL,
370μL
!
Sitagliptin
placebo
!
Semaglutide
1.0 mg,
1.34 mg/mL,
740μL
!
Sitagliptin
placebo
Follow-up 
!
Sitagliptin
!
Semaglutide
placebo 
(0.5 mg)
175
Screening 
!
Sitagliptin 
100 mg
!
Semaglutide
placebo
0 mg, 
190μL 
!
Sitagliptin
100 mg
!
Semaglutide
placebo
0 mg, 
370μL
!
Sitagliptin
100 mg
!
Semaglutide
placebo
0 mg, 
370μL
Follow-up 
!
Sitagliptin
!
Semaglutide
placebo
(1.0 mg)
175
Screening 
!
Sitagliptin
100 mg
!
Semaglutide
placebo
0 mg,
190μL
!
Sitagliptin
100 mg
!
Semaglutide
placebo
0 mg,
370μL
!
Sitagliptin
100 mg
!
Semaglutide
placebo
0 mg,
740μL
Follow-up 
All on background medication of metformin  ≥ 1500 mg (or maximum tolerated dose ≥ 1000 mg) throughout the trial.
After randomisation subjects will follow a fixed dose escalation for semaglutide and semaglutide 
placebo. The maintenance dose of 0.5 mg will be reached after 4 doses (4 weeks) of 0.25 mg. The 
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maintenance dose of 1.0 mg will be reached after 4 doses (4 weeks) of 0.25 mg, followed by 4 
doses (4 weeks) of 0.5 mg. Doses must not be changed during the trial after the maintenance dose 
has been reached.
Semaglutide injections should be administered in the thigh, abdomen or upper arm, and should be
taken on the same day of the week during the trial. Both semaglutide and sitagliptin can be taken 
any time of day irrespective of meals.
If necessary, the trial product may be discontinued for safety reasons. In case trial product is 
discontinued, subjects will not be withdrawn from trial but should continue to follow scheduled 
visits to the extent possible (see section 6.5.1).
Trial product will be add-on in subjects failing on metformin monotherapy.
Subjects must not be prescribed other GLP-1 RA in the period between V9 and V10 or V9A and 
V10A.
5.3.1
Missed dose
If a semaglutide dose is missed, it should be administered as soon as noticed, provided the time to 
the next scheduled dose is at least 2 days (48 hours). If a dose is missed and the next scheduled dose 
is less than 2 days (48 hours) away, the subject should not administer a dose until the next 
scheduled dose. A missed dose should not affect the scheduled dosing day of the week.
5.3.2
Background medication
Subjects should upon inclusion continue pre-trial background medication throughout the entire trial. 
The background medication should be maintained at the stable, pre-trial dose and frequency during 
the whole treatment period unless rescue medication is needed (see section 6.4). 
Metformin is considered background medication (non-investigational medicinal product) and will 
not be provided by Novo Nordisk A/S (except for Brazil where Metformin will be provided by 
Novo Nordisk Farmacêutica do Brasil Ltda). Metformin should be used in accordance with standard 
of care in the individual country at the discretion of the investigator and the daily dose should be 
unchanged throughout the trial unless the rescue criteria are met. However the maximum approved 
dose in the individual country must not be exceeded. Treatment with metformin extended/slow 
release formulations is allowed.
5.3.3
Treatment after end of trial
When discontinuing trial products the subject should be switched to a suitable marketed product at 
the discretion of the investigator. 
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(Brazil: After the study ending, if the investigator decides that the study medication is the best 
treatment option for the subject, the access to the study medication will be assured by the trial 
sponsor at no costs, according to the current regulations of Brazilian National Council of Health and 
Health Authority). 
5.4
Rationale for treatment
Semaglutide has been developed for s.c.administration. The doses of 0.5 mg and 1.0 mg once-
weekly has been chosen based on careful evaluation to strike a satisfactory balance of efficacy and 
safety that would satisfy the majority of patients. Hence duration and the dose of the randomised 
treatments are considered adequate for obtaining meaningful information on efficacy and safety in 
accordance with the trial objectives. Subjects will enrol for a treatment period of 30weeks in order 
to be able to evaluate full effect as well as durability of the primary and secondary endpoints as well 
as a reasonable safety assessment.
For further information please refer to Investigator’s Brochure, semaglutide(NN9535)
(subcutaneous administration),Type 2 Diabetesand any updates hereof27.
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6
Trial population
6.1
Number of subjects 
Planned number of subjects to be screened (i.e. documented informed consent): Up to 1750
Planned number of subjects to be randomised: 
1050
Expected number of subjects to complete the trial: 
840
Planned number of Chinese subjects to be randomised: 
792
Expected number of Chinese subjects to complete the trial: 
636
6.2
Inclusion criteria
For an eligible subject, all inclusion criteria must be answered "yes".
1. Informed consent obtained before any trial-related activities. Trial-related activities are any
procedures that are carried out as part of the trial, including activities to determine suitability for
the trial
2. Male or female, age ≥ 18 years at the time of signing informed consent
(For Korea: Male or female, age above or equal to 19 years at the time of signing informed
consent.)
3. Subjects diagnosed with type 2 diabetes and on stable treatment in a period of 60 days prior to
screening with metformin ≥ 1500 mg (or maximum tolerated dose ≥ 1000 mg). Stable is defined
as unchanged medication and unchanged daily dose
4. HbA1c 7.0 – 10.5 % (53-91 mmol/mol) (both inclusive)
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 informed consent
3. Female who is pregnant, breast-feeding or intends to become pregnant or is of childbearing
potential not using an adequate contraceptive method throughout the trial including the 5 week
follow-up period (adequate contraceptive measure as required by local regulation or practice)
(China: Sterilization, intrauterine device (IUD), oral contraceptives or barrier methods).
(Brazil: For women who expressly declare free of the risk of pregnancy, either by not engaging
in sexual activity or by having sexual activity with no birth potential risk, use of contraceptive
method will not be mandatory).
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4. Receipt of any investigational medicinal product within 90 days before screening (Brazil:
Participation in other trials within one year prior to screening visit (V1) unless there is a direct
benefit to the research subject at the Investigator´s discretion)
5. Any disorder which, in the opinion of the investigator, might jeopardise subject’s safety or
compliance with the protocol
6. Treatment with glucose lowering agent(s) other than stated in the inclusion criteria in a period
of 60 days before screening. An exception is short-term treatment (≤7 days in total) with insulin
in connection with inter-current illness
7. Use of non-herbal Chinese medicine or other non-herbal local medicine with
unknown/unspecified content. Herbal traditional Chinese medicine or other local herbal
medicines may, at the Investigator’s discretion, be continued throughout the trial
8. History of pancreatitis (acute or chronic)
9. Screening calcitonin value  ≥ 50 ng/L (pg/mL)
10. Personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine
neoplasia syndrome type 2 (MEN 2)
11. Impaired renal function defined as eGFR < 60 ml/min/1.73 m2 per MDRD formula (4 variable
version)
12. Acute coronary or cerebrovascular event within 90 days before  randomisation
13. Heart failure, New York Heart Association (NYHA) class IV
14. Proliferative retinopathy or maculopathy requiring acute treatment. Verified by fundus
photography or dilated fundoscopy performed within the past 90 days prior to randomisation in
accordance with the instructions in Section 8.4.8.
15. Diagnosis of malignant neoplasm in the previous 5 years (except basal cell skin cancer or
squamous cell skin cancer)
16. Mental inability, unwillingness or language barrier precluding adequate understanding of or
compliance with study procedures
6.4
Rescue criteria
If any of the fasting plasma glucose (FPG) values exceed the limits outlined below and no 
intercurrent cause of the hyperglycaemia can be identified the subject should be called for an 
unscheduled visit as soon as possible:
!
15.0 mmol/L (270 mg/dl) from week 0 to end of week 5
!
13.3 mmol/L (240 mg/dl) from week 6 to end of Week 11
!
11.1 mmol/L (200 mg/dl) from week 12 to end of trial
A confirmatory FPG should be obtained.If the confirmatory FPG exceeds the values described 
above the subject should be offered treatment intensification (rescue medication) at the discretion of 
the investigator and in accordance with ADA/European Association for the Study of Diabetes42, 43  
(excluding GLP-1 RAs, DPP-4 inhibitors and amylin analogues). Rescue medication 
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(intensification of existing background medication and/or initiation of new medication) and any 
changes hereto should be captured on the concomitant medication form in the eCRF. Rescue 
medication should be prescribed as add-on to randomized treatment unless contraindicated 
according to the local sitagliptin label. In this case trial medication should be discontinued before 
initiation of rescue therapy. Subjects should continue to follow the protocol-specified visit schedule 
even if rescue treatment has been initiated.
6.5
Withdrawal criteria
6.5.1
Discontinuation of trial product
All efforts should be made to keep the subjects on trial product. However in case of a safety 
concern or unacceptable intolerability the trial product may be discontinued at the investigator’s 
discretion.
Trial product must be discontinued in case of: 
!
Safety concern related to trial product or unacceptable intolerability
!
included in the trial in violation of any of the inclusion and/or exclusion criteria
!
Pregnancy
!
Intention to become pregnant
!
Simultaneous participation in another clinical trial of an approved or non-approved
investigational medicinal product
!
Calcitonin ≥ 100 ng/L (see appendix A)
For procedures to be performed in case of discontinuation of trial product (see section 8.1.6.2). 
Subjects discontinuing trial product prematurely should continue with the scheduled site contact. 
Subjects discontinued from trial product should be prescribed alternative therapy at the 
investigator´s discretion. However subjects must not be prescribed other GLP-1 RA in the period 
between V9 and V10 or V9A and V10A.
6.5.2
Withdrawal from trial
The subject may withdraw 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. Please see section 8.1.7 for procedure to be performed in case of subject withdrawal.
Subjects should stay in the trial irrespective of lack of adherence to randomised treatment, lack of 
adherence to visit schedule, missing assessments, trial product discontinuation due to AE (see 
section 6.5.1), unwillingness to cope with injection regimen, development of co-morbidities or 
clinical outcomes.
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A subject who agrees to provide information concerning morbidities which are relevant for the 
assessments of cardiovascular outcomes and/or other trial end-points at the planned end of the trial 
should not be considered withdrawn from the trial.
Subjects who consider withdrawing from the trial should as a minimum be encouraged to have 
procedures performed according to the end of treatment visit (V9) and the follow up visit (V10), 
please see 8.1.7.
Only subjects who decline any further contact with the site in relation to the trial, and hence do not 
agree to report information which is relevant for the assessments of cardiovascular outcomes and/or 
other trial end-points at the end of trial should be considered as withdrawn from the trial.
6.6
Subject replacement
Subjects who are withdrawn will not be replaced.
6.7
Rationale for trial population
This trial will be carried out in China and several other countries. The aim is to include a broad 
diabetes population, hence the limited number of exclusion criteria. Subjects with type 2 diabetes 
who are inadequately controlled on metformin monotherapy will be included in the trial. As
sitagliptin is indicated as monotherapy or in combination with metformin in China, subjects on 
other oral anti-diabetic drugs (OADs) are not included.
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7
Milestones
Planned duration of recruitment period (i.e. FPFV– LPFV): 
26 weeks
End of trial is defined as last patient last visit.
Planned date for first patient first visit (FPFV): 
28-Aug-2017
Planned date for last patient first visit (LPFV): 
26-Feb-2018
Planned date for last patient last visit (LPLV): 
19-Nov-2018
To ensure that only the required number of subjects is randomised, screened subjects will be 
monitored closely via interactive voice response system/interactive web response system (IWRS).
A recruitment strategy will be developed in corporation with the participating countries to secure 
sufficient number of subjects from China and the other participating countries.
Recruitment will be monitored on an on-going basis by sponsor. Prior to FPFV all sites should have 
a recruitment strategy in place detailing how many subjects they can recruit within a certain period. 
If a site has not enrolled the number of subjects according to the recruitment strategy, the remaining 
subjects may be reallocated. 
The screening and randomisation rate will be followed closely via IWRS in order to estimatewhen 
to stop screening. All investigators will be notified immediately when the enrolment period comes 
to an end, after which no subjects must be screened, and the IWRS will be closed for further 
screening. All subjects included in the screening period bythe time of IWRS closure and eligible 
for randomisation will be randomised.
Trial registration:
Information of the trial will be disclosed at clinicaltrials.gov, chinadrugtrials.org.cnand 
novonordisk-trials.com. According to the Novo Nordisk Code of Conduct for Clinical Trial 
Disclosure, it will also be disclosed according to other requirements such as those of the 
International Committee of Medical Journal Editors (ICMJE)48, the Food and Drug Administration 
Amendment Act (FDAAA)49, EuropeanCommission Regulation for EudraCT50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).
The investigator must keep a subject screening log, a subject identification code list and a subject 
enrolment log. The subject screening log and subject enrolment log may be combined in one list
and may be generated from the IWRS.
In addition, the investigator must keep a log of staff and delegation of task(s) at site. Investigator 
must sign the log of staff and delegation of task(s) at site at the time of delegation of tasks.
8.1.1
Screening visit 1 (V1)
For procedures and assessments performed at screening, please see flow chart (see section 2).
The IWRS must be contacted to register the subject as screened (see section 10). Subject will be
assigned a unique number (lowest available number allocated to site) which is maintained
throughout the trial. It must be stated in the medical record that the subject is participating in the 
current trial. 
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. The subjects should be reminded to show the card to other health care providers, as 
applicable.
Once all data relating to screening V1 have been obtained, these must be reviewed by the 
investigator to ensure that the subject is eligible to continue the trial.
8.1.1.1
Screen failures
For screening failures the screening failure form 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 case report form eCRF. Follow-up of SAEs must be carried out 
according to section 12.
A screening failure session must be made in the IWRS. The case book must be signed in eCRF.
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8.1.1.2
Re-screening
Re-sampling or re-screening is NOT allowed if the subject has failed one of the inclusion or 
exclusion criteria related to laboratory parameters.
8.1.2
Fasting visits
The subjects should attend several visits in a fasting state (see section 2). Fasting is defined as 
having consumed only water within the last 6 hours prior to the visit.. Glucose lowering agents and 
trial product cannot be taken until after blood sampling has been performed but other prescribed 
medication should be taken. An exception from this is the follow-up visit (V10) and follow-up 
premature discontinuation visit (V10A) where fasting is defined as having consumed only water 
within the last two hours prior to the visit. If the subject is not fasting as required, the subject must
be called in for a new visit within the visit window to have the fasting procedures done. 
8.1.3
Randomisation V2
For procedures and assessments performed at randomisation (see section 2).
Visit 2 will take place two weeks (±7 days) after screening V1.
Eligible subjects will be randomised into one of four treatment arms. The IWRS will allocate the
dispensing unit number (DUN) of trial product to be dispensed to the subject.
Trial product will be dispensed to the subject by the site, hospital pharmacy or equivalent with
different intervals during the trial. Subject will be instructed in administration of sc injection of trial
product and the investigator must document that a direction for use (DFU) is given orally and/or in
writing. Date, time and dose of first administration of trial product will be captured in the eCRF.
Please see section 9 for further information about the trial product.
8.1.4
Visits
For visit numbers, timing of site visits, phone contacts and visit windows during the trial period,
please refer to the flow chart (see section 2). Planned visits can be re-scheduled within the allowed 
visit window.
It is the responsibility of the investigator to ensure that all site visits and phone contacts occur 
according to the flow chart (2). 
8.1.5
Missed visits and unscheduled visits
If a visit is missed and it is not possible to re-schedule, every effort should be made to ensure 
information is collected at a telephone contact. Subjects will be invited for the next scheduled visit 
according to visit schedule.
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If a subject is unable or unwilling to attend the subsequent visit(s) the investigator should aim to at 
least have the subject attending the end of treatment visit and follow-up visit as these two visits 
should be performed for all subjects regardless of compliance with the protocol and adherence to 
the treatment (see section 8.1.6). 
If a subject attends the clinic for a visit not described in the protocol, an unscheduled visit form 
must be completed. This only applies if assessments are done, hence not for the purpose of re-test of 
blood- or urine sampling, or re-supply of trial product. In case of re-supply a dispensing session 
should be made in the IWRS selecting additional medication. Re-scheduling of fasting visit samples 
is not considered as an unscheduled visit.
8.1.6
End of treatment (V9/9A) and Follow-up (V10/10A)
8.1.6.1
Subjects completing the treatment period as per protocol
An end of treatment visit (V9) should be scheduled when the subject has completed the treatment 
period as described per protocol and a follow-up visit (V10) should be performed at least 5 weeks 
after (+7 days visit window). Please see the flow chart for details (section 2).
The follow-up visit serves to collect AEs, technical complaints, hypoglycaemic episodes, ECG, 
concomitant medication and blood sampling for anti-semaglutide antibodies .
8.1.6.2
Subjects who prematurely discontinue trial product
For subjects who discontinue trial product prematurely the visit end of treatment – premature 
discontinuation (V9A) should be scheduled shortly after subject has discontinued trial product. The 
visit follow-up – premature discontinuation (V10A) should be scheduled at least 5 weeks after
discontinuation of trial product (+7 days visit window). Please see the flow chart for details (section 
2).
Subjects discontinuing trial product prematurely should continue with the scheduled site contacts. If 
necessary, in order to retain the subject in the trial, site visits can be replaced by phone contacts 
after discontinuation of trial product. However, as a minimum these subjects will be called in for 
end of treatment (V9) and follow-up (V10) at the time of the scheduled completion of the trial.
8.1.7
Withdrawals
Subjects who consider withdrawing from the trial should as a minimum be encouraged to have 
procedures performed according to the end of treatment visit (V9) as soon as possible and the 
follow up visit (V10) at least 5 weeks after but not more than 6 weeks after, if possible. If a subject 
has already prematurely discontinued from trial product and previously attended visit V9A and visit 
V10A, no further visits should be attended.
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The End of Treatment and 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 site. The case book must be signed by the 
investigator in eCRF and a premature discontinuation of trial product session must be made in the 
IWRS (see section 10).
Although a subject is not obliged to give his/her reason(s) for withdrawing from a trial, the 
investigator must make a reasonable effort to ascertain the reason(s), while fully respecting the 
subject's rights. Where the reasons are obtained, the primary reason for not completing the trial
must be specified on the end-of-trial form in the CRF (see section 6.5).
8.1.8
Investigator’s assessment
Review of diaries, patient reported outcomes (PROs), laboratory reports, ECGs, eye examination 
(fundus photography/dilated fundoscopy), physical examination etc. must be documented either on 
the front page of the documents and/or in the subject's medical record. The signed 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? (No/Yes)
For laboratory report values outside the reference range, the investigator must specify whether the 
value is clinically significant or clinically non-significant. All laboratory printouts must be signed 
and dated by the investigator on the day of evaluation. The signed laboratory report is retained at 
the site as source documentation.
In case of abnormal clinical 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 subjects’ medical record and record this in the concomitant illness form in the eCRF. At 
subsequent visits any clinically significant changes or new clinically significant findings must be 
reported as an AE according to section 12.
Investigator or site staff must review the diary to ensure that AEs, including overall change in 
health and concomitant medication are reported. 
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.
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8.2
Subject related information 
8.2.1
Demography
The following information must to be recorded in the subject’s medical record and will be 
transcribed into eCRF at screening V1:
!
Date of birth(according to local regulation)
!
Sex
!
Race (according to local regulation)
!
Ethnicity (according to local regulation)
8.2.2
Diabetes history and diabetes complications
Diabetes history and diabetes complications will be recorded at screening and consists of:
!
Date of diagnosis of type 2 diabetes
!
Information regarding diabetes complications including date of onset
o
Diabetic retinopathy
o
Diabetic neuropathy
o
Diabetic nephropathy
o
Macroangiopathy (including peripheral vascular disease)
8.2.3
Concomitant illness and medical history
A concomitant illness is any illness that is present at the start of the trial (V1).
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. Pre-existing conditions, including 
those found as a result of screening procedures performed at V1 and V2 should be reported as 
medical history or concomitant illness.
The information collected for concomitant illness and medical history should include diagnosis, 
date of onset and date of resolution or continuation, as applicable.
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.
Concomitant illness and medical history must be recorded in the subject’s medical record and will 
be transcribed into eCRF.
The following must be recorded in the eCRF on the disease specific forms only, i.e. not on the 
medical history/concomitant illness form:
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!
History of cardiovascular disease (CVD) (e.g. ischaemic heart disease, MI, heart failure incl.
NYHA class, hypertension, stroke, peripheral arterial disease)
!
History of gallbladder disease (e.g. gallstone, cholecystitis, cholecystectomy)
It must be possible to verify the subject’s medical history in source documents such as subject’s 
medical record. If a subject is not from the investigators own practice; the investigator must make 
reasonable effort to obtain a copy of subject’s medical record from relevant party e.g. primary 
physician. The investigator must document any attempt to obtain external medical information by 
noting the date(s) when information was requested and who has been contacted.
8.2.4
Concomitant medication
A concomitant medication is any medication, other than the trial product, which is taken during 
the trial, including the screening and follow-up periods.
Details of any concomitant medication must be recorded at visit 1. Changes in concomitant 
medication, including antidiabetic treatment and rescue treatment, must be recorded at each visit as 
they occur. The eCRF should be updated accordingly.
The information collected for each concomitant medication includes trade name or generic name, 
indication, start date (only start year is applicable if more than one year) and stop date or 
continuation. Total daily dose is only applicable for antidiabetic medication.
If a change is due to an AE, then this must be reported according to Section12 . If the change 
influences the subject’s eligibility to continue in the trial, the monitor must be informed.
8.2.5
Tobacco use
Details of tobacco use must be recorded at V1. Smoking is defined as smoking at least one 
cigarette, cigar or pipe daily. The collected information should include whether or not the subject 
smokes or has smoked.
It must be recorded whether the subject is a smoker according to the following criteria:
!
Never smoked
!
Is a previous smoker
o
cessation date
o
average cigarettes per day
o
approximate years of smoking
!
Is a current smoker
o
average cigarettes per day
o
approximate years of smoking
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8.2.6
Childbearing potential  
It must be recorded in the eCRF whether female subjects are of childbearing potential. 
Pregnancy testing must be performed on female subjects of childbearing potential as described in 
Section 8.5.2.5. Female subjects of childbearing potential must be instructed to use adequate 
contraceptive methods throughout the trial and until 5 weeks after end of treatment. 
Female of non-childbearing potential is defined as:
!
Female who has undergone a hysterectomy, bilateral oophorectomy or bilateral tubal
ligation or are postmenopausal (e.g. women above the age of 50, who have been without
menstrual period for at least 1 year).
!
Other medical reasons preventing childbearing potential.
For Brazil only: For women who expressly declare free of the risk of pregnancy, either by not 
engaging in sexual activity or by having sexual activity with no birth potential risk, use of 
contraceptive method will not be mandatory.
8.2.7
Height
Height is measured without shoes in centimetres or inches and recorded in the eCRF to nearest ½ 
cm or 1/4 inch.
8.3
Assessments for efficacy
8.3.1
Body weight
Body weight must be measured in kilograms (kg) or pound (lb), with one decimal. The body weight 
should be measured without shoes and only wearing light clothing.
The same scale should preferably be used throughout the trial.
8.3.2
Waist circumference
The waist circumference is defined as the minimal abdominal circumferences located midway 
between the lower rib margin and the iliac crest.
Three consecutive measurements of waist circumference should be performed and recorded in the 
eCRF. The waist circumference will be measured in cm to the nearest ½ cm using a non-stretchable 
measuring tape (measuring tapes will be provided to the sites).
The subject should be measured in a standing position with an empty bladder and wearing light 
clothing with accessible waist. The subject should be standing with arms down their side and feet 
together. The tape should touch the skin but not compress soft tissue and twists in the tape should 
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be avoided. The subject should be asked to breathe normally and the measurement should be taken 
when the subject is breathing out gently.
8.3.3
BMI
BMI will be calculated by the eCRF using the equation as listed below:
BMI kg/m2 = Body weight (kg)/(Height (m) x Height (m)) or (kg/m2 = [lb/in2 x 703])
8.3.4
Systolic and diastolic blood pressure
The method for measuring systolic and diastolic blood pressure needs to follow the standard clinical 
practise at site, but as a minimum the following guidelines should be adhered to:
!
Avoid caffeine, smoking and exercise at least 30 minutes prior to measuring the blood
pressure
!
The blood pressure should be measured in a sitting position, with the legs uncrossed, the
back and arms supported
!
Subjects should be sitting for five minutes before the measurement is taken
!
Subject or the observer should not talk during the measurement
It is recommended to use the same arm as used at V1 for subsequent measurements. 
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8.4
Assessments for safety
The timing of the assessments for safety are outlined in the flow chart (see section 2).
8.4.1
Adverse events
AEs must be recorded at each visit in accordance with the procedures outlined in section 12.
Any clinically significant worsening from baseline of a previous finding must be reported as an AE.
8.4.2
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:
!
Trial product(s) involved
!
Classification of medication error
!
Whether the subject experienced any hypoglycaemic episode and/or adverse event(s) as a result
of the medication error
!
Suspected primary reason for the medication error
For definition of medication errors, see section 12.1.3
8.4.3
Adverse events requiring additional data collection
For the following AEs additional data collection is required and specific event forms must be 
completed 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
!
Hypersensitivity reaction
!
Neoplasm (excluding thyroid neoplasm)
!
Pancreatitis
!
Renal event
!
Thyroid disease (including thyroid neoplasm)
!
Hepatic event
!
Diabetic retinopathy
!
Laboratory outlier
See appendix B for details about the additional information to report. In case any of these events 
fulfil the criteria for a serious adverse event, please report accordingly, see Section 12.
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8.4.4
Hypoglycaemic episodes
Plasma glucose (PG) should always be measured and recorded when a hypoglycaemic episode is 
suspected.
All PG values:
!
≤ 3.9 mmol/L (70 mg/dL) or
!
3.9 mmol/L (70 mg/dL) occurring in conjunction with hypoglycaemic symptoms
should be reported in the diary according to the instructions below and section 8.6.2throughout the
trial from V1 to V10/10A.
All information must be transcribed into the eCRF (hypoglycaemic episode form) throughout the
trial. For Novo Nordisk classification of hypoglycaemia, see Section 17.4.2.2.
Upon onset of a hypoglycaemic episode the subject is recommended to measure PG every 15 
minutes until the SMPG value is >3.9mmol/L (70 mg/dL) and/orsymptoms have been resolved in 
accordance to current guidelines51.
A SMPG value ≤ 3.9 mmol/L (70 mg/dL) or hypoglycaemic symptoms must be recorded in the 
diary at the hypoglycaemic episode form by the subject. Repeated SMPG measurements and/or 
symptoms will by default be consideredas one hypoglycaemic episode until a succeeding SMPG 
value is > 3.9 mmol/L (70 mg/dL) and/or symptoms have been resolved. One hypoglycaemic 
episode form is to cover these measurements and/or symptoms.
In case of several low SMPG values within the hypoglycaemic episode, the lowest value is the one 
that will be reported as the SMPG value for the hypoglycaemic episode but the start time of the 
episode will remain as the time for the first SMPG value and/or symptom.
The record should include the following information:
!
Start date and time of the hypoglycaemic episode.
!
Stop date and time of the hypoglycaemic episode (stop time is the first time the PG value is
>3.9 mmol/L (70 mg/dL) and/or symptoms have been resolved).
!
If a stop date and time is not reported, a hypoglycaemic episode will cover a period of 60
minutes.
!
The PG level before treating the episode (if available) and any follow up measurements.
!
The lowest value measured during the hypoglycaemic episode will be reported as the PG
value for the episode, the remaining values will be kept as source data in the diary.
!
Whether the episode was symptomatic (Yes/No).
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!
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 other anti-diabetic medications prior to
theepisode.
!
Date and time of last main meal (not including snacks) prior to the episode.
!
Whether the episode occurred in relation to physical activity.
!
Change in any concomitant illness
!
Any sign of fever and/or other acute disease.
!
Whether the subject was asleep when the episode occurred.
– If yes, whether the symptoms of the episode woke up the subject.The answer to the
question: "Was the subject able to treat him/herself?" must be answered "No" foran episode
requiring assistance of another person to actively administer carbohydrate, glucagon, ortake
other corrective actions. PG concentrations may not be available during an event, but
neurological recovery following the return of PG to normal is considered sufficient evidence
thatthe event was induced by a low PG concentration51.
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),
miscalculation of doseof antidiabetic medication, other factors not listed or unknown)
!
Did the subject experience seizure?
!
Was the subject unconscious/comatose?
!
Did the subject experience any of the following symptoms52?
– Autonomic: sweating, trembling, hunger or palpitations (rapid or irregular heart beat)
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– 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. The subject must be questionedwhether any of the low values were severe, i.e. whether
the subject was able to self-treat or not. If the subject was not able to self-treat, it has to be reported
as a severe hypoglycaemic episode.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 data53, 54.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.
8.4.5
Electrocardiogram
12-lead electrocardiograms (ECG) will be performed locally by the investigator or delegated staff
during the trial (see section 2). The ECG print out must be interpreted, dated and signed by
investigator as described in section 8.1.8. ECG printed is source documentation.
Additional unscheduled ECG recordings can be performed at the investigator´s site at investigator´s 
discretion at other visits than the planned ECG visits.
8.4.6
Physical examination
A physical examination will be performed by the investigator according to local procedure (see 
section 2). A physical examination must include:
!
General appearance
!
Head, ears, eyes, nose, throat, neck
!
Thyroid glands
!
Respiratory system
!
Cardiovascular system
!
Gastrointestinalsystem including mouth
!
Musculoskeletal system
!
Central and peripheral nervous system
!
Skin
!
Lymph node palpation
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8.4.7
Pulse
Pulse (beats per minute) should be recorded in the eCRF at site visits after resting for 5 minutes in a 
sitting position.
8.4.8
Eye examination 
It is allowed to perform the baseline fundus photography or dilated fundoscopy between the 
screening visit and the randomisation visit.
Results of a fundus photography or dilated fundoscopy must be available and evaluated by the 
investigator before randomisation. If the subject had a fundus photography or dilated fundoscopy 
performed within 90 days prior to randomisation, the investigator may base their evaluation upon 
the results of that examination. However, the examination must be repeated before randomisation if 
the subject experienced worsening of visual function since the last examination. If the subject did 
not have a fundus photography or dilated fundoscopy performed within 90 days prior to 
randomisation, such examination must be performed by the investigator or other qualified health 
care professional prior to randomisation. If the applicable fundus photography or dilated 
fundoscopy was performed before the subject signed the informed consent form, it must be 
documented in the medical records that the reason for performing the examination was not related 
to this trial.
In addition, fundus photography /dilated fundoscopy must be performed at V9. In the case of 
premature discontinuation, the assessments must be performed both at V9A and at V9. The 
assessments at V9A and V9 can be performed in the period between V9A and V10A and between 
V9 and V10, respectively, but the results should be available no later than at V10A and V10, 
respectively. 
The investigator should indicate whether the outcome of the eye examination was normal or
abnormal, and, if abnormal, indicate whether clinically significant. Relevant findings as a result of 
this screening procedure must be recorded as diabetes history and diabetes complications or 
concomitant illness/medical history in accordance with Section 8.2.2 and 8.2.3 respectively.
8.5
Laboratory assessments
For laboratory analysis of efficacy and safety parameters will be drawn during the 37 weeks of the 
trial. The laboratory analyses will be performed by a central laboratory except for anti-semaglutide 
antibodies and IgE antibodies where a special laboratory will be used. In the situation of suspicion 
of acute pancreatitis or severe hypersensitivity described in appendix B, a local laboratory will be 
used. Laboratory samples comprise both urine and blood samples. 
Descriptions of assay methods, laboratory supplies and procedures for collecting, handling, storage 
and shipping of samples and information regarding who will perform the assessments will be 
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described in the laboratory manual provided by the central laboratory (for central and special 
laboratory details, see Attachment I).
Samples will be coded in order to keep subject identity anonymous.
Laboratory samples may be drawn at another day than on the day of the actual visit as long as it is 
within the visit window outlined 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 it is required for the sensitivity of the analysis that
the subject is fasting. 
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 must be reported to the investigator.
For Brazil: All laboratory results will be communicated to the investigators.
Central laboratory will provide laboratory results to the investigator on an on-going basis and the 
investigator must review all laboratory results for signs of concomitant illness and AEs and report 
these according to section 12. An exception to this is that anti-semaglutide antibody result will not 
be available to the investigator during the trial. However these results will be provided to the 
investigator upon request after the completion of the clinical trial report (CTR).
All laboratory samples will be destroyed on an on-going basis after analysis and no later than CTR, 
except for samples taken for anti-semaglutide antibody samples, which will be kept until market 
authorisation approval or rejection of file. (For Brazil: the laboratory samples for Brazilian subjects 
will be destroyed at the latest at the completion of the CTR, including samples for anti-semaglutide 
antibody analysis. No sample will be stored after the completion of CTR).
The investigator should ensure that the last samples are shipped to the central laboratory within 24 
hours after the last subject visit last at the site.
8.5.1
Laboratory assessments for efficacy
Blood samples must be drawn according to flow chart (see section 2) and analysed at the central 
laboratory to determine levels of the following efficacy laboratory parameters:
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8.5.1.1
Glucose metabolism
!
HbA1c
!
Fasting plasma glucose
!
Fasting insulin
!
Fasting C-peptide
!
Fasting glucagon
!
Fasting pro-insulin
8.5.1.2
Biomarker
!
hsCRP
8.5.1.3
Lipids (all fasting)
!
Total cholesterol
!
LDL-cholesterol
!
VLDL-cholesterol
!
HDL-cholesterol
!
Triglycerides
!
Free fatty acids
8.5.1.4
Self measured plasma glucose (SMPG)
At screening V1 subjects will be provided with a blood glucose meter including lancets, plasma-
calibrated test strips and control solutions. Oral and written directions for use of the device 
including the performance of calibrations according to the manufacturer’s instructions will be 
provided to the subject. Sites should, as necessary, repeat the directions for use to the subject at 
subsequent visits.
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. When using blood glucose meters the measurement is 
performed with capillary blood calibrated to plasma equivalent glucose values i.e. the measurement 
is performed on blood while the value is reported as plasma. It is important to be aware of this 
difference throughout the protocol. 
Only the blood glucose meter provided by Novo Nordisk should be used for the measurements 
required in the protocol.
Subjects should be instructed in how to record the results of the SMPG values in the diaries. The 
record of each SMPG value should include date, time and value. All data from the diary must be 
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transcribed into the eCRF during or following the contact. If obtained via phone and a discrepancy 
is later detected, 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.
8.5.1.5
7 point profile
The subject will be instructed to perform a SMPG 7-point profile, preferably within one week prior 
to the site visit according to the flow chart (see section 2) on a day where the subject does not 
anticipate unusual strenuous exercise.
Time points, including date and time, for the 7-point profile: 
!
before breakfast
!
90 min after start of breakfast
!
before lunch
!
90 min after start of lunch
!
before dinner
!
90 min after start of dinner
!
at bed time
8.5.2
Laboratory assessments for safety
Laboratory samples must be drawn according to flow chart (see section 2) and analysed at the 
central laboratory to determine levels of the following safety laboratory parameters:
8.5.2.1
Anti-semaglutide antibodies
Blood samples will be drawn for measurement of serum antibodies to semaglutide at selected visits 
in randomised subjects. Positive anti-semaglutide antibody samples will be further characterised for 
cross reactivity to native GLP-1 (see section 2). Samples taken at follow-up which are positive for 
anti-semaglutide antibodies will be further characterised for in vitro neutralising effect towards 
semaglutide. In addition, samples taken at follow-up which are positive for cross-reactivity against 
native GLP-1 will be further analysed for in vitro neutralising effect towards native GLP-1.
Follow-up antibody (taken at the follow-up V10/10A) samples must be taken fasting (as a minimum 
by only having consumed water for at least two hours).
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8.5.2.2
Biochemistry
!
Creatinine, including eGFR (per MDRD)
!
Alanine aminotransferase (ALT)
!
Aspartate aminotransferase (AST)
!
Alkaline phosphatase
!
Sodium
!
Potassium
!
Albumin
!
Bilirubin (total)
!
Total protein
!
Urea
!
Creatine kinase
!
Calcium total
!
Calcium, albumin corrected (calcium, ionized)
!
Lipase
!
Amylase
8.5.2.3
Haematology
!
Haemoglobin
!
Haematocrit
!
Thrombocytes
!
Erythrocytes
!
Leucocytes
!
Differential count:
o
eosinophils
o
neutrophils
o
basophils
o
monocytes
o
lymphocytes
8.5.2.4
Calcitonin
Blood samples for the measurement of calcitonin concentration will be drawn as per flow chart (see 
section 2). In case any calcitonin value at any time of the trial is ≥10 ng/L, the algorithm in 
appendix A should be followed.
8.5.2.5
Pregnancy test
Females of childbearing potential will have a serum pregnancy test performed at all site visits (see 
Section 2). At visit 2, a urine pregnancy test must be performed prior to randomisation.
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In case a menstrual period is missed or if pregnancy is suspected at any time during the trial, a urine 
pregnancy test should be performed. The subject should be instructed not to dose trial product 
before pregnancy has been ruled out.
Pregnancy testing will not be required (unless required by local law) for women of non-childbearing 
potential, such as but not limited to women who have undergone a hysterectomy, bilateral 
oophorectomy, bilateral tubal ligation or are postmenopausal (e.g. women above the age of 50, who 
have been without menstrual period for at least 1 year).
8.5.2.6
Urinalysis
Subjects will be asked to bring the first morning urine during the trial (see section 2). The urine 
sample will be analysed at the central laboratory to determine levels of the following parameters:
!
Urinary albumin to creatinine ratio (UACR)
!
Urinalysis by urine dip-stick: erythrocytes, protein, glucose and ketones, pH
8.6
Other assessments
8.6.1
Patient reported Outcome questionnaires
The following PRO questionnaires will be used in this trial:
!
SF-36v2TM
!
DTSQs
The questionnaires should be completed by the subject as specified in the flow chart (see section 2), 
preferably before any other trial related activities. It takes approximately 10 minutes to complete 
each questionnaire. The assessment must be reviewed as described in section 8.1.8. All results from 
the PRO questionnaires must be transcribed into the eCRF.
The PRO questionnaire will be used to assess subjects overall Health related Quality of Life and can 
also be used to estimate Quality Adjusted Life years (QALY) which is used in cost effectiveness 
calculations. 
8.6.1.1
SF-36v2TM
The SF-36v2™ questionnaire will be used to assess subjects overall Health related Quality of Life 
and can also be used to estimate QALY which is used in cost effectiveness calculations. This 
instrument contains 36 items and measures the individual overall health related quality of life on 8 
domains; physical functioning, role functioning, bodily pain, general health, vitality, social 
functioning, role emotional and mental health. 
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8.6.1.2
DTSQs
The DTSQs questionnaire will be used to assess subject’s treatment satisfaction. This instrument 
contains 8 items and measures the treatment for your diabetes (including insulin, tablets and/or diet) 
in terms of convenience, flexibility and general feelings regarding treatment. 
8.6.2
Subject diary
The subject must be provided with paper diaries at all visits, except the follow-up visit (V10 and 
V10A). If a subject prematurely discontinues trial product, diaries should not be dispensed and 
filled out by the subjects after the follow-up – premature discontinuation visit. For these subjects all 
available data will be collected. 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, time and dose of first dose of trial products (injection and tablet)
!
date, time and dose of last injection of trial product prior to each visit/phone contact
!
hypoglycaemic episodes
!
concomitant medication
!
AEs
!
SMPG 7-point profile
!
Urine pregnancy test for females of childbearing potential
The diaries should be collected at the visit described in the flow chart (see section 2). The 
recordings must be reviewed as described in section 8.1.8 and transcribed to the eCRF.
8.7
Subject compliance
Throughout the trial the investigator will remind the subjects to follow the trial procedures and 
requirements to ensure subject compliance. 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.
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 discovered to be non-compliant, the investigator must inform the subject of the 
importance of taking trial product as directed.
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Date:
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Version:
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EudraCT no.: NA
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9
Trial supplies
Trial supplies comprise trial products and auxiliary supplies. Additional details regarding trial 
supplies can be found in the Trial Materials Manual (TMM). 
Trial products must not be dispensed to any person not included in the trial. 
9.1
Trial products
The following trial products for subcutaneous injection will be provided by Novo Nordisk,
Denmark:
!
Semaglutide 1.34 mg/mL, solution for injection, 1.5 mL pre-filled PDS290 pen-injector
!
Semaglutide placebo, solution for injection, 1.5 mL pre-filled PDS290 pen-injector
The following trial products for oral administration will be provided by Novo Nordisk, Denmark:
!
Sitagliptin (Januvia®) 100 mg, tablet
!
Sitagliptin placebo, tablet
For both semaglutide and sitagliptin the placebo and active drug are identical with regard to 
appearance. 
Semaglutide both active drug and placebo are manufactured and supplied by Novo Nordisk, 
Denmark. Sitagliptin 100 mg and placebo is packed for use in clinical trials and supplied by Novo 
Nordisk, Denmark.
All trial products are considered investigational medicinal products (IMPs).
Refer to the appropriate IB or local label for more detailed information regarding the listed trial 
products. 
Each site will be supplied with sufficient trial products for the trial on an on-going basis controlled 
by the IWRS and according to enrolment and randomisation with different intervals during the trial. 
Subject will be instructed in administration of trial product and the investigator must document that 
a DFU is given orally and in writing at randomisation visit.
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9.2
Labelling
Labelling of the investigational medicinal products (IMPs) will be in accordance with Annex 1355,  
local law and trial requirements. Please refer to the TMM provided by Novo Nordisk for details 
regarding standard packages for the trial products.
9.3
Storage
Semaglutide preparations (both in-use and not in-use) must not be exposed to excessive heat or 
direct sunlight. Semaglutide preparations which have been frozen must not be used. Semaglutide 
must not be used, if it does not appear clear and colourless.
Trial product
Storage conditions
(not-in-use)
In-use conditions
Semaglutide 1.34 mg/mL and placebo
!
Store in a
refrigerator (2°C
to 8°C)
!
Do not freeze
!
Protect from
light
!
Store below 30°C
!
Do not refrigerate
!
Do not freeze
!
Protect from light
!
Use within 1
month*
Sitagliptin 100 mg and placebo
!
Do not store
above 30°C
!
Do not freeze
!
Do not
refrigerate
!
Protect from
light and
humidity
Not applicable
* In-use time starts when first dose is taken.
The investigator must ensure the availability of proper storage conditions, record and evaluate the 
temperature. The investigator must inform Novo Nordisk (via the assigned monitor) immediately if 
any trial product has been stored outside specified conditions (e.g. outside temperature range).
Fifteen minutes outside the indicated range is negligible, and should not be recorded as a deviation.
Trial products stored outside the temperature range are not to be used and must be stored separately 
within allowed temperature range until after evaluation of condition. Evaluation will be performed 
by Novo Nordisk. Trial products that have been stored improperly must not be dispensed to any 
subject before it has been re-evaluated and approved for further use by Novo Nordisk.
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Returned trial products (unused, partly used or used including empty packaging material) must be 
stored separately from non-allocated trial products.
The temperatures during storage should be monitored by a calibrated and stationary system. A 
temperature log must be kept to document storage within the right temperature interval and storage 
facilities should be checked frequently. Investigator must take appropriate action to avoid 
recurrence of the detected temperature deviation.
9.4
Drug accountability and destruction
The trial products will be dispensed to each subject as required according to treatment group. The 
IWRS will allocate trial product to the subject at each dispensing visit, starting at the randomisation 
visit. The correct DUN(s) must be dispensed to the subject.
The investigator or delegated person is responsible for ensuring that:
!
Trial products are not dispensed to any person not included in the trial
!
Drug accountability is performed using the IWRS drug accountability module
!
Subjects are instructed to return all used, partly used and unused trial product including
empty packaging material at each dispensing visit and at End of Treatment visit
!
All returned trial products (used/partial used and unused including empty packaging
material) is kept and stored separately from non-allocated trial products
Destruction of trial products will be done according to local law after accountability is finalised at 
site and reconciled by monitor. Destruction of trial products must be documented.
9.5
Auxiliary supplies
The following auxiliary supplies will be supplied by Novo Nordisk in accordance with the TMM:
!
Needles for pre-filled pen systems
!
Blood glucose meters, including lancets, plasma-calibrated test strips and control solutions
!
Directions for use for PDS290 pen-injector
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Date:
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Trial ID: NN9535-4114
Version:
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UTN: U1111-1149-0432 
Status:
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EudraCT no.: NA
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10
Interactive web response system
A trial-specific IWRS will be set up which can be accessed at any time via the internet or telephone. 
Access to the IWRS must be restricted to and controlled by authorised persons. 
IWRS is used for: 
!
Screening
!
Screening failure
!
Randomisation
!
Medication arrival
!
Dispensing
!
Treatment discontinuation
!
Treatment completion
!
Drug accountability
!
Data change
!
Dispensing verification (when barcode scanner is used)
IWRS user manuals will be provided to each trial site.
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Date:
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Version:
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EudraCT no.: NA
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11 Randomisation procedure and breaking of blinded codes
The trial is a double-blind trial. A randomisation session will be carried out for all subjects by using 
the IWRS. At the randomisation visit subjects meeting all inclusion/exclusion criteria will be 
randomised in a 2:2:1:1 manner to receive one of four parallel treatments groups:
!
Semaglutide 0.5 mg once-weekly + sitagliptin placebo once-daily
!
Semaglutide 1.0 mg once-weekly + sitagliptin placebo once-daily
!
Sitagliptin 100 mg once-daily + semaglutide placebo (0.5) mg once-weekly
!
Sitagliptin 100 mg once-daily + semaglutide placebo (1.0) mg once-weekly
Randomisation will be stratified by country. When grouping or analysing data by country, subjects 
from Hong Kong and Taiwan will be grouped with Chinese subjects if not otherwise specified.
11.1
Breaking of blinded codes
If the trial site needs to break the code, Novo Nordisk should if possible, be contacted before the 
code is broken. 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.
If the code has been broken the subject must be discontinued from trial product but be asked to 
continue in the trial (see section 8.1.6.2). A treatment discontinuation session should be completed 
in IWRS. 
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 
monitor should be contacted and if monitor cannot get access the IWRS vendor helpdesk should be 
contacted.
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Date:
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Trial ID: NN9535-4114
Version:
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UTN: U1111-1149-0432 
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EudraCT no.: NA
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12 Adverse events, and technical complaints and pregnancies
12.1
Definitions
Adverse event 
An adverse event (AE) is any untoward medical occurrence in a subject administered a product, and 
which does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom or disease temporally associated with the use of a product, whether or not 
considered related to the product. 
An AE includes:
!
A clinically significant worsening of a concomitant illness.
!
A clinical laboratory adverse event (CLAE): a clinical laboratory abnormality which is
clinically significant, ie an abnormality that suggests a disease and/or organ toxicity and is
of a severity that requires active management. Active management includes active treatment
or further investigations, for example change of medicine dose or more frequent follow-up
due to the abnormality.
The following should not be reported as AEs:
!
Pre-existing conditions, including those found as a result of screening procedures (pre-
existing conditions should be reported as medical history or concomitant illness).
!
Pre-planned procedures unless the condition for which the procedure was planned has
worsened from the first trial related activity after the subject has signed the informed
consent.
!
Non-serious hypoglycaemia is an AE, but is reported on a hypoglycaemic episode form
instead of on an AE form (see section 8.4.4).
The following three definitions are used when assessing an AE:
!
Severity assessment
–
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 assessment
The following terms are used when assessing the relationship between an AE and the relevant
trial product(s):
–
Probable - Good reason and sufficient documentation to assume a causal relationship.
–
Possible - A causal relationship is conceivable and cannot be dismissed.
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–
Unlikely - The event is most likely related to aetiology other than the trial product.
!
Final outcome
–
Recovered/resolved - The subject has fully recovered, or by medical or surgical
treatment the condition has returned to the level observed at the first trial-related activity
after the subject signed the informed consent.
–
Recovering/resolving - The condition is improving and the subject is expected to
recover from the event. This term is only applicable if the subject has completed the trial
or has died from another AE.
–
Recovered/resolved with sequelae - The subject has recovered from the condition, but
with lasting effect due to a disease, injury, treatment or procedure. If a sequela meets an
SAE criterion, the AE must be reported as an SAE.
–
Not recovered/not resolved - The condition of the subject has not improved and the
symptoms are unchanged, or the outcome is not known.
–
Fatal - This term is only applicable if the subject died from a condition related to the
reported AE. Outcomes of other reported AEs in a subject before he/she died should be
assessed as "recovered/resolved", "recovering/resolving", "recovered/resolved with
sequelae" or "not recovered/not resolved". An AE with fatal outcome must be reported
as an SAE.
–
Unknown - This term is only applicable if the subject is lost to follow-up.
12.1.1
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 (eg following the
event or clinical investigation the subject has significant, persistent or permanent change,
impairment, damage or disruption in his/her body function or structure, physical activity and/or
quality of life).
d. For example intensive treatment in an emergency room or at home of allergic bronchospasm,
blood dyscrasiasis or convulsions that do not result in hospitalisation, or development of drug
dependency or drug abuse.
The following adverse events must always be reported as an SAE using the important medical event 
criterion if no other seriousness criteria are applicable:
!
suspicion of transmission of infectious agents via the trial product
!
risk of liver injury defined as ALT or AST >3 x UNL and total bilirubin >2 x UNL, where no
alternative aetiology exists (Hy's law).
Additional assessments should be made for events meeting the criterion of Hy’s law as stated above 
(see appendix B).
12.1.2
Non-serious adverse event
A non-serious AE is any AE which does not fulfil the definition of an SAE.
12.1.3
Medication errors
Medication errors concerning trial products are defined as:
–
Administration of wrong drug. Note: Use of wrong DUN is not considered a medication
error.
–
Wrong route of administration, such as intramuscular instead of subcutaneous.
–
Administration of an overdose with the intention to cause harm (eg suicide attempt)
misuse or abuse of trial product.
–
Accidental administration of a lower or higher dose than intended. The administered
dose must deviate from the intended dose to an extend 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 8.4.2.
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Version:
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12.1.4
Adverse events requiring additional data collection
AEs requiring additional data collection are AEs where the additional data will benefit the 
evaluation of the safety of the trial product.
In this trial the following AEs require the completion of specific event forms in the eCRF, see Table 
12–1
Table 12–1
Adverse events requiring completion of specific event forms and/or are subject 
to event adjudication
Event
Specific event form
Event adjudication
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)
Hypersensitivity reaction
Yes
No
Neoplasm (excluding thyroid neoplasm)
Yes
Yes (only if malignant)
Pancreatitis
Yes
Yes (only if acute pancreatitis)
Renal event
Yes
No
Thyroid disease (including thyroid neoplasm)
Yes
Yes (only if malignant thyroid 
neoplasm or C-cell hyperplasia)
Death
No
Yes
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
Diabetic retinopathy
Yes
No
Laboratory outlier
Yes
No
For details about specific event form, see appendix B
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Version:
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12.1.5
Technical complaint
A technical complaint is any written, electronic, or oral communication that alleges product 
(medicine or device) defects. The technical complaint may be associated with an AE, but does not 
concern the AE itself.
Examples of technical complaints:
!
The physical or chemical appearance of trial products (eg discoloration, particles or
contamination)
!
The packaging material including labelling
!
Problems related to devices (eg to the injection mechanism, dose setting mechanism, push
button or interface between the pen and the needle)
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 (see section 2). 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. 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. 
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.
Some events will undergo event adjudication by the Event Adjudication Committee (EAC), please 
refer to Section 12.7.2. For AEs qualifying for event adjudication, the 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.
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Timelines for initial reporting of AEs:
The investigator must complete the following forms in the eCRF within the specified timelines:
!
SAEs: The AE form within 24 hours and the safety information form within 5 calendar
days of the investigator's first knowledge of the SAE.
!
SAEs requiring reporting on a specific event form : In addition to above, the specific
eventI form within 14 calendar days of the investigator's first knowledge of the AE.
!
Events for adjudication: The event adjudication  form must be completed within 14
calendar days of investigator’s first knowledge of the AE, see section 12.7.2. The
investigator should 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-m ail or courier within the same timelines as stated above. When the 
eCRF becomes available again, the investigator must re-enter the information on the form into the 
eCRF. 
Contact details (fax, telephone, e-mail and address) are provided in the investigators trial master 
file. 
Figure 12–1
Reporting of AEs
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Novo Nordisk assessment of AE expectedness:
Novo Nordisk assessment of AE expectedness is performed according to the following reference
documents:
!
Semaglutide: NN9535 IB27(subcutaneous administration), Type 2 diabetes, current version
and any updates thereto
!
Sitagliptin (Januvia®): EU Summary of Product Characteristics (SmPC)56current version.
Reporting of trial product-related SUSARs by the sponsor:
Novo Nordisk will notify the investigator of trial product-related suspected unexpected serious 
adverse reactions (SUSARs) in accordance with local requirements and ICH GCP1In addition, the 
investigator will be informed of any trial-related SAEs that may warrant a change in any trial
procedure. 
In accordance with regulatory requirements, Novo Nordisk will inform the regulatory authorities, 
including European Medicines Agency(EMA), of trial product-related SUSARs. In addition, Novo 
Nordisk will inform the 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
If an AE is considered to have a causal relationship with a Novo Nordisk marketed product used as 
concomitant medication in the trial, it is important that the suspected relationship is reported to 
Novo Nordisk, e.g. in the alternative aetiology section on the safety information form. Novo 
Nordisk may need to report this adverse event to relevant regulatory authorities.
12.3
Follow-up of adverse events
The investigator must record follow-up information by updating 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 (eg corrections or additional) 
information and must be reported within 24 hours of the investigator's first knowledge of the 
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information. This is also the case for previously non-serious AEs which subsequently become 
SAEs. 
!
Non-serious AEs: Non-serious AEs must be followed until the outcome of the event is
"recovering/resolving", "recovered/resolved" or "recovered/resolved with sequelae" or until
the end of the follow-up period stated in the protocol, whichever comes first, and until all
queries related to these AEs have been resolved. Cases of chronic conditions, cancer or AEs
ongoing at time of death (where death is due to another AE) may be closed with the
outcome "recovering/resolving" or "not recovered/not resolved". Cases can be closed with
the outcome of "recovering/resolving" when the subject has completed the follow-up period
and is expected by the investigator to recover.
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 
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 and on any of the following products: 
!
Semaglutide 1.34 mg/mL solution for injection, 1.5 mL pre-filled PDS290 pen-injector
!
Semaglutide placebo, solution for injection, 1.5 mL pre-filled PDS290 pen-injector
!
Sitagliptin (Januvia®) 100 mg, tablet
!
Sitagliptin placebo, tablet
!
Needles for pre-filled pen systems
which occur from the time of first usage of the product until the time of the last usage of the 
product, must be collected and reported to Customer Complaint Center, Novo Nordisk.
Contact details (fax, e-mail and address) are provided in Attachment I to the protocol.
The investigator must assess whether the technical complaint is related to any AEsand/orSAEs..
Technical complaints must be reported on a separate technical complaint form:
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!
One technical complaint form must be completed for each affected DUN
!
If DUN is not available, a technical complaint form for each code or lot number must be
completed
The investigator must complete the technical complaint form in the eCRF within the following 
timelines of the trial site obtaining knowledge of the technical complaint:
!
Technical complaint assessed as related to an SAE within 24 hours
!
All other technical complaints within 5 calendar days
If the eCRF is unavailable or when reporting a technical complaint that is not subject related, the 
information must be provided on a paper form by fax, e-mail or courier to Customer Complaint 
Center, Novo Nordisk, within the same timelines as stated above. When the eCRF becomes
available again, the investigator must enter the information on the technical complaint form in the 
eCRF.
12.4.2
Collection, storage and shipment of technical complaint samples
The investigator must collect the technical complaint sample and notify the monitor within 5 
calendar days of obtaining the sample at trial site. The monitor must coordinate the shipment to 
Customer Complaint Center, Novo Nordisk (the address is provided in Attachment I) and ensure 
that the sample is sent as soon as possible. A print or copy of the technical complaint form must be 
sent with the sample. If several samples are returned in one shipment, the individual sample and the 
corresponding technical complaint form must be clearly separated.
The investigator must ensure that the technical complaint sample contains the batch or lot number 
and, if available, the DUN. All parts of the DUN should be returned.
If the technical complaint sample is unobtainable, the investigator must specify on the technical 
complaint form why it is unobtainable. 
Storage of the technical complaint sample must be done in accordance with the conditions 
prescribed for the product.
12.5
Pregnancies
12.5.1
Pregnancies in female subjects
Female subjects must be instructed to notify the investigator immediately if they become pregnant 
during the trial. The investigator must report any pregnancy in subjects who have received trial 
product(s).
The investigator must follow the pregnancy until the pregnancy outcome and the newborn infant is 
one month of age.
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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 
(eg 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 (ie congenital anomalies, foetal death including
spontaneous abortion and/or any anomalies of the foetus observed at gross examination or
during autopsy), and/or when a congenital anomaly is diagnosed within the first month,
further information has to be reported for the female subject on maternal form 2. In addition,
information from the male partner has to be reported on the paternal form, after an informed
consent has been obtained from the male partner.
Initial reporting and follow-up information must be reported within 14 calendar days of the
investigator's first knowledge of initial or follow-up information.
2. Reporting of AE information
The investigator has to report AEs in connection with the pregnancy as well as in the foetus
and newborn infant(s). The SAEs that must be reported include abnormal outcome, such as
foetal death (including spontaneous abortion), and congenital anomalies (including those
observed at gross examination or during autopsy of the foetus), as well as other pregnancy
complications fulfilling the criteria of an SAE.
Forms and timelines for reporting AEs:
Non-serious AEs: 
–
AE form* within 14 calendar days of the investigator's first knowledge of the initial or
follow-up information to the non-serious AE.
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SAEs: 
–
AE form* 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.
*
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
Semaglutide
Events of nausea, vomiting and headache have been reported in connection with accidental 
administration of up to 4.0 mg semaglutide. No symptoms of hypoglycaemia have been reported in 
connection with overdose of semaglutide. In the event of overdose, appropriate supportive treatment 
should be initiated according to the subject’s clinical signs and symptoms. 
For other precautions, please see section 3.5.1.
Sitagliptin
During controlled clinical trials in healthy subjects, single doses of up to 800 mg sitagliptin were 
generally well tolerated. Minimal increases in QTc, not considered to be clinically relevant, were 
observed in one study at a dose of 800 mg sitagliptin. There is no experience with doses above 800 
mg in clinical studies. In Phase I multiple-dose studies, there were no dose-related clinical adverse 
reactions observed with sitagliptin with doses of up to 600 mg per day for periods of up to 10 days 
and 400 mg per day for periods of up to 28 days.
In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., remove 
unabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining 
an electrocardiogram), and institute supportive therapy if required. Sitagliptin is modestly 
dialysable. In clinical studies, approximately 13.5 % of the dose was removed over a 3- to 4-hour 
hemodialysis session. Prolonged hemodialysis may be considered if clinically appropriate. It is not 
known if sitagliptin is dialysable by peritoneal dialysis. 
For other precautions, please see section 3.5.5.
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12.7
Committees related to safety
12.7.1
Novo Nordisk safety committee
Novo Nordisk has constituted an internal semaglutide safety committee to perform ongoing safety 
surveillance. The 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 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 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 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section12.1.4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 Standardized Definitions57.
The EAC will review copies in English (translated if necessary) of medical documentation received 
in the adjudication package (for example X-ray, ECGs, ultrasound images, discharge summaries, 
pathology reports, and death certificates). The investigator mustprovide medical documentation as 
soon as possible, when receiving a request from Novo Nordisk or the event adjudication vendor.
The AEs for adjudication are listed in Table 12–2. 
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Table 12–2
Adverse events for adjudication
Events
Description
Adjudication outcome
Death*
!
All-cause death
!
Cardiovascular death
(including
undetermined cause of
death)
!
Non-Cardiovascular
death
Acute Coronary Syndrome
Acute Coronary Syndrome conditions include: 
!
ST-elevation acute myocardial infarction
(STEMI)
!
Non-ST elevation acute myocardial infarction
(NSTEMI)
!
Silent MI
!
Unstable angina pectoris (UAP) requiring
hospitalisation
!
Acute myocardial
infarction (STEMI or
NSTEMI), silent MI
!
Unstable angina
pectoris requiring
hospitalisation
Cerebrovascular events
!
Episode of focal or global neurological
dysfunction caused by brain, spinal cord, or
retinal vascular injury as a result of
haemorrhage or infarction
!
Transient Ischaemic Attack (TIA) is defined
as a transient episode (< 24 hours) of focal
neurological dysfunction caused by brain,
spinal cord, or retinal ischaemia, without acute
infarction
!
Ischaemic stroke
!
Haemorrhagic stroke
!
Undetermined stroke
!
TIA
Heart failure requiring 
hospitalisation
!
Hospitalisation with a primary diagnosis of
heart failure (new episode or worsening of
existing heart failure)
!
Heart failure requiring
hospitalisation
Acute pancreatitis
The diagnosis of acute pancreatitis requires two of the 
following three features:
!
Abdominal pain consistent with acute
pancreatitis (acute onset of a persistent,
severe, epigastric pain often radiating to the
back)
!
Serum lipase activity (and/or amylase activity)
at least three times greater than the upper limit
of normal
!
Characteristic findings of acute pancreatitis on
imaging
Acute pancreatitis
!
Mild
!
Moderate severe
!
Severe
Malignant neoplasm
Malignant neoplasms are defined as: 
!
Neoplasms in which abnormal cells divide
without control and can invade nearby tissues
and/or spread to other parts of the body
through the blood and lymph systems
!
Thyroid neoplasms are excluded in this event
category
!
Malignant neoplasm
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
!
Malignant thyroid
neoplasm
!
C-cell hyperplasia
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*Death is not a separate event, but an outcome
There are different processes for capturing events for adjudication:
!
Direct reporting by investigator:
- All AEs need to be assessed by the investigator if any AE category is applicable. If the AE
category selected is in scope for adjudication, the event specific adjudication form will be
populated for sites to complete
- AEs with fatal outcome
!
Screening:
- All AEs will be screened by NN for potential missed events for adjudication and if needed,
the investigator will be asked to provide additional information such as an alternative
aetiology, underlying cause(s) and/or clinical details.
!
EAC identified events:
- The EAC can decide to have an AE adjudicated even if not initially reported as an event
for adjudication by the investigator.
Event adjudication will be performed for AEs in randomised subjects including AEs with an onset 
date during the screening period. Event adjudication will not be performed for AEs in screening 
failures.
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. The 
outcome of adjudication will be kept in the clinical trial database.
through the blood and lymph systems
!
C-cell hyperplasia, defined as hyperplasia of
the parafollicular C-cells of the thyroid gland
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13 Case report forms 
Novo Nordisk will provide a system for the electronic case report forms (eCRF). This system and 
support services to the system will be supplied by a vendor.
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 (eg is not 
applicable), indicate this according to the data entry instructions.
The following will be provided as paper CRFs:
!
Pregnancy forms
In addition paper AE forms and safety information forms will be provided. These must be used 
when access to the eCRF is revoked. 
The investigator must ensure that all information is consistent with the source documentation. By 
electronically signing the case book in the eCRF, the investigator confirms that the information in 
the eCRF and related forms is complete and correct.
13.1
Corrections to case report forms 
Corrections to the CRF data may be made by the investigator or the investigator's authorised staff. 
An audit trail will be maintained in the CRF application containing as a minimum: the old and the 
new data, identification of the person entering the data, date and time of the entry and reason for the 
correction.
If corrections are made by the investigator's authorised staff after the date the investigator has 
signed the case book, the case book must be signed and dated again by the investigator.
13.2
Case report form flow 
13.2.1
Electronic 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 trial the investigator must ensure that all remaining data have been entered into the 
eCRF no later than 3 days after the last subject’s last visit 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 investigator site 
after the trial database is released and access to update the trial data on the EDC application has 
been removed. This data will be retained by the site.
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When the final CTR is available the data will be archived by Novo Nordisk.
13.2.2
Paper case report form flow
The pregnancy forms are paper based CRFs. 
Also, the SIF, technical complaint form, and AE form will be provided in paper but are only to be 
used if for any reason the eCRF is unavailable.
The investigator must ensure that data are recorded in these forms as soon as possible and ensure 
that Novo Nordisk receives these forms within the required timeline (see section 12).
Corrections to the data in the CRFs may only be made by drawing a straight line through the 
incorrect data and then writing the correct entry next to the data that were crossed out. Each 
correction must be initialled, dated and explained (if necessary) by the investigator or the 
investigator’s authorised staff.
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14 Monitoring procedures 
During the course of the trial, the monitor will visit the trial site to ensure that the protocol is 
adhered to, that all issues have been recorded, to perform source data verification and to monitor 
drug accountability. The first monitoring visit will be performed as soon as possible after FPFV or 
FSFV and no later than 4 weeks after. The monitoring visit intervals will depend on the outcome of 
the remote monitoring of the CRFs, the trial site's recruitment rate and the compliance of the trial 
site to the protocol and GCP, but will not exceed 12 weeks until LSLV at the trial site.
The intervals between monitoring visits can be shorter. Factors to be considered in this 
determination may include objective, endpoints, purpose, design, complexity, blinding, number of 
subjects and expected recruitment rate. 
The monitor must be given direct access to source documents (original documents, data and 
records). Direct access includes permission to examine, analyse, verify and reproduce any record(s) 
and report(s) that are important to the evaluation of the trial. If the electronic medical record does 
not have a visible audit trail, the investigator must provide the monitor with signed and dated 
printouts. In addition the relevant trial site staff should be available for discussions at monitoring 
visits and between monitoring visits (eg by telephone).
All data must be verifiable in source documentation other than the CRF.
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. Considering the 
electronic source data environment, it is accepted that the earliest practically retainable record 
should be considered as the location of the source data. Therefore transcription to the diary from the 
blood glucose meter is considered the source document for BG values.
Source data generated by the trial site can be corrected by another person than the person entering 
the source data, if accepted by local regulations; any correction must be explained, signed and dated 
by the person making the correction.
The original diaries and PROs are considered as source data and must not be removed from the trial 
site.
The monitor will ensure that the CRFs are completed on an on-going basis within the agreed 
timelines.
The monitor must ensure that all required eCRF forms for screening failures are completed, (e.g. 
screening failure form and the case book sign of (affirmation statement) is electronically signed by 
the investigator).
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Monitors must review the subject's medical records and other source data (eg the diaries and PROs) 
to ensure consistency and/or identify omissions compared to the CRF. If discrepancies are found, 
the investigator must be questioned about these.
When data has been source verified and all queries have been resolved the case book must be 
signed by the investigator in the eCRF.
A follow-up letter (paper or electronic) will be sent to the investigator following each monitoring 
visit addressing 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 an external CRO. 
Appropriate measures, including encryption of data files containing person identifiable data, will be 
used to ensure confidentiality of subject data, when they are transmitted over open networks. 
Data from central laboratories will be transferred electronically from the laboratory performing the 
analyses. 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 identification number. 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
If necessary, a statistical analysis plan (SAP) may be written in addition to the protocol, including a 
more technical and detailed elaboration of the statistical analyses. The SAP will be finalised before 
database lock. 
Results from the statistical analysis will generally be presented by two-sided confidence intervals 
with a confidence level of 95% and associated p-value. Superiority will be formulated and tested as 
one-sided hypotheses at a 2.5% significance level. Non-inferiority between two treatments will be 
evaluated by comparing the upper limit of the associated two-sided 95% confidence interval for the 
difference with the pre-defined non-inferiority margin.
When grouping or analysing data by country, subjects from Hong Kong and Taiwan will be 
grouped with Chinese subjects if not otherwise specified.
Handling of missing data
In the case of missing data no general imputation will be performed for the analyses, unless 
otherwise specified. If an assessment has been made both at screening and randomisation, the value 
from the randomisation visit will be used as the baseline value. If the value measured at the 
randomisation visit is missing and the assessment also has been made at screening, then the 
screening value will be used as the baseline value.
Laboratory values below the lower limit of quantification (LLOQ) will be set to ½ LLOQ.
The primary analysis model will be the mixed model for repeated measurements (MMRM), see 
section 17.3 for further details. One of the assumptions behind (MMRM) is that the missing data 
mechanism is missing at random (MAR). This means that given the observed data, the mechanism 
generating missing values is independent of the unobserved data that is the missing data. The 
MMRM and the negative binomial model both rely on the MAR assumption for generating 
unbiased estimates of treatment differences.
Based on previous semaglutide trials in subjects with type 2 diabetes, the  treatment discontinuation 
rate from randomised treatment and trial withdrawal is expected to be about 20%. The treatments in 
this trial should be effective, given the historical documentation, and this should minimise treatment 
discontinuation due to ineffective therapy. The main reasons for treatment discontinuation are 
expected to be AEs, ineffective therapy and non-eligibility (subjects randomised although not 
fulfilling inclusion/exclusion criteria). Treatment discontination due to non-eligibility can be 
regarded as missing completely at random (MCAR), i.e. it does not depend on the observed or 
missing data values. This category of missing data is not expected to introduce bias in the estimated 
treatment differences. Treatment discontinuation due to lack of efficacy is expected to be reflected 
in the observed data obtained prior to the discontinuation from randomised treatment, and the 
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corresponding missing data can therefore be assumed as MAR to some extent. Missing data due to 
AEs is expected to be similar between groups except for, potentially, a slightly higher incidence in 
the semaglutide treatment group due to gastrointestinal side effects. Together with potential 
withdrawals from trial due to the own will of the subject, the MAR assumption may be less 
adequate for this category of drop-outs.
Several different sensitivity analyses will be used to investigate whether the results from the 
MMRM approach are robust towards deviations from the assumption of MAR.
17.1
Sample size calculation
The primary objective is to compare the effect of two dose levels of semaglutide once-weekly 
treatment (0.5 mg or 1.0 mg) with sitagliptin 100 mg on the primary endpoint, change from baseline 
in HbA1c after 30 weeks of treatment. In the calculations determining the sample size it is presumed 
that in the analysis the two sitagliptin/semaglutide placebo groups will be pooled assuming no 
correlation between endpoints and placebo volume.
In total 1050 subjects will be randomised in a 2:2:1:1 manner. Assuming 20% of subjects 
discontinuing randomised treatment, and further taking the assumption that these subjects are 
excluded from the per protocol (PP) analysis set, 280 subjects in each group are expected to be 
included in the PP analysis set.
The sample size calculation is based on demonstrating HbA1c non-inferiority for semaglutide 0.5 
mg vs. sitagliptin 100 mg and HbA1c non-inferiority for semaglutide 1.0 mg vs. sitagliptin 100 mg.
The two hypothesis tests are assumed to be independent and for each of the hypothesis the power 
calculation is based on a t-statistic under the assumption of a one-sided test of size 2.5%. Using a 
non-inferiority margin of 0.3%, and assuming a true HbA1c difference (semaglutide minus 
sitagliptin) of 0% and a standard deviation (SD) of 1.1%, a total of 280 subjects per group in the PP 
analysis set will give 90% marginal power to conclude HbA1c non-inferiority for the comparison of 
a semaglutide dose vs. sitagliptin 100 mg.
Assuming the same HbA1c effect for the two dose levels of semaglutide, the overall power to 
demonstrate HbA1c non-inferiority for the two dose levels of semaglutide vs. sitagliptin will be at 
least 80%.
For change in body weight, the power calculation is based on the assumptions of a true difference of 
-1.5 kg and a SD of 4.0 kg. In addition, 50% efficacy retention is assumed for the anticipated 20%
of subjects discontinuing randomised treatment giving an expected treatment difference of -1.35 kg,
which is the number used in the power calculation. With the above assumptions, a total of 350
subjects per group in the full analysis set (FAS) will give more than 99% marginal power to
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conclude superiority in body weight for the comparison of a semaglutide dose vs. sitagliptin 100 
mg.
17.2
Definition of analysis sets
The following analysis sets are defined in accordance with the ICH-E9 guideline58.
Full Analysis Set (FAS): includes all randomised subjects.  Subjectsin the FASwill contribute to 
the evaluation “as randomised”.
Per Protocol (PP) Analysis Set:
Includes all subjects in the FAS who fulfil the following criteria:
!
have not violated any inclusion criteria
!
have not fulfilled any exclusion criteria
!
have a non-missing HbA1c measurement at screening and /or randomisation
!
have at least 23 weeks actual treatment weeks of expose
!
have at least one non-missing HbA1c measurement after 23 actual weeks of expoures
Subjects in the PP Analysis Set will contribute to the analysis “as treated”.
Safety Analysis Set (SAS): includes all subjects exposed to at least one dose of trial product.
Subjects in the SAS will contribute to the evaluation based on the trial product received for the 
majority of the period they were on treatment. This will be referred to as contributing to the 
evaluation “as treated”.
Before data are locked for statistical analysis, a review of all data will take place. Any decision to 
exclude a subject or single observations from the statistical analysis is the joint responsibility of the 
members of the internal 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 CTR.
Data selections and observation periods
Subjects and data to be used in an analysis will be selected in a two-step manner.
!
Firstly, subjects will be selected based on the specified analysis set
!
Secondly, data points on the selected subjects from first step will be selected based on the
specified observation period
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Definition of the observation periods:
In-trial: This observation period represents the time period where subjects are considered to be in 
the trial after randomisation, regardless of discontinuation of trial product or initiation of rescue 
medication. The in-trial observation period starts at randomisation (as registered in IWRS) and ends 
at the date of: 
!
The last direct subject-site contact, which is scheduled to take place 5 weeks after planned
last dose of trial product at a follow-up visit
!
Withdrawal for subjects who withdraw their informed consent
!
The last subject-investigator contact as defined by the investigator for subjects who are lost
to follow-up
!
Death for subjects who dies before any of the above
For subjects not randomised but exposed to trial product the in-trial periods starts at the date of first 
dose of trial product
On-treatment: This observation period represents the time period where subjects are considered 
treated with trial product. The observation period is a sub-set 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 according to the flow chart. For adjudicated events, ECG’s and 
AEs including hypoglycaemic episodes, the observation period ends at the first date of any of the 
following: 
!
the follow-up visit (V10)
!
the follow-up prematurely discontinuation visit (V10A)
!
the last date on trial product + 42 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 subcutaneous semaglutide. The visit window for 
the follow-up visit is + 7 days, which is the reason for the 42 days specified in the bullet above. 
Hence, for those assessments this period reflects the period in which subjects are exposed.
For efficacy and other safety assessments (laboratory assessments, physical examination and vital 
signs) the observation period ends at the last date on trial product + 7 days in accordance with trial 
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flow chart and assessment times. This ascertainment window corresponds to the dosing interval and 
will be used to avoid attenuation of a potential treatment effect on endpoints for which the effect is 
reversible shortly after treatment discontinuation. Hence, for those assessments this period reflects 
the period in which subjects are treated.
On-treatment without rescue medication: This observation period is a sub-set 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 +7 days
!
initiation of rescue medication
The ’on-treatment without rescue medication’ observation period will be the primary observation 
period for efficacy evaluations. The in-trial observation period will be considered supportive for 
efficacy evaluation. Safety will be evaluated based on the in-trial and the on-treatment observation 
periods unless otherwise specified.
For subjects who have no post-baseline scheduled assessments available in the on-treatment without 
rescue period, the baseline value will be carried forward to the first scheduled visit for the 
associated endpoint to ensure that all randomised subjects will contribute to the statistical analysis. 
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.
17.3
Primary endpoint
The primary endpoint is change from baseline in HbA1c after 30 weeks of treatment. In the analysis 
the two sitagliptin/semaglutide placebo groups will be pooled assuming no correlation between 
HbA1c change after 30 weeks and placebo volume.
The primary endpoint will be based on FAS using data from the ‘on-treatment without rescue 
medication’ observation period in a Mixed Model for Repeated Measures (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 30 data as dependent 
variables. The independent effects included in the model will be treatment and country as fixed 
effects and baseline response as covariate, all nested within visit. An unstructured covariance matrix 
will be employed for measurements within the same subjects, assuming that measurements across 
subjects are independent. Regarding missing data this analysis approach relies on the assumption 
that data are missing at random (MAR). From this mode, the two by dose level estimated treatment 
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differences between s.c.semaglutide versus sitagliptin at week 30 will be presented together with 
associated two-sided 95% confidence intervals and unadjusted two sided p-values (nominal 
alpha=0.05) for testing non-inferiority and superiority. In order to preserve the overall type 1 error 
the conclusion of non-inferiority and superiority with treatment of each semaglutide dose versus 
sitagliptin after 30 weeks will be evaluated hierarchically according to the sequence below, and 
starting with the first. In this testing sequence it is necessary to fulfil the test criteria, which is to 
reject the corresponding null hypothesis in order to go to the next step. If the corresponding null 
hypothesis is not rejected, the testing will stop and no further conclusions will be drawn. 
The following ordering in the statistical test sequence will be used:
1. Non-inferiority in change in HbA1c for semaglutide 1.0 mg vs. sitagliptin
2. Non-inferiority in change in HbA1c for semaglutide 0.5 mg vs. sitagliptin
3. Superiority in change in HbA1c for semaglutide 1.0 mg vs. sitagliptin
4. Superiority in change in body weight for semaglutide 1.0 mg vs. sitagliptin
5. Superiority in change in body weight for semaglutide 0.5 mg vs. sitagliptin
6. Superiority in change in HbA1c for semaglutide 0.5 mg vs. sitagliptin
Non-inferiority will be concluded if the upper limit of the two-sided 95% confidence interval for the 
estimated difference in HbA1c between semaglutide and sitagliptin is less than 0.3%. Superiority for 
either change in HbA1c or change in body weight will be claimed if the upper limit of the two-sided 
95% confidence interval for the estimated difference is below 0% or 0 kg respectively.  
When establishing non-inferiority the analysis will be based on the full analysis set (FAS) and 
supplemented by an analysis with the per protocol population using the data from the ‘on treatment 
without rescue medication’ observation period as supportive evidence. The FAS population will be 
used in the analysis when concluding superiority.
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Sensitivity analysis
To investigate the sensitivity of the main results, complimentary and separate analyses for primary 
endpoint and the confirmatory secondary endpoint will be performed, using the FAS only, except 
for HbA1c, where the PP analysis set will be used in a sensitivity analysis regarding the non-
inferiority evaluation. These analyses will investigate the sensitivity of the results due to the impact 
of missing values.
The primary analysis regarding non-inferiority of the primary endpoint change in HbA1c after 30 
weeks will also be performed separately based on the data in the PP analysis set only.
The primary endpoint and the secondary confirmatory endpoint will be evaluated in the following 
sensitivity analyses:
!
An analysis of covariance (ANCOVA) model will be analysed with imputation of missing
values according to the last observation carried forward (LOCF) method. based on the FAS
using the data  from the ‘on-treatment without rescue medication’ observation period. The
model will include terms for treatment, country, and the corresponding baseline value as a
covariate. The response variable will be the last available value obtained within the 30
weeks period of the trial
!
The MMRM will be analysed based on all data from the ‘in-trial’ observation period The
MMRM will be analysed based on data only from subjects that completed the trial without
receiving rescue treatment.
A pattern mixture model based on the FAS using the ‘on-treatment without rescue medication’ 
observation period approach mimicking an ITT scenario where withdrawn subjects are assumed to 
be switched to a treatment inferior to the control treatment after treatment discontinuation will be 
performed for evaluation of non-inferiority for the primary endpoint change in HbA1c at 30 weeks.
!
In the first step intermittent missing values 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 500 copies of the dataset will be generated.
!
In the second step, for each of the 500 copies of the dataset, an analysis of variance model
with the same factors as the primary model, and baseline HbA1c and HbA1c at 4 weeks (V3)
as covariate is fitted to the change in HbA1c from baseline to 8 weeks (V5) for the sitagliptin
group only. The estimated parameters, and their variance, from this model are used to
impute missing value at 8 weeks for subjects in all treatment groups, based on country and
HbA1c at baseline and 4 weeks.
!
In the third step, for each of the 500 copies of the dataset, missing HbA1c values at 12
weeks (V6) are imputed in the same way as for 8 weeks. Now the imputation are based on
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an analysis of variance model with the same factors and the HbA1c values at baseline, 4 
weeks and 8 weeks as covariates, fitted to the control group.
!
This stepwise procedure is then repeated sequentially over the available planned visits,
adding one visit in each step until the last planned visit at 30 weeks (V9).
!
For each withdrawn subject in the investigational treatment group, a value of 0.3% (the non-
inferiority limit) is added to the change in HbA1c at 30 weeks.
!
For each of the complete data sets, the change from baseline to week 30 is analysed using an
analysis of variance model with the same set of factors and the baseline HbA1c value as a
covariate.
!
The estimates and standard deviations for the 500 data sets are pooled to one estimate and
associated standard deviation using Rubin’s rule(page 255-257)59From these pooled
estimates the confidence interval for the treatment differences and the associated p-value are
calculated.
A pattern mixture model approach mimicking an ITT scenario where withdrawn subjects are 
assumed to be switched to the control treatment after treatment discontinuation will be performed 
separately for the evaluation of superiority in the primary endpoint change in HbA1c and change in 
body weight at 30 weeks. The same types of approach as used for the non-inferiority assessment in 
change in HbA1c will be employed, see above. However, the step where 0.3%, the non-inferiority 
limit, is added to the change in HbA1c at 30 weeks will not be performed in this sensitivity analysis.
Chinese/Korean subgroup analyses
Subgroup analyses for the primary endpoint and the confirmatory secondary endpoint will be 
performed by country with the aim to assess the treatment effect in China and Korea. They will be 
performed in a combined model using all data similar to the main analysis of the respective 
parameter but with an interaction between treatment and country. In addition the safety in China 
and Korea will be assessed.
17.4
Secondary endpoints
The planned secondary endpoints used to support the primary objective will be analysed as outlined 
in this section.
17.4.1
Confirmatory secondary endpoints
Weight loss
A confirmatory secondary variable is change in body weight after 30 weeks of treatment. This 
variable will be analysed in the same type of model as the primary endpoint although with baseline 
body weight as covariate.
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17.4.2
Supportive secondary endpoints
17.4.2.1
Efficacy endpoints
All efficacy endpoints in this section will be summarised and evaluated using the FAS.
Continuous variables
Change from baseline to week 30 in:
!
FPG
!
Insulin
!
C-peptide
!
glucagon
!
pro-insulin
!
pro-insulin/insulin ratio
!
HOMA-B
!
HOMA-IR
!
fasting blood lipids (total cholesterol, LDL-cholesterol, VLDL-cholesterol, HDL-
cholesterol, triglycerides and free fatty acids)
!
BMI
!
waist circumference
!
systolic and diastolic blood pressure
!
hsCRP
will all be analysed based on the same data and type of model as the primary endpoint, but with the 
associated baseline value as a covariate.
Except for FPG, BMI, waist circumference, and blood pressure the values of the variables will be 
log transformed subject to analysis.
Beta-cell function
Beta-cell function (fasting HOMA-B and fasting HOMA-IR) will be calculated based on fasting 
insulin and FPG. The calculation will be done at the same time points as for fasting insulin and FPG 
samples (section 2).
The calculation of the fasting HOMA endpoints will be done as follows:
Fasting HOMA-B (%) = 20 x fasting insulin [μU/ml]/(FPG[mmol/l]-3.5)
Fasting HOMA-IR (%) = fasting insulin [μU/ml] x FPG [mmol/l]/22.5
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PRO outcomes
The PRO outcome endpoints:
!
PRO questionnaire outcome DTSQs (individual items and treatment satisfaction score (6 of
the 8 items summed)), and
!
PRO questionnaire outcome SF-36v2TM short Form health survey: Total scores (physical
component and mental component) and scores from the 8 domains will be analysed
separately using the ANCOVA model based on the data from the on-treatment without
rescue medication observation period. Factors in the model will be treatment and country.
The baseline value of the corresponding endpoint will be used as covariate in the analysis
model.
7-point profile
Subjects will be asked to perform SMPG measurements see section 8.5.1.5.
The endpoints from the 7-point profiles that will be analysed at week 30 are:
!
Mean of the 7-point profile, defined as the area under the profile, calculated using the
trapezoidal method, divided by the measurement time
!
Mean increment over all meals
The mean of the 7-point profile and the mean of the post prandial increments at week 30 will be 
analysed separately with the same data and type of methods as primary endpoint but with the 
corresponding baseline assessment as a covariate.
Response in HbA1c and/or weight loss after 30 weeks
The secondary variables related to fixed response in HbA1c and/or weight loss at 30 weeks will be:
!
Responder in HbA1c after 30 weeks of treatment (yes/no) defined as HbA1c <7.0% (<53
mmol/mol) – ADA target
!
Responder in HbA1c after 30 weeks of treatment (yes/no) defined as HbA1c ≤6.5% (48
mmol/mol) – AACE target
!
Weight loss ≥5%
!
Weight loss ≥10%
!
HbA1c <7.0% (53 mmol/mol) without severe or confirmed symptomatic hypoglycaemia
(plasma glucose ≤3.1 mmol/L) and no weight gain
All these variables will be analysed based on the ‘on-treatment without rescue medication’ 
observation period separately in the same type of logistic regression model. The model will include 
factors for treatment and country. For the two responder in HbA1c endpoints, baseline HbA1c will be 
included in the model as a covariate, whereas for the weight responder endpoint (≥5% and ≥10% 
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weight loss), baseline weight will be included instead. For the composite endpoint (cf. last bullet), 
both baseline HbA1c and baseline weight will be included. 
Missing response data at 30 weeks will be imputed from respectively the MMRM used for the 
primary analysis of HbA1c and the confirmatory secondary endpoint change in body weight at 30 
weeks. The results will be described by the odds ratio and the associated 95% confidence interval 
for the odds ratio.
17.4.2.2
Safety endpoints
The safety endpoints will be evaluated based on SAS using both the on-treatment observation 
period and the in-trial observation period unless otherwise stated. 
The following secondary endpoints are used to support the safety objectives:
!
Number of treatment emergent AEs during 30 weeks of treatment
!
Number of  treatment emergent severe or BG confirmed symptomatic hypoglycaemic
episodes during 30 weeks of treatment
!
Severe or BG confirmed symptomatic hypoglycaemic episodes during 30 weeks of
treatment (yes/no)
Change in safety endpoints assessed from baseline to 30 weeks of treatment and/or follow up:
!
Haematology
!
Biochemistry
!
Calcitonin
!
Urinalysis
!
UACR
!
Pulse
!
ECG evaluation
!
Physical examination evaluation
!
Eye examination
Occurrence of semaglutide antibodies during 35 weeks of study duration (yes/no):
!
Anti-semaglutide antibodies
o
Anti-semaglutide antibodies with in vitro neutralising effect
o
Anti-semaglutide antibodies cross reacting with endogenous GLP-1

Cross reacting antibodies with in vitro neutralising effect to endogenous
GLP-1
Anti-semaglutide antibody level during and after 30 weeks of treatment
All safety endpoints will be summarised and evaluated by descriptive statistics using the SAS.
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Adverse events
The following endpoint related to adverse events is used to support the safety objective;
!
Number of treatment emergent adverse events (TEAEs)
A treatment-emergent AE is an event that has onset date (or increase in severity) during the on-
treatment observation period. These will therefore be referred to as ‘on-treatment AEs’ hereafter. 
On-treatment adverse events are summarised descriptively 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 years (R). These summaries are replicated by outputs including all
‘in-trial’ adverse events (i.e., adverse events with onset date [or increase in severity] during the ‘in-
trial’ observation period). Adverse events with onset after the end of the ‘in-trial’ observation
period will be reported in a listing. The development over time in gastrointestinal AEs will be
presented graphically.
The most frequent adverse events will be defined as preferred terms (PTs) that are experienced by at 
least 5% of the subjects in any of the treatment arms. 
All AEs will be coded using the most recent version of the Medical Dictionary for Regulatory 
Activities (MedDRA) coding.
Pulse
Pulse will be analysed separately using an analysis similar to the primary analysis of the primary 
endpoint. However this analysis will be based on FAS using the data from the on-treatment 
observation period but with the pulse value at baseline as a covariate.
Laboratory assessments
Amylase and lipase will be analysed separately with the same type of methods as for pulse with the 
corresponding baseline assessment as a covariate. The values will be log transformed in the 
analysis.
Calcitonin
Calcitonin will be displayed in terms of the number of subjects (N), the percentage of subjects (%) 
and the event rate per 1000 years of exposure (R). The following criteria are defined for tabulations:
Persistent (all post baseline measurements)
!
From <upper normal limit (UNL) to persistently ≥UNL
!
From <UNL to persistently ≥1.5 UNL
!
From <UNL to persistently ≥20 ng/L
!
From <UNL to persistently ≥50 ng/L
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!
From <20 ng/L to persistently ≥20 ng/L
!
From <50 ng/L to persistently ≥50 ng/L
Incidental (at least one post baseline measurements)
!
From <UNL to ≥UNL
!
From <UNL to ≥1.5 UNL
!
From <UNL to ≥20 ng/L
!
From <UNL to ≥50 ng/L
!
From <20 ng/L to ≥20 ng/L
!
From <50 ng/L to ≥50 ng/L
Summaries tables of calcitonin continuous measurements, will include number and percentage of 
observations < and≥LLOQ, minimum, Q25, median, Q75 and maximum. Summaries will be 
presented for all subjects and by gender.
Classification of Hypoglycaemia 
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: are episodes with time of onset 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)60. Therefore, Novo Nordisk has included hypoglycaemia with plasma glucose 
levels below this cut-off pointof hypoglycaemia.
In this trial Novo Nordisk use the following classificationin addition to the ADA classification(see 
Figure 17–1):
!
Severe or BG confirmed symptomatic hypoglycaemia: An episode that is severe according
to the ADA classification51or BG confirmed by a plasma glucose value <3.1 mmol/L (56
mg/dL) with symptoms consistent with hypoglycaemia.
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Hypoglycaemic
episode
PG ≤ 3.9 mmol/L 
(70 mg/dL) 
or 
Alleviation of 
symptoms 
or
Seizure, coma or 
fatal 
SMPG
measurement
PG < 3.1 mmol/L
(56 mg/dL)
with symptoms
PG < 3.1 mmol/L
(56 mg/dL)
without
symptoms
Symptomatic BG 
confirmed 
hypoglycaemia
Asymptomatic BG 
confirmed 
hypoglycaemia
Yes
No
Severe or 
BG confirmed 
symptomatic 
hypoglycaemia
BG confirmed 
hypoglycaemia
Severe or BG 
confirmed 
hypoglycaemia
Note: Glucose measurements are performed with capillary blood calibrated to plasma equivalent glucose values
BG: blood glucose  PG: plasma glucose  SMPG: Self-measured plasma glucose  
Subject 
able to 
treat him/
herself
Severe 
hypoglycaemia
(ADA 2013)
Figure 17–1 Novo Nordisk classification of hypoglycaemia
ADA classificationof hypoglycaemia51
!
Severe hypoglycaemia: An episode requiring assistance of another person to actively
administer carbohydrate, glucagon, or take of other corrective actions. Plasma glucose
concentration 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).
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Hypoglycaemic 
episode 
PG ≤ 3.9 mmol/L 
(70 mg/dL) 
or 
Alleviation of 
symptoms 
or
Seizure, coma or 
fatal 
SMPG
measurement
Asymptomatic 
hypoglycaemia
Documented 
symptomatic 
hypoglycaemia
Pseudo-
hypoglycaemia
Probable 
symptomatic 
hypoglycaemia
No
Yes
No measurement 
with symptoms
PG > 3.9 mmol/L 
(70 mg/dL)
with symptoms
PG ≤3.9 mmol/L 
(70 mg/dL)
with symptoms
PG ≤3.9 mmol/L 
(70 mg/dL)
without symptoms
No
Yes
Note: Glucose measurements are performed with capillary blood calibrated to plasma equivalent glucose values
PG: plasma glucose  SMPG: Self-measured plasma glucose  
Subject 
able to 
treat him/
herself
Severe 
hypoglycaemia
(ADA 2013)
Figure 17–2
ADA classification of hypoglycaemia
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Number of severe or BG confirmed symptomatic hypoglycaemic episodes
Data on treatment emergent hypoglycaemic episodes are 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 episodes rate per 100 years of exposure. Summaries of treatment 
emergent hypoglycaemic episodes will be presented as an overview including all episodes and 
episodes by severity.
The number of severe or BG confirmed symptomatic hypoglycaemic episodes during 30 weeks 
treatment will be analysed using a negative binomial regression model with a log-link function and 
the logarithm of the time period, from the randomisation and up to the time point in which an 
occurrence of a hypoglycaemic episode is considered treatment emergent as offset assuming MAR. 
The model will include factors for treatment, country as fixed factors and baseline HbA1c as 
covariate. The SAS will be used for the analysis.
Number of nocturnal hypoglycaemic episodes
The number of nocturnal (00:01-05:59 am) severe or BG confirmed symptomatic hypoglycaemic 
episodes during 30 weeks of treatment will be analysed separately in the same type of model as the 
number of severe or BG confirmed symptomatic hypoglycaemic episodes during 30 weeks 
treatment.
Severe or BG confirmed symptomatic hypoglycaemic episodes (yes/no)
The binary endpoint indicating whether a subject has no treatment emergent severe or BG 
confirmed symptomatic hypoglycaemic episodes or at least one will be analysed using a logistic 
regression model with treatment, country as fixed factors and baseline HbA1c as covariate.
Nocturnal severe or BG confirmed symptomatic hypoglycaemic episodes (yes/no)
The binary endpoint indicating whether a subject has no treatment emergent nocturnal (00:01-05:59 
am) severe or BG confirmed symptomatic hypoglycaemic episodes or at least one will be analysed 
using the same type model as severe or BG confirmed symptomatic hypoglycaemic episodes during 
30 weeks treatment.
17.5
Health economics and/or patient reported outcomes
The PRO questionnaires, SF-36v2TM and DTSQs, will be used to evaluate the objective regarding 
Quality of Life, see section 17.4.2.1for the details of the corresponding statistical analysis.
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18 Ethics
The trial will be conducted in compliance with ICH GCP1and applicable regulatory requirements, 
and in accordance with the Declaration of Helsinki2.
All subjects will be included after a thorough evaluation in regards to in-and exclusion criteria 
defined in order to ensure that subjects are eligible for trial treatment. Subjects will be treated 
within a regimen anticipated to be better than or equal to the treatment they receive at the time of 
entry into the trial. Subjects will have to spend some extra time, as additional assessments and visits 
to the clinic are required. It is the responsibility of the investigator to ensure the best possible care 
according to the principles outlined in Diabetes Care 2013 Standards of Medical Care in Diabetes61, 
or any updates thereof.
It is concluded that the potential benefits from participating in the trial outweigh the potential risks. 
The safety profile of semaglutide generated from the clinical and nonclinical development 
programme has not revealed any safety issues that would prohibit administration of once weekly 
doses of 0.5 mg or 1.0 mg semaglutide in accordance with the planned clinical trial. It is concluded 
that the risk to the subjects in this trial is low and acceptable in view of the benefits a long-acting 
GLP-1 analogue would provide to people with type 2 diabetes (please see 3.5)
The trial products may be associated with AEs, but relevant precautions have been implemented in 
the design and planned conduct of the trial in order to minimise the risks and inconveniences of 
participation in the trial. These precautions include thorough information regarding the correct 
administration of the trial products and gradual dose adjustment. Furthermore, subjects are fully 
informed about possible AEs and inconveniences and will be instructedto contact the investigator 
in case of any concerns regarding the trial participation.
When treatment with trial products ends, the subject and investigator will decide on the best 
available treatment.
18.1
Informed consent 
In seeking and documenting informedconsent, the investigator must comply with applicable 
regulatory requirement(s) and adhere to ICH GCP1and the requirements in the Declaration of 
Helsinki2.
Before any trial-related activity, the investigator must give the subject verbal and written 
information about the trial and the procedures involved in a form that the subject can read and 
understand. 
The subjects must be fully informed of their rights and responsibilities while participating in the 
trial as well as possible disadvantages of being treated with the trial products.
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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 task may 
be delegated by the investigator 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.
18.2
Data handling
If the subject is withdrawn from the trial or lost to follow up, then the subject's data will be handled 
as follows:
!
Data already collected and data collected at the end-of-trial visit will be retained by Novo
Nordisk, entered into the database and used for the trial report.
!
Safety events will be reported to Novo Nordisk and regulatory authorities according to
local/national requirements.
If data is used, it will always be in accordance with local regulations and IRBs/IECs.
18.3
Information to subject during trial
The site will be offered a communication package to the subject during the conduct of the
trial. The package content is issued by Novo Nordisk. The communication package will
contain the letters intended for distribution to the subjects. The letters will be translated
and adjusted to local requirements and distributed to the subject by discretion of the
investigator. The subject may receive a “welcome to the trial letter” and a “thank for
your participation letter” at the end of the trial. Further the subject may receive trial
letters during the trial period.
All information to the subjects will be submitted to the health authorities and IECs/IRBs
for approval according to local regulations.
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18.4
Premature termination of the trial and/or trial site
Novo Nordisk, the investigator, the IRBs/IECs or a regulatory authority may decide to stop the trial, 
part of the trial or a trial site at any time, but agreement on procedures to be followed must be 
obtained.
If a trial is suspended or prematurely terminated, the investigator must inform the subjects promptly 
and ensure appropriate therapy and follow-up. The investigator and/or Novo Nordisk must also 
promptly inform the IRBs/IECs and provide a detailed written explanation. The relevant regulatory 
authorities must be informed.
If, after the termination of the trial, the risk/benefit analysis changes, the new evaluation must be 
provided to the IRBs/IECs in case it has an impact on the planned follow-up of subjects who have 
participated in the trial. If it has an impact, the actions needed to inform and protect the subjects 
should be described.
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19 Protocol compliance
Deviations from the protocol should be avoided.
If deviations do occur, the investigator must inform the monitor and the implications of the 
deviation must be reviewed and discussed.
Deviations must be documented and explained in a protocol deviation by stating the reason, date, 
and the action(s) taken. Some deviations, for which corrections are not possible, can be 
acknowledged and confirmed via edit checks in the eCRF or via listings from the clinical database. 
Documentation on protocol deviations must be kept in the investigator's trial file and Novo Nordisk 
trial master file.
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20 Audits and inspections
Any aspect of the clinical trial may be subject to audits conducted by Novo Nordisk or inspections 
from domestic or foreign regulatory authorities or from IRBs/IECs. Audits and inspections may 
take place during or after the trial. The investigator and the site staff as well as Novo Nordisk staff 
have an obligation to cooperate and assist in audits and inspections. This includes giving auditors 
and inspectors direct access to all source documents and other documents at the trial site relevant to 
the clinical trial. This includes permission to examine, analyse, verify and reproduce any record(s) 
and report(s) that are relevant to the evaluation of the trial.
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21
Critical documents
Before a trial site is allowed to start screening subjects, the following documents must be available 
to Novo Nordisk:
!
Regulatory approval and/or acknowledgement of notification as required
!
Approval/favourable opinion from IRBs/IECs clearly identifying the documents reviewed as
follows: protocol, any protocol amendments, subject information/informed consent form,
any other written information to be provided to the subject and subject recruitment materials
!
List of IRB/IEC members and/or constitution
!
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 and local label for comparator
!
Signed and dated agreement on the final protocol
!
Signed and dated agreement on protocol amendment, if applicable
!
Financial agreement(s)
!
Source document agreement
!
Central laboratory certification and normal ranges
!
Insurance statement, if applicable
!
Signed and dated Investigator Agreement
!
Financial disclosure form from investigator and sub-investigator(s)
Novo Nordisk will analyse and report data from all sites together.
By signing the protocol, each investigator agrees to comply fully with ICH GCP1, applicable 
regulatory requirements and the Declaration of Helsinki2. 
By signing the protocol, each investigator also agrees to allow Novo Nordisk making 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
All staff Novo Nordisk, site, Central Laboratories, CRO etc. must conduct the trial in compliance 
with ICH GCP1, applicable regulatory requirements, and in accordance with the Declaration of 
Helsinki2.
The investigator is accountable for the conduct of the trial at his/her site. If any tasks are delegated, 
the investigator must maintain a list of appropriately qualified personsto whom he/she has 
delegated specified significant trial-related duties. The investigator must ensure that there is 
adequate training for all staff participating in the conduct of the trial. It is the investigator's 
responsibility to supervise the conductof the trial and to protect the rights, safety, and well-being of 
the subjects.
A qualified physician, who is an investigator or a sub-investigator for the trial, must be responsible 
for all trial-related medical decisions.
The investigator must ensure adequate supervision of the conduct of the trial at the trial site. 
The investigator will follow instructions from Novo Nordisk when processing data.
The investigator is responsible for filing essential documents (ie those documents which 
individually and collectively permit evaluation of the conduct of a trial and the quality of the data 
produced) in the investigator's trial file. The documents should be kept in a secure locked facility, 
so no unauthorized persons can get access to the data. The subject identification code list must be 
kept securely and separate from the personal 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 (eg 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 Novo Nordisk for regulatory purposes and 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.
One principal investigator will be appointed to review and sign the clinical trial report (signatory 
investigator) on behalf of all participating investigators. The signatory investigator will be 
appointed based upon the criteria defined by the International Committee of Medical Journal 
Editors for research publications62. 
23.1
Communication of results
Novo Nordisk commits to communicating, and otherwise making available for public disclosure, 
results of trials regardless of outcome. Public disclosure includes publication of a paper in a 
scientific journal, abstract submission with a poster or oral presentationat a scientific meeting, or 
disclosure by other means.
The results of this trial will be subject to public disclosure on external web sites according to 
international and national regulations, as reflected in the Novo Nordisk Code of Conduct for 
Clinical Trial Disclosure.
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.
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.
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Where required by the journal, the principal 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 Editors62(sometimes referred to as the Vancouver 
Criteria).
At the end of the trial, one or more publications (abstracts, posters, manuscripts) will be prepared 
for submission to scientific congresses and peer-reviewed journals in collaboration between Novo 
Nordisk and investigator(s) appointed by Novo Nordisk. These investigator(s) must meet the 
ICMJE authorship criteria to be named authors on publications.
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 for publication of such primary 
policy 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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Date:
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24 Retention of clinical trial documentation and human biospecimens
24.1
Retention of clinical trial documentation
Subject's medical records must be kept for the maximum period permitted by the hospital, 
institution or private practice.
The investigator must agree to archive the documentation (this includes both electronic and paper-
based records) pertaining to the trial in an archive after completion or discontinuation of the trial if 
not otherwise notified. The investigator should not destroy any documents without prior permission 
from Novo Nordisk. If the investigator cannot archive the documents at the trial site, Novo Nordisk 
can refer the investigator to an independent archive provider that has a system in place to allow only 
the investigator to access the files.
The investigator must be able to access his/her trial documents without involving Novo Nordisk in 
any way. Site-specific CRFs and other subject data (in an electronic readable format or as paper 
copies or prints) will be provided to the investigator before access is revoked to the systems and/or 
electronic devices supplied by Novo Nordisk. These data must be retained by the trial site. If the 
Novo Nordisk provided data (eg the CD-ROM) is not readable during the entire storage period, the 
investigator can request a new copy. A copy of all data will be stored by Novo Nordisk.
Novo Nordisk will maintain Novo Nordisk documentation pertaining to the trial for as long as the 
product is on the market plus 20 years. 
The files from the investigator site/institution must be retained for 15 years after the completion of 
the trial, or longer if required by local regulations. The deletion process must ensure confidentiality 
of data and must be done in accordance with local regulatory requirements.
24.2
Retention of human biospecimens
Antibody samples may be stored until market authorisation in case Health Authorities requests 
further characterisation of the antibody response.
(For Brazil: the laboratory samples for BR subjects will be destroyed at the latest at the completion 
of the CTR, including samples for anti-semaglutide antibody analysis. No sample will be stored 
after the completion of CTR).
None of the data will be identified by name. Antibody samples and thyroid tissue will be identified 
only by a subject number, a visit number and a trial identification number. The trial staff is 
responsible for maintaining a code list which links to the subject number. The code list must be kept 
for at least 15 years. The code list may be reviewed by Novo Nordisk staff including auditors or 
representatives from regulatory authorities, but no copies will be made of this list.
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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 sponsor, 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 risk/benefit 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's trial 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 local laws/acts/guidelines.
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27 References
1.
International Conference on Harmonisation. ICH Harmonised Tripartite Guideline for Good
Cinical Practice. Geneva, Switzerland. 5/1/1996 1996.
2.
World Medical Association. WMA Declaration of Helsinki - Ethical Principles for Medical
Research Involving Human Subjects. Last amended by the 64th WMA General Assembly,
Fortaleza, Brazil. October 2013.
3.
DeFronzo RA. Pathogenesis of type 2 diabetes mellitus. Med Clin North Am.
2004;88(4):787-835, ix.
4.
UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with
sulphonylureas or insulin compared with conventional treatment and risk of complications
in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352(9131):837-53.
5.
The effect of intensive treatment of diabetes on the development and progression of long-
term complications in insulin-dependent diabetes mellitus. The Diabetes Control and
Complications Trial Research Group. N Engl J Med. 1993;329(14):977-86.
6.
Chuang LM, Tsai ST, Huang BY, Tai TY, Diabcare-Asia Study Group. The status of
diabetes control in Asia--a cross-sectional survey of 24 317 patients with diabetes mellitus
in 1998. Diabet Med. 2002;19(12):978-85.
7.
Liebl A, Mata M, Eschwege E, Board ODEA. Evaluation of risk factors for development of
complications in Type II diabetes in Europe. Diabetologia. 2002;45(7):S23-8.
8.
Ford ES, Li C, Little RR, Mokdad AH. Trends in A1C concentrations among U.S. adults
with diagnosed diabetes from 1999 to 2004. Diabetes Care. 2008;31(1):102-4.
9.
Harris MI, Eastman RC, Cowie CC, Flegal KM, Eberhardt MS. Racial and ethnic
differences in glycemic control of adults with type 2 diabetes. Diabetes Care.
1999;22(3):403-8.
10.
Holst JJ, Vilsboll T, Deacon CF. The incretin system and its role in type 2 diabetes mellitus.
Mol Cell Endocrinol. 2009;297(1-2):127-36.
11.
Kieffer TJ, Habener JF. The glucagon-like peptides. Endocr Rev. 1999;20(6):876-913.
12.
Bagger JI, Knop FK, Lund A, Vestergaard H, Holst JJ, Vilsboll T. Impaired regulation of
the incretin effect in patients with type 2 diabetes. J Clin Endocrinol Metab. 2011;96(3):737-
45.
13.
Nauck M, Stockmann F, Ebert R, Creutzfeldt W. Reduced incretin effect in type 2 (non-
insulin-dependent) diabetes. Diabetologia. 1986;29(1):46-52.
14.
Nauck MA, Vardarli I, Deacon CF, Holst JJ, Meier JJ. Secretion of glucagon-like peptide-1
(GLP-1) in type 2 diabetes: what is up, what is down? Diabetologia. 2011;54:10-8.
15.
Perley MJ, Kipnis DM. Plasma insulin responses to oral and intravenous glucose: studies in
normal and diabetic sujbjects. J Clin Invest. 1967;46(12):1954-62.
16.
Hojberg PV, Vilsboll T, Rabol R, Knop FK, Bache M, Krarup T, et al. Four weeks of near-
normalisation of blood glucose improves the insulin response to glucagon-like peptide-1 and
glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes. Diabetologia.
2009;52(2):199-207.
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Version:
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17.
Meier JJ. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. 
Nat Rev Endocrinol. 2012;8(12):728-42.
18.
Flint A, Raben A, Astrup A, Holst JJ. Glucagon-like peptide 1 promotes satiety and 
suppresses energy intake in humans. J Clin Invest. 1998;101(3):515-20.
19.
Nauck MA, Niedereichholz U, Ettler R, Holst JJ, Orskov C, Ritzel R, et al. Glucagon-like 
peptide 1 inhibition of gastric emptying outweighs its insulinotropic effects in healthy 
humans. Am J Physiol. 1997;273(5 Pt 1):E981-8.
20.
Nauck MA, Kleine N, Orskov C, Holst JJ, Willms B, Creutzfeldt W. Normalization of 
fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7-36 amide) in type 2 (non-
insulin-dependent) diabetic patients. Diabetologia. 1993;36(8):741-4.
21.
Nauck MA. Incretin-based therapies for type 2 diabetes mellitus: properties, functions, and 
clinical implications. Am J Med. 2011;124(1 Suppl):S3-18.
22.
Toft-Nielsen MB, Damholt MB, Madsbad S, Hilsted LM, Hughes TE, Michelsen BK, et al. 
Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic 
patients. J Clin Endocrinol Metab. 2001;86(8):3717-23.
23.
Nauck MA, Petrie JR, Sesti G, Mannucci E, Courrèges, J.P., et al. A Phase 2, Randomized, 
Dose-Finding Study of the Novel Once-Weekly Human GLP-1 Analog, Semaglutide, 
Compared With Placebo and Open-Label Liraglutide in Patients With Type 2 Diabetes. 
Diabetes Care. 2016;39(2):231-41.
24.
Lau J, Bloch P, Schäffer L, Pettersson I, Spetzler J, Kofoed J, et al. Discovery of the Once-
Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide. J Med Chem. 
2015;58(18):7370-80.
25.
ICH Harmonised Tripartite Guideline. Guidance on non-clinical safety studies for the 
conduct of human clinical trials and marketing authorization for pharmaceuticals M3(R2). 
2009.
26.
Waser B, Blank A, Karamitopoulou E, Perren A, Reubi JC. Glucagon-like-peptide-1 
receptor expression in normal and diseased human thyroid and pancreas. Mod Pathol. 
2015;28(3):391-402.
27.
Investigator's Brochure for s.c. Semaglutide (NN9535), Edition 11 or any updates hereof. 
2016.
28.
Sorli C HS, Tsoukas G, Unger J, Derving Karsbol J, Hansen T, Bain S. Efficacy and safety 
of once-weekly semaglutide monotherapy versus placebo in subjects with type 2 diabetes 
(SUSTAIN 1).  ENDO 2016 - 98th Annual Meeting of the Endocrine Society2016.
29.
Ahmann A CM, Charpentier G, Dotta F, Henkel E, Lingvay I, Gaarsdal Holst A, Chang D, 
Aroda V. Efficacy and Safety of Once-weekly Semaglutide vs Exenatide ER After 56 
Weeks in Subjects With Type 2 Diabetes (SUSTAIN 3). Diabetes. 2016.
30.
Ahrén B CL, Kumar H, Sargin M, Derving Karsbøl J, Jacobsen SH, Chow F. Efficacy and 
Safety of Once-weekly Semaglutide vs Sitagliptin as add-on to Metformin and/or 
Thiazolidinediones After 56 Weeks in Subjects With Type 2 Diabetes (SUSTAIN 2). 
Diabetes. 2016.
31.
Aroda V BS, Cariou B, Piletic M, Rose L, Axelsen MB, Everton R, de Vries JH. Efficacy 
and safety of once-weekly semaglutide vs once-daily insulin glargine in insulin-naïve 
subjects with type 2 diabetes (SUSTAIN 4). Endocrine practice. 2016.
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Trial ID: NN9535-4114
Version:
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32.
Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, et al. Semaglutide and 
Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2016.
33.
Bailey T TR, Tinahones FJ, Rao P, Tsoukas GM, Thomsen AB,, Kaltoft MS aMM. Efficacy 
and safety of switching from sitagliptin to liraglutide in subjects with type 2 diabetes (LIRA-
SWITCH™): a randomized, double-blind, double-dummy, active-controlled 26-week trial. 
Diabetes, Obesity and Metabolim2016.
34.
Zang L, Liu Y, Geng J, Luo Y, Bian F, Lv X, et al. Efficacy and safety of liraglutide versus 
sitagliptin, both in combination with metformin, in Chinese patients with type 2 diabetes: a 
26-week, open-label, randomized, active comparator clinical trial. Diabetes Obes Metab. 
2016;18(8):803-11.
35.
Pratley R, Nauck M, Bailey T, Montanya E, Cuddihy R, Filetti S, et al. One year of 
liraglutide treatment offers sustained and more effective glycaemic control and weight 
reduction compared with sitagliptin, both in combination with metformin, in patients with 
type 2 diabetes: a randomised, parallel-group, open-label trial. International Journal of 
Clinical Practice. 2011;65(4):397-407.
36.
Limited MSD. JANUVIA – Labelling FDA. 4/27/2015 2015.
37.
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.
38.
Effect of intensive blood-glucose control with metformin on complications in overweight 
patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) 
Group. Lancet. 1998;352(9131):854-65.
39.
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.
40.
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.
41.
American Diabetes Association. Standards of medical care in diabetes - 2016. Diabetes 
Care. 2016;39 (Suppl. 1):S1-S109.
42.
Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. 
Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position 
statement of the American Diabetes Association (ADA) and the European Association for 
the Study of Diabetes (EASD). Diabetes Care. 2012;35(6):1364-79.
43.
Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. 
Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position 
statement of the American Diabetes Association (ADA) and the European Association for 
the Study of Diabetes (EASD). Diabetologia. 2012;55(6):1577-96.
44.
Standards of Medical Care in Diabetes-2016: Summary of Revisions. Diabetes Care. 
2016;39 Suppl 1:S4-5.
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45.
Merck & Co. I. JANUVIA - Labelling FDA. 2013 2013.
46.
Limited MSDAP. JANUVIA - Labelling CFDA. 2011 2011.
47.
Charbonnel B, Karasik A, Liu J, Wu M, Meininger G, Sitagliptin Study G. Efficacy and 
safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy 
in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes 
Care. 2006;29(12):2638-43.
48.
De Angelis C, Drazen JM, Frizelle FA, Haug C, Hoey J, Horton R, et al. Clinical trial 
registration: a statement from the International Committee of Medical Journal Editors. N 
Engl J Med. 2004;351(12):1250-1.
49.
U.S. Department of Health and Human Services, Food and Drug Administration. Food and 
Drug Administration Amendments Act of 2007. 27 September 2007.
50.
European Commission Regulation for EudraCT. 2011 2011.
51.
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.
52.
McAulay V, Deary IJ, Frier BM. Symptoms of hypoglycaemia in people with diabetes. 
Diabet Med. 2001;18(9):690-705.
53.
U.S. Department of Health and Human Services, Food and Drug Administration. Guidance 
for Industry. Patient-Reported Outcome Measures: Use in Medical Product Development to 
Support Labeling Claims. December 2009.
54.
Stull DE, Leidy NK, Parasuraman B, Chassany O. Optimal recall periods for patient-
reported outcomes: challenges and potential solutions. Curr Med Res Opin. 2009;25(4):929-
42.
55.
European Commission. The Rules Governing Medicinal Products in the European Union, 
Volume 4, Annex 13, Investigational Medicinal Products (ENTR/F/2/AM/an D[2010] 
3374). 03 Feb 2010.
56.
Limited MSD. JANUVIA - European Summary of Product Characteristics Annex 1. 
5/26/2015 2015.
57.
Hicks KA, Hung HMJ, Mahaffey KW, Mehran R, Nissen SE, Strockbridge NL, et al. 
Standardized Definitions for Cardiovascular and Stroke End Point Events in Clinical Trials 
(Draft). 20 Aug 2014.
58.
Phillips A, Haudiquet V. ICH E9 guideline 'Statistical principles for clinical trials': a case 
study. Stat Med. 2003;22(1):1-11; discussion 3-7.
59.
Little RJA, Rubin DB. Statistical analysis with missing data: New York: John Wiley & 
Sons. 1987.
60.
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.
61.
American Diabetes Association. Standards of medical care in diabetes (2013). Diabetes 
Care. 2013;36 Suppl 1:S11-66.
62.
International Committee of Medicinal Journal Editors. Uniform Requirements for 
Manuscripts submitted to Biomedical Journals.: N Engl J Med; 1997 1997. p. 309-15.
CONFIDENTIAL


Semaglutide
CONFIDENTIAL
Date:
14 April 2014
Novo Nordisk
Trial ID: NN9535-4114
Version:
1.0
Protocol - Appendix A
Status:
Final
EudraCT No.: NA
Page:
1 of 7
Appendix A
NN9535-4114
Medical events of special interest
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.


Semaglutide
Protocol - Appendix A
Date:
14 April 2014
Status:
Final
Novo Nordisk
Trial ID: NN9535-4114
EudraCT No.: NA
Version:
1.0
Page:
2 of 7
Event
Appendix A
Definition
Rationale
EAC
1
Medication errors 
concerning trial products
1) Administration of wrong drug or use of wrong device
2) Wrong route of administration, such as intramuscular
instead of subcutaneous
3) Administration of a high dose with the intention to cause
harm, e.g. suicide attempt
4) Accidental administration of a lower or higher dose than
intended. That is a dose of semaglutide 10% lower or
higher than 1.0 mg week (± 24h) or of sitagliptin that is
lower or higher than 100 mg/day; however the
administered dose must deviate from the intended dose to
an extend where clinical consequences for the trial subject
were likely to happen as judged by the investigator,
although not necessarily did happen.
Standard MESI in all Novo 
Nordisk clinical trials. 
Medication errors are 
captured to collect 
information which may be 
used to improve the design, 
name or packaging of the 
product and/or information 
which may have an impact on 
product labelling (for 
example information about 
substantial overdoses).
No
2
Fatal events (if not 
covered by another 
MESI)
All cause death: 
 Cardiovascular death,
 Non-cardiovascular death,
 Undetermined cause of death2,3
A FDA guidance document1
requests that sponsors 
demonstrate the 
cardiovascular safety profile 
of any newtherapy for type 2 
diabetes in order to ensure, 
that the new therapy does not 
increase the cardiovascular 
risk to an unacceptable 
extent.
All events will be 
adjudicated


Semaglutide
Protocol - Appendix A
Date:
14 April 2014
Status:
Final
Novo Nordisk
Trial ID: NN9535-4114
EudraCT No.: NA
Version:
1.0
Page:
3 of 7
3
Acute coronary 
syndrome3:
!
Myocardial
Infarction
!
Hospitalisation for
unstable angina
All types of myocardial infarction (MI) must be reported:
!
Spontaneous MI (including re-infarction and MI
associated with stent thrombosis)
!
Percutaneous coronary
intervention (PCI) related MI
!
Coronary artery bypass graft surgery (CABG) related
MI
!
Silent MI2
All events with symptoms of myocardial ischemia
requiring hospitalization must be reported.
Requested in FDA guidance 
document1
All events will be 
adjudicated
4
Cerebrovascular event 
(stroke or transient 
ischemic attack)
Stroke (Ischemic, haemorrhagic, undetermined) 
Stroke is defined as an acute episode of neurological 
dysfunction caused by focal or global brain, spinal cord, or 
retinal vascular injury2,3.
Transient Ischemic Attack
Transient ischemic attack (TIA) is defined as a transient 
(<24 hours) episode of neurological dysfunction caused by 
focal brain, spinal cord, or retinal ischemia, without acute 
infarction2,3.
Requested in FDA guidance 
document1
All events will be 
adjudicated
5
Coronary 
Revascularisation 
Procedure
Coronary Revascularisation Procedure (Coronary Artery 
Bypass Graft surgery (CABG), Percutaneous Coronary 
Intervention (PCI)):A coronary revascularisation 
procedure is a catheter-based or open surgical procedure 
designed to improve myocardial blood flow2,3.
Requested in FDA guidance 
document1
All events will be 
adjudicated


Semaglutide
Protocol - Appendix A
Date:
14 April 2014
Status:
Final
Novo Nordisk
Trial ID: NN9535-4114
EudraCT No.: NA
Version:
1.0
Page:
4 of 7
6
Peripheral Arterial 
Revascularisation 
Procedure
Peripheral Arterial Revascularisation Procedure (lower 
extremity, renal, mesenteric, iliac, subclavian, aortic etc.):
A peripheral arterial revascularisation procedure is a 
catheter-based or open surgical procedure designed to 
improve peripheral arterial blood flow. This procedure may 
include thrombectomy, embolectomy, atherectomy, 
dissection repair, angioplasty, and stent placement. 
Pre-planned procedures of peripheral revascularisation 
should not be reported as MESI.
Requested in FDA guidance 
document1
No
7
Heart failure requiring 
hospital admission
Clinical manifestations of new episode or worsening of 
existing heart failure2,3.
Requested inFDA guidance 
document1
All events will be 
adjudicated
8
Neoplasm (excluding 
thyroid neoplasm)
All types of neoplasms must be reported including:
• Malign neoplasm
• In situ neoplasm
• Benign neoplasm
• Neoplasms of uncertain or unknown behaviour
For operational reasons thyroid neoplasm will be reported 
as per thyroid disease MESI.
Neoplasm is an event Novo 
Nordisk follows closely for 
GLP-1 analogues due to non-
clinical findings in rats and 
mice treated with GLP-1 
receptor agonists.
All events will be
adjudicated
9
Thyroid disease 
(including thyroid 
neoplasm)
All disorders of thyroid gland must be reported. For 
operational reasons thyroid neoplasm will be reported as 
per thyroid disease MESI
Thyroid C-cell carcino-
genicity has been reported in 
rats and mice treated with 
GLP-1 receptor agonists in 
non-clinical studies 
Only adjudicated 
if  thyroid 
neoplasm or 
resulting in 
thyroidectomy


Semaglutide
Protocol - Appendix A
Date:
14 April 2014
Status:
Final
Novo Nordisk
Trial ID: NN9535-4114
EudraCT No.: NA
Version:
1.0
Page:
5 of 7
10
Pancreatitis or clinical 
symptoms leading to 
suspicion of pancreatitis
Two of following diagnostic criteria fulfilling the diagnosis 
of acute pancreatitis: 
1) Severe acute abdominal pain
2) elevated blood levels of pancreatic enzymes (lipase,
amylase) > 3xUNR
3) characteristic imaging finding (ultrasound, CT, MRI)
Chronic pancreatitis will be defined by characteristic 
imaging finding (ultrasound, CT, MRI) with abnormal 
pancreatic function tests or characteristic histological 
findings
Treatment with GLP-1 
receptor agonists has been 
associated with acute 
pancreatitis and Novo
Nordisk therefore monitors 
these events closely
All events will be 
adjudicated
11
Immunogenicity events 
(allergic reactions, 
immune complex 
disease, and anti-
semaglutide antibody 
formation)
All events suspected to involve an immune reaction to trial 
product must be reported:
Events to be reported can be defined according to the 
below:
A) Immediate hypersensitivity reactions.
Typically occurring within minutes after administration of 
the antigen. Clinical symptoms include (but are not limited 
to):
!
Urticaria
!
Angioedema
!
Allergic rhinitis
!
Exacerbation of pre-existing, or de novo development
of, allergic asthma
!
Systemic anaphylactic reaction
All protein based drugs have 
a risk of hypersensitivity 
reactions
No


Semaglutide
Protocol - Appendix A
Date:
14 April 2014
Status:
Final
Novo Nordisk
Trial ID: NN9535-4114
EudraCT No.: NA
Version:
1.0
Page:
6 of 7
B) Delayed hypersensitivity reactions
Typically occurring 48 to 72 hours after exposure to the
antigen and manifested by various types of skin reactions
with or without pruritus
C) Immune complex disease
Either de novo development or exacerbation of pre-existing 
immune complex disease. Most frequent clinical 
syndromes include:
!
Lupus erythematosus
!
Vasculitis syndromes
!
Non-viral hepatitis
!
Pneumonitis
!
Arthritis
!
Glomerulonephritis
D) Anti-semaglutide antibody formation
Hypersensitivity reactions very rarely occur at the first 
administration of antigen and will always reoccur if 
exposed again. Hypersensitivity reactions can be present at 
the injection site, but are not equivalent to local irritative 
injection site reactions caused by trauma. 
1. Guidance for Industry. Diabetes Mellitus – Evaluating cardiovascular Risk in new Antidiabetic Therapies to Treat Type 2 Diabetes. FDA,
Center for Drug Evaluation and Research (CDER). December 2008. Clinical/medical or any updates hereof.


Semaglutide
Protocol - Appendix A
Date:
14 April 2014
Status:
Final
Novo Nordisk
Trial ID: NN9535-4114
EudraCT No.: NA
Version:
1.0
Page:
7 of 7
2. Standardized Definitions for Cardiovascular and Stroke End Point Events in Clinical Trials (DRAFT). Karen A. Hicks, H. M. James
Hung, Kenneth W. Mahaffey, Roxana Mehran, Steven E. Nissen, Norman L. Stockbridge, Shari L. Targum, Robert Temple; on behalf of
the Standardized Data Collection for Cardiovascular Trials Initiative. November 9, 2012 or any updates hereof.


Protocol - Appendix A
CONFIDENTIAL
Date:
28 October 2016
Novo Nordisk
Trial ID: NN9535-4114
Version:
1.0
UTN: U1111-1149-0432 
Status:
Final
EudraCT No.: NA
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:
28 October 2016
Novo Nordisk
Trial ID: NN9535-4114
Version:
1.0
UTN: U1111-1149-0432 
Status:
Final
EudraCT No.: NA
Page:
2 of 6
1
Background
Treatment with GLP-1 receptor agonists has been 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:
28 October 2016
Novo Nordisk
Trial ID: NN9535-4114
Version:
1.0
UTN: U1111-1149-0432 
Status:
Final
EudraCT No.: NA
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 
CONFIDENTIAL


Protocol - Appendix A
CONFIDENTIAL
Date:
28 October 2016
Novo Nordisk
Trial ID: NN9535-4114
Version:
1.0
UTN: U1111-1149-0432 
Status:
Final
EudraCT No.: NA
Page:
4 of 6
product). The subject should remain in the trial; however, all medications suspected to relate to this 
condition must be discontinued until diagnosis has been established.
Background: These values were found in 9 (0.15%) of a population of 5817 patients with thyroid 
nodular disease 1. All of these patients were diagnosed with MTC, resulting in a positive predictive 
value of 100 %.
Diagnostic evaluation should include:
!
thyroid ultrasound examination
!
fine needle aspiration of any nodules > 1 cm
!
potentially, surgery with neck dissection
In case a subject is diagnosed with MTC, it is common clinical practice to explore the family 
history of MTC or MEN2 and perform a genetic test for RET proto-oncogene mutation.
2.2
Calcitonin ≥ 50 and < 100 ng/L
Action: The subject should be referred to a thyroid specialist for further evaluation. The subject 
should remain in the trial and continuation on trial product should be based on the evaluation done 
by the thyroid specialist. 
Background: These values were found in 8 (0.14%) of the population of 5817 patients with thyroid 
nodular disease 1. Two of these subjects were diagnosed with MTC and two were diagnosed with 
C-cell hyperplasia, resulting in a positive predictive value of a C-cell anomaly of 50%.
Diagnostic evaluation should include: 
!
thyroid ultrasound examination
!
if available, and if there are no contraindications, 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 disease 1. The predictive value of a C-cell anomaly 
CONFIDENTIAL


Protocol - Appendix A
CONFIDENTIAL
Date:
28 October 2016
Novo Nordisk
Trial ID: NN9535-4114
Version:
1.0
UTN: U1111-1149-0432 
Status:
Final
EudraCT No.: NA
Page:
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 al.1 identified 216 (3.7%) patients. One 
patient out of the 216 had a subsequent basal (unstimulated) calcitonin value 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 CT > 10 and < 20 
ng/L to allow conclusions 2, 3.
CONFIDENTIAL


Protocol - Appendix A
CONFIDENTIAL
Date:
28 October 2016
Novo Nordisk
Trial ID: NN9535-4114
Version:
1.0
UTN: U1111-1149-0432 
Status:
Final
EudraCT No.: NA
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, A m, drosten R. Sporadic hypercalcitoninemia: clinica and 
therapeutic consequences. Endocrine Related 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 A
CONFIDENTIAL
Date:
09 December 2016
Novo Nordisk
Trial ID: NN9535-4114
Version:
3.0
UTN: U1111-1149-0432 
Status:
Final
EudraCT No.: NA
Page:
1 of 7
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:
09 December 2016
Novo Nordisk
Trial ID: NN9535-4114
Version:
3.0
UTN: U1111-1149-0432 
Status:
Final
EudraCT No.: NA
Page:
2 of 7
Table of Contents   
Page
Table of Contents..............................................................................................................................................2
1
Background................................................................................................................................................3
2
Calcitonin monitoring...............................................................................................................................4
2.1
Calcitonin ≥ 100 ng/L....................................................................................................................4
2.2
Calcitonin ≥ 50 and < 100 ng/L.....................................................................................................5
2.3
Calcitonin ≥ 10 and < 50 ng/L.......................................................................................................5
3
References..................................................................................................................................................7
CONFIDENTIAL


Protocol - Appendix A
CONFIDENTIAL
Date:
09 December 2016
Novo Nordisk
Trial ID: NN9535-4114
Version:
3.0
UTN: U1111-1149-0432 
Status:
Final
EudraCT No.: NA
Page:
3 of 7
1
Background
Treatment with GLP-1 receptor agonists has been 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:
09 December 2016
Novo Nordisk
Trial ID: NN9535-4114
Version:
3.0
UTN: U1111-1149-0432 
Status:
Final
EudraCT No.: NA
Page:
4 of 7
2
Calcitonin monitoring
A blood sample will be drawn at pre-specified trial visits for measurement of calcitonin.
In case a subject has a calcitonin value ≥ 10 ng/L, the algorithm outlined in Figure 1 and described 
below should be followed. The algorithm applies for all calcitonin values in the trial.
Calcitonin < 10ng/L
Calcitonin  ≥ 10 ng/L and 
< 50 ng/L
Calcitonin  ≥ 50 ng/L and 
< 100 ng/L
Calcitonin  ≥ 100 ng/L
Evaluation of 
calcitonin results
Calcitonin  ≥ 10 ng/L and 
last measurement in the 
trial
No action
●Investigate potential confounding 
factors
●Continue sampling of calcitonin 
according to protocol
●Refer to thyroid specialist
●Discontinue trial product
●Refer to thyroid specialist
●Refer to thyroid specialist
Figure 1
Flow of calcitonin monitoring
2.1
Calcitonin ≥ 100 ng/L  
Action: The subject must immediately be referred to a thyroid specialist for further evaluation and 
the trial product must be discontinued (see protocol Section 6.5 premature discontinuation of trial 
CONFIDENTIAL


Protocol - Appendix A
CONFIDENTIAL
Date:
09 December 2016
Novo Nordisk
Trial ID: NN9535-4114
Version:
3.0
UTN: U1111-1149-0432 
Status:
Final
EudraCT No.: NA
Page:
5 of 7
product). The subject should remain in the trial; however, all medications suspected to relate to this 
condition must be discontinued until diagnosis has been established.
Background: These values were found in 9 (0.15%) of a population of 5817 patients with thyroid 
nodular disease 1. All of these patients were diagnosed with MTC, resulting in a positive predictive 
value of 100 %.
Diagnostic evaluation should include:
!
thyroid ultrasound examination
!
fine needle aspiration of any nodules > 1 cm 
!
potentially, surgery with neck dissection
In case a subject is diagnosed with MTC, it is common clinical practice to explore the family 
history of MTC or MEN2 and perform a genetic test for RET proto-oncogene mutation.
2.2
Calcitonin ≥ 50 and < 100 ng/L
Action: The subject should be referred to a thyroid specialist for further evaluation. The subject 
should remain in the trial and continuation on trial product should be based on the evaluation done 
by the thyroid specialist. 
Background: These values were found in 8 (0.14%) of the population of 5817 patients with thyroid 
nodular disease 1. Two of these subjects were diagnosed with MTC and two were diagnosed with 
C-cell hyperplasia, resulting in a positive predictive value of a C-cell anomaly of 50%.
Diagnostic evaluation should include: 
!
thyroid ultrasound examination 
!
if available, and if there are no contraindications, 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 disease 1. The predictive value of a C-cell anomaly 
CONFIDENTIAL


Protocol - Appendix A
CONFIDENTIAL
Date:
09 December 2016
Novo Nordisk
Trial ID: NN9535-4114
Version:
3.0
UTN: U1111-1149-0432 
Status:
Final
EudraCT No.: NA
Page:
6 of 7
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 al.1 identified 216 (3.7%) patients. One 
patient out of the 216 had a subsequent basal (unstimulated) calcitonin value 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 CT > 10 and < 20 
ng/L to allow conclusions 2, 3.
CONFIDENTIAL


Protocol - Appendix A
CONFIDENTIAL
Date:
09 December 2016
Novo Nordisk
Trial ID: NN9535-4114
Version:
3.0
UTN: U1111-1149-0432 
Status:
Final
EudraCT No.: NA
Page:
7 of 7
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, A m, drosten R. Sporadic hypercalcitoninemia: clinica and 
therapeutic consequences. Endocrine Related 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


Semaglutide
CONFIDENTIAL
Date:
14 April 2014
Novo Nordisk
Trial ID: NN9535-4114
Version:
1.0
Protocol - Appendix B
Status:
Final
EudraCT No.: NA
Page:
1 of 6
Appendix B
NN9535-4114
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.


Semaglutide
CONFIDENTIAL
Date:
14 April 2014
Novo Nordisk
Trial ID: NN9535-4114
Version:
1.0
Protocol - Appendix B
Status:
Final
EudraCT No.: NA
Page:
2 of 6
Table of Contents
Page
Table of Contents..............................................................................................................................................2
1
Background................................................................................................................................................3
2
Calcitonin and C-cell abnormalities - evaluation and follow-up ..........................................................4
2.1
Calcitonin values ≥100 ng/L..........................................................................................................4
2.2
Calcitonin values ≥50 and <100 ng/L............................................................................................4
2.3
Calcitonin values ≥20 and <50 ng/L..............................................................................................5
2.4
Calcitonin values ≥10 and <20 ng/L..............................................................................................5
3
References..................................................................................................................................................6
CONFIDENTIAL


Semaglutide
CONFIDENTIAL
Date:
14 April 2014
Novo Nordisk
Trial ID: NN9535-4114
Version:
1.0
Protocol - Appendix B
Status:
Final
EudraCT No.: NA
Page:
3 of 6
1
Background
Semaglutide treatment is associated with thyroid C-cell changes in rodents but not in the non-
human primate. The proliferative C-cell changes in rodents are a known effect following GLP-1 
receptor activation by GLP-1 receptor agonists and 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 a 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 can 
become challenging. 
There are several known confounding factors affecting calcitonin levels, namely renal dysfunction, 
smoking, autoimmune thyroiditis and several drug classes (eg proton pump inhibitors, beta-
blockers, H2-blockers and glucocorticoids). Physiology of C-cell activation in various clinical 
conditions and in different patient populations (ie 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


Semaglutide
CONFIDENTIAL
Date:
14 April 2014
Novo Nordisk
Trial ID: NN9535-4114
Version:
1.0
Protocol - Appendix B
Status:
Final
EudraCT No.: NA
Page:
4 of 6
2
Calcitonin and C-cell abnormalities - evaluation and follow-up
Subjects with a personal or family history of medullar thyroid cancer (MTC) or multiple endocrine 
neoplasia syndrome type 2 (MEN 2) or with a screening calcitonin ≥50 ng/L will be excluded from 
the NN9535-4114 trial.
A blood sample will be drawn at pre-specified trial visits for measurement of calcitonin. In case a 
subject has an calcitonin value ≥10 ng/L the algorithm outlined below (see Section 2.1 to 2.4) 
should be followed. The algorithm applies for all calcitonin values including screening values.
All calcitonin values ≥20 ng/L will be submitted to an independent Calcitonin Monitoring 
Committee (CMC) of thyroid experts, together with relevant supplementary data, ie subject’s 
demographics, diabetes history, concomitant medical history, concomitant medications, smoking 
status as well as information about relevant adverse events reported during the trial.
The CMC will provide recommendations to the investigators with regards to further investigation 
and treatment of the individual subject. The CMC will be blinded to trial treatment. 
The summary for the rationale for the use of specific calcitonin values to trigger medical evaluation 
is provided in section 2.1 to 2.4.
2.1
Calcitonin values ≥100 ng/L
The value will be submitted to the CMC and the subject should be discontinued from trial product. 
If the value is a screening value the subject cannot be randomised and the subject must be referred 
to a thyroid specialist. 
These values were found in 0.15% of the population published by Costante et al1 and in one subject 
(on active comparator) in the liraglutide development program. For a calcitonin value of ≥100 ng/L, 
the subject should be assumed to have significant C-cell disease and a high likelihood of having 
medullary carcinoma of the thyroid. Diagnostic evaluation should consist of thyroid ultrasound, fine 
needle aspiration of any nodules >1 cm and potentially surgery with neck dissection. Family history 
of MTC or MEN 2 should be evoked and a RET proto-oncogene analysis should be performed.
2.2
Calcitonin values ≥50 and <100 ng/L
The value will be submitted to the CMC and the investigator will receive guidance from the CMC 
with regards to continuation of trial product. If the value is a screening value the subject cannot be 
randomised and the subject should be referred to a thyroid specialist.
These values were found in 0.18% of a population with thyroid nodular disease published by 
Costante et al.1 Diagnostic evaluation will likely include ultrasound examination and if available 
CONFIDENTIAL


Semaglutide
CONFIDENTIAL
Date:
14 April 2014
Novo Nordisk
Trial ID: NN9535-4114
Version:
1.0
Protocol - Appendix B
Status:
Final
EudraCT No.: NA
Page:
5 of 6
and if there is no contraindication, subjects should undergo a pentagastrin stimulation test (Europe). 
Subjects with positive pentagastrin stimulation tests will be considered to undergo surgery. In the 
US where pentagastrin is not available, thyroid ultrasound and fine needle aspiration biopsy may 
add important clinical information informing the need for surgery.
2.3
Calcitonin values ≥20 and <50 ng/L
The value will be submitted to the CMC. If the subject is a screen failure the subject should be 
referred to a thyroid specialist for further evaluation.
These values are expected to be found in up to 1% of subjects. Based on data from Costante et al1, 
the predictive value calcitonin levels ≥20 and <50 ng/L clinically significant C-cell disease begins 
to fall. However, up to 25% of these subjects had a positive pentagastrin stimulation test. The 
likelihood of having a medullary carcinoma >1 cm with calcitonin in this range is extremely low.
2.4
Calcitonin values ≥10 and <20 ng/L
Confounding factors should be evaluated. If drugs potentially affecting calcitonin can be 
discontinued safely, calcitonin measurement can be repeated after a washout period. Gastrin levels 
return to the normal range by ~ 10 days after stopping proton-pump inhibitors (PPIs).2No further 
actions are needed during the trial if the next calcitonin values remain below 20 ng/L.
If the subject is a screening failure or if the value is the last one taken in the trial, the subject should 
preferably be referred to a thyroid specialist for further evaluation.
These values may be found in ~ 2.5 to 4% of the trial population. Costante et al1had 216 patients in 
this category. One out of 216 patients had a subsequent basal (unstimulated) calcitonin of 33 ng/L, 
and had C-cell hyperplasia at surgery, a lesion of unknown clinical significance. Two other studies 
used a cutoff of CT > 10 ng/L to screen for C-cell disease, but they do not provide sufficient 
information on patients with basal CT >10 and <20 ng/L to allow conclusions.3,4
CONFIDENTIAL


Semaglutide
CONFIDENTIAL
Date:
14 April 2014
Novo Nordisk
Trial ID: NN9535-4114
Version:
1.0
Protocol - Appendix B
Status:
Final
EudraCT No.: NA
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):450-455.
2 
Klinkenberg-Knol EC, Jansen JB, Lamers CB, Nelis F, Meuwissen SG. 
Temporary cessation of long-term maintenance treatment with omeprazole in patients with H2-
receptor-antagonist-resistant reflux oesophagitis. Effects on symptoms, endoscopy, serum gastrin, 
and gastric acid output. Scand J Gastroenterol 1990; 25(11):1144-1150.
3 
Scheuba C, Kaserer K, moritz A, drosten R. Sporadic 
hypercalcitoninemia: clinica and therapeutic consequences. Endocrine Related Cancer 2009; 
16(1):243-253.
4 
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:
28 October 2016
Novo Nordisk
Trial ID: NN9535-4114
Version:
2.0
UTN: U1111-1149-0432
Status:
Final
EudraCT No.: NA
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:
28 October 2016
Novo Nordisk
Trial ID: NN9535-4114
Version:
2.0
UTN: U1111-1149-0432
Status:
Final
EudraCT No.: NA
Page:
2 of 9
Table of Contents
Table of Contents..............................................................................................................................................2
1
Adverse events requiring additional data collection..............................................................................3
1.1
Acute coronary syndrome (myocardial infarction or hospitalisation for unstable angina)............3
1.2
Cerebrovascular event (stroke or TIA) ..........................................................................................3
1.3
Heart failure requiring hospitalisation ...........................................................................................4
1.4
Hypersensitivity reactions..............................................................................................................4
1.5
Neoplasm .......................................................................................................................................5
1.6
Pancreatitis.....................................................................................................................................5
1.7
Renal event ....................................................................................................................................6
1.8
Thyroid disease..............................................................................................................................6
1.9
Hepatic event .................................................................................................................................7
1.10
Diabetic retinopathy.......................................................................................................................7
1.11
Laboratory outlier ..........................................................................................................................8
2
References..................................................................................................................................................9
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
28 October 2016
Novo Nordisk
Trial ID: NN9535-4114
Version:
2.0
UTN: U1111-1149-0432
Status:
Final
EudraCT No.: NA
Page:
3 of 9
1
Adverse events requiring additional data collection
For the following AEs, additional data collection is required and specific event forms must be 
completed in addition to the AE form. In case any of these events fulfil the criteria for an SAE, 
please report accordingly, see Section 12.1.1.
!
Acute coronary syndrome (myocardial infarction or hospitalisation for unstable angina)
!
Cerebrovascular event (stroke or transient ischaemic attack [TIA])
!
Heart failure
!
Hypersensitivity reaction
!
Neoplasm (excluding thyroid neoplasm)
!
Pancreatitis
!
Renal event
!
Thyroid disease (including thyroid neoplasm)
!
Hepatic event
!
Diabetic retinopathy
!
Laboratory outlier
Additional information on a specific form is also required for hypoglycaemic episode and 
medication errors. The hypoglycaemia form is described in protocol section 8.4.4 and medication 
errors are described in protocol section 12.1.3and 8.4.2
1.1
Acute coronary syndrome (myocardial infarction or hospitalisation for unstable 
angina)
If an event of acute coronary syndrome (ranging from unstable angina pectoris to myocardial 
infarction) is observed during the trial, the following additional information must be reported if 
available:
!
Duration of symptoms
!
Changes in ECG
!
Collection of cardiac biomarkers
!
Cardiac imaging
!
Cardiac stress testing
!
Angiography
!
Use of thrombolytic drugs
!
Revascularisation procedures
1.2
Cerebrovascular event (stroke or TIA)
If a cerebrovascular event (e.g. TIA, stroke) is observed during the trial, the following additional 
information must be reported if available:
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
28 October 2016
Novo Nordisk
Trial ID: NN9535-4114
Version:
2.0
UTN: U1111-1149-0432
Status:
Final
EudraCT No.: NA
Page:
4 of 9
!
Type of event (e.g. TIA, stroke)
!
Contributing condition
!
Neurologic signs and symptoms
!
History of neurologic disease
!
Imaging supporting the condition
!
Treatment given for the condition
1.3
Heart failure requiring hospitalisation
If an event of heart failure requiring hospitalisation (admission to an in-patient unit or a visit to an
emergency department that results in at least a 24 hour stay) is applicable for reporting the
following additional information must be reported, if available:
!
Signs and symptoms of heart failure
!
NYHA Class
!
Supportive imaging
!
Supportive laboratory measurements
!
Initiation or intensification of treatment for this condition
1.4
Hypersensitivity reactions
All events of hypersensitivity reactions must be reported and the following additional information 
must be reported if available:
!
Signs and symptoms associated with the event
!
Time of appearance after administration of trial drug
!
Relevant immunological tests performed
!
Treatment given for the reaction
!
Previous history of similar reactions
!
Risk or confounding factors identified
!
Assessments in case of suspicion of hypersensitivity reactions
In case of suspicion of a severe immediate systemic hypersensitivity reaction1to the trial product, 
the subject must be discontinued from trial product but should remain in the trial (see protocol 
section 6.5).
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 
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
28 October 2016
Novo Nordisk
Trial ID: NN9535-4114
Version:
2.0
UTN: U1111-1149-0432
Status:
Final
EudraCT No.: NA
Page:
5 of 9
hypersensitivity reaction, and if this is achieved, a tryptase sample should also be drawn 2 weeks 
after theevent.
Furthermore, a blood sample for assessment of anti-semaglutide IgE antibodies should be drawn 
after 2 weeks and sent to central laboratory (see attachment I). Tryptase concentrations, if 
available, should be included in the specific event form whenreporting the AE.
In case of suspicion of immune complex disease1, the subject must be discontinued from trial 
product but should remain in the trial (see Section 6.5). 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. 
1.5
Neoplasm
All events of neoplasms (excluding thyroid neoplasms, which will be reported under thyroid 
disease) must be reported during the trial and the following additional information must be reported 
if available:
!
Type of neoplasm
!
Symptoms leading to identification of event
!
Diagnostic imaging
!
Pathological examination results
!
Treatment for the event
!
Participation in screening programs
!
Risk factors associated with the event
1.6
Pancreatitis
For all confirmed events of pancreatitis the following additional information must be reported if 
available:
!
Signs and symptoms of pancreatitis
!
Specific laboratory test supporting a diagnosis of pancreatitis:
!
Imaging performed and consistency with pancreatic disease
!
Treatment for and complications of the event
!
Relevant risk factors for pancreatic disease
!
Family history of pancreatitis
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 
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
28 October 2016
Novo Nordisk
Trial ID: NN9535-4114
Version:
2.0
UTN: U1111-1149-0432
Status:
Final
EudraCT No.: NA
Page:
6 of 9
intensity within 30 min, is frequently unbearable, and characteristically persists for more than 24 
hours without relief2.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 pancreatitis2. In general, serum lipase is thought 
to be more sensitive and specific than serum amylase in the diagnosis of acute pancreatitis.
In case of suspicion of acute pancreatitis, the trial product should promptly be interrupted (no 
treatment discontinuation call should be made in IWRS before diagnosis of acute pancreatitis is 
confirmed). Appropriate additional examinations must be performed, including local measurement 
of amylase and lipase.
The diagnosis of acute pancreatitis requires two of the following three features3:
!
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
normal limit
!
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 in IWRS), but should remain in the trial (see Section 6.5).
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
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:
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
28 October 2016
Novo Nordisk
Trial ID: NN9535-4114
Version:
2.0
UTN: U1111-1149-0432
Status:
Final
EudraCT No.: NA
Page:
7 of 9
!
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
1.9
Hepatic event
!
ALT or AST > 5 × UNL and total bilirubin ≤ 2 × UNL
!
ALT or AST > 3 × UNL and total bilirubin > 2 × UNL*
!
Hepatic event leading to trial product discontinuation
If one of the above events is observed during the trial, the following additional information must be 
reported if available:
!
Signs and symptoms associated with the event
!
Risk factors
!
Relevant laboratory test results
!
Diagnostic imaging performed
!
Possible cause(s) of the event
!
Assessments in case of increased levels of aminotransferases
The above mentioned hepatic events should prompt repeat testing (at the central laboratory) 
including ALT, AST, ALP and total bilirubin, and discontinuation of trial product should be 
considered. Thereafter, repeat testing (at the 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.
*Please note that risk of liver injury defined asALT or AST > 3 × UNL and total bilirubin > 2 ×
UNL, where no alternative aetiology exits (Hy’s law), should also be reported as a SAE (important
medical event, according to section 12.1.1).
1.10
Diabetic retinopathy
If an event of diabetic retinopathy (new onset or worsening of) is observed during the trial the 
following additional information should be reported if available on the diabetic retinopathy form: 
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
28 October 2016
Novo Nordisk
Trial ID: NN9535-4114
Version:
2.0
UTN: U1111-1149-0432
Status:
Final
EudraCT No.: NA
Page:
8 of 9
!
Signs and symptoms associated with the event
!
Results of the eye examination
!
!
Treatment for and complications of the event
!
Contributing conditions
1.11
Laboratory outlier
As a minimum but not limiting to the specified cut-offs for the following laboratory parameters a 
value above or below are considered to be clinically significant4 and should be reported as a 
laboratory outlier by completing both an AE and a laboratory outlier form. 
!
Alkaline phosphatase: > 20x ULN
!
Total bilirubin: > 10x ULN
!
Serum creatinine: > 6x ULN
!
Leucocyte count: < 1000/mm3 or 1x109/L
!
Thrombocyte count: < 25000/mm3 or 25x109/L
!
Total calcium (serum corrected): <1.5 mmol/L or > 3.4 mmol/L
!
Potassium:< 2.5 mmol/L or > 7 mmol/L
!
Sodium: < 120 mmol/L or > 160  mmol/L
!
Creatine Kinase (CK) > 10x ULN
If a laboratory outlier is observed, the following additional information must be reported, if 
available:
!
Signs and symptoms associated with the event
!
Risk factors
!
Relevant laboratory test results
!
Treatment for the event
!
Possible cause(s) of the event
Furthermore, repeated laboratory assessments should be obtained at the central laboratory until the 
value is within the normal range or back to baseline values.
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
28 October 2016
Novo Nordisk
Trial ID: NN9535-4114
Version:
2.0
UTN: U1111-1149-0432
Status:
Final
EudraCT No.: NA
Page:
9 of 9
2
References
1.
Food and Drug Administration. Guidance for Industry:Immunogenicity Assessment for
Therapeutic Protein Products. 8/2015 2015.
2.
Banks PA, Freeman ML, Practice Parameters Committee of the American College of
Gastroenterology. Practice guidelines in acute pancreatitis. Am J Gastroenterol.
2006;101(10):2379-400.
3.
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.
4.
National Cancer Institute. Common Terminology Criteria for Adverse Events v4.03 (NIH
publication # 09-7473). http://evsncinihgov/ftp1/CTCAE/CTCAE_403_2010-06-
14_QuickReference_5x7pdf. 2010.
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
09 December 2016
Novo Nordisk
Trial ID: NN9535-4114
Version:
3.0
UTN: U1111-1149-0432
Status:
Final
EudraCT No.: NA
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:
09 December 2016
Novo Nordisk
Trial ID: NN9535-4114
Version:
3.0
UTN: U1111-1149-0432
Status:
Final
EudraCT No.: NA
Page:
2 of 9
Table of Contents
Table of Contents..............................................................................................................................................2
1
Adverse events requiring additional data collection..............................................................................3
1.1
Acute coronary syndrome (myocardial infarction or hospitalisation for unstable angina)............3
1.2
Cerebrovascular event (stroke or TIA) ..........................................................................................3
1.3
Heart failure requiring hospitalisation ...........................................................................................4
1.4
Hypersensitivity reactions..............................................................................................................4
1.5
Neoplasm .......................................................................................................................................5
1.6
Pancreatitis.....................................................................................................................................5
1.7
Renal event ....................................................................................................................................6
1.8
Thyroid disease..............................................................................................................................6
1.9
Hepatic event .................................................................................................................................7
1.10
Diabetic retinopathy.......................................................................................................................7
1.11
Laboratory outlier ..........................................................................................................................8
2
References..................................................................................................................................................9
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
09 December 2016
Novo Nordisk
Trial ID: NN9535-4114
Version:
3.0
UTN: U1111-1149-0432
Status:
Final
EudraCT No.: NA
Page:
3 of 9
1
Adverse events requiring additional data collection
For the following AEs, additional data collection is required and specific event forms must be 
completed in addition to the AE form. In case any of these events fulfil the criteria for an SAE, 
please report accordingly, see Section 12.1.1.
!
Acute coronary syndrome (myocardial infarction or hospitalisation for unstable angina)
!
Cerebrovascular event (stroke or transient ischaemic attack [TIA])
!
Heart failure
!
Hypersensitivity reaction
!
Neoplasm (excluding thyroid neoplasm)
!
Pancreatitis
!
Renal event
!
Thyroid disease (including thyroid neoplasm)
!
Hepatic event
!
Diabetic retinopathy
!
Laboratory outlier
Additional information on a specific form is also required for hypoglycaemic episode and 
medication errors. The hypoglycaemia form is described in protocol section 8.4.4 and medication 
errors are described in protocol section 12.1.3 and 8.4.2
1.1
Acute coronary syndrome (myocardial infarction or hospitalisation for unstable 
angina)
If an event of acute coronary syndrome (ranging from unstable angina pectoris to myocardial 
infarction) is observed during the trial, the following additional information must be reported if 
available:
!
Duration of symptoms
!
Changes in ECG
!
Collection of cardiac biomarkers
!
Cardiac imaging
!
Cardiac stress testing
!
Angiography
!
Use of thrombolytic drugs
!
Revascularisation procedures
1.2
Cerebrovascular event (stroke or TIA)
If a cerebrovascular event (e.g. TIA, stroke) is observed during the trial, the following additional 
information must be reported if available:
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
09 December 2016
Novo Nordisk
Trial ID: NN9535-4114
Version:
3.0
UTN: U1111-1149-0432
Status:
Final
EudraCT No.: NA
Page:
4 of 9
!
Type of event (e.g. TIA, stroke)
!
Contributing condition
!
Neurologic signs and symptoms
!
History of neurologic disease
!
Imaging supporting the condition
!
Treatment given for the condition
1.3
Heart failure requiring hospitalisation
If an event of heart failure requiring hospitalisation (admission to an in-patient unit or a visit to an
emergency department that results in at least a 24 hour stay) is applicable for reporting the
following additional information must be reported, if available:
!
Signs and symptoms of heart failure
!
NYHA Class
!
Supportive imaging
!
Supportive laboratory measurements
!
Initiation or intensification of treatment for this condition
1.4
Hypersensitivity reactions
All events of hypersensitivity reactions must be reported and the following additional information 
must be reported if available:
!
Signs and symptoms associated with the event
!
Time of appearance after administration of trial drug
!
Relevant immunological tests performed
!
Treatment given for the reaction
!
Previous history of similar reactions
!
Risk or confounding factors identified
!
Assessments in case of suspicion of hypersensitivity reactions
In case of suspicion of a severe immediate systemic hypersensitivity reaction1 to the trial product, 
the subject must be discontinued from trial product but should remain in the trial (see protocol 
section 6.5).
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 
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
09 December 2016
Novo Nordisk
Trial ID: NN9535-4114
Version:
3.0
UTN: U1111-1149-0432
Status:
Final
EudraCT No.: NA
Page:
5 of 9
hypersensitivity reaction, and if this is achieved, a tryptase sample should also be drawn 2 weeks 
after the event.
Furthermore, a blood sample for assessment of anti-semaglutide IgE antibodies should be drawn 
after 2 weeks and sent to central laboratory (see attachment I). Tryptase concentrations, if available, 
should be included in the specific event form when reporting the AE.
In case of suspicion of immune complex disease1, the subject must be discontinued from trial 
product but should remain in the trial (see Section 6.5). 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. 
1.5
Neoplasm
All events of neoplasms (excluding thyroid neoplasms, which will be reported under thyroid 
disease) must be reported during the trial and the following additional information must be reported 
if available:
!
Type of neoplasm
!
Symptoms leading to identification of event
!
Diagnostic imaging
!
Pathological examination results
!
Treatment for the event
!
Participation in screening programs
!
Risk factors associated with the event
1.6
Pancreatitis
For all confirmed events of pancreatitis the following additional information must be reported if 
available:
!
Signs and symptoms of pancreatitis
!
Specific laboratory test supporting a diagnosis of pancreatitis:
!
Imaging performed and consistency with pancreatic disease
!
Treatment for and complications of the event
!
Relevant risk factors for pancreatic disease
!
Family history of pancreatitis
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 
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
09 December 2016
Novo Nordisk
Trial ID: NN9535-4114
Version:
3.0
UTN: U1111-1149-0432
Status:
Final
EudraCT No.: NA
Page:
6 of 9
intensity within 30 min, is frequently unbearable, and characteristically persists for more than 24 
hours without relief2.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 pancreatitis2. In general, serum lipase is thought 
to be more sensitive and specific than serum amylase in the diagnosis of acute pancreatitis.
In case of suspicion of acute pancreatitis, the trial product should promptly be interrupted (no 
treatment discontinuation call should be made in IWRS before diagnosis of acute pancreatitis is 
confirmed). Appropriate additional examinations must be performed, including local measurement 
of amylase and lipase.
The diagnosis of acute pancreatitis requires two of the following three features3:
!
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 
normal limit
!
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 in IWRS), but should remain in the trial (see Section 6.5).
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
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:
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
09 December 2016
Novo Nordisk
Trial ID: NN9535-4114
Version:
3.0
UTN: U1111-1149-0432
Status:
Final
EudraCT No.: NA
Page:
7 of 9
!
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
1.9
Hepatic event
!
ALT or AST > 5 × UNL and total bilirubin ≤ 2 × UNL
!
ALT or AST > 3 × UNL and total bilirubin > 2 × UNL*
!
Hepatic event leading to trial product discontinuation
If one of the above events is observed during the trial, the following additional information must be 
reported if available:
!
Signs and symptoms associated with the event
!
Risk factors
!
Relevant laboratory test results
!
Diagnostic imaging performed
!
Possible cause(s) of the event
!
Assessments in case of increased levels of aminotransferases
The above mentioned hepatic events should prompt repeat testing (at the central laboratory) 
including ALT, AST, ALP and total bilirubin, and discontinuation of trial product should be 
considered. Thereafter, repeat testing (at the 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.
*Please note that risk of liver injury defined as ALT or AST > 3 × UNL and total bilirubin > 2 × 
UNL, where no alternative aetiology exits (Hy’s law), should also be reported as a SAE (important 
medical event, according to section 12.1.1).
1.10
Diabetic retinopathy
If an event of diabetic retinopathy (new onset or worsening of) is observed during the trial the 
following additional information should be reported if available on the diabetic retinopathy form: 
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
09 December 2016
Novo Nordisk
Trial ID: NN9535-4114
Version:
3.0
UTN: U1111-1149-0432
Status:
Final
EudraCT No.: NA
Page:
8 of 9
!
Signs and symptoms associated with the event
!
Results of the eye examination
!
Treatment for and complications of the event
!
Contributing conditions
1.11
Laboratory outlier
As a minimum but not limiting to the specified cut-offs for the following laboratory parameters a 
value above or below are considered to be clinically significant4 and should be reported as a 
laboratory outlier by completing both an AE and a laboratory outlier form. 
!
Alkaline phosphatase: > 20x ULN
!
Total bilirubin: > 10x ULN 
!
Serum creatinine: > 6x ULN 
!
Leucocyte count: < 1000/mm3 or 1x109/L
!
Thrombocyte count: < 25000/mm3 or 25x109/L
!
Total calcium (serum corrected): <1.5 mmol/L or > 3.4 mmol/L
!
Potassium:< 2.5 mmol/L or > 7 mmol/L
!
Sodium: < 120 mmol/L or > 160  mmol/L
!
Creatine Kinase (CK) > 10x ULN
If a laboratory outlier is observed, the following additional information must be reported, if 
available:
!
Signs and symptoms associated with the event
!
Risk factors
!
Relevant laboratory test results
!
Treatment for the event
!
Possible cause(s) of the event
Furthermore, repeated laboratory assessments should be obtained at the central laboratory until the 
value is within the normal range or back to baseline values.
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
09 December 2016
Novo Nordisk
Trial ID: NN9535-4114
Version:
3.0
UTN: U1111-1149-0432
Status:
Final
EudraCT No.: NA
Page:
9 of 9
2
References
1.
Food and Drug Administration. Guidance for Industry:Immunogenicity Assessment for 
Therapeutic Protein Products. 8/2015 2015.
2.
Banks PA, Freeman ML, Practice Parameters Committee of the American College of 
Gastroenterology. Practice guidelines in acute pancreatitis. Am J Gastroenterol. 
2006;101(10):2379-400.
3.
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.
4.
National Cancer Institute. Common Terminology Criteria for Adverse Events v4.03 (NIH 
publication # 09-7473). http://evsncinihgov/ftp1/CTCAE/CTCAE_403_2010-06-
14_QuickReference_5x7pdf. 2010.
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:
Semaglutide s.c (Ozempic®)
Trial ID: NN9535-4114
Clinical Trial Report
Appendix 16.1.1
22 August 2019
1.0
Final
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
28 October 2016
Novo Nordisk
Trial ID: NN9535-4114-
Version:
1.0
UTN:U1111-1149-0432
Status:
Final
EudraCT No.: NA
Page:
1 of 14
Protocol Amendment
no 1
to Protocol, final version 1.0
dated 14 April 2014
Trial ID:NN9535-4114
SUSTAIN – CHINA MRCT
Efficacy and safety of semaglutide once-weekly versus sitagliptin once daily as add-on to 
metformin in subjects with type 2 diabetes
Trial phase: 3a
Applicable to all countries
Amendment originator:
Semagutide Diabetes & Diabetes Outcomes
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:
28 October 2016
Novo Nordisk
Trial ID: NN9535-4114-
Version:
1.0
UTN:U1111-1149-0432
Status:
Final
EudraCT No.: NA
Page:
2 of 14
Table of Contents   
Page
Table of Contents..............................................................................................................................................2
1
Introduction including rationale for the protocol amendment.............................................................3
2
Changes......................................................................................................................................................3
2.1
Minor editorial changes throughout the protocol due to new naming standards and/or
changes in the protocol template....................................................................................................3
2.2
Flow chart updates (section 2).......................................................................................................3
2.3
Background information and rationale for the trial (section 3)......................................................4
2.4
Supportive secondary endpoints (section 4.2.2.2) .........................................................................4
2.5
Trial design figure (section 5, Figure 5-1).....................................................................................4
Rationale: the figure has been re-drawn for better clarity regarding the dose escalations and for 
easier understanding regarding the trial.........................................................................................4
2.6
Inclusion criteria (section 6.2) .......................................................................................................4
2.7
Exclusion criteria (section 6.3) ......................................................................................................4
2.8
Discontinuation of trial product (section 6.5.1).............................................................................4
2.9
Milestones (section 7)....................................................................................................................4
2.10
Methods and assessments (section 8) ............................................................................................4
2.11
Trial Supplies (section 9)...............................................................................................................5
2.12
Interactive voice/web response system (section 10)......................................................................5
2.13
Adverse events and technical complaints and pregnancies (section 12)........................................5
2.14
Statistical considerations (section 17)............................................................................................6
2.15
References (section 27)..................................................................................................................7
3
Changes to the SI/IC.................................................................................................................................8
3.1
Introduction section .......................................................................................................................8
3.2
Purpose of the trial.........................................................................................................................8
3.3
Procedures if you participate in the trial........................................................................................8
3.4
Overview of the procedures.........................................................................................................10
3.5
Premature discontinuation of trial product ..................................................................................11
3.6
Stop participating in the trial........................................................................................................11
3.7
In case of thyroid surgery during the trial....................................................................................12
3.8
Information about the treatment procedure..................................................................................12
3.9
Information about the Risks/Benefits ..........................................................................................12
3.10
Confidential information..............................................................................................................12
3.11
Short summary.............................................................................................................................13
3.12
Informed Consent form................................................................................................................13
3.13
Signature page..............................................................................................................................13
3.14
Signature page to allow your trial doctor to contact your family doctor at end of trial...............13
4
Changes to SI/IC for male partner........................................................................................................14
4.1
Information about adverse effects on the developing offspring during pregnancy in animal 
studies ..........................................................................................................................................14
4.2
Informed consent form.................................................................................................................14
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
28 October 2016
Novo Nordisk
Trial ID: NN9535-4114-
Version:
1.0
UTN:U1111-1149-0432
Status:
Final
EudraCT No.: NA
Page:
3 of 14
1
Introduction including rationale for the protocol amendment
The CFDA approval of the final protocol version 1.0, dated 14 April 2014 were approved on 28 
September 2016. Since the preparation of the trial protocol in 2014, new information regarding the 
trial products is known and also some of the Novo Nordisk standards and processes have evolved 
and updated, which are the primary reasons for preparing the amendment and updating the protocol. 
Secondly, this is in accordance with the feed-back received from CFDA, refer to below text copied 
from the approval letter, optimisation of the protocol is allowed:
“Before the clinical trial, clinical research organization should further refine and optimize the 
protocol, pay attention to the exposed and potential safety risk of the product, and make a risk 
management plan.”
While amending the protocol, special attention has been on patient safety and reporting, data quality 
and GCP compliance. This means, that minor refinements have been made throughout the protocol 
with the purpose of improving data quality and clarifying issues, where applicable.
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
Minor editorial changes throughout the protocol due to new naming standards and/or 
changes in the protocol template
Rationale: Since the approval of this protocol the protocol template has been extensively updated 
included improved explanation of several procedures. Accordingly throughout the protocol changes 
have been made in order to incorporate some of these changes
2.2
Flow chart updates (section 2)
Rationale: flow chart has been updated to align to the CDISC terminology. Clarification on the 
completion of end of trial and end of treatment forms in eCRF. Eye examination has been updated 
to also taken at end of treatment visit(s) V9 and V9A in line with FDA recommendations. Training 
in trial product and pen handling has been amended to coincide with dose escalation. Fasting 
definition has been updated to project standard definition.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
28 October 2016
Novo Nordisk
Trial ID: NN9535-4114-
Version:
1.0
UTN:U1111-1149-0432
Status:
Final
EudraCT No.: NA
Page:
4 of 14
2.3
Background information and rationale for the trial (section 3)
Rationale: Since the protocol was written in 2014, a phase 3a program on semaglutide s.c. has been 
completed and update information has been included into this section. Sitigliptin has also had some 
updated information since the protocol was written.
2.4
Supportive secondary endpoints (section 4.2.2.2)
Rationale: Eye examination added as supportive secondary safety endpoint
2.5
Trial design figure (section 5, Figure 5-1)
Rationale: the figure has been re-drawn for better clarity regarding the dose escalations and for 
easier understanding regarding the trial.
2.6
Inclusion criteria (section 6.2)
Rationale: Inclusion criteria updated to have Korean specific requirement regarding age.
2.7
Exclusion criteria (section 6.3)
Rationale: Exclusion criteria 14 updated to include dilated fundoscopy/fundus photography 
performed within the past 90 days.
2.8
Discontinuation of trial product (section 6.5.1)
Rationale: Include discontinuation criteria regarding calcitonin, safety concern and simultaneous 
participation in other clinical trials.
2.9
Milestones (section 7)
Rationale: Updated to be in line with new planned dates.
2.10
Methods and assessments (section 8)
Rationale: In this section the following have been updated:
!
Screening visit (section 8.1.1) updated to remove the requirement for subjects to 
demonstrate ability and willingness  to self-inject with a semaglutide placebo test pen as test 
pens for human use is not used in the rest of the SUSTAIN project.
!
Diabetes history and diabetes complication (section 8.2.2) updated to reflect the correct form
in the standard templates in the eCRF.
!
Concomitant medication (section 8.2.4) updated to reflect the correct form in the standard 
templates in the eCRF.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
28 October 2016
Novo Nordisk
Trial ID: NN9535-4114-
Version:
1.0
UTN:U1111-1149-0432
Status:
Final
EudraCT No.: NA
Page:
5 of 14
!
Childbearing potential (section 8.2.6) updated in relation to childbearing potential added.
!
Medication error (section 8.4.2) updated to current classification.
!
Adverse events requiring additional data collection (section 8.4.3) updated from old 
terminology (MESI).
!
Hypoglycemic episodes (section 8.4.4) updated to current classification.
!
Eye examination (section 8.4.6) section updated to current project standards and moved to 
assessment for safety (section 8.4) due to the fact that eye examination will now be 
performed at EOT and has been added as a safety endpoint
!
Calcitonin (section 8.5.2.4) CMC no longer required.
!
Pregnancy test (section 8.5.2.5) updated with better description.
!
In case of specific safety issues (section 8.8) section has been deleted as the description is 
already contained in appendix B and central pathologist for thyroidectomy is no longer used
2.11
Trial Supplies (section 9)
Rationale: semaglutide placebo test pen has been removed  as subjects will no longer demonstrate 
ability and willingness  to self-inject with a semaglutide placebo test pen as test pens for human use 
is not used in the rest of the SUSTAIN project.
2.12
Interactive voice/web response system (section 10)
Rationale: detail regarding using barcode scanner is added.
2.13
Adverse events and technical complaints and pregnancies (section 12)
Rationale: In this section the following have been updated:
!
Serious adverse event (section 12.1.1) definitions that always must be added as SAEs added 
(including Hy’s law).
!
Medications errors (section 12.1.3) updated to current standards.
!
Adverse events requiring additional data collection (section 12.1.4) section updated from 
older terminology and diabetic retinopathy, laboratory outlier and hepatic event added 
according to current project standards.
!
Events adjudication committee (section 12.7.2) updated to current project definitions.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
28 October 2016
Novo Nordisk
Trial ID: NN9535-4114-
Version:
1.0
UTN:U1111-1149-0432
Status:
Final
EudraCT No.: NA
Page:
6 of 14
!
Calcitonin monitoring committee (section 12.7.3) deleted as no longer required.
2.14
Statistical considerations (section 17)
Rationale: In this section the following have been updated
!
Definitions of treatment discontinuation and withdrawal from trial have been clarified and 
specified according to current project standards.
!
FAS and SAS (section 17.2) updated to current project definitions according to current
project standards.
!
The concept of observation periods has been introduced to further clarify data selections for 
all analyses. The observation periods specified include: an in-trial,   an on-treatment, and an 
on-treatment without rescue medication observation period (section 17.2), all in line with 
current project standards.
!
Specified observation periods added to clarify the data foundation for analyses (section 17.3)
according to current project definitions.
!
Number of imputations in the multiple imputation analysis has been increased from 100 to 
500 according to current project decision. This has been done based on experience obtained 
from the completed phase 3a trials to further reduce the sample variation in analysis results.
!
Due to that patient-reported outcomes (PRO) only will be assessed at baseline and at end-of-
trial the analyses model for the PRO outcomes has been changed from a MMRM to an
ANCOVA. In contrary, due to that the SMPG 7-point profile also will be assessed at an 
intermediate trial visit the analysis has been changed from an ANCOVA to a MMRM 
(section 17.4.2.2). Both changes are in accordance with current project standards.
!
Evaluation of safety endpoints (section 17.4.2.2) have been clarified in context of the 
specified observation periods and, hence, aligned with the current project standards.
!
Eye examination (section 17.4.2.2) added to align with section 4 and the additional safety 
assessment included.
!
The definition of treatment emergent adverse events and hypoglycaemic episodes has been 
clarified in context of the on-treatment observation period and, hence, aligned with the 
current project definitions (section 17.4.2.2).
!
Novo Nordisk classification of hypoglycaemia (section 17.4.2.2, Figure 17-1) figure 
describing Novo Nordisk classification of hypoglycaemia has been added.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
28 October 2016
Novo Nordisk
Trial ID: NN9535-4114-
Version:
1.0
UTN:U1111-1149-0432
Status:
Final
EudraCT No.: NA
Page:
7 of 14
2.15
References (section 27)
Rationale: References updated according to the update of the protocol.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
28 October 2016
Novo Nordisk
Trial ID: NN9535-4114-
Version:
1.0
UTN:U1111-1149-0432
Status:
Final
EudraCT No.: NA
Page:
8 of 14
3 Changes to the SI/IC
3.1
Introduction section
Rationale: 
New country allocation has been approved by GTA since protocol was approved in 2014.
Impact:
The trial is planned to include a total of approximately 1050 subjects in 56 countries.
3.2
Purpose of the trial
Rationale:
Clinical trials investigating efficacy have been completed since protocol was approved in 2014.
Impact:
Some clinical trials have already been completed to investigate the efficacy and safety of 
semaglutide so far. 
3.3
Procedures if you participate in the trial
Physical examination:
Rationale: 
To align with the CDISC terminology.
Impact:
You will be asked some general questions about your health, medical conditions, smoking habits 
tobacco use and your current medication (other medication than the trial products) and previous 
diabetes treatment.
Rationale:
Section was updated to be in alignment with Semaglutide project standards on eye examination. 
Impact:
You will also go through a general examination of your body, have a heart examination 
(electrocardiogram) and an eye examination (fundus photography or dilated fundoscopy) 
performed. 
Fasting visits:
Rationale:
To align with the fasting requirement for the other SUSTAIN protocols
Impact:
Fasting is defined as having consumed only water within the last 6 hours prior to the visit since 
midnight. Trial products and any other anti-diabetic medication which should be taken with or after 
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
28 October 2016
Novo Nordisk
Trial ID: NN9535-4114-
Version:
1.0
UTN:U1111-1149-0432
Status:
Final
EudraCT No.: NA
Page:
9 of 14
a meal should be withheld on the day of the visit until blood sampling hasve been taken. Other 
medication should be taken as prescribed.
Body measurements:
Rationale:
Wrong visit number
Impact:
Height will be measured only once at visit 12, weight and waist circumference will be measured 
from visit 2 and forward.
Blood samples:
Rationale:
Amount of blood drawn was not defined in the protocol approved in 2014.
Impact:
You will have blood samples drawn from the arm and approximately xxx130 ml blood will be 
drawn in total for all visits. 
Pregnancy test:
Rationale:
To align with the phrasing in other SUSTAIN protocols
Impact:
If you are female of childbearing age potential the blood sample will also include a pregnancy test.
Urine samples:
Rationale:
Deletion of typo and aligning wording to other SUSTAIN protocols
Impact:
The urine will be used to access your kidney function. You will receive material to collect the first 
morning your urine at home and bring it to the clinic. During the trial urine pregnancy tests must be 
performed at home if you are female of childbearing age potential and a menstrual period is missed 
or as required by local law.
Eye examination:
Rationale: 
Eye examination added as supportive secondary safety endpoint and will be performed at EOT. 
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
28 October 2016
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Trial ID: NN9535-4114-
Version:
1.0
UTN:U1111-1149-0432
Status:
Final
EudraCT No.: NA
Page:
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Impact:
An eye examination called fundosphotography or dilated fundoscopy should be performed. If you 
have a recent fundoscopy or fundosphotography eye examination performed within 90 days prior to 
visit 2 this will be acceptable if the results are available for evaluation at visit 2. 
An eye examination will also be performed at your end of treatment visit. 
Self measured plasma blood sugar (named SMPG 7 point profile):
Rationale:
Wrong listing of visit numbers. 
Impact:
You will also be asked to measure your own blood sugar values seven times (see Diaries below) 
prior to visit 2, visit 7 and visit 9 and record the values in a diary.
Diaries:
Rationale:
To be aligned with update of protocol and diaries. 
Impact:
!
Date, time and dose and site of first dose of injection trial products (injection and tablet)
!
Date, time and dose of first tablet
3.4
Overview of the procedures
Rationale:
To align with updates of protocol and CDISC terminology.
Impact:
Trial Periods
Treatment period
End of 
Treat-
ment
Follow 
Up
End of 
Treatment 
premature 
disconti-
nuation
Follow Up
premature 
disconti-
nuation
Visit (V) or Phone (P) 
number
V
1
V
2
V
3
P
4
V
5
V
6
V
7
V
8
V9
V10
V9A
V10A
Weeks in relation to visit 
2
-2
0
4
6
8
12
16
23
30
35
Fasting visits
x
x
x
x
x
x
x
x
x
x
Informed consent
x
Dispense trial identity card
x
Physical examination
x
x
x
Randomisation 
x
Medical History 
x
Diagnosis of diabetes and 
treatment history Diabetes 
history and diabetes 
complication
x
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
28 October 2016
Novo Nordisk
Trial ID: NN9535-4114-
Version:
1.0
UTN:U1111-1149-0432
Status:
Final
EudraCT No.: NA
Page:
11 of 14
Trial Periods
Treatment period
End of 
Treat-
ment
Follow 
Up
End of 
Treatment 
premature 
disconti-
nuation
Follow Up
premature 
disconti-
nuation
Visit (V) or Phone (P) 
number
V
1
V
2
V
3
P
4
V
5
V
6
V
7
V
8
V9
V10
V9A
V10A
Concomitant medication
x
x
x
x
x
x
x
x
x
x
x
x
Smoking habits Tobacco 
use
x
Body measurements
x
x
x
x
x
x
x
x
Vital signs
x
x
x
x
x
x
x
x
x
ECG
x
x
x
x
x
Blood samples
x
x
x
x
x
x
x
x
x
x
x
Pregnancy test
x
x
x
x
x
x
x
x
x
x
x
Urinalysis 
x
x
x
x
Eye examination
x
x
x
SMPG 7 point profile  
x
x
x
x
Adverse events
x
x
x
x
x
x
x
x
x
x
x
2 questionnaires
x
x
x
Supply & instruction in BG 
meter use
x
Training in trial product and 
pen handling
x
x
x
x
Receive trial products
x
x
x
Return trial products
x
x
x
x
Receive diary and 
instruction for use
x
x
x
x
x
x
x
x
x
x
x
3.5
Premature discontinuation of trial product
Rationale:
To clarify the term discontinuation. 
Impact: 
In addition to those visits you are encouraged to it is important that you attend the scheduled visits
approximately 30 and 35 weeks after first dose of trial product. 
3.6
Stop participating in the trial 
Rationale:
Text was deleted, as it was misleading.
Impact:
If for any reason you decide to stop your participation in the trial (see section 1.8), you will need to 
inform the trial staff who will encourage you to come in for the end of treatment visit as soon as 
possible and the follow-up visit 5 weeks later for safety evaluation., and also encourage you to 
continue with the scheduled vists.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
28 October 2016
Novo Nordisk
Trial ID: NN9535-4114-
Version:
1.0
UTN:U1111-1149-0432
Status:
Final
EudraCT No.: NA
Page:
12 of 14
3.7
In case of thyroid surgery during the trial
Rationale:
It has been agreed not to collect information on thyroid surgery during the trial.
Impact:
If for any reason you are scheduled to have an operation to remove your thyroid gland or part of it 
during the trial, you need to inform your trial doctor well in advance. You will be asked to consent 
to another subject information form to allow for additional safety assessment to be made. 
Samples of the removed thyroid tissue will be investigated. Such tissue samples are routinely made 
after operations of the thyroid gland of the hospital where the operation is performed. The tissue 
samples will allow specialists at your hospital to examine the thyroid cells under the microscope in 
order to determine the exact diagnosis. The tissue samples will be sent to another expert for a 
second opinion. When the tissue samples have been examined they will be sent back to the hospital 
where you had your operation. Your trial doctor will be informed about the findings of both the 
hospital specialist and the expert and you will be able to discuss the results with him/her. 
3.8
Information about the treatment procedure
Rationale:
Test pens will not be provided. 
Impact:
If you do not have experience with injecting medicine yourself, you will have the option to try this 
at the trial clinic with a test pen containing semaglutide placebo.
3.9
Information about the Risks/Benefits 
Rationale:
To align with the newest MMST for Semaglutide, which has been updated to version 11.0.
Impact:
The entire section on Semaglutide was re-written in alignment with the MMST.
The entire section on Sitagliptin was re-written according to newest safety text provided by Global 
Safety representative.
3.10
Confidential information
Rationale: 
To meet local requirements to obtain export license of samples out of the country. 
Impact: 
In order to standardise the sample analysis used in this trial, some samples including yours, will be 
shipped to a special laboratory outside of your country. This is to ensure the comparability of 
results from subjects at all investigational sites involved in the trial.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
28 October 2016
Novo Nordisk
Trial ID: NN9535-4114-
Version:
1.0
UTN:U1111-1149-0432
Status:
Final
EudraCT No.: NA
Page:
13 of 14
3.11
Short summary
Rationale:
Text has been changed, as it was misleading.  
Impact:
Your discontinuation withdrawal will not affect the standard of care that you receive.
3.12
Informed Consent form
Rationale:
To allow a legally acceptable/authorised representative to consent for the subject. 
To ensure subject related information can be obtained from other sources than trial doctor. 
Impact:
!
I or my legally acceptable/authorised representative will receive a copy of this subject 
information/informed consent form signed and dated to bring home.
!
I accept that the trial doctor may obtain trial relevant information from other sources, for 
example my primary physician (family doctor).
3.13
Signature page
Rationale:
To allow a legally acceptable/authorised representative to consent for the subject.
Impact:
Impartial Witness and/or legal representative, if applicable:
Date:
Signature:
Name 
(print):
3.14
Signature page to allow your trial doctor to contact your family doctor at end of trial
Rationale:
This part was moved to the Informed Consent Form.
Impact:
The entire section has been deleted.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
28 October 2016
Novo Nordisk
Trial ID: NN9535-4114-
Version:
1.0
UTN:U1111-1149-0432
Status:
Final
EudraCT No.: NA
Page:
14 of 14
4
Changes to SI/IC for male partner
4.1
Information about adverse effects on the developing offspring during pregnancy in 
animal studies
Rationale:
Safety text on Semaglutide has been updated
Impact:
In animal studies, semaglutide caused reduced food intake and less weight gain during pregnancy.
In rats, bone and blood vessel abnormalities were observed in the offspring at doses below a 
normal human dose. In rabbits and monkeys, a possible link between an excessive weight loss of the
pregnant animal and observations of early pregnancy loss and foetal abnormalities could not be
excluded. The potential risk for an unborn human child is unknown and therefore pregnancy should
be avoided when taking semaglutide.
The effect of semaglutide on fertility and foetal development has been investigated in rats and 
monkeys. In both species exposure to semaglutide caused reduction of the amount of food eaten and 
weight gained by the mother during pregnancy. The monkey studies gave no reason to suspect an 
effect of semaglutide on foetal development in monkeys, but there was a possible link between the 
mother’s loss of body weight and an increased risk for early pregnancy loss. In rats, bone and major 
blood vessel abnormalities were observed in the offspring at doses below a normal human dose. The 
potential risk to humans is unknown and therefore pregnancy should be avoided when taking 
semaglutide.
4.2
Informed consent form
Rationale:
To allow a legally acceptable/authorised representative to consent for the subject.
Impact:
!
I or my legally acceptable/authorised representative will receive a copy of this subject 
information/informed consent form signed and dated
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
09 December 2016
Novo Nordisk
Trial ID: NN9535-4114
Version:
2.0
UTN: U1111-1149-0432
Status:
Final
EudraCT No.: NA
Page:
1 of 5
Protocol Amendment
no 2
to Protocol, final version 2.0
dated 28 October 2016
Trial ID:NN9535-4114
SUSTAIN – CHINA MRCT
Efficacy and safety of semaglutide once-weekly versus sitagliptin once daily as 
add-on to metformin in subjects with type 2 diabetes
Trial phase: 3a
Applicable to all countries 
Amendment originator:
Semaglutide Diabetes & Diabetes Outcomes
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol Amendment
CONFIDENTIAL
Date:
09 December 2016
Novo Nordisk
Trial ID: NN9535-4114
Version:
2.0
UTN: U1111-1149-0432
Status:
Final
EudraCT No.: NA
Page:
2 of 5
Table of Contents   
Page
Table of Contents..............................................................................................................................................2
1
Introduction including rationale for the protocol amendment.............................................................3
2
Changes......................................................................................................................................................3
2.1
Milestones (section 7)....................................................................................................................3
2.2
Biochemistry (section 8.5.2.2).......................................................................................................3
2.3
Randomisation procedure and breaking of blinded codes (section 11) .........................................3
2.4
Statistical considerations (section 17)............................................................................................4
2.5
Primary analysis (section 17.3)......................................................................................................4
3
Changes to the SI/IC.................................................................................................................................5
3.1
Financial Issues (section 4)............................................................................................................5
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
09 December 2016
Novo Nordisk
Trial ID: NN9535-4114
Version:
2.0
UTN: U1111-1149-0432
Status:
Final
EudraCT No.: NA
Page:
3 of 5
1
Introduction including rationale for the protocol amendment
Protocol amendment and protocol version 2.0 were finalised on 28 October 2016. On 31 October 
GTA finalised reallocation of 60 subjects from China to Hong Kong and Taiwan. The subjects will 
be grouped together with Chinese subjects in the stratification and analysis. The protocol 
amendment has been created to specify this information in the protocol. 
Additionally, minor refinements have been made and insurance text in SI/IC has been updated.   
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
Milestones (section 7)
Rationale: 
Timelines updated to include visit windows. 
Impact: 
Planned date for last patient last visit (LPLV): 
1905-Nov-2018
2.2
Biochemistry (section 8.5.2.2)
Rationale:
Added to specify that GFR, estimated (per MDRD formula), should be calculated in this trial. 
Added to be in alignment with exclusion criteria 11.
Impact:
!
Creatinine, including eGFR (per MDRD formula)
2.3
Randomisation procedure and breaking of blinded codes (section 11)
Rationale:
To clarify that the subjects allocated to Taiwan and Hong Kong will be grouped together with the 
Chinese subjects in the stratification, to support the regulatory submission to Chinese HA (CFDA). 
Impact: 
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
09 December 2016
Novo Nordisk
Trial ID: NN9535-4114
Version:
2.0
UTN: U1111-1149-0432
Status:
Final
EudraCT No.: NA
Page:
4 of 5
Randomisation will be stratified by country. When grouping or analysing data by country, subjects 
from Hong Kong and Taiwan will be grouped with Chinese subjects if not otherwise specified.
2.4
Statistical considerations (section 17)
Rationale:
To clarify that the subjects allocated to Taiwan and Hong Kong will be grouped together with the 
Chinese subjects, to support the regulatory submission to Chinese HA (CFDA). 
Impact: 
Non-inferiority between two treatments will be evaluated by comparing the upper limit of the 
associated two-sided 95% confidence interval for the difference with the pre-defined non-inferiority 
margin.
When grouping or analysing data by country, subjects from Hong Kong and Taiwan will be 
grouped with Chinese subjects if not otherwise specified.
2.5
Primary analysis (section 17.3) 
Rationale:
To clarify that the subgroup analysis will be focused on Chinese and Korean subjects to support
NDA submission in China and Korea. 
Impact:
Chinese/Korean subgroup analyses
A number of sSubgroup analyses for the primary endpoint and the confirmatory secondary endpoint
by country will be performed by country with the aim to assess the treatment effect in the individual 
countries including China and Korea. They will be performed in a combined model using all data 
similar to the main analysis of the respective parameter but with an interaction between treatment
and country. In addition the safety in China and Korea will be assessed.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
09 December 2016
Novo Nordisk
Trial ID: NN9535-4114
Version:
2.0
UTN: U1111-1149-0432
Status:
Final
EudraCT No.: NA
Page:
5 of 5
3
Changes to the SI/IC 
3.1
Financial Issues (section 4) 
Rationale:
To include newest SOP template text on liability and insurance, as this was not sufficiently 
described. 
Impact:
Product liability 
Novo Nordisk carries product liability for its products and liability assumed under the special laws, 
acts and/or guidelines for conducting trials in any country, unless others have shown negligence. 
If you feel something has gone wrong during the course of this trial, please contact the trial doctor 
or study nurse staff in the first instance.
What if something goes wrong?
If you suffer any injury as a direct result of the administration of the Novo Nordisk trial product 
under investigation or trial procedures to which you would not have been exposed if you had not 
participated in this trial, Novo Nordisk will ensure that you receive necessary medical care for such 
injuries in accordance with local laws. Novo Nordisk assumes liability as sponsor in accordance 
with the applicable laws and guidelines in the countries where the trial is conducted, unless others 
have shown negligence. Novo Nordisk has appropriate insurance coverage in place to cover its 
liability as defined above. If you have any questions or believe that you may have suffered an injury 
as a result of your participation in the trial or administration of the trial product, you should
promptly inform your trial doctor. Some countries have other mandatory ‘Compensation for injury’
clauses approved by Global Legal that can replace this paragraph without PRC approval.
CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
22 March 2018
Novo Nordisk
Trial ID:NN9535-4114
Version:
1.0
     
Status:
Final
     
Page:
1 of 6
Protocol Amendment
no 3
to Protocol, version 3
dated 09 December 2016
Trial ID: NN9535-4114
SUSTAIN – CHINA MRCT
Efficacy and safety of semaglutide once-weekly versus sitagliptin once-
daily as
add-on to metformin in subjects with type 2 diabetes
Trial phase: 3a
Applicable to all countries
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol Amendment no 3
CONFIDENTIAL
Date:
22 March 2018
Novo Nordisk
Trial ID:NN9535-4114
Version:
1.0
     
Status:
Final
     
Page:
2 of 6
Table of Contents   
1
Introduction including rationale for the protocol amendment...........................................................3
2
Changes ................................................................................................................................................3
2.1
Type of trial (section 5.1)..........................................................................................................3
2.2
Number of subjects (section 6.1) ...............................................................................................3
2.3
Milestones (section 7) ...............................................................................................................4
2.4
Hypoglycaemic episodes (section 8.4.4)....................................................................................4
2.5
Sample size calculation (section 17.1) .......................................................................................5
2.6
Retention of human biospecimens (section 24.2) .......................................................................6
CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
22 March 2018
Novo Nordisk
Trial ID:NN9535-4114
Version:
1.0
     
Status:
Final
     
Page:
3 of 6
1
Introduction including rationale for the protocol amendment
The sample size calculations for this trial were performed before the results for the phase 3a 
programme were available and estimated based on limited evidence (phase 2 global data). The 
semaglutide phase 3a results showed significant reductions in HbA1c and body weight versus all 
comparators that were larger than assumed, why a reconsideration of the sample size in this trial 
seems appropriate. The aim is to ensure a sample size that is sufficient to show efficacy for region 
China (China, Hong Kong and Taiwan). The number of subjects in trial NN9535-4114 can be 
reduced without compromising the efficacy and safety evaluation
Re-estimating the sample size in this trial is acceptable as it is based on blinded data, thus the 
integrity of the trial will be maintained.
Reducing the sample size is also considered relevant from an ethical standpoint, and the trial 
integrity will not be compromised. The number of planned randomised subjects is suggested to be 
reduced from a total of 1050 subjects to 858 subjects. This mainly affects region China, where the 
number of planned randomised subjects will be reduced from 792 to 600.
Additionally, minor refinements have been made.
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
Type of trial (section 5.1)
Rationale: 
Planned number of subjects to be screened and randomised has decreased in accordance to the new 
statistical considerations in section 17.
Impact: 
A planned total of 1050 858 subjects will be randomised whereof approximately 792 600 subjects 
will be from region China (China mainland, Hong Kong and Taiwan). Randomisation will be 
stratified by country.
2.2
Number of subjects (section 6.1)
Rationale: 
Planned number of subjects to be screened and randomised has decreased in accordance to the new
sample size calculations in section 17.
CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
22 March 2018
Novo Nordisk
Trial ID:NN9535-4114
Version:
1.0
     
Status:
Final
     
Page:
4 of 6
Impact:
Planned number of subjects to be screened (i.e. documented informed consent): Up to 1750 1420
Planned number of subjects to be randomised:
1050 858
Planned number of subjects to complete the trial:
840 686
Planned number of Chinese subjects to be randomised:
792 600
Expected number of Chinese subjects to complete the trial:
636 450
2.3
Milestones (section 7)
Rationale:
Dates have changed in line with the speed of recruitment.
Impact:
Planned duration of recruitment period (i.e. FPFV– LPFV): 26 56 weeks
End of trial is defined as last patient last visit.
Planned date for first patient first visit (FPFV): 28-Aug-2017
Planned date for last patient first visit (LPFV): 26-Feb-2018 27-Aug-2018
Planned date for last patient last visit (LPLV): 19-Nov-2018 20-May-2019
2.4
Hypoglycaemic episodes (section 8.4.4)
Rationale: 
A typographical error was made when a > sign was missed.
Impact:
Plasma glucose (PG) should always be measured and recorded when a hypoglycaemic episode is 
suspected.
All PG values:
!
≤ 3.9 mmol/L (70 mg/dL) or
!
>3.9 mmol/L (70 mg/dL) occurring in conjunction with hypoglycaemic symptoms
CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
22 March 2018
Novo Nordisk
Trial ID:NN9535-4114
Version:
1.0
     
Status:
Final
     
Page:
5 of 6
should be reported in the diary according to the instructions below and section 8.6.2 throughout the 
trial from V1 to V10/10A.
2.5
Sample size calculation (section 17.1)
Rationale: 
The sample size calculations for trial NN9535-4114 were performed before the results for the phase 
3a programme were available and estimated based on limited evidence (phase 2 global data). The 
semaglutide phase 3a results showed significant reductions in HbA1c and body weight versus all 
comparators that were larger than assumed, why a reconsideration of the sample size in trial 
NN9535-4114 seems appropriate. 
Impact: 
The primary objective is to compare the effect of two dose levels of semaglutide once-weekly 
treatment (0.5 mg or 1.0 mg) with sitagliptin 100 mg on the primary endpoint, change from baseline 
in HbA1c after 30 weeks of treatment. In the power calculations below determining the sample size
it is presumed that in the analysis the two sitagliptin/semaglutide placebo groups will be pooled 
assuming no correlation between endpoints and placebo volume.
At the time of finalising the first version of the protocol, the regulatory guidance in China was to 
have 300 subjects in region China treated with semaglutide. To ensure an adequate and robust 
evaluation of safety and efficacy in the subjects from China 300 subjects completing treatment with 
semaglutide is used. In the following, subjects from Hong Kong and Taiwan will be grouped with 
the Chinese subjects and referred to as region China. Assuming a treatment discontinuation rate of 
25% in this region and considering the 2:2:1:1 randomisation, this means that 600 subjects need to 
be randomised in region China. Trial NN9535-4114 is a multi-regional clinical trial, and 258 
subjects are planned to be randomised outside region China as has already been approved by local 
authorities for these countries. For some countries the allocated subject number is required to 
support local NDA submissions. In total, 858 subjects are planned to be randomised In total 1050 
subjects will be randomised in a 2:2:1:1 manner. Assuming that 20% of all randomised subjects 
discontinuing discontinue randomised treatment, and further taking the assumption that these 
subjects are excluded from the per protocol (PP) analysis set, 280 228 subjects in each group are 
expected to be included in the PP analysis set.
The sample size calculation is based on demonstrating HbA1c non-inferiority for semaglutide 0.5 
mg vs. sitagliptin 100 mg and HbA1c non-inferiority for semaglutide 1.0 mg vs. sitagliptin 100 mg.
CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
22 March 2018
Novo Nordisk
Trial ID:NN9535-4114
Version:
1.0
     
Status:
Final
     
Page:
6 of 6
In total six confirmatory hypotheses are to be tested (see section 17.3). The two six hypothesis tests 
are assumed to be independent and for each of the hypotheses the power calculation is based on a t-
statistic under the assumption of a one-sided test of size 2.5%. 
Using a non-inferiority margin of 0.3%-point, and assuming a true HbA1c difference (semaglutide 
minus sitagliptin) of 0% and a standard deviation (SD) of 1.1%-point and a total of 280 228 
subjects per group in the PP analysis set will give 90% marginal power to conclude HbA1c non-
inferiority for the comparison of a semaglutide dose vs. sitagliptin 100 mg if the true HbA1c
treatment difference (semaglutide minus sitagliptin) is as low as -0.03 %-point. Thereby, Assuming 
the same HbA1c effect for the two dose levels of semaglutide, the overall power to demonstrate 
HbA1c non-inferiority for the two dose levels of semaglutide vs. sitagliptin will be at least 80%, 
even if the true treatment difference for the low dose comparison is as low as -0.03 %-point. With 
286 subjects per group in the full analysis set (FAS), a marginal power of at least 90% for 
demonstrating HbA1c superiority, for any dose of the two dose level comparisons, is obtained if the 
true treatment difference is as low as -0.30%-point.
For change in body weight, using a SD of 4 kg and 286 subjects per group, a marginal power of at 
least 90% for demonstrating superiority for the comparison of a semaglutide dose vs. sitagliptin 
100 mg is obtained if the true treatment difference is as low as -1.09 kg body weight.
For change in body weight, the power calculation is based on the assumptions of a true difference of 
-1.5 kg and a SD of 4.0 kg. In addition, 50% efficacy retention is assumed for the anticipated 20% 
of subjects discontinuing randomised treatment giving an expected treatment difference of -1.35 kg, 
which is the number used in the power calculation. With the above assumptions, a total of 350 
subjects per group in the full analysis set (FAS) will give more than 99% marginal power to 
conclude superiority in body weight for the comparison of a semaglutide dose vs. sitagliptin 100 
mg.
In SUSTAIN 2, the mother trial of NN9535-4114, semaglutide showed marked and significant 
reductions in HbA1c and body weight vs sitagliptin at week 56. The change over time in HbA1c and 
body weight in SUSTAIN 2 showed marked reductions in both endpoints already at week 30 which 
supports that the above mentioned true treatment differences for trial NN9535-4114. 
2.6
Retention of human biospecimens (section 24.2)
Rationale: A typographical error was made when “thyroid tissue” was not removed from the 
previous version of the protocol.
Impact: 
None of the data will be identified by name. Antibody samples and thyroid tissue will be identified 
only by a subject number, a visit number and a trial identification number.
CONFIDENTIAL

SAP_001.pdf: 
Cover Page for Statistical Analysis Plan 
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT03061214  
Sponsor trial ID: 
NN9535-4114 
Official title of study: 
SUSTAINTM CHINA - Efficacy and safety of semaglutide 
once-weekly versus sitagliptin once-daily as add-on to 
metformin in subjects with type 2 diabetes 
Document date: 
22 August 2019 
 


List of contents
Statistical analysis plan...................................................................................................................... /LQN
Statistical documentation................................................................................................................... /LQN
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
Semaglutide s.c (Ozempic®)
Trial ID: NN9535-4114
Clinical Trial Report
Appendix 16.1.9
22 August 2019
1.0
Final
16.1.9 Documentation of statistical methods
CONFIDENTIAL
Redacted VWDWLVWLFDODQDO\VLVSODQ 
Includes redaction of personal identifiable information only. 
. 


Statistical Analysis Plan
CONFIDENTIAL
Date:
28 May 2019
Novo Nordisk
Trial ID: NN9535-4114
Version:
1.0
UTN:U1111-1149-0432
Status:
Final
EudraCT No.:NA
Page:
1 of 30
Statistical Analysis Plan
Trial ID: NN9535-4114
Efficacy and safety of semaglutide once-weekly versus sitagliptin 
once-daily as add-on to metformin in subjects with type 2 
diabetes
Author
Biostatistics Semaglutide s.c.
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Statistical Analysis Plan
CONFIDENTIAL
Date:
28 May 2019
Novo Nordisk
Trial ID: NN9535-4114
Version:
1.0
UTN:U1111-1149-0432
Status:
Final
EudraCT No.:NA
Page:
2 of 30
Table of contents   
Page
Table of contents.........................................................................................................................................2
List of abbreviations ...................................................................................................................................3
1
Introduction .........................................................................................................................................4
1.1
Trial information.......................................................................................................................4
1.2
Scope of the statistical analysis plan..........................................................................................4
2
Statistical considerations .....................................................................................................................5
2.1
General considerations ..............................................................................................................5
2.2
Sample size calculation .............................................................................................................6
2.3
Definition of analysis sets..........................................................................................................7
2.4
Primary endpoint.....................................................................................................................10
2.5
Secondary endpoints ...............................................................................................................16
2.5.1
Confirmatory secondary endpoints.........................................................................16
2.5.2
Supportive secondary endpoints .............................................................................18
2.5.2.1
Efficacy endpoints............................................................................18
2.5.2.2
Safety endpoints...............................................................................20
2.6
Health economics and/or patient reported outcomes.................................................................25
2.7
China cohort ...........................................................................................................................25
3
Changes to the statistical analyses planned in the protocol..............................................................27
4
References ..........................................................................................................................................30
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
28 May 2019
Novo Nordisk
Trial ID: NN9535-4114
Version:
1.0
UTN:U1111-1149-0432
Status:
Final
EudraCT No.:NA
Page:
3 of 30
List of abbreviations
AACE
American Association of Clinical Endocrinologists
ADA
American Diabetes Association
AE
adverse event
ANCOVA
analysis of covariance
BG
blood glucose
BMI
body mass index
CTR
clinical trial report
DTSQ
Diabetes Treatment Satisfaction Questionnaire status
EAC
event adjudication committee
ECG
electrocardiogram
FAS
full analysis set
GLP-1
glucagon-like peptide-1
HDL
high density lipoprotein
hsCRP
highly sensitive C-reactive protein
ITT
intention to treat
IWRS
interactive voice/web response system
LLOQ
lower limit of quantification
LOCF
last observation carried forward
MAR
missing at random
MCAR
missing completely at random
MCMC
markow chain Monte Carlo
MedDRA
Medical Dictionary for Regulatory Activities
NDA
new drug application
PP
per protocol
PRO
patient reported outcome
PT
preferred term
REML
restricted maximum likelihood
SAP
statistical analysis plan
SAS
safety analysis set
s.c.                subcutanous
SD
standard deviation
SE
standard error
TEAE
treatment emergent adverse event
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Statistical Analysis Plan
CONFIDENTIAL
Date:
28 May 2019
Novo Nordisk
Trial ID: NN9535-4114
Version:
1.0
UTN:U1111-1149-0432
Status:
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1
Introduction
1.1
Trial information
This is a 30-week randomised, double-blind, double-dummy, active-controlled, multi-centre, 
multinational trial, four-armed, parallel-group trial comparing semaglutide 0.5 mg and 1.0 mg once
weekly against sitagliptin 100 mg once-daily.
Primary objective
To compare the effect of once-weekly dosing of two dose levels of semaglutide versus sitagliptin
100 mg once-daily on glycaemic control after 30 weeks of treatment.
To further detail the primary objective an estimand is defined which is an efficacy estimand. The 
scientific question is:
!
What is the treatment difference between semaglutide and sitagliptin at week 30 for all 
randomised subjects if all subjects completed treatment and did not initiate rescue 
medication
!
The population is defined by the inclusion/exclusion criteria of the trial
!
The primary endpoint is change from baseline in HbA1c after 30 weeks of treatment
!
Only data collected before the occurrence of the intercurrent events initiation of rescue 
medication and discontinuation of trial product are used in the analysis.  
Secondary objectives
To compare the effects of once-weekly dosing of two dose levels of semaglutide versus sitagliptin
100 mg once-daily after 30 weeks of treatment on:
!
Inducing and maintaining weight loss
!
Other parameters of efficacy, safety and tolerability
An estimand similar to the one for the primary objective is defined for the secondary objective as 
addressed by weight loss, however with ‘change from baseline in HbA1c after 30 weeks’ replaced 
by ‘change from baseline in body weight after 30 weeks of treatment’. 
1.2
Scope of the statistical analysis plan
This SAP is based on the protocol “Efficacy and safety of semaglutide once-weekly versus
sitagliptin once-daily as add-on to metformin in subjects with type 2 diabetes”, version 3.0, and 
amendment 3. The SAP is relevant both for the analysis of data for the entire trial population and 
for the analysis of the China cohort by it self. See Section 2.7. 
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Statistical Analysis Plan
CONFIDENTIAL
Date:
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Trial ID: NN9535-4114
Version:
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UTN:U1111-1149-0432
Status:
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EudraCT No.:NA
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2
Statistical considerations
2.1
General considerations
Results from the statistical analysis will generally be presented by two-sided confidence intervals
with a confidence level of 95% and associated p-value. Superiority will be formulated and tested as
one-sided hypotheses at a 2.5% significance level. Non-inferiority between two treatments will be
evaluated by comparing the upper limit of the associated two-sided 95% confidence interval for the
difference with the pre-defined non-inferiority margin.
The two sitagliptin/semaglutide placebo groups will be pooled in all outputs if not otherwise 
specified.
When grouping or analysing data by country, subjects from Hong Kong and Taiwan will be
grouped with Chinese subjects if not otherwise specified. The same is done when grouping or 
analysing by region China/Other where subjects from South Africa, Korea, Brazil and Ukraine will 
be analysed together in the group referred to as “Other”.
Data transformations
A number of the continuous parameters will be log-transformed prior to statistical analysis. The 
output tables and figures will show the results of the analysis back-transformed to the original scale, 
implying that log-treatment-differences are reported as treatment ratios. Confidence intervals for the 
treatment ratios will be calculated as exponentiated upper and lower limits for log-treatment 
difference confidence intervals. The standard errors (SE) of the back-transformed mean and ratio to 
baseline estimates are also provided; these SEs are calculated using the delta-method (first order 
Taylor approximation), whereby the SE on the original scale is calculated as the product of the SE 
on log-scale and the exponentiated estimate of the mean (geometric mean).
Handling of missing data
In the case of missing data no general imputation will be performed for the analyses, unless
otherwise specified. If an assessment has been made both at screening and randomisation, the value
from the randomisation visit will be used as the baseline value. If the value measured at the
randomisation visit is missing and the assessment also has been made at screening, then the
screening value will be used as the baseline value.
Laboratory values below the lower limit of quantification (LLOQ) will be set to ½ LLOQ.
The primary analysis model will be the mixed model for repeated measurements (MMRM), see
Section 2.4 for further details. One of the assumptions behind MMRM is that the missing data
mechanism is missing at random (MAR). This means that given the observed data, the mechanism
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
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Novo Nordisk
Trial ID: NN9535-4114
Version:
1.0
UTN:U1111-1149-0432
Status:
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EudraCT No.:NA
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generating missing values is independent of the unobserved data, that is the missing data. The
MMRM rely on the MAR assumption for generating unbiased estimates of treatment differences.
Based on previous semaglutide trials in subjects with type 2 diabetes, the treatment discontinuation
rate from randomised treatment and trial withdrawal is expected to be about 20%. The treatments in
this trial should be effective, given the historical documentation, and this should minimise treatment
discontinuation due to ineffective therapy. The main reasons for treatment discontinuation are
expected to be AEs, ineffective therapy and non-eligibility (subjects randomised although not
fulfilling inclusion/exclusion criteria). Treatment discontinuation due to non-eligibility can be
regarded as missing completely at random (MCAR), i.e. it does not depend on the observed or
missing data values. This category of missing data is not expected to introduce bias in the estimated
treatment differences. Treatment discontinuation due to lack of efficacy is expected to be reflected
in the observed data obtained prior to the discontinuation from randomised treatment, and the 
corresponding missing data can therefore be assumed as MAR to some extent. Missing data due to
AEs is expected to be similar between groups except for, potentially, a slightly higher incidence in
the semaglutide treatment group due to gastrointestinal side effects. Together with potential
withdrawals from trial due to the own will of the subject, the MAR assumption may be less
adequate for this category of drop-outs.
Several different sensitivity analyses described in subsequent sections will be used to investigate 
whether the results from the MMRM approach are robust towards deviations from the assumption 
of MAR.
2.2
Sample size calculation
The primary objective is to compare the effect of two dose levels of semaglutide once-weekly 
treatment (0.5 mg or 1.0 mg) with sitagliptin 100 mg on the primary endpoint, change from baseline 
in HbA1c after 30 weeks of treatment. In the power calculations below it is presumed that in the 
analysis the two sitagliptin/semaglutide placebo groups will be pooled assuming no correlation 
between endpoints and placebo volume.
At the time of finalising the first version of the protocol, the regulatory guidance in China was to 
have 300 subjects in region China treated with semaglutide. To ensure an adequate and robust 
evaluation of safety and efficacy in the subjects from China 300 subjects completing treatment with 
semaglutide is used. In the following, subjects from Hong Kong and Taiwan will be grouped with 
the Chinese subjects and referred to as region China. Assuming a treatment discontinuation rate of 
25% in this region and considering the 2:2:1:1 randomisation, this means that 600 subjects need to 
be randomised in region China. Trial NN9535-4114 is a multi-regional clinical trial, and 258 
subjects are planned to be randomised outside region China as has already been approved by local 
authorities for these countries. For some countries the allocated subject number is required to 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
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Novo Nordisk
Trial ID: NN9535-4114
Version:
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Status:
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support local NDA submissions. In total, 858 subjects are planned to be randomised in a 2:2:1:1 
manner. Assuming that 20% of all randomised subjects discontinue randomised treatment, and 
further taking the assumption that these subjects are excluded from the per protocol (PP) analysis 
set, 228 subjects in each group are expected to be included in the PP analysis set.
In total six confirmatory hypotheses are to be tested (see Section 2.4). The six hypothesis tests are 
assumed to be independent and for each of the hypotheses the power calculation is based on a t-
statistic under the assumption of a one-sided test of size 2.5%. 
Using a non-inferiority margin of 0.3%-point, a standard deviation (SD) of 1.1%-point and a total of 
228 subjects per group in the PP analysis set will give 90% marginal power to conclude HbA1c non-
inferiority for the comparison of a semaglutide dose vs. sitagliptin 100 mg if the true HbA1c
treatment difference (semaglutide minus sitagliptin) is as low as -0.03 %-point. Thereby, the overall 
power to demonstrate HbA1c non-inferiority for the two dose levels of semaglutide vs. sitagliptin 
will be at least 80%, even if the true treatment difference for the low dose comparison is as low 
as -0.03 %-point. With 286 subjects per group in the full analysis set (FAS), a marginal power of at 
least 90% for demonstrating HbA1c superiority, for any dose of the two dose level comparisons, is 
obtained if the true treatment difference is as low as -0.30%-point.
For change in body weight, using a SD of 4 kg and 286 subjects per group, a marginal power of at 
least 90% for demonstrating superiority for the comparison of a semaglutide dose vs. sitagliptin 100 
mg is obtained if the true treatment difference is as low as -1.09 kg body weight.
In SUSTAIN 2, the mother trial of NN9535-4114, semaglutide showed marked and significant 
reductions in HbA1c and body weight vs sitagliptin at week 56. The change over time in HbA1c and 
body weight in SUSTAIN 2 showed marked reductions in both endpoints already at week 30 which 
supports the above mentioned true treatment differences for trial NN9535-4114. 
2.3
Definition of analysis sets
The following analysis sets are defined in accordance with the ICH-E9 guideline58 .
Full Analysis Set (FAS): includes all randomised subjects.  Subjects in the FAS will contribute to 
the evaluation “as randomised”.
Per Protocol (PP) Analysis Set:
Includes all subjects in the FAS who fulfil the following criteria:
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Statistical Analysis Plan
CONFIDENTIAL
Date:
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Trial ID: NN9535-4114
Version:
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!
have not violated any inclusion criteria
!
have not fulfilled any exclusion criteria
!
have a non-missing HbA1c measurement at screening and /or randomisation
!
have at least 23 weeks actual treatment weeks of exposure
!
have at least one non-missing HbA1c measurement after 23 actual weeks of exposure
Subjects in the PP Analysis Set will contribute to the analysis “as treated”.
Safety Analysis Set (SAS): includes all subjects exposed to at least one dose of trial product. 
Subjects in the SAS will contribute to the evaluation based on the trial product received for the 
majority of the period they were on treatment. This will be referred to as contributing to the 
evaluation “as treated”.
Before data are locked for statistical analysis, a review of all data will take place. Any decision to 
exclude a subject or single observations from the statistical analysis is the joint responsibility of the 
members of the internal 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 CTR.
Data selections and observation periods
Subjects and data to be used in an analysis will be selected in a two-step manner.
!
Firstly, subjects will be selected based on the specified analysis set
!
Secondly, data points on the selected subjects from first step will be selected based on the 
specified observation period 
Definition of the observation periods:
In-trial: This observation period represents the time period where subjects are considered to be in 
the trial after randomisation, regardless of discontinuation of trial product or initiation of rescue 
medication. The in-trial observation period starts at randomisation (as registered in IWRS) and ends 
at the date of: 
!
The last direct subject-site contact, which is scheduled to take place 5 weeks after planned 
last dose of trial product at a follow-up visit 
!
Withdrawal for subjects who withdraw their informed consent
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Statistical Analysis Plan
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Trial ID: NN9535-4114
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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 dies before any of the above
For subjects not randomised but exposed to trial product the in-trial periods starts at the date of first 
dose of trial product
On-treatment: This observation period represents the time period where subjects are considered 
treated with trial product. The observation period is a sub-set 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 according to the flow chart. For adjudicated events, ECG’s and 
AEs including hypoglycaemic episodes, the observation period ends at the first date of any of the 
following: 
!
the follow-up visit (V10)
!
the follow-up prematurely discontinuation visit (V10A)
!
the last date on trial product + 42 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 subcutaneous semaglutide. The visit window for 
the follow-up visit is + 7 days, which is the reason for the 42 days specified in the bullet above. 
Hence, for those assessments this period reflects the period in which subjects are exposed.
For efficacy and other safety assessments (laboratory assessments, physical examination and vital 
signs) the observation period ends at the last date on trial product + 7 days in accordance with trial 
flow chart and assessment times. This ascertainment window corresponds to the dosing interval and 
will be used to avoid attenuation of a potential treatment effect on endpoints for which the effect is 
reversible shortly after treatment discontinuation. Hence, for those assessments this period reflects 
the period in which subjects are treated.
On-treatment without rescue medication: This observation period is a sub-set 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 +7 days
!
initiation of rescue medication
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
28 May 2019
Novo Nordisk
Trial ID: NN9535-4114
Version:
1.0
UTN:U1111-1149-0432
Status:
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Page:
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The ’on-treatment without rescue medication’ observation period will be the primary observation 
period for efficacy evaluations. The in-trial observation period will be considered supportive for 
efficacy evaluation. Safety will be evaluated based on the in-trial and the on-treatment observation 
periods unless otherwise specified.
For subjects who have no post-baseline scheduled assessments available in the on-treatment without 
rescue period, the baseline value will be carried forward to the first scheduled visit for the 
associated endpoint to ensure that all randomised subjects will contribute to the statistical analysis. 
This will not be done for the PRO assessments which are only taken at baseline and the week 30 
visit.
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.
2.4
Primary endpoint
The primary endpoint is change from baseline in HbA1c after 30 weeks of treatment. In the analysis 
the two sitagliptin/semaglutide placebo groups will be pooled assuming no correlation between 
HbA1c change after 30 weeks and placebo volume.
The primary endpoint will be based on FAS using data from the ‘on-treatment without rescue 
medication’ observation period in a Mixed Model for Repeated Measures (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 30 data as dependent 
variables. The independent effects included in the model will be treatment and region China/Other
as fixed effects and baseline response as covariate, all nested within visit. An unstructured 
covariance matrix will be employed for measurements within the same subjects, assuming that 
measurements across subjects are independent. Regarding missing data this analysis approach relies 
on the assumption that data are missing at random (MAR). From this model, the two dose level 
estimated treatment differences between s.c. semaglutide versus sitagliptin at week 30 will be 
presented together with associated two-sided 95% confidence intervals and unadjusted two sided p-
values (nominal alpha=0.05) for testing non-inferiority and superiority.  In order to preserve the 
overall type 1 error the conclusion of non-inferiority and superiority with treatment of each 
semaglutide dose versus sitagliptin after 30 weeks will be evaluated hierarchically according to the 
sequence below, and starting with the first. In this testing sequence it is necessary to fulfil the test 
criteria, which is to reject the corresponding null hypothesis in order to go to the next step. If the 
corresponding null hypothesis is not rejected, the testing will stop and no further conclusions will be 
drawn. 
The following ordering in the statistical test sequence will be used:
1. Non-inferiority in change in HbA1c for semaglutide 1.0 mg vs. sitagliptin
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Statistical Analysis Plan
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2. Non-inferiority in change in HbA1c for semaglutide 0.5 mg vs. sitagliptin
3. Superiority in change in HbA1c for semaglutide 1.0 mg vs. sitagliptin
4. Superiority in change in body weight for semaglutide 1.0 mg vs. sitagliptin
5. Superiority in change in body weight for semaglutide 0.5 mg vs. sitagliptin
6. Superiority in change in HbA1c for semaglutide 0.5 mg vs. sitagliptin
Non-inferiority will be concluded if the upper limit of the two-sided 95% confidence interval for the 
estimated difference in HbA1c between semaglutide and sitagliptin is less than 0.3%. Superiority for 
either change in HbA1c or change in body weight will be claimed if the upper limit of the two-sided 
95% confidence interval for the estimated difference is below 0% or 0 kg respectively.  
When establishing non-inferiority the analysis will be based on the full analysis set (FAS) and 
supplemented by an analysis with the per protocol population using the data from the ‘on treatment 
without rescue medication’ observation period as supportive evidence. The FAS population will be 
used in the analysis when concluding superiority.
Sensitivity analysis
To investigate the sensitivity of the main results, complimentary and separate analyses for primary 
endpoint and the confirmatory secondary endpoint will be performed, using the FAS only, except 
for HbA1c, where the PP analysis set will be used in a sensitivity analysis regarding the non-
inferiority evaluation. These analyses will investigate the sensitivity of the results due to the impact 
of missing values.
The primary analysis regarding non-inferiority of the primary endpoint change in HbA1c after 30 
weeks will also be performed separately based on the data in the PP analysis set only.
The primary endpoint and the secondary confirmatory endpoint will be evaluated in the following 
sensitivity analyses:
!
An analysis of covariance (ANCOVA) model will be analysed with imputation of missing 
values according to the last observation carried forward (LOCF) method based on the FAS 
and using the data  from the ‘on-treatment without rescue medication’ observation period. 
The model will include terms for treatment, region China/Other, and the corresponding 
baseline value as a covariate. The response variable will be the last available value obtained 
within the 30 weeks period of the trial
!
The MMRM will be analysed based on all data from the ‘in-trial’ observation period 
A MMRM model will be analysed based on data only from subjects that completed treatment
without receiving rescue treatment and who has a valid HbA1c assessment at visit 9 (week 30).
The model will include terms for treatment, region China/Other, and the corresponding baseline 
value as a covariate. 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
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Trial ID: NN9535-4114
Version:
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A pattern mixture model based on the FAS using the ‘on-treatment without rescue medication’ 
observation period approach mimicking an ITT scenario where withdrawn subjects are assumed to 
be switched to a treatment inferior to the control treatment after treatment discontinuation will be 
performed for evaluation of non-inferiority for the primary endpoint change in HbA1c at 30 weeks.
!
In the first step intermittent missing values 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 500 copies of the dataset will be generated.
!
In the second step, for each of the 500 copies of the dataset, an analysis of variance model 
with the same factors as the primary model, and baseline HbA1c and HbA1c at 4 weeks (Visit 
3) as covariate is fitted to the change in HbA1c from baseline to 8 weeks (Visit 5) for the 
sitagliptin group only. The estimated parameters, and their variance, from this model are 
used to impute missing value at 8 weeks for subjects in all treatment groups, based on region 
China/Other and HbA1c at baseline and 4 weeks.  
!
In the third step, for each of the 500 copies of the dataset, missing HbA1c values at 12 
weeks (Visit 6) are imputed in the same way as for 8 weeks. Now the imputations are based 
on an analysis of variance model with the same factors and the HbA1c values at baseline, 4 
weeks and 8 weeks as covariates, fitted to the control group.
!
This stepwise procedure is then repeated sequentially over the available planned visits, 
adding one visit in each step until the last planned visit at 30 weeks (Visit 9).
!
For each subject with imputed values in the investigational treatment groups, a value of 
0.3% (the non-inferiority limit) is added to the change in HbA1c at 30 weeks.
!
For each of the complete data sets, the change from baseline to week 30 is analysed using an 
analysis of variance model with the same set of factors and the baseline HbA1c value as a 
covariate.
!
The estimates and standard deviations for the 500 data sets are pooled to one estimate and 
associated standard deviation using Rubin’s rule (page 255-257)59 From these pooled 
estimates the confidence interval for the treatment differences and the associated p-value are 
calculated. The upper limit of the two sided 95% confidence interval will be compared to the 
non-inferiority limit of 0.3%.
A pattern mixture model approach mimicking an ITT scenario where subjects after initiation of 
rescue medication or premature treatment discontinuation are assumed to be switched to the control 
treatment after treatment discontinuation will be performed separately for the evaluation of 
superiority in the primary endpoint change in HbA1c and change in body weight at 30 weeks. The 
same types of approach as used for the non-inferiority assessment in change in HbA1c will be 
employed, see above. However, the step where 0.3%, the non-inferiority limit, is added to the 
change in HbA1c at 30 weeks will not be performed in this sensitivity analysis.
Furthermore to align with recent phase 3b trials evaluating safety and efficacy of semaglutide s.c.,
the following sensitivity analyses have been added:
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Statistical Analysis Plan
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Trial ID: NN9535-4114
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!
Tipping-point analysis (pattern mixture model like) based on the FAS using the ’on-
treatment without rescue medication’ observation period. In this analysis, subjects from the 
semaglutide group under investigation with missing observations will be given a penalty, 
i.e., it is assumed that subjects with missing observations who are randomised to 
semaglutide will receive a treatment that is worse than subjects with observed values who 
are randomised to semaglutide. The idea is to gradually increase the penalty to evaluate at 
which level the superiority/non-inferiority conclusion of the analyses in terms of statistical 
significance is changed for each of the two semaglutide dose levels separately. The tipping 
point is the penalty level, at which the magnitude of efficacy reduction in subjects with 
missing data creates a shift in the treatment effect of semaglutide from being statistically 
significantly better than sitagliptin to being non-statistically significantly better for the 
superiority test and similarly for the non-inferiority test. Technically, this analysis will be 
implemented in the following way:
o
Intermittent missing values 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 of the treatment groups separately and 500 copies of the 
dataset will be generated.
o
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 last planned visit at week 30. A model used to impute missing 
values at each planned visit will be fitted for each of the treatment groups using 
observed data. The model will include stratification factor region China/Other as a 
categorical effect and baseline and post-baseline HbA1c values observed or imputed 
prior to the visit in question as covariates. This step is similar to the detailed 
description given for the pattern mixture model approach described above.
o
Subsequently, increasing penalty values will be added at week 30 to imputed 
observations in the semaglutide group under investigation. Specifically, when 
evaluating treatment differences involving the 0.5 mg semaglutide group, only 
subjects in this group are given a penalty, and vice versa for treatment differences 
involving the1.0 mg semaglutide group. For each penalty and each of the 500 
complete data set, HbA1c at week 30 will be analysed using an ANCOVA with 
treatment, and the stratification factor (region China/other) as categorical effects and 
baseline HbA1c as a covariate. Rubin’s rules will be used to combine the analysis 
results in order to draw inference. 
!
Retrieved drop-out analysis based on the FAS using post-baseline measurements up to and 
including week 30 from the in-trial observation period. Missing data will be imputed using 
the same approach as described for the tipping point analysis above. However, the 
imputation will be done within the same group defined not only by the randomised treatment 
(semaglutide (0.5mg or 1.0 mg) /sitagliptin) but also by the status of treatment completion 
(still on randomised treatment at week 30 yes/no). It is hereby assumed that the likely values 
of what the missing data would have been if available are best described by information 
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Statistical Analysis Plan
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from subjects who at week 30 are similar in terms of randomised treatment and treatment 
completion status. The analysis model for the retrieved drop-out analysis is the same as for 
the tipping point analysis. This analysis could be considered addressing a treatment policy
estimand. The retrieved drop-out is carried out for the superiority testing only.
In Table 1 below a schematic overview of the different sensitivity analyses is provided.
Table 1 Summary of statistical analyses of the primary endpoint (HbA1c) 
Population
Period
Statistical 
model
Imputation1)
Hypothesis to 
be tested
Primary non-inferiority analysis
FAS 
On-treatment 
without rescue 
medication
MMRM2)
Baseline values 
will be carried 
forward to 
week 4 for 
subjects with 
missing week 4 
values.
Non-
inferiority
Primary superiority analysis
FAS 
On-treatment 
without rescue 
medication
MMRM2)
Baseline values 
will be carried 
forward to 
week 4 for 
subjects with 
missing week 4 
values.
Superiority
Sensitivity analyses
PP
On-treatment 
without rescue 
medication
MMRM
Baseline values 
will be carried 
forward to 
week 4 for 
subjects with 
missing week 4 
values.
Non-
inferiority
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Statistical Analysis Plan
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Complete 
cases
On-treatment 
without rescue 
medication
MMRM
Not applicable
Superiority
FAS
On-treatment 
without rescue 
medication
ANCOVA4)
Last 
observation 
carried forward 
for subjects 
with missing 
value at week 
30
Superiority
FAS
In-trial
MMRM
Baseline values 
will be carried 
forward to 
week 4 for 
subjects with 
missing week 4 
values
Superiority
FAS
On-treatment 
without rescue 
medication
Pattern 
mixture model 
using an 
ANCOVA4)
Multiple 
imputation
Non-
inferiority
FAS
On-treatment 
without rescue 
medication
Pattern 
mixture model 
using an 
ANCOVA4)
Multiple 
imputation
Superiority
FAS
On-treatment 
without rescue 
medication
Tipping point 
analysis using 
an 
ANCOVA4)5)
model
Multiple 
imputation
Non-
inferiority
FAS
On-treatment 
without rescue 
medication
Tipping point 
analysis using 
an ANCOVA 
model4)
Multiple 
imputation
Superiority
FAS
In-trial
Retrieved 
dropout 
analysis, using 
an ANCOVA 
Multiple 
imputation
Superiority
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Statistical Analysis Plan
CONFIDENTIAL
Date:
28 May 2019
Novo Nordisk
Trial ID: NN9535-4114
Version:
1.0
UTN:U1111-1149-0432
Status:
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model3)4)
1) If a subject is missing baseline assessment the screening assessment will be used as the baseline 
assessment. If no measurement(s) have been obtained, at or prior to randomisation, the baseline 
value will be left missing.
2) MMRM model will be used to estimate the efficacy estimand
3) Retrieved dropout analysis, using an ANCOVA model, will be used to estimate the treatment 
policy estimand
4) Baseline and week 30 measurements will be used in the analysis
5) The non-inferiority margin of 0.3 is added as a penalty to imputed values in the semaglutide 
treatment groups
2.5
Secondary endpoints
The planned secondary endpoints used to support the primary and secondary objectives will be 
analysed as outlined in this section.
2.5.1
Confirmatory secondary endpoints
Weight loss
A confirmatory secondary variable is change in body weight after 30 weeks of treatment. This 
variable will be analysed in the same type of model as the primary endpoint although with baseline 
body weight as covariate and with similar sensitivity analyses.
In Table 2 an overview of the sensitivity analyses for the confirmatory secondary endpoint is 
provided.
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Statistical Analysis Plan
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Date:
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Trial ID: NN9535-4114
Version:
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Table 2 Summary of statistical analyses of confirmatory secondary endpoint (Body weight) 
Population
Period
Statistical 
model
Imputation1)
Hypothesis to 
be tested
Confirmatory analysis
FAS 
On-treatment 
without rescue 
medication
MMRM2)
Baseline values 
will be carried 
forward to 
week 4 for 
subjects with 
missing week 4 
values.
Superiority
Sensitivity analyses
Complete 
cases
On-treatment 
without rescue 
medication
MMRM
Not applicable
Superiority
FAS
On-treatment 
without rescue 
medication
ANCOVA4)
Last 
observation 
carried forward 
for subjects 
with missing 
value at week 
30
Superiority
FAS
In-trial
MMRM
Baseline values 
will be carried 
forward to 
week 4 for 
subjects with 
missing week 4 
values
Superiority
FAS
On-treatment 
without rescue 
medication
Pattern 
mixture model 
using an 
ANCOVA 
model4)
Multiple 
imputation
Superiority
FAS
On-treatment 
without rescue 
Tipping point 
analysis using 
an ANCOVA 
Multiple 
imputation
Superiority
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Statistical Analysis Plan
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Date:
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Trial ID: NN9535-4114
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medication
model4)
FAS
In-trial
Retrieved 
dropout 
analysis, using 
an ANCOVA 
model3) 4)
Multiple 
imputation
Superiority
1) If a subject is missing baseline assessment the screening assessment will be used as the baseline 
assessment. If no measurement(s) have been obtained, at or prior to randomisation, the baseline 
value will be left missing.
2) MMRM model will be used to estimate the efficacy estimand
3) Retrieved dropout analysis, using an ANCOVA model, will be used to estimate the treatment 
policy estimand
4) Baseline and week 30 measurements will be used in the analysis
2.5.2
Supportive secondary endpoints
2.5.2.1
Efficacy endpoints
All efficacy endpoints in this section will be summarised and evaluated using the FAS.
Continuous variables
Change from baseline to week 30 in:
!
FPG
!
Insulin
!
C-peptide
!
glucagon
!
pro-insulin
!
pro-insulin/insulin ratio
!
HOMA-B
!
HOMA-IR
!
fasting blood lipids (total cholesterol, LDL-cholesterol, VLDL-cholesterol, HDL-
cholesterol, triglycerides and free fatty acids)
!
BMI
!
waist circumference
!
systolic and diastolic blood pressure
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Statistical Analysis Plan
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Date:
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Version:
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!
hsCRP
will all be analysed based on the same observation period and type of model as the primary 
endpoint, but with the associated baseline value as a covariate.
Except for FPG, BMI, waist circumference, and blood pressure the values of the variables will be 
log transformed subject to analysis.
Beta-cell function
Beta-cell function (fasting HOMA-B and fasting HOMA-IR) will be calculated based on fasting 
insulin and FPG. The calculation will be done at the same time points as for fasting insulin and FPG 
samples.
The calculation of the fasting HOMA endpoints will be done as follows:
Fasting HOMA-B (%) = 20 x fasting insulin [μU/ml]/(FPG[mmol/l]-3.5)
Fasting HOMA-IR (%) = fasting insulin [μU/ml] x FPG [mmol/l]/22.5
PRO outcomes
The PRO outcome endpoints:
!
PRO questionnaire outcome DTSQs (individual items and treatment satisfaction score (6 of 
the 8 items summed)), and
!
PRO questionnaire outcome SF-36v2TM short Form health survey: Total scores (physical 
component and mental component) and scores from the 8 domains will be analysed 
separately using the ANCOVA model based on the data from the on-treatment without 
rescue medication observation period. Factors in the model will be treatment and region 
China/Other. The baseline value of the corresponding endpoint will be used as covariate in 
the analysis model.
7-point profile
Subjects will be asked to perform SMPG measurements as described in the protocol Section 8.5.1.5.
The endpoints from the 7-point profiles that will be analysed at week 30 are:
!
Mean of the 7-point profile, defined as the area under the profile, calculated using the 
trapezoidal method, divided by the measurement time
!
Mean increment over all meals
The mean of the 7-point profile and the mean of the post prandial increments at week 30 will be 
analysed separately with the same data and type of methods as primary endpoint but with the 
corresponding baseline assessment as a covariate.
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Statistical Analysis Plan
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Date:
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Response in HbA1c and/or weight loss after 30 weeks
The secondary variables related to fixed response in HbA1c and/or weight loss at 30 weeks will be:
!
Responder in HbA1c after 30 weeks of treatment (yes/no) defined as HbA1c <7.0% (<53 
mmol/mol) – ADA target
!
Responder in HbA1c after 30 weeks of treatment (yes/no) defined as HbA1c ≤6.5% (48 
mmol/mol) – AACE target
!
Weight loss ≥5%
!
Weight loss ≥10%
!
HbA1c <7.0% (53 mmol/mol) without severe or confirmed symptomatic hypoglycaemia 
(plasma glucose ≤3.1 mmol/L) and no weight gain
All these variables will be analysed based on the ‘on-treatment without rescue medication’ 
observation period separately in the same type of logistic regression model. The model will include 
factors for treatment and region China/Other. For the two responder in HbA1c endpoints, baseline 
HbA1c will be included in the model as a covariate, whereas for the weight responder endpoint 
(≥5% and ≥10% weight loss), baseline weight will be included instead. For the composite endpoint 
(cf. last bullet), both baseline HbA1c and baseline weight will be included. 
Missing response data at 30 weeks will be imputed from respectively the MMRM used for the 
primary analysis of HbA1c and the confirmatory secondary endpoint change in body weight at 30 
weeks. The results will be described by the odds ratio and the associated 95% confidence interval 
for the odds ratio.
2.5.2.2
Safety endpoints
The safety endpoints will be evaluated based on SAS using both the on-treatment observation 
period and the in-trial observation period unless otherwise stated. 
The following secondary endpoints are used to support the safety objectives:
!
Number of treatment emergent AEs during 30 weeks of treatment
!
Number of treatment emergent severe or BG confirmed symptomatic hypoglycaemic 
episodes during 30 weeks of treatment
!
Treatment emergent severe or BG confirmed symptomatic hypoglycaemic episodes 
during 30 weeks of treatment (yes/no)
Change in safety endpoints assessed from baseline to 30 weeks of treatment and/or follow up:
!
Haematology
!
Biochemistry
!
Calcitonin
!
Urinalysis
!
UACR
!
Pulse
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Statistical Analysis Plan
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Date:
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Trial ID: NN9535-4114
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!
ECG evaluation
!
Physical examination evaluation
!
Eye examination
Occurrence of semaglutide antibodies during 35 weeks of study duration (yes/no):
!
Anti-semaglutide antibodies
o
Anti-semaglutide antibodies with in vitro neutralising effect
o
Anti-semaglutide antibodies cross reacting with endogenous GLP-1

Cross reacting antibodies with in vitro neutralising effect to endogenous 
GLP-1
Anti-semaglutide antibody level during and after 30 weeks of treatment
All safety endpoints will be summarised and evaluated by descriptive statistics using the SAS.
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Statistical Analysis Plan
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Novo Nordisk
Trial ID: NN9535-4114
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Adverse events
The following endpoint related to adverse events is used to support the safety objective;
!
Number of treatment emergent adverse events (TEAEs)
A treatment-emergent AE is an event that has onset date (or increase in severity) during the on-
treatment observation period. These will therefore be referred to as ‘on-treatment AEs’ hereafter. 
On-treatment adverse events are summarised descriptively 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 years (R). These summaries are replicated by outputs including all 
‘in-trial’ adverse events (i.e., adverse events with onset date [or increase in severity] during the ‘in-
trial’ observation period). Adverse events with onset after the end of the ‘in-trial’ observation 
period will be reported in a listing. The development over time in gastrointestinal AEs will be 
presented graphically.
The most frequent adverse events will be defined as preferred terms (PTs) that are experienced by at 
least 5% of the subjects in any of the treatment arms. 
All AEs will be coded using the most recent version of the Medical Dictionary for Regulatory 
Activities (MedDRA) coding.
Pulse
Pulse will be analysed separately using an analysis similar to the primary analysis of the primary 
endpoint. However, this analysis will be based on SAS using the data from the on-treatment 
observation period but with the pulse value at baseline as a covariate.
Laboratory assessments
Amylase and lipase will be analysed separately with the same type of methods as for pulse with the 
corresponding baseline assessment as a covariate. The values will be log transformed in the 
analysis.
Calcitonin
In addition to the descriptive statistics and categorical summary showing number of values in the 
categories normal, high, >20 ng/L, 50 ng/L and >100 ng/L, all subjects with any post-baseline value 
of calcitonin above 20 ng/L will be assessed.
Classification of Hypoglycaemia 
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Statistical Analysis Plan
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Trial ID: NN9535-4114
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Treatment emergent: hypoglycaemic episodes will be defined as treatment emergent if the onsetof 
the episode occurswithin the on-treatment observation period (see definition of observation periods 
in Section 2.3.  
Nocturnal hypoglycaemic episodes: are episodes with time of onset 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)1. Therefore, Novo Nordisk has included hypoglycaemia with plasma glucose 
levels below this cut-off point of hypoglycaemia.
In this trial Novo Nordisk use the following classification in addition to the ADA classification (see
Figure 2–1):
!
Severe or BG confirmed symptomatic hypoglycaemia: An episode that is severe according
to the ADA classification2 or BG confirmed by a plasma glucose value <3.1 mmol/L
(56 mg/dL) with symptoms consistent with hypoglycaemia.
Hypoglycaemic
episode
PG ≤ 3.9 mmol/L 
(70 mg/dL) 
or 
Alleviation of 
symptoms 
or
Seizure, coma or 
fatal 
SMPG
measurement
PG < 3.1 mmol/L
(56 mg/dL)
with symptoms
PG < 3.1 mmol/L
(56 mg/dL)
without
symptoms
Symptomatic BG 
confirmed 
hypoglycaemia
Asymptomatic BG 
confirmed 
hypoglycaemia
Yes
No
Severe or 
BG confirmed 
symptomatic 
hypoglycaemia
BG confirmed 
hypoglycaemia
Severe or BG 
confirmed 
hypoglycaemia
Note: Glucose measurements are performed with capillary blood calibrated to plasma equivalent glucose values
BG: blood glucose  PG: plasma glucose  SMPG: Self-measured plasma glucose  
Subject 
able to 
treat him/
herself
Severe 
hypoglycaemia
(ADA 2013)
Figure 2–1
Novo Nordisk classification of hypoglycaemia
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Statistical Analysis Plan
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Trial ID: NN9535-4114
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ADA classification of hypoglycaemia2
!
Severe hypoglycaemia: An episode requiring assistance of another person to actively
administer carbohydrate, glucagon, or take of other corrective actions. Plasma glucose
concentration 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)
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Statistical Analysis Plan
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Figure 2–2
ADA classification of hypoglycaemia
Number of severe or BG confirmed symptomatic hypoglycaemic episodes
Data on treatment emergent hypoglycaemic episodes are 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 episodes rate per 100 years of exposure. Summaries of treatment 
emergent hypoglycaemic episodes will be presented as an overview including all episodes and 
episodes by severity.
The summary will include the number of severe or BG confirmed symptomatic hypoglycaemic 
episodes
Number of nocturnal hypoglycaemic episodes
The number of nocturnal (00:01-05:59 am) treatment emergent episodes will be displayed as 
described above for hypoglycaemic episodes.
Treatment emergent severe or BG confirmed symptomatic hypoglycaemic episodes (yes/no)
The number of subjects with treatment emergent severe or BG confirmed symptomatic 
hypoglycaemic episodes (yes/no) including nocturnal severe or BG confirmed symptomatic 
hypoglycaemic episodes (yes/no) can be assessed from the above described tables.
2.6
Health economics and/or patient reported outcomes
The PRO questionnaires, SF-36v2TM and DTSQs, will be used to evaluate the objective regarding 
Quality of Life, see Section 2.5.2.1for the details of the corresponding statistical analysis.
2.7
China cohort
In order to assess the effect of semaglutide in the Chinese population all analyses will be done in the 
same way as described for the entire trial, but only including subjects from region China. For the 
sensitivity analyses using multiple imputations the imputations for each subject based on the entire 
population will be used.
CONFIDENTIAL


Statistical Analysis Plan
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Date:
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Novo Nordisk
Trial ID: NN9535-4114
Version:
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UTN:U1111-1149-0432
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Statistical Analysis Plan
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3
Changes to the statistical analyses planned in the protocol
The changes to the statistical analyses planned in the protocol are described in the table below.
Change to planned statistical analysis
Rationale for change
A description of the estimand pertaining to the 
primary objective and primary endpoint has 
been added.
Similarly is done for the secondary objective 
and confirmatory secondary endpoint. See 
Section 1.1
Updated for clarification and to be in line with 
the use of estimands.
It is clarified that the SAP is relevant both for 
the analysis of data for the entire trial 
population and for the analysis of the China 
cohort by it self. See Section 2.1
A separate report describing the results for the 
Chinese cohort will be made. To clarify that the 
SAP is relevant for both the report for 
NN9535-4114 as well as the report for the 
Chinese cohort, this statement was added
A statement regarding which subjects belong in 
region China and which subjects belong in 
region Other was added. See Section2.1
Stratification was not done by country as 
specified in the protocol but by region 
China/Other. Therefore, this specification is 
needed.
“country” replaced by “region China/Other” in 
all statistical analyses throughout the document
Due to the change in stratification this change 
is necessary to comply with ICH E9.
A section describing data transformations has 
been added. See Section 2.1
Updated for clarification
The completer analysis has been separated 
from the “in-trial” analysis. Furthermore, a 
detailed description of the completer definition 
has been added. See Section 2.4
Updated for clarification.
In the description of the pattern mixture model 
sensitivity analysis it has been clarified that 
subjects should have initiated rescue 
medication or discontinued treatment 
prematurely to be assumed switched to control 
treatment. See Section 2.4
Updated for clarification.
In the description of the pattern mixture model 
sensitivity analysis it has been clarified in 
bullet 5 that it is subjects with an imputed value 
at visit 9 (week 30) who will have a penalty 
added. See Section 2.4
Updated for clarification.
Two extra sensitivity analyses – a tipping point 
analysis and a retrieved dropout analysis – have
The extra sensitivity analyses have been added 
to be in line with the sensitivity analyses used 
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Statistical Analysis Plan
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been added to the section regarding sensitivity 
analyses. See Section 2.4
in recent phase 3b trials investigating the effect
of semaglutide s.c.
A table has been added to get a schematic 
overview of all the sensitivity analyses for the 
primary endpoint. See Section 2.4
Updated for clarification.
The statistical subgroup analysis of the 
interaction effect between treatment and 
country has been removed as well as the 
evaluation of safety for China and Korea. See 
Section 2.4
Since the stratification has been changed to be 
by region China/Other the planned subgroup 
analysis and safety assessment for China and 
Korea were less relevant. Furthermore for the 
Chinese cohort, a separate report including all 
analyses planned for the entire trial population 
will be made.
A table has been added to get a schematic 
overview of all the sensitivity analyses for the 
primary endpoint. See Section 2.5.1
Updated for clarification.
“data” has been changed to “observation 
period” in the description on how to analyse 
supportive secondary efficacy endpoints. See 
Section 2.5.1
Updated for clarification
Treatment emergent has been added to the 
definition of “Treatment emergent severe or 
BG confirmed symptomatic hypoglycaemic 
episodes during 30 weeks of treatment 
(yes/no)” and to the definition of nocturnal 
hypoglycaemic episodes. See Section 2.5.2.2
Updated for clarification
It has been clarified that analysis of pulse is 
based on SAS instead of FAS. See Section
2.5.2.2
Pulse is a safety measure.
The description of how calcitonin will be 
reported has been updated. See Section
2.5.2.2
The update is to be in line with how calcitonin 
was reported in SUSTAIN 2 (trial NN9535-
3626) which is the mother trial for NN9535-
4114
The analyses of number of severe or BG 
confirmed hypoglycaemic episodes, number of 
nocturnal severe or BG confirmed 
hypoglycaemic episodes, number of subjects 
with severe or BG confirmed hypoglycaemic 
episodes and number of subjects with nocturnal 
severe or BG confirmed hypoglycaemic 
episodes have been removed. See Section 2.1
and Section 2.5.2.2
The number of severe or BG confirmed 
episodes is so low that a statistical analysis is 
not meaningful.
A paragraph describing the analyses that will 
be done for the Chinese cohort has been added. 
See Section 2.7
Updated for clarification.
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A number of typos and a updates to wordings 
have been added throughout the document.
To ease readability and understanding
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4
References
                                               
1 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
2 Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, et al. Hypoglycemia and diabetes: a report of a 
workgroup of the American Diabetes Association and the Endocrine Society. Diabetes Care. 2013;36(5):1384-95.
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Clinical Trial Report
Section 16.1.9
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Table of contents
Page
16.1.9.1 Pre-defined MedDRA search - list of preferred terms.......................................................................3
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16.1.9 Documentation of statistical methods
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16.1.9.1 Pre-defined MedDRA search - list of preferred terms
————————————————————————————————————————————————————————————————————————————————————————————————————
Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Acute gallstone disease                 AIDS cholangiopathy
                                        Ampulla of Vater stenosis
                                        Bile culture positive
                                        Bile duct necrosis
                                        Bile duct obstruction
                                        Bile duct pressure increased
                                        Bile duct stenosis
                                        Bile duct stenosis traumatic
                                        Bile duct stent insertion
                                        Bile duct stent removal
                                        Bile duct stone
                                        Bile output abnormal
                                        Bile output decreased
                                        Bile output increased
                                        Biliary abscess
                                        Biliary anastomosis
                                        Biliary anastomosis complication
                                        Biliary ascites
                                        Biliary cast syndrome
                                        Biliary cirrhosis
                                        Biliary colic
                                        Biliary dilatation
                                        Biliary dyskinesia
                                        Biliary fibrosis
                                        Biliary fistula
                                        Biliary fistula repair
                                        Biliary ischaemia
                                        Biliary sepsis
                                        Biliary sphincterotomy
                                        Biliary tract dilation procedure
                                        Biliary tract disorder
                                        Biliary tract infection
                                        Biliary tract operation
                                        Biliary-bronchial fistula
                                        Biliary-vascular fistula
                                        Bilirubin conjugated abnormal
                                        Bilirubin conjugated increased
                                        Bilirubin excretion disorder
                                        Biloma
                                        Biloma rupture
                                        Biopsy bile duct abnormal
                                        Biopsy gallbladder abnormal
                                        Blood bilirubin abnormal
                                        Blood bilirubin increased
                                        Cholangiectasis acquired
                                        Cholangiogram abnormal
                                        Cholangiolitis
                                        Cholangiostomy
                                        Cholangitis
                                        Cholangitis acute
                                        Cholangitis chronic
                                        Cholangitis infective
                                        Cholangitis sclerosing
                                        Cholecystectomy
                                        Cholecystitis
                                        Cholecystitis acute
                                        Cholecystitis chronic
                                        Cholecystitis infective
                                        Cholecystocholangitis
                                        Cholecystoenterostomy
                                        Cholecystogram intravenous abnormal
                                        Cholecystogram oral abnormal
————————————————————————————————————————————————————————————————————————————————————————————————————
MedDRA version 21.1
                                                                   nn9535/nn9535-4114/20190704_rm_er
                                                      02JUL2019:18:22:33 - l_meddra.sas/l_meddra.txt
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Section 16.1.9
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Pre-defined MedDRA search - list of preferred terms
————————————————————————————————————————————————————————————————————————————————————————————————————
Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Acute gallstone disease                 Cholecystostomy
                                        Choledochectomy
                                        Choledochoenterostomy
                                        Choledocholithotomy
                                        Choledochostomy
                                        Choledochotomy
                                        Cholelithiasis
                                        Cholelithiasis migration
                                        Cholelithiasis obstructive
                                        Cholelithotomy
                                        Cholelithotripsy
                                        Cholestasis
                                        Cholestasis of pregnancy
                                        Dilatation intrahepatic duct acquired
                                        Emphysematous cholecystitis
                                        Endoscopic retrograde cholangiopancreatography abnormal
                                        Endoscopy biliary tract abnormal
                                        Gallbladder abscess
                                        Gallbladder cholesterolosis
                                        Gallbladder disorder
                                        Gallbladder empyema
                                        Gallbladder enlargement
                                        Gallbladder fibrosis
                                       Gallbladder fistula
                                        Gallbladder fistula repair
                                        Gallbladder hyperfunction
                                        Gallbladder hypofunction
                                        Gallbladder injury
                                        Gallbladder mucocoele
                                        Gallbladder necrosis
                                        Gallbladder obstruction
                                        Gallbladder oedema
                                        Gallbladder operation
                                        Gallbladder palpable
                                        Gallbladder rupture
                                        Gallbladder varices
                                        Gallbladder volvulus
                                        Gallstone ileus
                                        Haemobilia
                                        Hepatitis cholestatic
                                        Hepatobiliary disease
                                        Hepatobiliary infection
                                        Hepatolithectomy
                                       Hydrocholecystis
                                        Hyperbilirubinaemia
                                        Hyperplastic cholecystopathy
                                        Jaundice
                                        Jaundice cholestatic
                                        Jaundice extrahepatic obstructive
                                        Lemmel's syndrome
                                        Limy bile syndrome
                                        Malignant biliary obstruction
                                        Pancreatobiliary sphincterotomy
                                        Parenteral nutrition associated liver disease
                                        Perforation bile duct
                                        Porcelain gallbladder
                                        Post cholecystectomy syndrome
                                        Post procedural bile leak
                                        Primary biliary cholangitis
                                        Pseudocholelithiasis
                                        Reynold's syndrome
                                        Sphincter of Oddi dysfunction
                                        Ultrasound biliary tract abnormal
————————————————————————————————————————————————————————————————————————————————————————————————————
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CONFIDENTIAL


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NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
5 of 152
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————————————————————————————————————————————————————————————————————————————————————————————————————
Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Acute gallstone disease                 Vanishing bile duct syndrome
                                        X-ray hepatobiliary abnormal
Acute renal failure                     Acute kidney injury
                                        Acute phosphate nephropathy
                                        Albuminuria
                                        Anuria
                                        Azotaemia
                                        Blood creatinine abnormal
                                        Blood creatinine increased
                                        Blood urea abnormal
                                        Blood urea increased
                                        Blood urea nitrogen
                                        creatinine ratio increased
                                        Continuous haemodiafiltration
                                        Creatinine renal clearance abnormal
                                        Creatinine renal clearance decreased
                                        Creatinine urine abnormal
                                        Creatinine urine decreased
                                        Crystal nephropathy
                                        Dialysis
                                        Foetal renal impairment
                                        Fractional excretion of sodium
                                        Glomerular filtration rate abnormal
                                        Glomerular filtration rate decreased
                                        Haemodialysis
                                        Haemofiltration
                                        Hypercreatininaemia
                                        Hyponatriuria
                                        Intradialytic parenteral nutrition
                                        Kidney injury molecule-1
                                        Neonatal anuria
                                        Nephritis
                                        Nephropathy toxic
                                        Oedema due to renal disease
                                        Oliguria
                                        Peritoneal dialysis
                                        Prerenal failure
                                        Protein urine present
                                        Proteinuria
                                        Renal failure
                                        Renal failure neonatal
                                        Renal function test abnormal
                                        Renal impairment
                                        Renal impairment neonatal
                                        Renal transplant
                                        Renal tubular disorder
                                        Renal tubular dysfunction
                                        Renal tubular injury
                                        Renal tubular necrosis
                                        Tubulointerstitial nephritis
                                        Urea renal clearance decreased
                                        Urine output decreased
Allergic reactions                      Acquired C1 inhibitor deficiency
                                        Acute generalised exanthematous pustulosis
                                        Administration related reaction
                                        Administration site dermatitis
                                        Administration site eczema
                                        Administration site hypersensitivity
                                        Administration site rash
                                        Administration site recall reaction
                                        Administration site urticaria
————————————————————————————————————————————————————————————————————————————————————————————————————
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CONFIDENTIAL


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NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
6 of 152
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————————————————————————————————————————————————————————————————————————————————————————————————————
Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Allergic reactions                      Administration site vasculitis
                                        Allergic bronchitis
                                       Allergic colitis
                                        Allergic cough
                                        Allergic cystitis
                                        Allergic eosinophilia
                                        Allergic gastroenteritis
                                        Allergic hepatitis
                                        Allergic keratitis
                                        Allergic oedema
                                        Allergic otitis externa
                                        Allergic otitis media
                                        Allergic pharyngitis
                                        Allergic reaction to excipient
                                        Allergic respiratory disease
                                        Allergic respiratory symptom
                                        Allergic sinusitis
                                        Allergic stomatitis
                                        Allergic transfusion reaction
                                        Allergy alert test positive
                                        Allergy test positive
                                        Allergy to immunoglobulin therapy
                                        Allergy to surgical sutures
                                        Allergy to vaccine
                                        Alveolitis allergic
                                        Anaphylactic reaction
                                        Anaphylactic shock
                                        Anaphylactic transfusion reaction
                                        Anaphylactoid reaction
                                        Anaphylactoid shock
                                        Anaphylaxis treatment
                                        Angioedema
                                        Anti-neutrophil cytoplasmic antibody positive vasculitis
                                        Antiallergic therapy
                                        Antiendomysial antibody positive
                                        Application site dermatitis
                                        Application site eczema
                                        Application site hypersensitivity
                                        Application site rash
                                        Application site recall reaction
                                        Application site urticaria
                                        Application site vasculitis
                                        Arthritis allergic
                                        Aspirin-exacerbated respiratory disease
                                        Atopic cough
                                        Atopy
                                        Blepharitis allergic
                                        Blood immunoglobulin E abnormal
                                        Blood immunoglobulin E increased
                                        Bromoderma
                                        Bronchospasm
                                        Catheter site dermatitis
                                        Catheter site eczema
                                        Catheter site hypersensitivity
                                        Catheter site rash
                                        Catheter site urticaria
                                        Catheter site vasculitis
                                        Chronic eosinophilic rhinosinusitis
                                        Chronic hyperplastic eosinophilic sinusitis
                                        Circulatory collapse
                                        Circumoral oedema
                                        Circumoral swelling
                                        Conjunctival oedema
————————————————————————————————————————————————————————————————————————————————————————————————————
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CONFIDENTIAL


NN9535
NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
7 of 152
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Allergic reactions                      Conjunctivitis allergic
                                        Contact stomatitis
                                        Contrast media allergy
                                        Contrast media reaction
                                        Corneal oedema
                                        Cutaneous vasculitis
                                        Dennie-Morgan fold
                                        Dermatitis
                                        Dermatitis acneiform
                                        Dermatitis allergic
                                        Dermatitis atopic
                                        Dermatitis bullous
                                        Dermatitis contact
                                        Dermatitis exfoliative
                                        Dermatitis exfoliative generalised
                                        Dermatitis herpetiformis
                                        Dermatitis infected
                                        Dermatitis psoriasiform
                                        Device allergy
                                        Dialysis membrane reaction
                                        Distributive shock
                                        Documented hypersensitivity to administered product
                                        Drug eruption
                                        Drug hypersensitivity
                                        Drug provocation test
                                        Drug reaction with eosinophilia and systemic symptoms
                                        Eczema
                                        Eczema infantile
                                        Eczema nummular
                                        Eczema vaccinatum
                                        Eczema vesicular
                                        Eczema weeping
                                        Encephalitis allergic
                                        Encephalopathy allergic
                                        Eosinophilic granulomatosis with polyangiitis
                                        Epidermal necrosis
                                        Epidermolysis
                                        Epidermolysis bullosa
                                        Epiglottic oedema
                                        Erythema multiforme
                                        Erythema nodosum
                                        Exfoliative rash
                                        Eye allergy
                                        Eye oedema
                                       Eye swelling
                                        Eyelid oedema
                                        Face oedema
                                        Fixed eruption
                                        Giant papillary conjunctivitis
                                        Gingival oedema
                                        Gingival swelling
                                        Gleich's syndrome
                                        Haemorrhagic urticaria
                                        Hand dermatitis
                                        Henoch-Schonlein purpura
                                        Henoch-Schonlein purpura nephritis
                                        Heparin-induced thrombocytopenia
                                        Hereditary angioedema
                                        Hereditary angioedema with C1 esterase inhibitor deficiency
                                        Hypersensitivity
                                        Hypersensitivity myocarditis
                                        Hypersensitivity vasculitis
                                        Idiopathic angioedema
————————————————————————————————————————————————————————————————————————————————————————————————————
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CONFIDENTIAL


NN9535
NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
8 of 152
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Allergic reactions                      Idiopathic urticaria
                                        Immediate post-injection reaction
                                        Immune thrombocytopenic purpura
                                        Immune tolerance induction
                                        Immune-mediated adverse reaction
                                        Implant site dermatitis
                                        Implant site hypersensitivity
                                        Implant site rash
                                        Implant site urticaria
                                        Incision site dermatitis
                                        Incision site rash
                                        Infusion related reaction
                                        Infusion site dermatitis
                                        Infusion site eczema
                                        Infusion site hypersensitivity
                                        Infusion site rash
                                        Infusion site recall reaction
                                        Infusion site urticaria
                                        Infusion site vasculitis
                                        Injection related reaction
                                        Injection site dermatitis
                                        Injection site eczema
                                        Injection site hypersensitivity
                                        Injection site rash
                                        Injection site recall reaction
                                        Injection site urticaria
                                        Injection site vasculitis
                                        Instillation site hypersensitivity
                                        Instillation site rash
                                        Instillation site urticaria
                                        Interstitial granulomatous dermatitis
                                        Intestinal angioedema
                                        Iodine allergy
                                        Kaposi's varicelliform eruption
                                        Kounis syndrome
                                        Laryngeal oedema
                                        Laryngitis allergic
                                        Laryngospasm
                                        Laryngotracheal oedema
                                        Limbal swelling
                                        Lip oedema
                                        Lip swelling
                                        Mast cell degranulation present
                                        Medical device site dermatitis
                                        Medical device site eczema
                                        Medical device site hypersensitivity
                                        Medical device site rash
                                        Medical device site recall reaction
                                        Medical device site urticaria
                                        Mouth swelling
                                        Mucocutaneous rash
                                        Multiple allergies
                                        Nephritis allergic
                                        Nikolsky's sign
                                        Nodular rash
                                        Oculomucocutaneous syndrome
                                        Oculorespiratory syndrome
                                        Oedema mouth
                                        Oral allergy syndrome
                                        Oropharyngeal blistering
                                        Oropharyngeal oedema
                                        Oropharyngeal spasm
                                        Oropharyngeal swelling
————————————————————————————————————————————————————————————————————————————————————————————————————
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CONFIDENTIAL


NN9535
NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
9 of 152
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Allergic reactions                      Palatal oedema
                                        Palatal swelling
                                        Palisaded neutrophilic granulomatous dermatitis
                                        Palpable purpura
                                        Pathergy reaction
                                        Perioral dermatitis
                                        Periorbital oedema
                                        Periorbital swelling
                                        Pharyngeal oedema
                                        Procedural shock
                                        Pruritus allergic
                                        Radioallergosorbent test positive
                                        Rash
                                        Rash erythematous
                                        Rash follicular
                                        Rash generalised
                                        Rash macular
                                        Rash maculo-papular
                                        Rash maculovesicular
                                        Rash morbilliform
                                        Rash neonatal
                                        Rash papulosquamous
                                        Rash pruritic
                                        Rash pustular
                                        Rash rubelliform
                                        Rash scarlatiniform
                                        Rash vesicular
                                        Reaction to azo-dyes
                                        Reaction to colouring
                                        Reaction to excipient
                                        Reaction to preservatives
                                        Red man syndrome
                                        Rhinitis allergic
                                        Scleral oedema
                                        Scleritis allergic
                                        Scrotal oedema
                                        Serum sickness
                                        Serum sickness-like reaction
                                        Shock
                                        Shock symptom
                                        Skin necrosis
                                        Skin reaction
                                        Skin test positive
                                        Solar urticaria
                                        Solvent sensitivity
                                        Stevens-Johnson syndrome
                                        Stoma site hypersensitivity
                                        Stoma site rash
                                        Swelling face
                                        Swelling of eyelid
                                        Swollen tongue
                                       Symmetrical drug-related intertriginous and flexural
                                        exanthema
                                        Therapeutic product cross-reactivity
                                        Tongue oedema
                                        Toxic epidermal necrolysis
                                        Toxic skin eruption
                                        Tracheal oedema
                                        Type I hypersensitivity
                                        Type II hypersensitivity
                                        Type III immune complex mediated reaction
                                        Type IV hypersensitivity reaction
                                        Urticaria
————————————————————————————————————————————————————————————————————————————————————————————————————
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CONFIDENTIAL


NN9535
NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
10 of 152
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Allergic reactions                      Urticaria cholinergic
                                        Urticaria chronic
                                        Urticaria contact
                                        Urticaria papular
                                        Urticaria physical
                                        Urticaria pigmentosa
                                        Urticaria vesiculosa
                                        Urticarial vasculitis
                                        Vaccination site dermatitis
                                        Vaccination site eczema
                                        Vaccination site exfoliation
                                        Vaccination site hypersensitivity
                                        Vaccination site rash
                                        Vaccination site recall reaction
                                        Vaccination site urticaria
                                        Vaccination site vasculitis
                                        Vaccination site vesicles
                                        Vaginal exfoliation
                                        Vaginal ulceration
                                        Vasculitic rash
                                        Vernal keratoconjunctivitis
                                        Vessel puncture site rash
                                        Vessel puncture site vesicles
                                        Vulval ulceration
                                        Vulvovaginal rash
                                        Vulvovaginal ulceration
                                        Vulvovaginitis allergic
Antibody                                Antibody test
                                        Antibody test abnormal
                                        Antibody test positive
                                        Autoantibody positive
                                        Autoantibody test
                                        Drug specific antibody
                                        Drug specific antibody present
                                        Inhibiting antibodies
                                        Neutralising antibodies
                                        Neutralising antibodies positive
                                        Non-neutralising antibodies positive
Cardiovascular disorders                Abnormal precordial movement
                                        Accelerated idioventricular rhythm
                                        Accessory cardiac pathway
                                        Acquired cardiac septal defect
                                        Acute aortic syndrome
                                        Acute cardiac event
                                        Acute coronary syndrome
                                        Acute haemorrhagic oedema of infancy
                                        Acute kidney injury
                                        Acute left ventricular failure
                                        Acute myocardial infarction
                                        Acute pulmonary oedema
                                        Acute respiratory failure
                                        Acute right ventricular failure
                                        Adams-Stokes syndrome
                                        Administration site thrombosis
                                        Administration site vasculitis
                                        Adrenal thrombosis
                                        Agnosia
                                        Agonal rhythm
                                        Alcohol septal ablation
                                        Amaurosis
                                        Amaurosis fugax
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CONFIDENTIAL


NN9535
NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
11 of 152
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Cardiovascular disorders                Amyloid related imaging abnormalities
                                        Amyloid related imaging abnormality-microhaemorrhages and
                                        haemosiderin deposits
                                        Amyloid related imaging abnormality-oedema
                                        effusion
                                        Anaphylactic reaction
                                        Anaphylactic shock
                                        Anaphylactic transfusion reaction
                                        Anaphylactoid reaction
                                        Anaphylactoid shock
                                        Angina pectoris
                                        Angina unstable
                                        Anginal equivalent
                                        Angiogram abnormal
                                        Angiogram cerebral abnormal
                                        Angiogram peripheral abnormal
                                        Angioplasty
                                        Anomalous atrioventricular excitation
                                        Anti-neutrophil cytoplasmic antibody positive vasculitis
                                        Antibody test abnormal
                                        Antibody test positive
                                        Antineutrophil cytoplasmic antibody increased
                                        Antineutrophil cytoplasmic antibody positive
                                        Anuria
                                        Aortic bypass
                                        Aortic embolus
                                        Aortic surgery
                                        Aortic thrombosis
                                        Aortitis
                                        Aortogram abnormal
                                        Aphasia
                                        Application site thrombosis
                                        Application site vasculitis
                                        Arrhythmia
                                        Arrhythmia neonatal
                                        Arrhythmia supraventricular
                                        Arrhythmogenic right ventricular dysplasia
                                        Arterectomy
                                        Arterectomy with graft replacement
                                        Arterial angioplasty
                                        Arterial bypass occlusion
                                        Arterial bypass operation
                                        Arterial bypass thrombosis
                                        Arterial graft
                                        Arterial occlusive disease
                                        Arterial stent insertion
                                        Arterial therapeutic procedure
                                        Arterial thrombosis
                                        Arteriogram abnormal
                                        Arteriogram carotid abnormal
                                        Arteriogram coronary abnormal
                                        Arteriosclerosis coronary artery
                                        Arteriospasm coronary
                                        Arteriotomy
                                        Arteriovenous fistula occlusion
                                        Arteriovenous fistula thrombosis
                                        Arteriovenous graft thrombosis
                                        Arteritis
                                        Arteritis coronary
                                        Artificial blood vessel occlusion
                                        Artificial heart implant
                                        Ascites
                                        Atherectomy
————————————————————————————————————————————————————————————————————————————————————————————————————
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CONFIDENTIAL


NN9535
NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
12 of 152
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Cardiovascular disorders                Atherosclerotic plaque rupture
                                        Atrial appendage closure
                                        Atrial appendage resection
                                        Atrial conduction time prolongation
                                        Atrial enlargement
                                        Atrial fibrillation
                                        Atrial flutter
                                        Atrial hypertrophy
                                        Atrial natriuretic peptide abnormal
                                        Atrial natriuretic peptide increased
                                        Atrial parasystole
                                        Atrial pressure increased
                                        Atrial septal defect acquired
                                        Atrial tachycardia
                                        Atrial thrombosis
                                        Atrioventricular block
                                        Atrioventricular block complete
                                        Atrioventricular block first degree
                                        Atrioventricular block second degree
                                        Atrioventricular conduction time shortened
                                        Atrioventricular dissociation
                                        Atrioventricular node dispersion
                                        Autoimmune myocarditis
                                        Axillary vein thrombosis
                                        Balint's syndrome
                                        Basal ganglia haematoma
                                        Basal ganglia haemorrhage
                                        Basal ganglia infarction
                                        Basal ganglia stroke
                                        Baseline foetal heart rate variability disorder
                                        Basilar artery aneurysm
                                        Basilar artery occlusion
                                        Basilar artery perforation
                                        Basilar artery stenosis
                                        Basilar artery thrombosis
                                        Behcet's syndrome
                                        Bendopnoea
                                        Bezold-Jarisch reflex
                                        Bifascicular block
                                        Biopsy heart abnormal
                                        Blindness transient
                                        Blood brain barrier defect
                                        Blood creatine phosphokinase MB abnormal
                                        Blood creatine phosphokinase MB increased
                                        Blood creatine phosphokinase abnormal
                                        Blood creatine phosphokinase increased
                                        Blood pressure diastolic abnormal
                                        Blood pressure diastolic decreased
                                        Blood pressure diastolic increased
                                        Blood pressure fluctuation
                                        Blood pressure immeasurable
                                        Blood pressure inadequately controlled
                                        Blood pressure systolic abnormal
                                        Blood pressure systolic decreased
                                        Blood pressure systolic increased
                                        Blood viscosity increased
                                        Bone infarction
                                        Brachiocephalic arteriosclerosis
                                        Brachiocephalic artery occlusion
                                        Brachiocephalic artery stenosis
                                        Brachiocephalic vein occlusion
                                        Brachiocephalic vein thrombosis
                                        Bradyarrhythmia
————————————————————————————————————————————————————————————————————————————————————————————————————
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CONFIDENTIAL


NN9535
NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
13 of 152
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Cardiovascular disorders                Bradycardia
                                        Bradycardia foetal
                                        Bradycardia neonatal
                                        Brain hypoxia
                                        Brain injury
                                        Brain natriuretic peptide abnormal
                                        Brain natriuretic peptide increased
                                        Brain stem embolism
                                        Brain stem haematoma
                                        Brain stem haemorrhage
                                        Brain stem infarction
                                        Brain stem ischaemia
                                        Brain stem microhaemorrhage
                                        Brain stem stroke
                                        Brain stem thrombosis
                                        Brain stent insertion
                                        Brugada syndrome
                                        Budd-Chiari syndrome
                                        Bundle branch block
                                        Bundle branch block bilateral
                                        Bundle branch block left
                                        Bundle branch block right
                                        CADASIL
                                        CARASIL syndrome
                                        CSF bilirubin positive
                                        CSF red blood cell count positive
                                        CT hypotension complex
                                        Capillaritis
                                        Capsular warning syndrome
                                        Cardiac amyloidosis
                                        Cardiac aneurysm
                                        Cardiac arrest
                                        Cardiac arrest neonatal
                                        Cardiac asthma
                                        Cardiac cirrhosis
                                        Cardiac contractility modulation therapy
                                        Cardiac death
                                        Cardiac dysfunction
                                        Cardiac electrophysiologic study abnormal
                                        Cardiac failure
                                        Cardiac failure acute
                                        Cardiac failure chronic
                                        Cardiac failure congestive
                                        Cardiac failure high output
                                        Cardiac fibrillation
                                        Cardiac flutter
                                        Cardiac function test abnormal
                                        Cardiac hypertrophy
                                        Cardiac imaging procedure abnormal
                                        Cardiac index abnormal
                                        Cardiac index decreased
                                        Cardiac index increased
                                        Cardiac iron overload
                                        Cardiac monitoring abnormal
                                        Cardiac operation
                                        Cardiac output decreased
                                        Cardiac pseudoaneurysm
                                        Cardiac resynchronisation therapy
                                        Cardiac sarcoidosis
                                        Cardiac septal hypertrophy
                                        Cardiac stress test abnormal
                                        Cardiac telemetry abnormal
                                        Cardiac ventricular scarring
————————————————————————————————————————————————————————————————————————————————————————————————————
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CONFIDENTIAL


NN9535
NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
14 of 152
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Cardiovascular disorders                Cardiac ventricular thrombosis
                                        Cardiac ventriculogram abnormal
                                        Cardiac ventriculogram left abnormal
                                        Cardiac ventriculogram right abnormal
                                        Cardio-respiratory arrest
                                        Cardio-respiratory arrest neonatal
                                        Cardio-respiratory distress
                                        Cardiogenic shock
                                        Cardiomegaly
                                        Cardiomyopathy
                                        Cardiomyopathy acute
                                        Cardiomyopathy alcoholic
                                        Cardiomyopathy neonatal
                                        Cardiopulmonary exercise test abnormal
                                        Cardiopulmonary failure
                                        Cardiorenal syndrome
                                        Cardiothoracic ratio increased
                                        Cardiotoxicity
                                        Cardiovascular disorder
                                        Cardiovascular event prophylaxis
                                        Cardiovascular function test abnormal
                                        Cardiovascular insufficiency
                                        Carotid aneurysm rupture
                                        Carotid angioplasty
                                        Carotid arterial embolus
                                        Carotid arteriosclerosis
                                       Carotid artery aneurysm
                                        Carotid artery bypass
                                        Carotid artery disease
                                        Carotid artery dissection
                                        Carotid artery dolichoectasia
                                        Carotid artery insufficiency
                                        Carotid artery occlusion
                                        Carotid artery perforation
                                        Carotid artery restenosis
                                        Carotid artery stenosis
                                        Carotid artery stent insertion
                                        Carotid artery stent removal
                                        Carotid artery thrombosis
                                        Carotid endarterectomy
                                        Carotid revascularisation
                                        Catheter site thrombosis
                                        Catheterisation venous
                                        Cavernous sinus thrombosis
                                        Central bradycardia
                                        Central nervous system haemorrhage
                                        Central nervous system vasculitis
                                        Central pain syndrome
                                        Central venous catheterisation
                                        Central venous pressure increased
                                        Cerebellar artery occlusion
                                        Cerebellar artery thrombosis
                                        Cerebellar embolism
                                        Cerebellar haematoma
                                        Cerebellar haemorrhage
                                        Cerebellar infarction
                                        Cerebellar ischaemia
                                        Cerebellar microhaemorrhage
                                        Cerebellar stroke
                                        Cerebral amyloid angiopathy
                                        Cerebral aneurysm perforation
                                        Cerebral aneurysm ruptured syphilitic
                                        Cerebral arteriosclerosis
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Section 16.1.9
CONFIDENTIAL
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03 July 2019
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Version:
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Status:
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Cardiovascular disorders                Cerebral arteriovenous malformation haemorrhagic
                                        Cerebral arteritis
                                        Cerebral artery embolism
                                        Cerebral artery occlusion
                                        Cerebral artery perforation
                                        Cerebral artery restenosis
                                        Cerebral artery stenosis
                                        Cerebral artery thrombosis
                                        Cerebral capillary telangiectasia
                                        Cerebral circulatory failure
                                        Cerebral congestion
                                        Cerebral endovascular aneurysm repair
                                        Cerebral gas embolism
                                        Cerebral haematoma
                                        Cerebral haemorrhage
                                        Cerebral haemorrhage foetal
                                        Cerebral haemorrhage neonatal
                                        Cerebral haemosiderin deposition
                                        Cerebral hypoperfusion
                                        Cerebral infarction
                                        Cerebral infarction foetal
                                        Cerebral ischaemia
                                        Cerebral microangiopathy
                                        Cerebral microembolism
                                        Cerebral microhaemorrhage
                                        Cerebral reperfusion injury
                                        Cerebral revascularisation
                                        Cerebral septic infarct
                                        Cerebral small vessel ischaemic disease
                                        Cerebral thrombosis
                                        Cerebral vascular occlusion
                                        Cerebral vasoconstriction
                                        Cerebral venous thrombosis
                                        Cerebral ventricular rupture
                                        Cerebrospinal thrombotic tamponade
                                        Cerebrovascular accident
                                        Cerebrovascular accident prophylaxis
                                        Cerebrovascular arteriovenous malformation
                                        Cerebrovascular disorder
                                        Cerebrovascular insufficiency
                                        Cerebrovascular operation
                                        Cerebrovascular stenosis
                                        Chagas' cardiomyopathy
                                        Charcot-Bouchard microaneurysms
                                        Chest X-ray abnormal
                                        Chest pain
                                        Choroidal infarction
                                        Chronic left ventricular failure
                                        Chronic pigmented purpura
                                        Chronic right ventricular failure
                                        Chronotropic incompetence
                                        Circulatory collapse
                                        Coeliac artery occlusion
                                        Cogan's syndrome
                                        Collateral circulation
                                        Compression garment application
                                        Computerised tomogram coronary artery abnormal
                                        Computerised tomogram thorax abnormal
                                        Conduction disorder
                                        Congenital cerebrovascular anomaly
                                        Congenital hemiparesis
                                        Congestive cardiomyopathy
                                        Cor pulmonale
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CONFIDENTIAL


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NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
16 of 152
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Cardiovascular disorders                Cor pulmonale acute
                                        Cor pulmonale chronic
                                        Coronary angioplasty
                                        Coronary arterial stent insertion
                                        Coronary artery bypass
                                        Coronary artery compression
                                        Coronary artery disease
                                        Coronary artery dissection
                                        Coronary artery embolism
                                        Coronary artery insufficiency
                                        Coronary artery occlusion
                                        Coronary artery reocclusion
                                        Coronary artery restenosis
                                        Coronary artery stenosis
                                        Coronary artery surgery
                                        Coronary artery thrombosis
                                        Coronary brachytherapy
                                        Coronary bypass stenosis
                                        Coronary bypass thrombosis
                                        Coronary endarterectomy
                                        Coronary no-reflow phenomenon
                                        Coronary ostial stenosis
                                        Coronary revascularisation
                                        Coronary vascular graft occlusion
                                        Coronary vascular graft stenosis
                                        Coxsackie carditis
                                        Coxsackie myocarditis
                                        Cryoglobulinaemia
                                        Cryoglobulins present
                                        Cutaneous vasculitis
                                        Cytomegalovirus myocarditis
                                        Cytotoxic cardiomyopathy
                                        Decreased ventricular preload
                                        Deep vein thrombosis
                                        Deep vein thrombosis postoperative
                                        Defect conduction intraventricular
                                        Delayed ischaemic neurological deficit
                                        Device embolisation
                                        Device occlusion
                                        Device related thrombosis
                                        Diabetic arteritis
                                        Diabetic cardiomyopathy
                                        Diabetic coronary microangiopathy
                                        Diastolic dysfunction
                                        Diffuse vasculitis
                                        Dilatation atrial
                                        Dilatation ventricular
                                        Diplegia
                                        Directional Doppler flow tests abnormal
                                        Dissecting coronary artery aneurysm
                                        Disseminated intravascular coagulation
                                        Disseminated intravascular coagulation in newborn
                                        Distributive shock
                                        Dural arteriovenous fistula
                                        Dysarthria
                                        Dyspnoea
                                        Dyspnoea paroxysmal nocturnal
                                        ECG P wave inverted
                                        ECG electrically inactive area
                                        ECG signs of myocardial infarction
                                        ECG signs of myocardial ischaemia
                                        ECG signs of ventricular hypertrophy
                                        Echocardiogram abnormal
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NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
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Status:
Final
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————————————————————————————————————————————————————————————————————————————————————————————————————
Cardiovascular disorders                Ejection fraction abnormal
                                        Ejection fraction decreased
                                        Electrocardiogram P wave abnormal
                                        Electrocardiogram PQ interval prolonged
                                        Electrocardiogram PQ interval shortened
                                        Electrocardiogram PR prolongation
                                        Electrocardiogram PR segment depression
                                        Electrocardiogram PR shortened
                                        Electrocardiogram Q wave abnormal
                                        Electrocardiogram QRS complex prolonged
                                        Electrocardiogram QT interval abnormal
                                        Electrocardiogram QT prolonged
                                        Electrocardiogram RR interval prolonged
                                        Electrocardiogram ST segment abnormal
                                       Electrocardiogram ST segment depression
                                        Electrocardiogram ST segment elevation
                                        Electrocardiogram ST-T segment abnormal
                                        Electrocardiogram ST-T segment depression
                                        Electrocardiogram ST-T segment elevation
                                        Electrocardiogram T wave abnormal
                                        Electrocardiogram T wave inversion
                                        Electrocardiogram U wave inversion
                                        Electrocardiogram U wave present
                                        Electrocardiogram U-wave abnormality
                                        Electrocardiogram abnormal
                                        Electrocardiogram ambulatory abnormal
                                        Electrocardiogram change
                                       Electrocardiogram delta waves abnormal
                                        Electrocardiogram repolarisation abnormality
                                        Embolia cutis medicamentosa
                                        Embolic cerebral infarction
                                        Embolic pneumonia
                                        Embolic stroke
                                        Embolism
                                        Embolism arterial
                                        Embolism venous
                                        Endarterectomy
                                        Endocardial fibroelastosis
                                        Endotoxic shock
                                        Eosinophilic granulomatosis with polyangiitis
                                        Eosinophilic myocarditis
                                        Epidural haemorrhage
                                        Erythema induratum
                                        Exercise electrocardiogram abnormal
                                        Exercise test abnormal
                                        External counterpulsation
                                        Extra-axial haemorrhage
                                        Extradural haematoma
                                        Extraischaemic cerebral haematoma
                                        Extrasystoles
                                        Femoral artery embolism
                                        Foetal arrhythmia
                                        Foetal cerebrovascular disorder
                                        Foetal heart rate acceleration abnormality
                                        Foetal heart rate deceleration abnormality
                                        Foetal heart rate disorder
                                        Foetal tachyarrhythmia
                                        Gonococcal heart disease
                                        Goodpasture's syndrome
                                        Graft thrombosis
                                        Granulomatosis with polyangiitis
                                        Grey syndrome neonatal
                                        HIV cardiomyopathy
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CONFIDENTIAL


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NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
18 of 152
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Cardiovascular disorders                Haemorrhage coronary artery
                                        Haemorrhage intracranial
                                        Haemorrhagic adrenal infarction
                                        Haemorrhagic cerebral infarction
                                        Haemorrhagic infarction
                                        Haemorrhagic stroke
                                        Haemorrhagic transformation stroke
                                        Haemorrhagic vasculitis
                                        Haemorrhoids thrombosed
                                        Heart alternation
                                        Heart and lung transplant
                                        Heart block congenital
                                        Heart rate abnormal
                                        Heart rate decreased
                                        Heart rate increased
                                        Heart rate irregular
                                        Heart transplant
                                        Hemianaesthesia
                                        Hemiasomatognosia
                                        Hemihyperaesthesia
                                        Hemiparaesthesia
                                        Hemiparesis
                                        Hemiplegia
                                        Henoch-Schonlein purpura
                                        Henoch-Schonlein purpura nephritis
                                        Heparin-induced thrombocytopenia
                                        Hepatic artery embolism
                                        Hepatic artery occlusion
                                        Hepatic artery thrombosis
                                        Hepatic congestion
                                        Hepatic infarction
                                        Hepatic vascular thrombosis
                                        Hepatic vein dilatation
                                        Hepatic vein embolism
                                        Hepatic vein occlusion
                                        Hepatic vein thrombosis
                                        Hepatojugular reflux
                                        Hepatomegaly
                                        Hepatorenal failure
                                        Homans' sign positive
                                        Hyperdynamic left ventricle
                                        Hypersensitivity myocarditis
                                        Hypersensitivity vasculitis
                                        Hypertensive cardiomyopathy
                                        Hypertensive cerebrovascular disease
                                        Hypertrophic cardiomyopathy
                                        Hypoperfusion
                                        Hypothenar hammer syndrome
                                        Hypovolaemic shock
                                        Hypoxic-ischaemic encephalopathy
                                        Iliac artery embolism
                                        Iliac artery occlusion
                                        Iliac vein occlusion
                                        Implant site thrombosis
                                        Incision site vessel occlusion
                                        Increased ventricular preload
                                        Infarction
                                        Inferior vena cava syndrome
                                        Inferior vena caval occlusion
                                        Infusion site thrombosis
                                        Infusion site vasculitis
                                        Injection site thrombosis
                                        Injection site vasculitis
————————————————————————————————————————————————————————————————————————————————————————————————————
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CONFIDENTIAL


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NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
19 of 152
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Cardiovascular disorders                Inner ear infarction
                                        Instillation site thrombosis
                                        Internal carotid artery kinking
                                        Intestinal infarction
                                        Intra-aortic balloon placement
                                        Intra-cerebral aneurysm operation
                                        Intracardiac mass
                                        Intracardiac pressure increased
                                        Intracardiac thrombus
                                        Intracerebral haematoma evacuation
                                        Intracranial aneurysm
                                        Intracranial artery dissection
                                        Intracranial haematoma
                                        Intracranial tumour haemorrhage
                                        Intracranial venous sinus thrombosis
                                        Intraoperative cerebral artery occlusion
                                        Intraventricular haemorrhage
                                        Intraventricular haemorrhage neonatal
                                        Irregular breathing
                                        Ischaemic cardiomyopathy
                                        Ischaemic cerebral infarction
                                        Ischaemic mitral regurgitation
                                        Ischaemic stroke
                                        Jugular vein distension
                                        Jugular vein occlusion
                                        Jugular vein thrombosis
                                        Junctional ectopic tachycardia
                                        Kawasaki's disease
                                        Kounis syndrome
                                        Labile blood pressure
                                        Lacunar infarction
                                        Lacunar stroke
                                        Langerhans' cell histiocytosis
                                        Lateral medullary syndrome
                                        Lateropulsion
                                        Left atrial dilatation
                                        Left atrial enlargement
                                        Left ventricular diastolic collapse
                                        Left ventricular dilatation
                                        Left ventricular dysfunction
                                        Left ventricular end-diastolic pressure decreased
                                        Left ventricular enlargement
                                        Left ventricular failure
                                        Left ventricular heave
                                        Lenegre's disease
                                        Leriche syndrome
                                        Long QT syndrome
                                        Long QT syndrome congenital
                                        Loss of consciousness
                                        Low cardiac output syndrome
                                        Lower respiratory tract congestion
                                        Lown-Ganong-Levine syndrome
                                        Lupus myocarditis
                                        Lupus vasculitis
                                        Lyme carditis
                                        MAGIC syndrome
                                        Mahler sign
                                        Malarial myocarditis
                                        May-Thurner syndrome
                                        Medical device site thrombosis
                                        Medical device site vasculitis
                                        Meningorrhagia
                                        Mental status changes
————————————————————————————————————————————————————————————————————————————————————————————————————
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CONFIDENTIAL


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NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
20 of 152
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Cardiovascular disorders                Mesenteric arterial occlusion
                                        Mesenteric arteriosclerosis
                                        Mesenteric artery embolism
                                        Mesenteric artery stenosis
                                        Mesenteric artery stent insertion
                                        Mesenteric artery thrombosis
                                        Mesenteric vascular insufficiency
                                        Mesenteric vascular occlusion
                                        Mesenteric vein thrombosis
                                        Mesenteric venous occlusion
                                        Metabolic cardiomyopathy
                                        Microembolism
                                        Microscopic polyangiitis
                                        Microvascular coronary artery disease
                                        Migrainous infarction
                                        Millard-Gubler syndrome
                                        Modified Rankin score decreased
                                        Modified Rankin score increased
                                        Monoparesis
                                        Monoplegia
                                        Moyamoya disease
                                        Multiple gated acquisition scan abnormal
                                        Multiple organ dysfunction syndrome
                                        Myocardiac abscess
                                        Myocardial calcification
                                        Myocardial depression
                                        Myocardial fibrosis
                                        Myocardial haemorrhage
                                        Myocardial hypoxia
                                        Myocardial infarction
                                        Myocardial ischaemia
                                        Myocardial necrosis
                                        Myocardial necrosis marker increased
                                        Myocardial reperfusion injury
                                        Myocardial stunning
                                        Myocarditis
                                        Myocarditis bacterial
                                        Myocarditis helminthic
                                        Myocarditis infectious
                                        Myocarditis meningococcal
                                        Myocarditis mycotic
                                        Myocarditis post infection
                                        Myocarditis septic
                                        Myocarditis syphilitic
                                        Myocarditis toxoplasmal
                                        Myoglobinaemia
                                        Myoglobinuria
                                        N-terminal prohormone brain natriuretic peptide abnormal
                                        N-terminal prohormone brain natriuretic peptide increased
                                        NIH stroke scale abnormal
                                        NIH stroke scale score decreased
                                        NIH stroke scale score increased
                                        Neonatal anuria
                                        Neonatal cardiac failure
                                        Neonatal multi-organ failure
                                        Neonatal respiratory failure
                                        Neonatal tachycardia
                                        Neurogenic shock
                                        Nocturia
                                        Nocturnal dyspnoea
                                        Nodal arrhythmia
                                        Nodal rhythm
                                        Nodular vasculitis
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CONFIDENTIAL


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NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
21 of 152
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Cardiovascular disorders                Non-obstructive cardiomyopathy
                                        Nonreassuring foetal heart rate pattern
                                        Nuclear magnetic resonance imaging thoracic abnormal
                                        Obesity cardiomyopathy
                                        Obstetrical pulmonary embolism
                                        Obstructive shock
                                        Ocular vasculitis
                                        Oedema
                                        Oedema blister
                                        Oedema due to cardiac disease
                                       Oedema neonatal
                                        Oedema peripheral
                                        Ophthalmic artery thrombosis
                                        Ophthalmic vein thrombosis
                                        Optic nerve infarction
                                        Organ failure
                                        Orthopnoea
                                        Orthostatic hypotension
                                        Ovarian vein thrombosis
                                        Pacemaker generated arrhythmia
                                        Pacemaker syndrome
                                        Paget-Schroetter syndrome
                                        Palpable purpura
                                        Palpitations
                                        Pancreatic infarction
                                        Papillary muscle disorder
                                        Papillary muscle haemorrhage
                                        Papillary muscle infarction
                                        Paradoxical embolism
                                        Paralysis
                                        Paraneoplastic thrombosis
                                        Paraparesis
                                        Paraplegia
                                        Parasystole
                                        Paresis
                                        Paroxysmal arrhythmia
                                        Paroxysmal atrioventricular block
                                        Pelvic venous thrombosis
                                        Penile artery occlusion
                                        Penile vein thrombosis
                                        Percutaneous coronary intervention
                                        Perinatal stroke
                                        Peripartum cardiomyopathy
                                        Peripheral arterial occlusive disease
                                        Peripheral arterial reocclusion
                                        Peripheral artery angioplasty
                                        Peripheral artery bypass
                                        Peripheral artery occlusion
                                        Peripheral artery stent insertion
                                        Peripheral artery thrombosis
                                        Peripheral embolism
                                        Peripheral endarterectomy
                                        Peripheral oedema neonatal
                                        Peripheral revascularisation
                                        Peripheral swelling
                                        Periprocedural myocardial infarction
                                        Periventricular haemorrhage neonatal
                                        Phlebectomy
                                        Pituitary haemorrhage
                                        Pituitary infarction
                                        Placental infarction
                                        Plasma viscosity abnormal
                                        Pneumatic compression therapy
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CONFIDENTIAL


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NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
22 of 152
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Cardiovascular disorders                Polyarteritis nodosa
                                        Polymyalgia rheumatica
                                        Popliteal artery entrapment syndrome
                                        Portal shunt procedure
                                        Portal vein cavernous transformation
                                        Portal vein occlusion
                                        Portal vein thrombosis
                                        Portosplenomesenteric venous thrombosis
                                        Post angioplasty restenosis
                                        Post cardiac arrest syndrome
                                        Post procedural myocardial infarction
                                        Post procedural pulmonary embolism
                                        Post procedural stroke
                                        Post stroke depression
                                        Post thrombotic syndrome
                                        Posthaemorrhagic hydrocephalus
                                        Postinfarction angina
                                        Postoperative thrombosis
                                        Postpartum thrombosis
                                        Postpartum venous thrombosis
                                        Precerebral arteriosclerosis
                                        Precerebral artery occlusion
                                        Precerebral artery thrombosis
                                        Prerenal failure
                                        Primary familial brain calcification
                                        Prinzmetal angina
                                        Procedural shock
                                        Profundaplasty
                                        Prohormone brain natriuretic peptide abnormal
                                        Prohormone brain natriuretic peptide increased
                                        Propofol infusion syndrome
                                        Prosthetic cardiac valve thrombosis
                                        Prosthetic vessel implantation
                                        Pseudovasculitis
                                        Pulmonary arterial wedge pressure increased
                                        Pulmonary artery occlusion
                                        Pulmonary artery therapeutic procedure
                                        Pulmonary artery thrombosis
                                        Pulmonary congestion
                                        Pulmonary embolism
                                        Pulmonary endarterectomy
                                        Pulmonary infarction
                                        Pulmonary microemboli
                                        Pulmonary oedema
                                        Pulmonary oedema neonatal
                                        Pulmonary thrombosis
                                        Pulmonary tumour thrombotic microangiopathy
                                        Pulmonary vasculitis
                                        Pulmonary vein occlusion
                                        Pulmonary veno-occlusive disease
                                        Pulmonary venous thrombosis
                                        Pulse absent
                                        Pulseless electrical activity
                                        Putamen haemorrhage
                                        Quadriparesis
                                        Quadriplegia
                                        Radiation associated cardiac failure
                                        Radiation myocarditis
                                        Radiation vasculitis
                                        Rebound tachycardia
                                        Renal arteritis
                                        Renal artery angioplasty
                                        Renal artery occlusion
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CONFIDENTIAL


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NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
23 of 152
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Cardiovascular disorders                Renal artery thrombosis
                                        Renal embolism
                                        Renal failure
                                        Renal failure neonatal
                                        Renal infarct
                                        Renal vascular thrombosis
                                        Renal vasculitis
                                        Renal vein embolism
                                        Renal vein occlusion
                                        Renal vein thrombosis
                                        Reperfusion arrhythmia
                                        Respiratory failure
                                        Respiratory sinus arrhythmia magnitude abnormal
                                        Respiratory sinus arrhythmia magnitude decreased
                                        Respiratory sinus arrhythmia magnitude increased
                                        Restrictive cardiomyopathy
                                        Retinal artery embolism
                                        Retinal artery occlusion
                                        Retinal artery thrombosis
                                        Retinal infarction
                                        Retinal vascular thrombosis
                                        Retinal vasculitis
                                        Retinal vein occlusion
                                        Retinal vein thrombosis
                                        Retrograde p-waves
                                        Reversible cerebral vasoconstriction syndrome
                                        Reversible ischaemic neurological deficit
                                        Rheumatoid vasculitis
                                        Rhythm idioventricular
                                        Right atrial dilatation
                                        Right atrial enlargement
                                        Right atrial pressure increased
                                        Right hemisphere deficit syndrome
                                        Right ventricle outflow tract obstruction
                                        Right ventricular diastolic collapse
                                        Right ventricular dilatation
                                        Right ventricular dysfunction
                                        Right ventricular ejection fraction decreased
                                        Right ventricular enlargement
                                        Right ventricular failure
                                        Right ventricular heave
                                        Right ventricular systolic pressure decreased
                                        Ruptured cerebral aneurysm
                                        SI QIII TIII pattern
                                        Scan myocardial perfusion abnormal
                                        Segmented hyalinising vasculitis
                                        Septic shock
                                       Shock
                                        Shock haemorrhagic
                                        Shock hypoglycaemic
                                        Shock symptom
                                        Shunt occlusion
                                        Shunt thrombosis
                                        Silent myocardial infarction
                                        Sinoatrial block
                                        Sinus arrest
                                        Sinus arrhythmia
                                        Sinus bradycardia
                                        Sinus node dysfunction
                                        Sinus tachycardia
                                        Sneddon's syndrome
                                        Spinal artery embolism
                                        Spinal artery thrombosis
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CONFIDENTIAL


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NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
24 of 152
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Cardiovascular disorders                Spinal cord haematoma
                                        Spinal cord haemorrhage
                                        Spinal cord infarction
                                        Spinal cord ischaemia
                                        Spinal epidural haematoma
                                        Spinal epidural haemorrhage
                                        Spinal subarachnoid haemorrhage
                                        Spinal subdural haematoma
                                        Spinal subdural haemorrhage
                                        Spinal vascular disorder
                                        Spinal vessel congenital anomaly
                                        Splenic artery thrombosis
                                        Splenic embolism
                                        Splenic infarction
                                        Splenic thrombosis
                                        Splenic vein occlusion
                                        Splenic vein thrombosis
                                        Stoma site thrombosis
                                        Stress cardiomyopathy
                                        Stress echocardiogram abnormal
                                        Stroke in evolution
                                        Stroke volume decreased
                                        Subarachnoid haematoma
                                        Subarachnoid haemorrhage
                                        Subarachnoid haemorrhage neonatal
                                        Subclavian artery embolism
                                        Subclavian artery occlusion
                                        Subclavian artery thrombosis
                                        Subclavian coronary steal syndrome
                                        Subclavian steal syndrome
                                        Subclavian vein occlusion
                                        Subclavian vein thrombosis
                                        Subdural haematoma
                                        Subdural haematoma evacuation
                                        Subdural haemorrhage
                                        Subdural haemorrhage neonatal
                                        Subendocardial ischaemia
                                        Sudden cardiac death
                                        Sudden death
                                        Superficial siderosis of central nervous system
                                        Superior sagittal sinus thrombosis
                                       Superior vena cava occlusion
                                        Superior vena cava syndrome
                                        Supraventricular extrasystoles
                                        Supraventricular tachyarrhythmia
                                        Supraventricular tachycardia
                                        Surgical vascular shunt
                                        Surgical ventricular restoration
                                        Susac's syndrome
                                        Syncope
                                        Systolic anterior motion of mitral valve
                                        Systolic dysfunction
                                        Tachyarrhythmia
                                        Tachycardia
                                        Tachycardia foetal
                                        Tachycardia induced cardiomyopathy
                                        Tachycardia paroxysmal
                                        Takayasu's arteritis
                                        Temporal arteritis
                                        Testicular infarction
                                        Thalamic infarction
                                        Thalamus haemorrhage
                                        Thrombectomy
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CONFIDENTIAL


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NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
25 of 152
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Cardiovascular disorders                Thromboangiitis obliterans
                                        Thromboembolectomy
                                        Thrombolysis
                                        Thrombophlebitis
                                        Thrombophlebitis migrans
                                        Thrombophlebitis neonatal
                                        Thrombophlebitis superficial
                                        Thrombosed varicose vein
                                        Thrombosis
                                        Thrombosis corpora cavernosa
                                        Thrombosis in device
                                        Thrombosis mesenteric vessel
                                        Thrombosis prophylaxis
                                        Thrombotic cerebral infarction
                                        Thrombotic microangiopathy
                                        Thrombotic stroke
                                        Thrombotic thrombocytopenic purpura
                                        Thyroid infarction
                                        Thyrotoxic cardiomyopathy
                                        Torsade de pointes
                                        Toxic shock syndrome
                                        Transient ischaemic attack
                                        Transverse sinus thrombosis
                                        Trifascicular block
                                        Troponin I increased
                                        Troponin T increased
                                        Troponin increased
                                        Truncus coeliacus thrombosis
                                        Tumour embolism
                                        Tumour thrombosis
                                        Type 2 lepra reaction
                                        Ultrasonic angiogram abnormal
                                        Ultrasound Doppler abnormal
                                        Umbilical cord occlusion
                                        Umbilical cord thrombosis
                                        Urticarial vasculitis
                                        Vaccination site thrombosis
                                        Vaccination site vasculitis
                                        Vascular access site thrombosis
                                        Vascular device occlusion
                                        Vascular encephalopathy
                                        Vascular graft
                                        Vascular graft occlusion
                                        Vascular graft thrombosis
                                        Vascular operation
                                        Vascular pseudoaneurysm thrombosis
                                        Vascular purpura
                                        Vascular resistance pulmonary increased
                                        Vascular stent insertion
                                        Vascular stent occlusion
                                        Vascular stent stenosis
                                        Vascular stent thrombosis
                                        Vasculitic rash
                                        Vasculitis
                                        Vasculitis gastrointestinal
                                        Vasculitis necrotising
                                        Vasodilation procedure
                                        Vein of Galen aneurysmal malformation
                                        Vena cava embolism
                                        Vena cava filter insertion
                                        Vena cava filter removal
                                        Vena cava thrombosis
                                        Venogram abnormal
————————————————————————————————————————————————————————————————————————————————————————————————————
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CONFIDENTIAL


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NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
26 of 152
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Cardiovascular disorders                Venoocclusive disease
                                        Venoocclusive liver disease
                                        Venous angioplasty
                                        Venous occlusion
                                        Venous operation
                                        Venous pressure increased
                                        Venous pressure jugular abnormal
                                        Venous pressure jugular increased
                                        Venous recanalisation
                                        Venous repair
                                        Venous stent insertion
                                        Venous thrombosis
                                        Venous thrombosis in pregnancy
                                        Venous thrombosis limb
                                        Venous thrombosis neonatal
                                        Ventricular arrhythmia
                                        Ventricular assist device insertion
                                        Ventricular asystole
                                        Ventricular compliance decreased
                                        Ventricular dysfunction
                                        Ventricular dyskinesia
                                       Ventricular dyssynchrony
                                        Ventricular enlargement
                                        Ventricular extrasystoles
                                        Ventricular failure
                                        Ventricular fibrillation
                                        Ventricular flutter
                                        Ventricular hyperkinesia
                                        Ventricular hypertrophy
                                        Ventricular hypokinesia
                                        Ventricular parasystole
                                        Ventricular pre-excitation
                                        Ventricular remodelling
                                        Ventricular septal defect acquired
                                        Ventricular tachyarrhythmia
                                        Ventricular tachycardia
                                        Vertebral artery aneurysm
                                        Vertebral artery dissection
                                        Vertebral artery occlusion
                                        Vertebral artery perforation
                                        Vertebral artery stenosis
                                        Vertebral artery thrombosis
                                        Vertebrobasilar dolichoectasia
                                        Vertebrobasilar insufficiency
                                        Vessel puncture site occlusion
                                        Vessel puncture site thrombosis
                                        Viral cardiomyopathy
                                        Viral myocarditis
                                        Viral vasculitis
                                        Visceral venous thrombosis
                                        Visual acuity reduced transiently
                                        Visual agnosia
                                        Visual midline shift syndrome
                                        Wall motion score index abnormal
                                        Wandering pacemaker
                                        Wellens' syndrome
                                        Withdrawal arrhythmia
                                        Wolff-Parkinson-White syndrome
                                        Wolff-Parkinson-White syndrome congenital
Diabetic retinopathy Phase 3a search   Amaurosis
                                        Cystoid macular oedema
                                        Diabetic blindness
————————————————————————————————————————————————————————————————————————————————————————————————————
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CONFIDENTIAL


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NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Diabetic retinopathy Phase 3a search    Diabetic eye disease
                                        Diabetic glaucoma
                                        Diabetic retinal oedema
                                        Diabetic retinopathy
                                        Diabetic uveitis
                                        Exudative retinopathy
                                        Macular ischaemia
                                        Macular oedema
                                        Macular opacity
                                        Macular pseudohole
                                        Maculopathy
                                        Night blindness
                                        Papilloedema
                                        Papillophlebitis
                                        Retinal deposits
                                        Retinal detachment
                                        Retinal exudates
                                        Retinal haemorrhage
                                        Retinal ischaemia
                                        Retinal neovascularisation
                                        Retinal oedema
                                        Retinal pallor
                                        Retinal vascular occlusion
                                        Retinopathy
                                        Retinopathy proliferative
                                        Sudden visual loss
                                        Visual acuity reduced
                                        Visual acuity reduced transiently
                                        Vitreal cells
                                        Vitreous detachment
                                        Vitreous haemorrhage
                                        Vitreous opacities
Gastrointestinal adverse events         Abdominal adhesions
                                        Abdominal compartment syndrome
                                        Abdominal discomfort
                                        Abdominal distension
                                        Abdominal fat apron
                                        Abdominal hernia
                                        Abdominal hernia obstructive
                                        Abdominal hernia perforation
                                        Abdominal incarcerated hernia
                                        Abdominal mass
                                        Abdominal migraine
                                        Abdominal pain
                                        Abdominal pain lower
                                        Abdominal pain upper
                                        Abdominal rebound tenderness
                                        Abdominal rigidity
                                        Abdominal strangulated hernia
                                        Abdominal symptom
                                        Abdominal tenderness
                                        Abdominal wall cyst
                                        Abdominal wall disorder
                                        Abdominal wall haematoma
                                        Abdominal wall haemorrhage
                                        Abdominal wall mass
                                        Abnormal faeces
                                        Acetonaemic vomiting
                                        Achlorhydria
                                        Acid peptic disease
                                        Acquired macroglossia
                                        Acquired oesophageal web
————————————————————————————————————————————————————————————————————————————————————————————————————
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                                                      02JUL2019:18:22:33 - l_meddra.sas/l_meddra.txt
CONFIDENTIAL


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NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
28 of 152
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Gastrointestinal adverse events         Acute abdomen
                                        Acute haemorrhagic ulcerative colitis
                                        Acute oesophageal mucosal lesion
                                        Aerophagia
                                        Alcoholic pancreatitis
                                        Alcoholic pancreopathy
                                        Allergic colitis
                                        Allergic gastroenteritis
                                        Allergic stomatitis
                                        Alveolar bone resorption
                                        Amalgam tattoo
                                        Ampullary polyp
                                        Anal dilatation
                                        Anal erosion
                                        Anal fissure
                                        Anal fissure haemorrhage
                                        Anal fistula
                                        Anal haemorrhage
                                        Anal hypoaesthesia
                                        Anal incontinence
                                        Anal inflammation
                                        Anal leukoplakia
                                        Anal paraesthesia
                                        Anal polyp
                                        Anal prolapse
                                        Anal pruritus
                                        Anal skin tags
                                        Anal spasm
                                        Anal sphincter atony
                                        Anal sphincter hypertonia
                                        Anal stenosis
                                        Anal trichiasis
                                        Anal ulcer
                                        Anal ulcer haemorrhage
                                        Anastomotic ulcer perforation
                                        Anastomotic ulcer, obstructive
                                        Angina bullosa haemorrhagica
                                        Ankyloglossia acquired
                                        Anogenital dysplasia
                                        Anorectal discomfort
                                        Anorectal disorder
                                        Anorectal sensory loss
                                        Anorectal squamous cell metaplasia
                                        Anorectal stenosis
                                        Anorectal swelling
                                        Anorectal ulcer
                                        Anorectal varices
                                        Anorectal varices haemorrhage
                                        Anovulvar fistula
                                        Aorto-oesophageal fistula
                                        Aortoenteric fistula
                                        Aphthous ulcer
                                        Apical granuloma
                                        Apoptotic colonopathy
                                        Appendiceal mucocoele
                                        Appendicitis noninfective
                                        Appendicolith
                                        Appendix disorder
                                        Aptyalism
                                        Ascites
                                        Atrophic glossitis
                                        Auriculotemporal syndrome
                                        Autoimmune colitis
————————————————————————————————————————————————————————————————————————————————————————————————————
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CONFIDENTIAL


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NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
29 of 152
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Gastrointestinal adverse events         Autoimmune enteropathy
                                        Autoimmune pancreatitis
                                        Barrett's oesophagus
                                        Bezoar
                                        Bile acid malabsorption
                                        Biliary ascites
                                        Bloody peritoneal effluent
                                        Bowel movement irregularity
                                        Breath odour
                                        Brunner's gland hyperplasia
                                        Buccal mucosal roughening
                                        Buccal polyp
                                        Buccoglossal syndrome
                                        Burning mouth syndrome
                                        Cardiospasm
                                        Cascade stomach
                                        Cemento osseous dysplasia
                                        Change of bowel habit
                                        Chapped lips
                                        Cheilitis
                                        Cheilitis granulomatosa
                                        Cheilosis
                                        Chilaiditi's syndrome
                                        Chronic cheek biting
                                        Chronic gastritis
                                        Chronic gastrointestinal bleeding
                                        Coating in mouth
                                        Cobble stone tongue
                                        Coeliac artery aneurysm
                                        Coeliac artery compression syndrome
                                        Coeliac artery stenosis
                                        Coeliac disease
                                        Colitis
                                        Colitis cystica profunda
                                        Colitis erosive
                                        Colitis ischaemic
                                        Colitis microscopic
                                        Colitis psychogenic
                                        Colitis ulcerative
                                        Colon dysplasia
                                        Colonic fistula
                                        Colonic haematoma
                                        Constipation
                                        Contact stomatitis
                                        Creatorrhoea
                                        Cricopharyngeal achalasia
                                        Crohn's disease
                                        Cronkhite-Canada syndrome
                                        Cryptitis
                                        Cyclic vomiting syndrome
                                        Defaecation disorder
                                        Defaecation urgency
                                        Dental abfraction
                                        Dental alveolar anomaly
                                        Dental caries
                                        Dental cyst
                                        Dental discomfort
                                        Dental dysaesthesia
                                        Dental necrosis
                                        Dental paraesthesia
                                        Dental plaque
                                        Dental pulp disorder
                                        Diabetic enteropathy
————————————————————————————————————————————————————————————————————————————————————————————————————
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                                                      02JUL2019:18:22:33 - l_meddra.sas/l_meddra.txt
CONFIDENTIAL


NN9535
NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
30 of 152
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Gastrointestinal adverse events         Diabetic gastroenteropathy
                                        Diabetic gastroparesis
                                        Diabetic gastropathy
                                        Diaphragmatic hernia
                                        Diaphragmatic hernia, obstructive
                                        Diarrhoea
                                        Diarrhoea haemorrhagic
                                        Diarrhoea neonatal
                                        Diastema
                                        Dieulafoy's vascular malformation
                                        Discoloured vomit
                                        Distal intestinal obstruction syndrome
                                        Diverticular fistula
                                        Diverticular hernia
                                        Diverticular perforation
                                        Diverticulitis oesophageal
                                        Diverticuloma
                                        Diverticulum
                                        Diverticulum gastric
                                        Diverticulum intestinal
                                        Diverticulum intestinal haemorrhagic
                                        Diverticulum oesophageal
                                        Dolichocolon acquired
                                        Douglas' pouch mass
                                        Dry mouth
                                        Dumping syndrome
                                        Duodenal obstruction
                                        Duodenal papillitis
                                        Duodenal perforation
                                        Duodenal polyp
                                        Duodenal stenosis
                                        Duodenal ulcer
                                        Duodenal ulcer haemorrhage
                                        Duodenal ulcer perforation
                                        Duodenal ulcer perforation, obstructive
                                        Duodenal ulcer, obstructive
                                       Duodenal varices
                                        Duodenal vascular ectasia
                                        Duodenitis
                                        Duodenitis haemorrhagic
                                        Duodenogastric reflux
                                        Dysbacteriosis
                                        Dyschezia
                                        Dyskinesia oesophageal
                                        Dyspepsia
                                        Dysphagia
                                        Dysphagia lusoria
                                        Ectopic gastric mucosa
                                        Enamel anomaly
                                        Encapsulating peritoneal sclerosis
                                        Enlarged uvula
                                        Enteric neuropathy
                                        Enteritis
                                        Enteritis leukopenic
                                        Enterocele
                                        Enterochromaffin cell hyperplasia
                                        Enterocolitis
                                        Enterocolitis haemorrhagic
                                        Enterocolonic fistula
                                        Enterocutaneous fistula
                                        Enterovesical fistula
                                       Eosinophilic colitis
                                        Eosinophilic oesophagitis
————————————————————————————————————————————————————————————————————————————————————————————————————
MedDRA version 21.1
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                                                      02JUL2019:18:22:33 - l_meddra.sas/l_meddra.txt
CONFIDENTIAL


NN9535
NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
31 of 152
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Gastrointestinal adverse events         Epigastric discomfort
                                        Epiploic appendagitis
                                        Epulis
                                        Erosive duodenitis
                                        Erosive oesophagitis
                                        Eructation
                                        Faecal vomiting
                                        Faecalith
                                        Faecaloma
                                        Faeces discoloured
                                        Faeces hard
                                        Faeces pale
                                        Faeces soft
                                        Feline oesophagus
                                        Femoral hernia
                                        Femoral hernia incarcerated
                                        Femoral hernia strangulated
                                        Femoral hernia, obstructive
                                        Fibrosing colonopathy
                                        Fistula of small intestine
                                        Fixed bowel loop
                                        Flatulence
                                        Fluorosis dental
                                        Food poisoning
                                        Frequent bowel movements
                                        Functional gastrointestinal disorder
                                       Gallstone ileus
                                        Gastric antral vascular ectasia
                                        Gastric atony
                                        Gastric cyst
                                        Gastric dilatation
                                        Gastric disorder
                                        Gastric dysplasia
                                        Gastric fibrosis
                                        Gastric fistula
                                        Gastric haemorrhage
                                        Gastric hypermotility
                                        Gastric hypertonia
                                        Gastric hypomotility
                                        Gastric ileus
                                        Gastric mucosa erythema
                                        Gastric mucosal calcinosis
                                        Gastric mucosal hypertrophy
                                        Gastric mucosal lesion
                                        Gastric perforation
                                        Gastric pneumatosis
                                        Gastric polyps
                                        Gastric prolapse
                                        Gastric stenosis
                                        Gastric ulcer
                                        Gastric ulcer haemorrhage
                                        Gastric ulcer haemorrhage, obstructive
                                        Gastric ulcer perforation
                                        Gastric ulcer perforation, obstructive
                                        Gastric ulcer, obstructive
                                        Gastric varices
                                        Gastric varices haemorrhage
                                        Gastric volvulus
                                        Gastric xanthoma
                                        Gastritis
                                        Gastritis alcoholic
                                        Gastritis alcoholic haemorrhagic
                                        Gastritis erosive
————————————————————————————————————————————————————————————————————————————————————————————————————
MedDRA version 21.1
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                                                      02JUL2019:18:22:33 - l_meddra.sas/l_meddra.txt
CONFIDENTIAL


NN9535
NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
32 of 152
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Gastrointestinal adverse events         Gastritis haemorrhagic
                                        Gastritis hypertrophic
                                        Gastrocoele
                                        Gastroduodenal haemorrhage
                                        Gastroduodenal ulcer
                                        Gastroenteritis eosinophilic
                                        Gastrointestinal amyloidosis
                                        Gastrointestinal angiectasia
                                        Gastrointestinal angiodysplasia
                                        Gastrointestinal disorder
                                        Gastrointestinal dysplasia
                                        Gastrointestinal erosion
                                        Gastrointestinal fistula
                                        Gastrointestinal haemorrhage
                                        Gastrointestinal hypermotility
                                        Gastrointestinal hypomotility
                                        Gastrointestinal inflammation
                                        Gastrointestinal ischaemia
                                        Gastrointestinal melanosis
                                        Gastrointestinal motility disorder
                                        Gastrointestinal mucocoele
                                        Gastrointestinal mucosa hyperaemia
                                        Gastrointestinal mucosal disorder
                                        Gastrointestinal mucosal exfoliation
                                        Gastrointestinal mucosal necrosis
                                        Gastrointestinal necrosis
                                        Gastrointestinal obstruction
                                        Gastrointestinal oedema
                                        Gastrointestinal pain
                                        Gastrointestinal perforation
                                        Gastrointestinal polyp
                                        Gastrointestinal polyp haemorrhage
                                        Gastrointestinal scarring
                                        Gastrointestinal sounds abnormal
                                        Gastrointestinal stenosis
                                        Gastrointestinal toxicity
                                        Gastrointestinal tract irritation
                                        Gastrointestinal tract mucosal discolouration
                                        Gastrointestinal tract mucosal pigmentation
                                        Gastrointestinal ulcer
                                        Gastrointestinal ulcer haemorrhage
                                        Gastrointestinal ulcer perforation
                                        Gastrointestinal vascular malformation
                                        Gastrointestinal vascular malformation haemorrhagic
                                        Gastrointestinal wall abnormal
                                        Gastrointestinal wall thickening
                                        Gastrointestinal wall thinning
                                        Gastrolithiasis
                                        Gastrooesophageal reflux disease
                                        Gastrooesophageal sphincter insufficiency
                                        Gastropleural fistula
                                        Gastroptosis
                                        Gastrosplenic fistula
                                        Giant cell epulis
                                        Gingival atrophy
                                        Gingival bleeding
                                        Gingival blister
                                        Gingival cyst
                                        Gingival discolouration
                                        Gingival discomfort
                                        Gingival disorder
                                        Gingival erosion
                                        Gingival erythema
————————————————————————————————————————————————————————————————————————————————————————————————————
MedDRA version 21.1
                                                                   nn9535/nn9535-4114/20190704_rm_er
                                                      02JUL2019:18:22:33 - l_meddra.sas/l_meddra.txt
CONFIDENTIAL


NN9535
NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
33 of 152
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————————————————————————————————————————————————————————————————————————————————————————————————————
Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Gastrointestinal adverse events         Gingival hyperpigmentation
                                        Gingival hypertrophy
                                        Gingival hypoplasia
                                        Gingival oedema
                                        Gingival pain
                                        Gingival polyp
                                        Gingival pruritus
                                        Gingival recession
                                        Gingival swelling
                                        Gingival ulceration
                                        Gingivitis ulcerative
                                        Glossitis
                                        Glossodynia
                                        Glossoptosis
                                        Glycogenic acanthosis
                                        Gut fermentation syndrome
                                        Haematemesis
                                        Haematochezia
                                        Haemorrhagic ascites
                                        Haemorrhagic erosive gastritis
                                        Haemorrhagic necrotic pancreatitis
                                        Haemorrhoidal haemorrhage
                                        Haemorrhoids
                                        Haemorrhoids thrombosed
                                        Hernial eventration
                                        Heyde's syndrome
                                        Hiatus hernia
                                        Hiatus hernia strangulated
                                        Hiatus hernia, obstructive
                                        Hypercementosis
                                        Hyperchlorhydria
                                        Hypergastrinaemia
                                        Hypertrophic anal papilla
                                        Hypertrophy of tongue papillae
                                        Hypoaesthesia oral
                                        Hypoaesthesia teeth
                                        Ileal perforation
                                        Ileal stenosis
                                        Ileal ulcer
                                        Ileal ulcer perforation
                                        Ileus
                                        Ileus paralytic
                                        Ileus spastic
                                        Impaired gastric emptying
                                        Incarcerated hiatus hernia
                                        Incarcerated inguinal hernia
                                        Incarcerated umbilical hernia
                                        Infantile colic
                                        Infantile spitting up
                                        Infantile vomiting
                                        Inflammatory bowel disease
                                        Infrequent bowel movements
                                        Inguinal hernia
                                        Inguinal hernia perforation
                                        Inguinal hernia strangulated
                                        Inguinal hernia, obstructive
                                        Internal hernia
                                        Intestinal angina
                                        Intestinal angioedema
                                        Intestinal calcification
                                        Intestinal congestion
                                        Intestinal cyst
                                        Intestinal diaphragm disease
————————————————————————————————————————————————————————————————————————————————————————————————————
MedDRA version 21.1
                                                                   nn9535/nn9535-4114/20190704_rm_er
                                                      02JUL2019:18:22:33 - l_meddra.sas/l_meddra.txt
CONFIDENTIAL


NN9535
NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
34 of 152
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Gastrointestinal adverse events         Intestinal dilatation
                                        Intestinal fibrosis
                                        Intestinal fistula
                                        Intestinal haematoma
                                        Intestinal haemorrhage
                                        Intestinal infarction
                                        Intestinal ischaemia
                                        Intestinal mass
                                        Intestinal metaplasia
                                        Intestinal mucosal atrophy
                                        Intestinal mucosal hypertrophy
                                        Intestinal obstruction
                                        Intestinal perforation
                                        Intestinal polyp
                                        Intestinal prolapse
                                        Intestinal pseudo-obstruction
                                        Intestinal smooth muscle hypertrophy
                                        Intestinal steatosis
                                        Intestinal stenosis
                                        Intestinal strangulation
                                        Intestinal ulcer
                                        Intestinal ulcer perforation
                                        Intestinal varices
                                        Intestinal varices haemorrhage
                                        Intestinal villi atrophy
                                        Intra-abdominal fluid collection
                                        Intra-abdominal haematoma
                                        Intra-abdominal haemorrhage
                                        Intrinsic factor deficiency
                                        Intussusception
                                        Irritable bowel syndrome
                                        Ischaemic enteritis
                                        Ischaemic gastritis
                                        Ischaemic pancreatitis
                                        Ischiatic hernia
                                        Ischiorectal hernia
                                        Jejunal perforation
                                        Jejunal stenosis
                                        Jejunal ulcer
                                        Jejunal ulcer perforation
                                        Large intestinal haemorrhage
                                        Large intestinal obstruction
                                        Large intestinal stenosis
                                        Large intestinal ulcer
                                        Large intestinal ulcer haemorrhage
                                        Large intestinal ulcer perforation
                                        Large intestine erosion
                                        Large intestine perforation
                                        Large intestine polyp
                                        Leukoplakia oesophageal
                                        Leukoplakia oral
                                        Levator syndrome
                                        Lip blister
                                        Lip discolouration
                                        Lip disorder
                                        Lip dry
                                        Lip erosion
                                        Lip erythema
                                        Lip exfoliation
                                        Lip haematoma
                                        Lip haemorrhage
                                        Lip oedema
                                        Lip pain
————————————————————————————————————————————————————————————————————————————————————————————————————
MedDRA version 21.1
                                                                   nn9535/nn9535-4114/20190704_rm_er
                                                      02JUL2019:18:22:33 - l_meddra.sas/l_meddra.txt
CONFIDENTIAL


NN9535
NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
35 of 152
Pre-defined MedDRA search - list of preferred terms
————————————————————————————————————————————————————————————————————————————————————————————————————
Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Gastrointestinal adverse events         Lip pruritus
                                        Lip swelling
                                        Lip ulceration
                                        Loose tooth
                                        Lower gastrointestinal haemorrhage
                                        Lower gastrointestinal perforation
                                        Lumbar hernia
                                        Lupus enteritis
                                        Lupus pancreatitis
                                        Lymphangiectasia intestinal
                                        Lymphocytic oesophagitis
                                        Lymphoid hyperplasia of intestine
                                        Malabsorption
                                        Malacoplakia gastrointestinal
                                        Malignant dysphagia
                                        Malignant gastrointestinal obstruction
                                        Mallory-Weiss syndrome
                                        Malocclusion
                                        Malpositioned teeth
                                        Mastocytic enterocolitis
                                        Mechanical ileus
                                        Meconium cyst
                                        Meconium ileus
                                        Meconium peritonitis
                                        Meconium plug syndrome
                                        Megacolon
                                        Melaena
                                        Melaena neonatal
                                        Melanoplakia oral
                                        Mesenteric arterial occlusion
                                        Mesenteric arteriosclerosis
                                        Mesenteric artery aneurysm
                                        Mesenteric artery embolism
                                        Mesenteric artery stenosis
                                        Mesenteric artery thrombosis
                                        Mesenteric cyst
                                        Mesenteric fibrosis
                                        Mesenteric haematoma
                                        Mesenteric haemorrhage
                                        Mesenteric panniculitis
                                        Mesenteric phlebosclerosis
                                        Mesenteric vascular insufficiency
                                        Mesenteric vascular occlusion
                                        Mesenteric vein thrombosis
                                        Mesenteric venous occlusion
                                        Mesenteritis
                                        Mikulicz's disease
                                        Mikulicz's syndrome
                                        Mouth cyst
                                        Mouth haemorrhage
                                        Mouth swelling
                                        Mouth ulceration
                                        Mucous stools
                                        Myochosis
                                        Narcotic bowel syndrome
                                        Nausea
                                        Necrotising colitis
                                        Necrotising enterocolitis neonatal
                                        Necrotising gastritis
                                        Necrotising oesophagitis
                                        Neonatal gastrointestinal disorder
                                        Neonatal gastrointestinal haemorrhage
                                        Neonatal intestinal dilatation
————————————————————————————————————————————————————————————————————————————————————————————————————
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CONFIDENTIAL


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NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
36 of 152
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Gastrointestinal adverse events         Neonatal intestinal obstruction
                                        Neonatal intestinal perforation
                                        Neurogenic bowel
                                        Neutropenic colitis
                                        Nicotinic stomatitis
                                        Noninfectious peritonitis
                                        Noninfective gingivitis
                                        Noninfective sialoadenitis
                                        Obstruction gastric
                                        Obstructive defaecation
                                        Obstructive pancreatitis
                                        Obturator hernia
                                        Odynophagia
                                        Oedema mouth
                                        Oedematous pancreatitis
                                        Oesophageal achalasia
                                        Oesophageal atony
                                        Oesophageal compression
                                        Oesophageal dilatation
                                        Oesophageal discomfort
                                        Oesophageal disorder
                                        Oesophageal dysplasia
                                        Oesophageal fibrosis
                                        Oesophageal fistula
                                        Oesophageal food impaction
                                        Oesophageal haemorrhage
                                        Oesophageal hypomotility
                                        Oesophageal intramural haematoma
                                        Oesophageal irritation
                                        Oesophageal mass
                                        Oesophageal motility disorder
                                        Oesophageal mucosa erythema
                                        Oesophageal mucosal blister
                                        Oesophageal mucosal dissection
                                        Oesophageal mucosal hyperplasia
                                        Oesophageal mucosal tear
                                        Oesophageal obstruction
                                        Oesophageal oedema
                                        Oesophageal pain
                                        Oesophageal perforation
                                        Oesophageal polyp
                                        Oesophageal rupture
                                        Oesophageal spasm
                                        Oesophageal stenosis
                                        Oesophageal stent stenosis
                                        Oesophageal ulcer
                                        Oesophageal ulcer haemorrhage
                                        Oesophageal ulcer perforation
                                        Oesophageal varices haemorrhage
                                        Oesophagitis
                                        Oesophagitis haemorrhagic
                                        Oesophagitis ulcerative
                                        Oesophagopleural fistula
                                        Omental infarction
                                        Omental necrosis
                                        Oral cavity fistula
                                        Oral contusion
                                        Oral discharge
                                        Oral discomfort
                                        Oral disorder
                                        Oral dysaesthesia
                                        Oral hyperaesthesia
                                        Oral hyperkeratosis
————————————————————————————————————————————————————————————————————————————————————————————————————
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CONFIDENTIAL


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NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
37 of 152
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Gastrointestinal adverse events         Oral leukoedema
                                        Oral lichen planus
                                        Oral mucosa atrophy
                                        Oral mucosa erosion
                                        Oral mucosa haematoma
                                        Oral mucosal blistering
                                        Oral mucosal discolouration
                                        Oral mucosal eruption
                                        Oral mucosal erythema
                                        Oral mucosal exfoliation
                                        Oral mucosal hypertrophy
                                        Oral pain
                                        Oral papule
                                        Oral pigmentation
                                        Oral pruritus
                                        Oral submucosal fibrosis
                                        Oral toxicity
                                        Oroantral fistula
                                        Palatal disorder
                                        Palatal dysplasia
                                        Palatal oedema
                                        Palatal swelling
                                        Palatal ulcer
                                        Pancreatic atrophy
                                        Pancreatic calcification
                                        Pancreatic cyst
                                        Pancreatic cyst rupture
                                        Pancreatic disorder
                                        Pancreatic duct dilatation
                                        Pancreatic duct obstruction
                                        Pancreatic duct stenosis
                                        Pancreatic enlargement
                                        Pancreatic enzyme abnormality
                                        Pancreatic failure
                                        Pancreatic fibrosis
                                        Pancreatic fistula
                                        Pancreatic haemorrhage
                                        Pancreatic infarction
                                        Pancreatic mass
                                        Pancreatic necrosis
                                        Pancreatic phlegmon
                                        Pancreatic pseudoaneurysm
                                        Pancreatic pseudocyst
                                        Pancreatic steatosis
                                        Pancreatic toxicity
                                        Pancreatitis
                                        Pancreatitis acute
                                        Pancreatitis chronic
                                        Pancreatitis haemorrhagic
                                        Pancreatitis necrotising
                                        Pancreatitis relapsing
                                        Pancreatolithiasis
                                        Papilla of Vater stenosis
                                        Paraesthesia oral
                                        Paresis anal sphincter
                                        Parotid duct obstruction
                                        Parotid gland enlargement
                                        Parotid gland haemorrhage
                                        Parotid lipomatosis
                                        Pelvic floor dyssynergia
                                        Peptic ulcer
                                        Peptic ulcer haemorrhage
                                        Peptic ulcer perforation
————————————————————————————————————————————————————————————————————————————————————————————————————
MedDRA version 21.1
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CONFIDENTIAL


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NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
38 of 152
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Gastrointestinal adverse events         Peptic ulcer perforation, obstructive
                                        Peptic ulcer, obstructive
                                        Perianal erythema
                                        Periodontal disease
                                        Periodontal inflammation
                                        Peripancreatic varices
                                        Peristalsis visible
                                        Peritoneal adhesions
                                        Peritoneal cloudy effluent
                                        Peritoneal cyst
                                        Peritoneal disorder
                                        Peritoneal fibrosis
                                        Peritoneal haematoma
                                        Peritoneal haemorrhage
                                        Peritoneal hernia
                                        Peritoneal lesion
                                        Peritoneal mesothelial hyperplasia
                                        Peritoneal necrosis
                                        Peritoneal perforation
                                        Peritoneocutaneous fistula
                                        Peritonitis lupus
                                        Pharyngo-oesophageal diverticulum
                                        Pigmentation lip
                                        Plicated tongue
                                        Pneumatosis intestinalis
                                        Pneumoperitoneum
                                        Pneumoretroperitoneum
                                        Poor dental condition
                                        Portal hypertensive colopathy
                                        Portal hypertensive enteropathy
                                        Portal hypertensive gastropathy
                                        Portal venous gas
                                        Post-tussive vomiting
                                        Pouchitis
                                        Prepyloric stenosis
                                        Presbyoesophagus
                                        Proctalgia
                                        Proctitis
                                        Proctitis haemorrhagic
                                        Proctitis ulcerative
                                        Proctoparalysis
                                        Protein-losing gastroenteropathy
                                        Protrusion tongue
                                        Pseudoachalasia
                                        Pseudodiverticular disease
                                        Pseudopolyposis
                                        Pudendal hernia
                                        Pyloric sphincter insufficiency
                                        Pylorospasm
                                        Pylorus dilatation
                                        Pyostomatitis vegetans
                                        Ranula
                                        Reactive gastropathy
                                        Rebound acid hypersecretion
                                        Rectal discharge
                                        Rectal fissure
                                        Rectal haemorrhage
                                        Rectal lesion
                                        Rectal obstruction
                                        Rectal perforation
                                        Rectal polyp
                                        Rectal prolapse
                                        Rectal spasm
————————————————————————————————————————————————————————————————————————————————————————————————————
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CONFIDENTIAL


NN9535
NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
39 of 152
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Gastrointestinal adverse events         Rectal stenosis
                                        Rectal tenesmus
                                        Rectal ulcer
                                        Rectal ulcer haemorrhage
                                        Rectourethral fistula
                                        Reflux gastritis
                                        Regurgitation
                                        Retained deciduous tooth
                                        Retching
                                        Retroperitoneal effusion
                                        Retroperitoneal fibrosis
                                        Retroperitoneal haematoma
                                        Retroperitoneal haemorrhage
                                        Retroperitoneal hernia
                                        Retroperitoneal mass
                                        Retroperitoneal oedema
                                        Retroperitoneum cyst
                                        Richter's hernia
                                        Saliva altered
                                        Saliva discolouration
                                        Salivary duct inflammation
                                        Salivary duct obstruction
                                        Salivary duct stenosis
                                        Salivary gland atrophy
                                        Salivary gland calculus
                                        Salivary gland cyst
                                        Salivary gland disorder
                                        Salivary gland enlargement
                                        Salivary gland fistula
                                        Salivary gland induration
                                        Salivary gland mass
                                        Salivary gland mucocoele
                                        Salivary gland pain
                                        Salivary hypersecretion
                                        Sandifer's syndrome
                                        Scalloped tongue
                                        Scaphoid abdomen
                                        Sciatic hernia
                                        Segmental diverticular colitis
                                        Sensitivity of teeth
                                        Short-bowel syndrome
                                        Sialadenosis
                                        Sialectasia
                                        Sialocele
                                        Sialodochitis fibrinosa
                                        Sialometaplasia
                                        Sideropenic dysphagia
                                        Small intestinal haemorrhage
                                        Small intestinal obstruction
                                        Small intestinal perforation
                                        Small intestinal stenosis
                                        Small intestinal ulcer haemorrhage
                                        Small intestinal ulcer perforation
                                        Small intestine polyp
                                        Small intestine ulcer
                                        Sordes
                                        Spigelian hernia
                                        Splenic artery aneurysm
                                        Splenic vein aneurysm
                                        Sprue-like enteropathy
                                        Stasis syndrome
                                        Steatorrhoea
                                        Stiff tongue
————————————————————————————————————————————————————————————————————————————————————————————————————
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CONFIDENTIAL


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NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
40 of 152
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Gastrointestinal adverse events         Stomach granuloma
                                        Stomach mass
                                        Stomatitis
                                        Stomatitis haemorrhagic
                                        Stomatitis necrotising
                                        Strangulated umbilical hernia
                                        Strawberry tongue
                                        Stress ulcer
                                        Subileus
                                        Submaxillary gland enlargement
                                        Superior mesenteric artery syndrome
                                        Supernumerary teeth
                                        Swollen tongue
                                        Teeth brittle
                                        Teething
                                        Thrombosis mesenteric vessel
                                        Tongue amyloidosis
                                        Tongue atrophy
                                        Tongue blistering
                                        Tongue coated
                                        Tongue cyst
                                        Tongue discolouration
                                        Tongue discomfort
                                        Tongue disorder
                                        Tongue dry
                                        Tongue dysplasia
                                        Tongue eruption
                                        Tongue erythema
                                        Tongue exfoliation
                                        Tongue geographic
                                        Tongue haematoma
                                        Tongue haemorrhage
                                        Tongue infarction
                                        Tongue movement disturbance
                                        Tongue necrosis
                                        Tongue oedema
                                        Tongue pigmentation
                                        Tongue polyp
                                        Tongue pruritus
                                        Tongue spasm
                                        Tongue ulceration
                                        Tooth ankylosis
                                        Tooth delamination
                                        Tooth demineralisation
                                        Tooth deposit
                                        Tooth development disorder
                                        Tooth discolouration
                                        Tooth disorder
                                        Tooth erosion
                                        Tooth impacted
                                        Tooth loss
                                        Tooth malformation
                                        Tooth pulp haemorrhage
                                        Tooth resorption
                                        Tooth socket haemorrhage
                                        Toothache
                                        Toxic dilatation of intestine
                                        Transient lingual papillitis
                                        Traumatic occlusion
                                        Traumatic ulcerative granuloma with stromal eosinophilia
                                        Trichoglossia
                                        Truncus coeliacus thrombosis
                                        Ulcerative duodenitis
————————————————————————————————————————————————————————————————————————————————————————————————————
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CONFIDENTIAL


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NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
41 of 152
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Gastrointestinal adverse events         Ulcerative gastritis
                                        Ultrafiltration failure
                                        Umbilical hernia
                                        Umbilical hernia perforation
                                        Umbilical hernia, obstructive
                                        Upper gastrointestinal haemorrhage
                                        Upper gastrointestinal perforation
                                        Uraemic gastropathy
                                        Urinary ascites
                                        Uvulitis
                                        Varices oesophageal
                                        Varicose veins of abdominal wall
                                        Varicose veins sublingual
                                        Vasculitis gastrointestinal
                                        Visceral venous thrombosis
                                        Visceroptosis
                                        Volvulus
                                        Volvulus of small bowel
                                        Vomiting
                                        Vomiting projectile
                                        White nipple sign
                                        Wischnewsky spots
Hepatic disorders                       5'nucleotidase increased
                                        Acquired antithrombin III deficiency
                                        Acquired hepatocerebral degeneration
                                        Acquired protein S deficiency
                                        Acute graft versus host disease in liver
                                        Acute hepatic failure
                                        Acute on chronic liver failure
                                        Acute yellow liver atrophy
                                        Alanine aminotransferase abnormal
                                        Alanine aminotransferase increased
                                        Allergic hepatitis
                                        Alloimmune hepatitis
                                        Ammonia abnormal
                                        Ammonia increased
                                        Anorectal varices
                                        Anorectal varices haemorrhage
                                        Anti factor X activity abnormal
                                        Anti factor X activity decreased
                                        Anti factor X activity increased
                                        Antithrombin III decreased
                                        Ascites
                                        Aspartate aminotransferase abnormal
                                        Aspartate aminotransferase increased
                                        Asterixis
                                        Autoimmune hepatitis
                                        Bacterascites
                                        Benign hepatic neoplasm
                                        Benign hepatobiliary neoplasm
                                        Bile output abnormal
                                        Bile output decreased
                                        Biliary ascites
                                        Biliary cirrhosis
                                        Biliary fibrosis
                                        Bilirubin conjugated abnormal
                                        Bilirubin conjugated increased
                                        Bilirubin excretion disorder
                                        Bilirubin urine present
                                        Biopsy liver abnormal
                                        Blood alkaline phosphatase abnormal
                                        Blood alkaline phosphatase increased
————————————————————————————————————————————————————————————————————————————————————————————————————
MedDRA version 21.1
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CONFIDENTIAL


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NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
42 of 152
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Hepatic disorders                       Blood bilirubin abnormal
                                        Blood bilirubin increased
                                        Blood bilirubin unconjugated increased
                                        Blood cholinesterase abnormal
                                        Blood cholinesterase decreased
                                        Blood fibrinogen abnormal
                                        Blood fibrinogen decreased
                                        Blood thrombin abnormal
                                        Blood thrombin decreased
                                        Blood thromboplastin abnormal
                                        Blood thromboplastin decreased
                                        Bromosulphthalein test abnormal
                                        Child-Pugh-Turcotte score abnormal
                                        Child-Pugh-Turcotte score increased
                                        Cholaemia
                                        Cholangiosarcoma
                                        Cholestasis
                                        Cholestatic liver injury
                                        Cholestatic pruritus
                                        Chronic graft versus host disease in liver
                                        Chronic hepatic failure
                                        Chronic hepatitis
                                        Coagulation factor IX level abnormal
                                        Coagulation factor IX level decreased
                                        Coagulation factor V level abnormal
                                        Coagulation factor V level decreased
                                        Coagulation factor VII level abnormal
                                        Coagulation factor VII level decreased
                                        Coagulation factor X level abnormal
                                        Coagulation factor X level decreased
                                        Coagulation factor decreased
                                        Coma hepatic
                                        Computerised tomogram liver
                                        Computerised tomogram liver abnormal
                                        Cryptogenic cirrhosis
                                        Deficiency of bile secretion
                                        Diabetic hepatopathy
                                        Drug-induced liver injury
                                        Duodenal varices
                                        Focal nodular hyperplasia
                                        Foetor hepaticus
                                        Galactose elimination capacity test abnormal
                                        Galactose elimination capacity test decreased
                                        Gallbladder varices
                                        Gamma-glutamyltransferase abnormal
                                        Gamma-glutamyltransferase increased
                                        Gastric variceal injection
                                        Gastric variceal ligation
                                        Gastric varices
                                        Gastric varices haemorrhage
                                        Glutamate dehydrogenase increased
                                        Glycocholic acid increased
                                        Graft versus host disease in liver
                                        Granulomatous liver disease
                                        Guanase increased
                                        Haemangioma of liver
                                        Haemorrhagic ascites
                                        Haemorrhagic hepatic cyst
                                        Hepaplastin abnormal
                                        Hepaplastin decreased
                                        Hepatectomy
                                        Hepatic adenoma
                                        Hepatic angiosarcoma
————————————————————————————————————————————————————————————————————————————————————————————————————
MedDRA version 21.1
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                                                      02JUL2019:18:22:33 - l_meddra.sas/l_meddra.txt
CONFIDENTIAL


NN9535
NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
43 of 152
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Hepatic disorders                       Hepatic artery flow decreased
                                        Hepatic atrophy
                                        Hepatic calcification
                                        Hepatic cancer
                                        Hepatic cancer metastatic
                                        Hepatic cancer recurrent
                                        Hepatic cancer stage I
                                        Hepatic cancer stage II
                                        Hepatic cancer stage III
                                        Hepatic cancer stage IV
                                        Hepatic cirrhosis
                                        Hepatic congestion
                                        Hepatic cyst
                                        Hepatic cyst ruptured
                                        Hepatic encephalopathy
                                        Hepatic encephalopathy prophylaxis
                                        Hepatic enzyme abnormal
                                        Hepatic enzyme decreased
                                        Hepatic enzyme increased
                                        Hepatic failure
                                        Hepatic fibrosis
                                        Hepatic fibrosis marker abnormal
                                        Hepatic fibrosis marker increased
                                        Hepatic function abnormal
                                        Hepatic haemangioma rupture
                                        Hepatic hamartoma
                                        Hepatic hydrothorax
                                        Hepatic hypertrophy
                                        Hepatic infiltration eosinophilic
                                        Hepatic lesion
                                        Hepatic lymphocytic infiltration
                                        Hepatic mass
                                        Hepatic necrosis
                                        Hepatic neoplasm
                                        Hepatic pain
                                        Hepatic sequestration
                                        Hepatic steato-fibrosis
                                        Hepatic steatosis
                                        Hepatic vascular resistance increased
                                        Hepatitis
                                        Hepatitis acute
                                        Hepatitis cholestatic
                                        Hepatitis chronic active
                                        Hepatitis chronic persistent
                                        Hepatitis fulminant
                                        Hepatitis toxic
                                        Hepatobiliary cancer
                                        Hepatobiliary cancer in situ
                                        Hepatobiliary cyst
                                        Hepatobiliary disease
                                        Hepatobiliary neoplasm
                                        Hepatobiliary scan abnormal
                                        Hepatoblastoma
                                        Hepatoblastoma recurrent
                                        Hepatocellular carcinoma
                                        Hepatocellular foamy cell syndrome
                                        Hepatocellular injury
                                        Hepatomegaly
                                        Hepatopulmonary syndrome
                                        Hepatorenal failure
                                        Hepatorenal syndrome
                                        Hepatosplenomegaly
                                        Hepatotoxicity
————————————————————————————————————————————————————————————————————————————————————————————————————
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                                                      02JUL2019:18:22:33 - l_meddra.sas/l_meddra.txt
CONFIDENTIAL


NN9535
NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
44 of 152
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Hepatic disorders                       Hyperammonaemia
                                        Hyperbilirubinaemia
                                       Hypercholia
                                        Hyperfibrinolysis
                                        Hypertransaminasaemia
                                        Hypoalbuminaemia
                                        Hypocoagulable state
                                        Hypofibrinogenaemia
                                        Hypoprothrombinaemia
                                        Hypothrombinaemia
                                        Hypothromboplastinaemia
                                        Icterus index increased
                                        Immune-mediated hepatitis
                                        International normalised ratio abnormal
                                        International normalised ratio increased
                                        Intestinal varices
                                        Intestinal varices haemorrhage
                                        Intrahepatic portal hepatic venous fistula
                                        Ischaemic hepatitis
                                        Jaundice
                                        Jaundice cholestatic
                                        Jaundice hepatocellular
                                        Kayser-Fleischer ring
                                        Leucine aminopeptidase increased
                                        Liver ablation
                                        Liver and small intestine transplant
                                        Liver carcinoma ruptured
                                        Liver dialysis
                                        Liver disorder
                                        Liver function test abnormal
                                        Liver function test decreased
                                        Liver function test increased
                                        Liver induration
                                        Liver injury
                                        Liver iron concentration abnormal
                                        Liver iron concentration increased
                                        Liver operation
                                        Liver palpable
                                        Liver sarcoidosis
                                        Liver scan abnormal
                                        Liver tenderness
                                        Liver transplant
                                        Lupoid hepatic cirrhosis
                                        Lupus hepatitis
                                        Minimal hepatic encephalopathy
                                        Mitochondrial aspartate aminotransferase increased
                                        Mixed hepatocellular cholangiocarcinoma
                                        Mixed liver injury
                                        Model for end stage liver disease score abnormal
                                        Model for end stage liver disease score increased
                                        Molar ratio of total branched-chain amino acid to tyrosine
                                        Nodular regenerative hyperplasia
                                        Non-alcoholic fatty liver
                                        Non-alcoholic steatohepatitis
                                        Non-cirrhotic portal hypertension
                                        Nuclear magnetic resonance imaging liver abnormal
                                        Ocular icterus
                                        Oedema due to hepatic disease
                                        Oesophageal varices haemorrhage
                                        Parenteral nutrition associated liver disease
                                        Perihepatic discomfort
                                        Peripancreatic varices
                                        Periportal oedema
————————————————————————————————————————————————————————————————————————————————————————————————————
MedDRA version 21.1
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CONFIDENTIAL


NN9535
NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
45 of 152
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Hepatic disorders                       Peritoneal fluid protein abnormal
                                        Peritoneal fluid protein decreased
                                        Peritoneal fluid protein increased
                                        Peritoneovenous shunt
                                        Pneumobilia
                                        Portal fibrosis
                                        Portal hypertension
                                        Portal hypertensive colopathy
                                        Portal hypertensive enteropathy
                                        Portal hypertensive gastropathy
                                        Portal shunt
                                        Portal shunt procedure
                                        Portal tract inflammation
                                        Portal vein cavernous transformation
                                        Portal vein dilatation
                                        Portal vein flow decreased
                                        Portal vein pressure increased
                                        Portopulmonary hypertension
                                        Primary biliary cholangitis
                                        Protein C decreased
                                        Protein S abnormal
                                        Protein S decreased
                                        Prothrombin level abnormal
                                        Prothrombin level decreased
                                        Prothrombin time abnormal
                                        Prothrombin time prolonged
                                        Prothrombin time ratio abnormal
                                        Prothrombin time ratio increased
                                       Radiation hepatitis
                                        Regenerative siderotic hepatic nodule
                                        Renal and liver transplant
                                        Retinol binding protein decreased
                                        Retrograde portal vein flow
                                        Reye's syndrome
                                        Reynold's syndrome
                                        Small-for-size liver syndrome
                                        Spider naevus
                                        Splenic varices
                                        Splenic varices haemorrhage
                                        Splenorenal shunt
                                       Splenorenal shunt procedure
                                        Spontaneous intrahepatic portosystemic venous shunt
                                        Steatohepatitis
                                        Stomal varices
                                        Subacute hepatic failure
                                        Thrombin time abnormal
                                        Thrombin time prolonged
                                        Total bile acids increased
                                        Transaminases abnormal
                                        Transaminases increased
                                        Ultrasound liver abnormal
                                        Urine bilirubin increased
                                        Urobilinogen urine decreased
                                        Urobilinogen urine increased
                                        Varices oesophageal
                                        Varicose veins of abdominal wall
                                        White nipple sign
                                        X-ray hepatobiliary abnormal
                                        Yellow skin
Immune complex                          Acute motor axonal neuropathy
                                        Acute motor-sensory axonal neuropathy
                                        Bickerstaff's encephalitis
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CONFIDENTIAL


NN9535
NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
46 of 152
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Immune complex                          Chronic inflammatory demyelinating polyradiculoneuropathy
                                        Demyelinating polyneuropathy
                                        Guillain-Barre syndrome
                                        Miller Fisher syndrome
                                        Subacute inflammatory demyelinating polyneuropathy
                                        Zika virus associated Guillain Barre syndrome
Injection site reactions                Administration site abscess
                                        Administration site abscess sterile
                                        Administration site anaesthesia
                                        Administration site atrophy
                                        Administration site bruise
                                        Administration site calcification
                                        Administration site cellulitis
                                        Administration site coldness
                                        Administration site cyst
                                        Administration site dermatitis
                                        Administration site discharge
                                        Administration site discolouration
                                        Administration site discomfort
                                        Administration site dryness
                                        Administration site dysaesthesia
                                        Administration site eczema
                                        Administration site erosion
                                        Administration site erythema
                                        Administration site exfoliation
                                        Administration site extravasation
                                        Administration site fibrosis
                                        Administration site granuloma
                                        Administration site haematoma
                                        Administration site haemorrhage
                                        Administration site hyperaesthesia
                                        Administration site hypersensitivity
                                        Administration site hypertrichosis
                                        Administration site hypertrophy
                                        Administration site hypoaesthesia
                                        Administration site indentation
                                        Administration site induration
                                        Administration site infection
                                        Administration site inflammation
                                        Administration site injury
                                        Administration site irritation
                                        Administration site ischaemia
                                        Administration site joint discomfort
                                        Administration site joint effusion
                                        Administration site joint erythema
                                        Administration site joint infection
                                        Administration site joint inflammation
                                        Administration site joint movement impairment
                                        Administration site joint pain
                                        Administration site joint warmth
                                        Administration site laceration
                                        Administration site lymphadenopathy
                                        Administration site macule
                                        Administration site mass
                                        Administration site movement impairment
                                        Administration site necrosis
                                        Administration site nerve damage
                                        Administration site nodule
                                        Administration site odour
                                        Administration site oedema
                                        Administration site pain
                                        Administration site pallor
————————————————————————————————————————————————————————————————————————————————————————————————————
MedDRA version 21.1
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CONFIDENTIAL


NN9535
NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
47 of 152
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————————————————————————————————————————————————————————————————————————————————————————————————————
Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Injection site reactions                Administration site papule
                                        Administration site paraesthesia
                                        Administration site phlebitis
                                        Administration site photosensitivity reaction
                                        Administration site plaque
                                        Administration site pruritus
                                        Administration site pustule
                                        Administration site rash
                                        Administration site reaction
                                        Administration site recall reaction
                                        Administration site scab
                                        Administration site scar
                                        Administration site streaking
                                        Administration site swelling
                                        Administration site thrombosis
                                        Administration site ulcer
                                        Administration site urticaria
                                        Administration site vasculitis
                                        Administration site vesicles
                                        Administration site warmth
                                        Application site abscess
                                        Application site abscess sterile
                                        Application site acne
                                        Application site alopecia
                                        Application site anaesthesia
                                        Application site atrophy
                                        Application site bruise
                                        Application site burn
                                        Application site calcification
                                        Application site cellulitis
                                        Application site coldness
                                        Application site cyst
                                        Application site dermatitis
                                        Application site discharge
                                        Application site discolouration
                                        Application site discomfort
                                        Application site dryness
                                        Application site dysaesthesia
                                        Application site eczema
                                        Application site erosion
                                        Application site erythema
                                        Application site exfoliation
                                        Application site extravasation
                                        Application site fibrosis
                                        Application site fissure
                                        Application site folliculitis
                                        Application site granuloma
                                        Application site haematoma
                                        Application site haemorrhage
                                        Application site hyperaesthesia
                                        Application site hypersensitivity
                                        Application site hypertrichosis
                                        Application site hypertrophy
                                        Application site hypoaesthesia
                                        Application site induration
                                        Application site infection
                                        Application site inflammation
                                        Application site injury
                                        Application site irritation
                                        Application site ischaemia
                                        Application site joint discomfort
                                        Application site joint effusion
                                        Application site joint erythema
————————————————————————————————————————————————————————————————————————————————————————————————————
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CONFIDENTIAL


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NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
48 of 152
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Injection site reactions                Application site joint infection
                                        Application site joint inflammation
                                        Application site joint movement impairment
                                        Application site joint pain
                                        Application site joint swelling
                                        Application site joint warmth
                                        Application site laceration
                                        Application site lymphadenopathy
                                        Application site macule
                                        Application site mass
                                        Application site movement impairment
                                        Application site necrosis
                                        Application site nerve damage
                                        Application site nodule
                                        Application site odour
                                        Application site oedema
                                        Application site pain
                                        Application site pallor
                                        Application site papules
                                        Application site paraesthesia
                                        Application site perspiration
                                        Application site phlebitis
                                        Application site photosensitivity reaction
                                        Application site plaque
                                        Application site pruritus
                                        Application site purpura
                                        Application site pustules
                                        Application site rash
                                        Application site reaction
                                        Application site recall reaction
                                        Application site scab
                                        Application site scar
                                        Application site streaking
                                        Application site swelling
                                        Application site telangiectasia
                                        Application site thrombosis
                                        Application site ulcer
                                        Application site urticaria
                                        Application site vasculitis
                                        Application site vesicles
                                        Application site warmth
                                        Application site wound
                                        Embolia cutis medicamentosa
                                        Infusion site abscess
                                        Infusion site abscess sterile
                                        Infusion site anaesthesia
                                        Infusion site atrophy
                                        Infusion site bruising
                                        Infusion site calcification
                                        Infusion site cellulitis
                                        Infusion site coldness
                                        Infusion site cyst
                                        Infusion site dermatitis
                                        Infusion site discharge
                                        Infusion site discolouration
                                        Infusion site discomfort
                                        Infusion site dryness
                                        Infusion site dysaesthesia
                                        Infusion site eczema
                                        Infusion site erosion
                                        Infusion site erythema
                                        Infusion site exfoliation
                                        Infusion site extravasation
————————————————————————————————————————————————————————————————————————————————————————————————————
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CONFIDENTIAL


NN9535
NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
49 of 152
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Injection site reactions                Infusion site fibrosis
                                        Infusion site granuloma
                                        Infusion site haematoma
                                        Infusion site haemorrhage
                                        Infusion site hyperaesthesia
                                        Infusion site hypersensitivity
                                        Infusion site hypertrichosis
                                        Infusion site hypertrophy
                                        Infusion site hypoaesthesia
                                        Infusion site induration
                                        Infusion site infection
                                        Infusion site inflammation
                                        Infusion site injury
                                        Infusion site irritation
                                        Infusion site ischaemia
                                        Infusion site joint discomfort
                                        Infusion site joint effusion
                                        Infusion site joint erythema
                                        Infusion site joint infection
                                        Infusion site joint inflammation
                                        Infusion site joint movement impairment
                                        Infusion site joint pain
                                        Infusion site joint swelling
                                        Infusion site joint warmth
                                        Infusion site laceration
                                        Infusion site lymphadenopathy
                                        Infusion site macule
                                        Infusion site mass
                                        Infusion site mobility decreased
                                        Infusion site necrosis
                                        Infusion site nerve damage
                                        Infusion site nodule
                                        Infusion site oedema
                                        Infusion site pain
                                        Infusion site pallor
                                        Infusion site papule
                                        Infusion site paraesthesia
                                        Infusion site phlebitis
                                        Infusion site photosensitivity reaction
                                        Infusion site plaque
                                        Infusion site pruritus
                                        Infusion site pustule
                                        Infusion site rash
                                        Infusion site reaction
                                        Infusion site recall reaction
                                        Infusion site scab
                                        Infusion site scar
                                        Infusion site streaking
                                        Infusion site swelling
                                        Infusion site thrombosis
                                        Infusion site ulcer
                                        Infusion site urticaria
                                        Infusion site vasculitis
                                        Infusion site vesicles
                                        Infusion site warmth
                                        Injected limb mobility decreased
                                        Injection site abscess
                                        Injection site abscess sterile
                                        Injection site alopecia
                                        Injection site anaesthesia
                                        Injection site atrophy
                                        Injection site bruising
                                        Injection site calcification
————————————————————————————————————————————————————————————————————————————————————————————————————
MedDRA version 21.1
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CONFIDENTIAL


NN9535
NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
50 of 152
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Injection site reactions                Injection site cellulitis
                                        Injection site coldness
                                        Injection site cyst
                                        Injection site deformation
                                        Injection site dermatitis
                                        Injection site discharge
                                        Injection site discolouration
                                        Injection site discomfort
                                        Injection site dryness
                                        Injection site dysaesthesia
                                        Injection site eczema
                                        Injection site erosion
                                        Injection site erythema
                                        Injection site exfoliation
                                        Injection site extravasation
                                        Injection site fibrosis
                                        Injection site granuloma
                                        Injection site haematoma
                                        Injection site haemorrhage
                                        Injection site hyperaesthesia
                                        Injection site hypersensitivity
                                        Injection site hypertrichosis
                                        Injection site hypertrophy
                                        Injection site hypoaesthesia
                                        Injection site indentation
                                        Injection site induration
                                        Injection site infection
                                        Injection site inflammation
                                        Injection site injury
                                        Injection site irritation
                                        Injection site ischaemia
                                        Injection site joint discomfort
                                        Injection site joint effusion
                                        Injection site joint erythema
                                       Injection site joint infection
                                        Injection site joint inflammation
                                        Injection site joint movement impairment
                                        Injection site joint pain
                                        Injection site joint swelling
                                        Injection site joint warmth
                                        Injection site laceration
                                        Injection site lymphadenopathy
                                        Injection site macule
                                        Injection site mass
                                        Injection site movement impairment
                                        Injection site necrosis
                                        Injection site nerve damage
                                        Injection site nodule
                                        Injection site oedema
                                        Injection site pain
                                        Injection site pallor
                                        Injection site papule
                                        Injection site paraesthesia
                                        Injection site phlebitis
                                        Injection site photosensitivity reaction
                                        Injection site plaque
                                        Injection site pruritus
                                        Injection site pustule
                                        Injection site rash
                                        Injection site reaction
                                        Injection site recall reaction
                                        Injection site scab
                                        Injection site scar
————————————————————————————————————————————————————————————————————————————————————————————————————
MedDRA version 21.1
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                                                      02JUL2019:18:22:33 - l_meddra.sas/l_meddra.txt
CONFIDENTIAL


NN9535
NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
51 of 152
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Injection site reactions                Injection site streaking
                                        Injection site swelling
                                        Injection site telangiectasia
                                        Injection site thrombosis
                                        Injection site ulcer
                                        Injection site urticaria
                                        Injection site vasculitis
                                        Injection site vesicles
                                        Injection site warmth
                                        Instillation site abscess
                                        Instillation site anaesthesia
                                        Instillation site atrophy
                                        Instillation site bruise
                                        Instillation site burn
                                        Instillation site coldness
                                        Instillation site complication
                                        Instillation site discharge
                                        Instillation site discolouration
                                        Instillation site discomfort
                                        Instillation site dryness
                                        Instillation site erosion
                                        Instillation site erythema
                                        Instillation site exfoliation
                                        Instillation site foreign body sensation
                                        Instillation site haematoma
                                        Instillation site haemorrhage
                                        Instillation site hyperaesthesia
                                        Instillation site hypersensitivity
                                        Instillation site hypoaesthesia
                                        Instillation site induration
                                        Instillation site infection
                                        Instillation site inflammation
                                       Instillation site irritation
                                        Instillation site lacrimation
                                        Instillation site necrosis
                                        Instillation site nodule
                                        Instillation site odour
                                        Instillation site oedema
                                        Instillation site pain
                                        Instillation site papules
                                        Instillation site paraesthesia
                                        Instillation site pruritus
                                        Instillation site pustules
                                        Instillation site rash
                                        Instillation site reaction
                                        Instillation site scab
                                        Instillation site swelling
                                        Instillation site thrombosis
                                        Instillation site ulcer
                                        Instillation site urticaria
                                        Instillation site vesicles
                                        Instillation site warmth
                                        Malabsorption from administration site
                                        Malabsorption from application site
                                        Malabsorption from injection site
                                        Oral administration complication
                                        Puncture site abscess
                                        Puncture site discharge
                                        Puncture site erythema
                                        Puncture site haemorrhage
                                        Puncture site hernia
                                        Puncture site hypoaesthesia
                                        Puncture site induration
————————————————————————————————————————————————————————————————————————————————————————————————————
MedDRA version 21.1
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                                                      02JUL2019:18:22:33 - l_meddra.sas/l_meddra.txt
CONFIDENTIAL


NN9535
NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
52 of 152
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Injection site reactions                Puncture site infection
                                        Puncture site oedema
                                        Puncture site pain
                                        Puncture site reaction
                                        Puncture site swelling
                                        Systemic leakage
                                        Vessel puncture site anaesthesia
                                        Vessel puncture site bruise
                                        Vessel puncture site cellulitis
                                        Vessel puncture site discharge
                                        Vessel puncture site erythema
                                        Vessel puncture site haematoma
                                        Vessel puncture site haemorrhage
                                        Vessel puncture site hypoaesthesia
                                        Vessel puncture site induration
                                        Vessel puncture site infection
                                        Vessel puncture site inflammation
                                        Vessel puncture site occlusion
                                        Vessel puncture site pain
                                        Vessel puncture site paraesthesia
                                        Vessel puncture site phlebitis
                                        Vessel puncture site pruritus
                                        Vessel puncture site rash
                                        Vessel puncture site reaction
                                        Vessel puncture site swelling
                                        Vessel puncture site thrombosis
                                        Vessel puncture site vesicles
Malignant neoplasms                     5q minus syndrome
                                        Abdominal wall neoplasm malignant
                                        Acinar cell carcinoma of pancreas
                                        Acinic cell carcinoma of salivary gland
                                        Acral lentiginous melanoma
                                        Acral lentiginous melanoma stage I
                                        Acral lentiginous melanoma stage II
                                        Acral lentiginous melanoma stage III
                                        Acral lentiginous melanoma stage IV
                                        Acute bilineal leukaemia
                                        Acute biphenotypic leukaemia
                                        Acute leukaemia
                                        Acute leukaemia in remission
                                        Acute lymphocytic leukaemia
                                        Acute lymphocytic leukaemia (in remission)
                                        Acute lymphocytic leukaemia recurrent
                                        Acute lymphocytic leukaemia refractory
                                        Acute megakaryocytic leukaemia
                                        Acute megakaryocytic leukaemia (in remission)
                                        Acute monocytic leukaemia
                                        Acute monocytic leukaemia (in remission)
                                        Acute myeloid leukaemia
                                        Acute myeloid leukaemia (in remission)
                                        Acute myeloid leukaemia recurrent
                                        Acute myeloid leukaemia refractory
                                        Acute myelomonocytic leukaemia
                                        Acute promyelocytic leukaemia
                                        Acute undifferentiated leukaemia
                                        Adenocarcinoma
                                        Adenocarcinoma gastric
                                        Adenocarcinoma of appendix
                                        Adenocarcinoma of colon
                                        Adenocarcinoma of salivary gland
                                        Adenocarcinoma of the cervix
                                        Adenocarcinoma pancreas
————————————————————————————————————————————————————————————————————————————————————————————————————
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CONFIDENTIAL


NN9535
NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
53 of 152
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Malignant neoplasms                     Adenoid cystic carcinoma
                                        Adenoid cystic carcinoma of external auditory canal
                                        Adenoid cystic carcinoma of salivary gland
                                        Adenosquamous carcinoma of the cervix
                                        Adenosquamous carcinoma of vagina
                                        Adenosquamous cell carcinoma
                                        Adenosquamous cell lung cancer
                                        Adenosquamous cell lung cancer recurrent
                                        Adenosquamous cell lung cancer stage 0
                                        Adenosquamous cell lung cancer stage I
                                        Adenosquamous cell lung cancer stage II
                                        Adenosquamous cell lung cancer stage III
                                        Adenosquamous cell lung cancer stage IV
                                        Adrenal gland cancer
                                        Adrenal gland cancer metastatic
                                        Adrenocortical carcinoma
                                        Adult T-cell lymphoma
                                        leukaemia
                                        Adult T-cell lymphoma
                                        leukaemia recurrent
                                        Adult T-cell lymphoma
                                        leukaemia refractory
                                        Adult T-cell lymphoma
                                        leukaemia stage I
                                        Adult T-cell lymphoma
                                        leukaemia stage II
                                        Adult T-cell lymphoma
                                        leukaemia stage III
                                        Adult T-cell lymphoma
                                        leukaemia stage IV
                                        Aesthesioneuroblastoma
                                        Aleukaemic leukaemia
                                        Alveolar rhabdomyosarcoma
                                        Alveolar soft part sarcoma
                                        Alveolar soft part sarcoma metastatic
                                        Alveolar soft part sarcoma recurrent
                                        Anal cancer
                                        Anal cancer metastatic
                                        Anal cancer recurrent
                                        Anal cancer stage 0
                                        Anal cancer stage I
                                        Anal cancer stage II
                                        Anal cancer stage III
                                        Anal cancer stage IV
                                        Anal squamous cell carcinoma
                                        Anaplastic astrocytoma
                                        Anaplastic large cell lymphoma T- and null-cell types
                                        Anaplastic large cell lymphoma T- and null-cell types
                                        recurrent
                                        Anaplastic large cell lymphoma T- and null-cell types
                                        refractory
                                        Anaplastic large cell lymphoma T- and null-cell types stage
                                        I
                                        Anaplastic large cell lymphoma T- and null-cell types stage
                                        II
                                        Anaplastic large cell lymphoma T- and null-cell types stage
                                        III
                                        Anaplastic large cell lymphoma T- and null-cell types stage
                                        IV
                                        Anaplastic large-cell lymphoma
                                        Anaplastic meningioma
                                        Anaplastic oligodendroglioma
                                        Anaplastic thyroid cancer
————————————————————————————————————————————————————————————————————————————————————————————————————
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CONFIDENTIAL


NN9535
NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
54 of 152
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Malignant neoplasms                     Angiocentric glioma
                                        Angiocentric lymphoma
                                        Angiocentric lymphoma recurrent
                                        Angiocentric lymphoma refractory
                                        Angiocentric lymphoma stage I
                                        Angiocentric lymphoma stage II
                                        Angiocentric lymphoma stage III
                                        Angiocentric lymphoma stage IV
                                        Angioimmunoblastic T-cell lymphoma
                                        Angioimmunoblastic T-cell lymphoma recurrent
                                        Angioimmunoblastic T-cell lymphoma refractory
                                        Angioimmunoblastic T-cell lymphoma stage I
                                        Angioimmunoblastic T-cell lymphoma stage II
                                        Angioimmunoblastic T-cell lymphoma stage III
                                        Angioimmunoblastic T-cell lymphoma stage IV
                                        Angiosarcoma
                                        Angiosarcoma metastatic
                                        Angiosarcoma non-metastatic
                                        Angiosarcoma recurrent
                                        Apocrine breast carcinoma
                                        Appendix cancer
                                        Astrocytoma
                                        Astrocytoma malignant
                                        Atypical teratoid
                                        rhabdoid tumour of CNS
                                        B precursor type acute leukaemia
                                        B-cell lymphoma
                                        B-cell lymphoma recurrent
                                        B-cell lymphoma refractory
                                        B-cell lymphoma stage I
                                        B-cell lymphoma stage II
                                        B-cell lymphoma stage III
                                        B-cell lymphoma stage IV
                                        B-cell prolymphocytic leukaemia
                                        B-cell small lymphocytic lymphoma
                                        B-cell small lymphocytic lymphoma recurrent
                                        B-cell small lymphocytic lymphoma refractory
                                        B-cell small lymphocytic lymphoma stage I
                                        B-cell small lymphocytic lymphoma stage II
                                        B-cell small lymphocytic lymphoma stage III
                                        B-cell small lymphocytic lymphoma stage IV
                                        B-cell type acute leukaemia
                                        B-cell unclassifiable lymphoma high grade
                                        B-cell unclassifiable lymphoma low grade
                                        Basal cell carcinoma
                                        Basosquamous carcinoma
                                        Basosquamous carcinoma of skin
                                        Bile duct adenocarcinoma
                                        Bile duct adenosquamous carcinoma
                                        Bile duct cancer
                                        Bile duct cancer recurrent
                                        Bile duct cancer stage 0
                                        Bile duct cancer stage I
                                        Bile duct cancer stage II
                                        Bile duct cancer stage III
                                        Bile duct cancer stage IV
                                        Bile duct squamous cell carcinoma
                                        Biliary cancer metastatic
                                        Biphasic mesothelioma
                                        Bladder adenocarcinoma recurrent
                                        Bladder adenocarcinoma stage 0
                                        Bladder adenocarcinoma stage I
                                        Bladder adenocarcinoma stage II
————————————————————————————————————————————————————————————————————————————————————————————————————
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CONFIDENTIAL


NN9535
NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
55 of 152
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Malignant neoplasms                     Bladder adenocarcinoma stage III
                                        Bladder adenocarcinoma stage IV
                                        Bladder adenocarcinoma stage unspecified
                                        Bladder cancer
                                        Bladder cancer recurrent
                                        Bladder cancer stage 0, with cancer in situ
                                        Bladder cancer stage 0, without cancer in situ
                                        Bladder cancer stage I, with cancer in situ
                                        Bladder cancer stage I, without cancer in situ
                                        Bladder cancer stage II
                                        Bladder cancer stage III
                                        Bladder cancer stage IV
                                        Bladder squamous cell carcinoma recurrent
                                        Bladder squamous cell carcinoma stage 0
                                        Bladder squamous cell carcinoma stage I
                                        Bladder squamous cell carcinoma stage II
                                        Bladder squamous cell carcinoma stage III
                                        Bladder squamous cell carcinoma stage IV
                                        Bladder squamous cell carcinoma stage unspecified
                                        Bladder transitional cell carcinoma
                                        Bladder transitional cell carcinoma metastatic
                                        Bladder transitional cell carcinoma recurrent
                                        Bladder transitional cell carcinoma stage 0
                                        Bladder transitional cell carcinoma stage I
                                        Bladder transitional cell carcinoma stage II
                                        Bladder transitional cell carcinoma stage III
                                        Bladder transitional cell carcinoma stage IV
                                        Blast cell crisis
                                        Blast crisis in myelogenous leukaemia
                                        Blastic plasmacytoid dendritic cell neoplasia
                                        Bone cancer
                                        Bone cancer metastatic
                                        Bone giant cell tumour malignant
                                        Bone marrow leukaemic cell infiltration
                                        Bone marrow tumour cell infiltration
                                        Bone sarcoma
                                        Bowen's disease
                                        Brain cancer metastatic
                                        Brain neoplasm malignant
                                        Brain sarcoma
                                        Brain stem glioma
                                        Breast angiosarcoma
                                        Breast angiosarcoma metastatic
                                        Breast cancer
                                        Breast cancer female
                                        Breast cancer in situ
                                        Breast cancer male
                                        Breast cancer metastatic
                                        Breast cancer recurrent
                                        Breast cancer stage I
                                       Breast cancer stage II
                                        Breast cancer stage III
                                        Breast cancer stage IV
                                        Breast sarcoma
                                        Breast sarcoma metastatic
                                        Breast sarcoma recurrent
                                        Bronchial carcinoma
                                        Bronchioloalveolar carcinoma
                                        Burkitt's leukaemia
                                        Burkitt's lymphoma
                                        Burkitt's lymphoma recurrent
                                        Burkitt's lymphoma refractory
                                        Burkitt's lymphoma stage I
————————————————————————————————————————————————————————————————————————————————————————————————————
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CONFIDENTIAL


NN9535
NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
56 of 152
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Malignant neoplasms                     Burkitt's lymphoma stage II
                                        Burkitt's lymphoma stage III
                                        Burkitt's lymphoma stage IV
                                        Buschke-Lowenstein's tumour
                                        CNS germinoma
                                        Cancer in remission
                                        Carcinoid tumour
                                        Carcinoid tumour of the appendix
                                        Carcinoid tumour of the caecum
                                        Carcinoid tumour of the duodenum
                                        Carcinoid tumour of the gastrointestinal tract
                                        Carcinoid tumour of the liver
                                        Carcinoid tumour of the ovary
                                        Carcinoid tumour of the pancreas
                                        Carcinoid tumour of the prostate
                                        Carcinoid tumour of the small bowel
                                        Carcinoid tumour of the stomach
                                        Carcinoid tumour pulmonary
                                        Carcinoma ex-pleomorphic adenoma
                                        Carcinoma in situ
                                        Carcinoma in situ of eye
                                        Carcinoma in situ of penis
                                        Carcinoma in situ of skin
                                        Carcinoma in situ of trachea
                                        Cardiac neoplasm malignant
                                        Central nervous system leukaemia
                                        Central nervous system lymphoma
                                        Central nervous system melanoma
                                        Central nervous system neuroblastoma
                                        Cervix cancer metastatic
                                        Cervix carcinoma
                                        Cervix carcinoma recurrent
                                        Cervix carcinoma stage 0
                                        Cervix carcinoma stage I
                                        Cervix carcinoma stage II
                                        Cervix carcinoma stage III
                                        Cervix carcinoma stage IV
                                        Chloroma
                                        Chloroma (in remission)
                                        Cholangiocarcinoma
                                        Cholangiosarcoma
                                        Chondrosarcoma
                                        Chondrosarcoma metastatic
                                        Chondrosarcoma recurrent
                                        Chordoma
                                        Choriocarcinoma
                                        Choroid melanoma
                                        Choroid plexus carcinoma
                                        Chromophobe renal cell carcinoma
                                        Chronic eosinophilic leukaemia
                                        Chronic leukaemia
                                        Chronic leukaemia in remission
                                        Chronic lymphocytic leukaemia
                                        Chronic lymphocytic leukaemia (in remission)
                                        Chronic lymphocytic leukaemia recurrent
                                        Chronic lymphocytic leukaemia refractory
                                       Chronic lymphocytic leukaemia stage 0
                                        Chronic lymphocytic leukaemia stage 1
                                        Chronic lymphocytic leukaemia stage 2
                                        Chronic lymphocytic leukaemia stage 3
                                        Chronic lymphocytic leukaemia stage 4
                                        Chronic lymphocytic leukaemia transformation
                                        Chronic myeloid leukaemia
————————————————————————————————————————————————————————————————————————————————————————————————————
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————————————————————————————————————————————————————————————————————————————————————————————————————
Malignant neoplasms                     Chronic myeloid leukaemia (in remission)
                                        Chronic myeloid leukaemia recurrent
                                        Chronic myeloid leukaemia transformation
                                        Chronic myelomonocytic leukaemia
                                        Chronic myelomonocytic leukaemia (in remission)
                                        Ciliary body melanoma
                                        Clear cell carcinoma of cervix
                                        Clear cell endometrial carcinoma
                                        Clear cell renal cell carcinoma
                                        Clear cell sarcoma of soft tissue
                                        Clear cell sarcoma of the kidney
                                        Colon cancer
                                        Colon cancer metastatic
                                        Colon cancer recurrent
                                        Colon cancer stage 0
                                        Colon cancer stage I
                                        Colon cancer stage II
                                        Colon cancer stage III
                                        Colon cancer stage IV
                                        Colorectal adenocarcinoma
                                        Colorectal cancer
                                        Colorectal cancer metastatic
                                        Colorectal cancer recurrent
                                        Colorectal cancer stage I
                                        Colorectal cancer stage II
                                        Colorectal cancer stage III
                                        Colorectal cancer stage IV
                                        Colorectal carcinoma stage 0
                                        Composite lymphoma
                                        Congenital fibrosarcoma
                                        Congenital malignant neoplasm
                                        Congenital retinoblastoma
                                        Conjunctival melanoma
                                        Cutaneous lymphoma
                                        Cystadenocarcinoma ovary
                                        Cystadenocarcinoma pancreas
                                        Dedifferentiated liposarcoma
                                        Dermatofibrosarcoma protuberans
                                        Dermatofibrosarcoma protuberans metastatic
                                        Desmoplastic melanoma
                                        Desmoplastic mesothelioma
                                        Desmoplastic small round cell tumour
                                        Diffuse large B-cell lymphoma
                                        Diffuse large B-cell lymphoma recurrent
                                        Diffuse large B-cell lymphoma refractory
                                        Diffuse large B-cell lymphoma stage I
                                        Diffuse large B-cell lymphoma stage II
                                        Diffuse large B-cell lymphoma stage III
                                        Diffuse large B-cell lymphoma stage IV
                                        Disseminated large cell lymphoma
                                        Double hit lymphoma
                                        Ductal adenocarcinoma of pancreas
                                        Ear neoplasm malignant
                                        Eccrine carcinoma
                                        Embryonal rhabdomyosarcoma
                                        Endocrine neoplasm malignant
                                        Endometrial adenocarcinoma
                                        Endometrial cancer
                                        Endometrial cancer metastatic
                                        Endometrial cancer recurrent
                                        Endometrial cancer stage 0
                                        Endometrial cancer stage I
                                        Endometrial cancer stage II
————————————————————————————————————————————————————————————————————————————————————————————————————
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Clinical Trial Report
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03 July 2019
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————————————————————————————————————————————————————————————————————————————————————————————————————
Malignant neoplasms                     Endometrial cancer stage III
                                        Endometrial cancer stage IV
                                        Endometrial sarcoma
                                        Endometrial sarcoma metastatic
                                        Endometrial sarcoma recurrent
                                        Endometrial stromal sarcoma
                                        Endotheliomatosis
                                        Enteropathy-associated T-cell lymphoma
                                        Eosinophilic leukaemia
                                        Ependymoma malignant
                                        Epididymal cancer
                                        Epiglottic carcinoma
                                        Epithelioid mesothelioma
                                        Epithelioid sarcoma
                                        Epithelioid sarcoma metastatic
                                        Epithelioid sarcoma recurrent
                                        Epstein-Barr virus associated lymphoma
                                        Erythraemic myelosis (in remission)
                                        Erythroleukaemia
                                        Ewing's sarcoma
                                        Ewing's sarcoma metastatic
                                        Ewing's sarcoma recurrent
                                        Ewing-like sarcoma
                                        Extra-osseous Ewing's sarcoma
                                        Extra-osseous Ewing's sarcoma metastatic
                                        Extra-osseous Ewing's sarcoma recurrent
                                        Extragonadal primary embryonal carcinoma
                                        Extragonadal primary germ cell tumour
                                        Extragonadal primary germ cell tumour mixed
                                        Extragonadal primary germ cell tumour mixed stage I
                                        Extragonadal primary germ cell tumour mixed stage II
                                        Extragonadal primary germ cell tumour mixed stage III
                                        Extragonadal primary malignant teratoma
                                        Extragonadal primary non-seminoma
                                        Extragonadal primary non-seminoma stage I
                                        Extragonadal primary non-seminoma stage II
                                        Extragonadal primary non-seminoma stage III
                                        Extragonadal primary non-seminoma stage IV
                                        Extragonadal primary seminoma (pure)
                                        Extragonadal primary seminoma (pure) stage I
                                        Extragonadal primary seminoma (pure) stage II
                                        Extragonadal primary seminoma (pure) stage III
                                        Extragonadal primary seminoma (pure) stage IV
                                        Extramammary Paget's disease
                                        Extranodal marginal zone B-cell lymphoma (BALT type)
                                        Extranodal marginal zone B-cell lymphoma (MALT type)
                                        Extranodal marginal zone B-cell lymphoma (MALT type)
                                        recurrent
                                        Extranodal marginal zone B-cell lymphoma (MALT type)
                                        refractory
                                        Extranodal marginal zone B-cell lymphoma (MALT type) stage I
                                       Extranodal marginal zone B-cell lymphoma (MALT type) stage
                                        II
                                        Extranodal marginal zone B-cell lymphoma (MALT type) stage
                                        III
                                        Extranodal marginal zone B-cell lymphoma (MALT type) stage
                                        IV
                                        Extraocular retinoblastoma
                                        Extraskeletal chondrosarcoma metastatic
                                        Extraskeletal chondrosarcoma recurrent
                                        Extraskeletal myxoid chondrosarcoma
                                        Extraskeletal osteosarcoma
                                        Extraskeletal osteosarcoma metastatic
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03 July 2019
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————————————————————————————————————————————————————————————————————————————————————————————————————
Malignant neoplasms                     Extraskeletal osteosarcoma recurrent
                                        Fallopian tube cancer
                                        Fallopian tube cancer metastatic
                                        Fallopian tube cancer stage I
                                        Fallopian tube cancer stage II
                                        Fallopian tube cancer stage III
                                        Fallopian tube cancer stage IV
                                        Familial medullary thyroid cancer
                                        Female reproductive tract carcinoma in situ
                                        Fibrosarcoma
                                        Fibrosarcoma metastatic
                                        Follicle centre lymphoma diffuse small cell lymphoma
                                        Follicle centre lymphoma diffuse small cell lymphoma
                                        recurrent
                                        Follicle centre lymphoma diffuse small cell lymphoma
                                        refractory
                                        Follicle centre lymphoma diffuse small cell lymphoma stage I
                                        Follicle centre lymphoma diffuse small cell lymphoma stage
                                        II
                                        Follicle centre lymphoma diffuse small cell lymphoma stage
                                        III
                                        Follicle centre lymphoma diffuse small cell lymphoma stage
                                        IV
                                        Follicle centre lymphoma, follicular grade I, II, III
                                        Follicle centre lymphoma, follicular grade I, II, III
                                        recurrent
                                        Follicle centre lymphoma, follicular grade I, II, III
                                        refractory
                                        Follicle centre lymphoma, follicular grade I, II, III stage
                                        I
                                        Follicle centre lymphoma, follicular grade I, II, III stage
                                        II
                                        Follicle centre lymphoma, follicular grade I, II, III stage
                                        III
                                        Follicle centre lymphoma, follicular grade I, II, III stage
                                        IV
                                        Follicular dendritic cell sarcoma
                                        Follicular thyroid cancer
                                        Gallbladder adenocarcinoma
                                        Gallbladder adenosquamous carcinoma
                                        Gallbladder cancer
                                        Gallbladder cancer metastatic
                                        Gallbladder cancer recurrent
                                        Gallbladder cancer stage 0
                                        Gallbladder cancer stage I
                                        Gallbladder cancer stage II
                                        Gallbladder cancer stage III
                                        Gallbladder cancer stage IV
                                        Gallbladder squamous cell carcinoma
                                        Ganglioglioma
                                        Ganglioneuroblastoma
                                        Gastric cancer
                                        Gastric cancer recurrent
                                        Gastric cancer stage 0
                                        Gastric cancer stage I
                                        Gastric cancer stage II
                                        Gastric cancer stage III
                                        Gastric cancer stage IV
                                        Gastric sarcoma
                                        Gastrinoma malignant
                                        Gastroenteropancreatic neuroendocrine tumour disease
                                        Gastrointestinal adenocarcinoma
                                        Gastrointestinal cancer metastatic
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Clinical Trial Report
Section 16.1.9
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03 July 2019
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Status:
Final
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————————————————————————————————————————————————————————————————————————————————————————————————————
Malignant neoplasms                     Gastrointestinal carcinoma
                                        Gastrointestinal carcinoma in situ
                                        Gastrointestinal lymphoma
                                        Gastrointestinal melanoma
                                        Gastrointestinal stromal cancer
                                        Gastrooesophageal cancer
                                        Gastrooesophageal cancer recurrent
                                        Genital cancer male
                                        Genital cancer male in situ
                                        Genital neoplasm malignant female
                                        Genitourinary melanoma
                                        Germ cell cancer
                                        Germ cell cancer metastatic
                                        Gestational trophoblastic tumour
                                        Gingival cancer
                                        Glioblastoma
                                        Glioblastoma multiforme
                                        Glioma
                                        Gliomatosis cerebri
                                        Glioneuronal tumour
                                        Gliosarcoma
                                        Glottis carcinoma
                                        Glucagonoma
                                        HER-2 positive breast cancer
                                        HER-2 positive gastric cancer
                                        Haemangiopericytoma
                                        Haemangiopericytoma of meninges
                                        Haematological malignancy
                                        Hairy cell leukaemia
                                        Hairy cell leukaemia recurrent
                                        Head and neck cancer
                                        Head and neck cancer metastatic
                                        Head and neck cancer stage I
                                        Head and neck cancer stage II
                                        Head and neck cancer stage III
                                        Head and neck cancer stage IV
                                        Hepatic angiosarcoma
                                        Hepatic cancer
                                        Hepatic cancer metastatic
                                        Hepatic cancer recurrent
                                        Hepatic cancer stage I
                                        Hepatic cancer stage II
                                        Hepatic cancer stage III
                                        Hepatic cancer stage IV
                                        Hepatobiliary cancer
                                        Hepatobiliary cancer in situ
                                        Hepatoblastoma
                                        Hepatoblastoma recurrent
                                        Hepatocellular carcinoma
                                        Hepatosplenic T-cell lymphoma
                                        Hereditary leiomyomatosis renal cell carcinoma
                                        Hereditary papillary renal carcinoma
                                        Hidradenocarcinoma
                                        High grade B-cell lymphoma Burkitt-like lymphoma
                                        High grade B-cell lymphoma Burkitt-like lymphoma recurrent
                                        High grade B-cell lymphoma Burkitt-like lymphoma refractory
                                        High grade B-cell lymphoma Burkitt-like lymphoma stage I
                                        High grade B-cell lymphoma Burkitt-like lymphoma stage II
                                        High grade B-cell lymphoma Burkitt-like lymphoma stage III
                                        High grade B-cell lymphoma Burkitt-like lymphoma stage IV
                                        High-grade B-cell lymphoma
                                        Histiocytic medullary reticulosis
                                        Histiocytic sarcoma
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Clinical Trial Report
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————————————————————————————————————————————————————————————————————————————————————————————————————
Malignant neoplasms                     Hodgkin's disease
                                        Hodgkin's disease lymphocyte depletion stage I site
                                        unspecified
                                        Hodgkin's disease lymphocyte depletion stage I subdiaphragm
                                        Hodgkin's disease lymphocyte depletion stage I
                                        supradiaphragm
                                        Hodgkin's disease lymphocyte depletion stage II site
                                        unspecified
                                        Hodgkin's disease lymphocyte depletion stage II subdiaphragm
                                        Hodgkin's disease lymphocyte depletion stage II
                                        supradiaphragm
                                        Hodgkin's disease lymphocyte depletion type recurrent
                                        Hodgkin's disease lymphocyte depletion type refractory
                                        Hodgkin's disease lymphocyte depletion type stage III
                                        Hodgkin's disease lymphocyte depletion type stage IV
                                        Hodgkin's disease lymphocyte depletion type stage
                                        unspecified
                                        Hodgkin's disease lymphocyte predominance stage I site
                                        unspec
                                        Hodgkin's disease lymphocyte predominance stage I
                                        subdiaphragm
                                        Hodgkin's disease lymphocyte predominance stage I
                                        supradiaphragm
                                        Hodgkin's disease lymphocyte predominance stage II site
                                        unspec
                                        Hodgkin's disease lymphocyte predominance stage II
                                        subdiaphragm
                                        Hodgkin's disease lymphocyte predominance stage II
                                        supradiaphragm
                                        Hodgkin's disease lymphocyte predominance type recurrent
                                        Hodgkin's disease lymphocyte predominance type refractory
                                        Hodgkin's disease lymphocyte predominance type stage III
                                        Hodgkin's disease lymphocyte predominance type stage IV
                                        Hodgkin's disease lymphocyte predominance type stage
                                        unspecified
                                        Hodgkin's disease mixed cellularity recurrent
                                        Hodgkin's disease mixed cellularity refractory
                                        Hodgkin's disease mixed cellularity stage I site unspecified
                                        Hodgkin's disease mixed cellularity stage I subdiaphragmatic
                                        Hodgkin's disease mixed cellularity stage I
                                        supradiaphragmatic
                                        Hodgkin's disease mixed cellularity stage II
                                        subdiaphragmatic
                                        Hodgkin's disease mixed cellularity stage II
                                        supradiaphragmatic
                                        Hodgkin's disease mixed cellularity stage III
                                        Hodgkin's disease mixed cellularity stage IV
                                        Hodgkin's disease mixed cellularity stage unspecified
                                        Hodgkin's disease nodular sclerosis
                                        Hodgkin's disease nodular sclerosis recurrent
                                        Hodgkin's disease nodular sclerosis refractory
                                        Hodgkin's disease nodular sclerosis stage I
                                        Hodgkin's disease nodular sclerosis stage II
                                        Hodgkin's disease nodular sclerosis stage III
                                        Hodgkin's disease nodular sclerosis stage IV
                                        Hodgkin's disease recurrent
                                        Hodgkin's disease refractory
                                        Hodgkin's disease stage I
                                        Hodgkin's disease stage II
                                        Hodgkin's disease stage III
                                        Hodgkin's disease stage IV
                                        Hodgkin's disease unclassifiable
                                        Hormone refractory breast cancer
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Clinical Trial Report
Section 16.1.9
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03 July 2019
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————————————————————————————————————————————————————————————————————————————————————————————————————
Malignant neoplasms                     Hormone-dependent prostate cancer
                                        Hormone-refractory prostate cancer
                                        Huerthle cell carcinoma
                                        Hypopharyngeal cancer
                                        Hypopharyngeal cancer recurrent
                                        Hypopharyngeal cancer stage 0
                                        Hypopharyngeal cancer stage I
                                        Hypopharyngeal cancer stage II
                                        Hypopharyngeal cancer stage III
                                        Hypopharyngeal cancer stage IV
                                        Immune reconstitution inflammatory syndrome associated
                                        Kaposi's sarcoma
                                        Immunoblastic lymphoma
                                        Inflammatory carcinoma of breast recurrent
                                        Inflammatory carcinoma of breast stage III
                                        Inflammatory carcinoma of breast stage IV
                                        Inflammatory carcinoma of the breast
                                        Inflammatory malignant fibrous histiocytoma
                                        Inflammatory myofibroblastic tumour
                                        Intestinal T-cell lymphoma recurrent
                                        Intestinal T-cell lymphoma refractory
                                        Intestinal T-cell lymphoma stage I
                                        Intestinal T-cell lymphoma stage II
                                        Intestinal T-cell lymphoma stage III
                                        Intestinal T-cell lymphoma stage IV
                                        Intestinal adenocarcinoma
                                        Intestinal metastasis
                                        Intracranial germ cell tumour
                                        Intracranial meningioma malignant
                                        Intraductal papillary breast neoplasm
                                        Intraductal papillary-mucinous carcinoma of pancreas
                                        Intraductal proliferative breast lesion
                                        Intraocular melanoma
                                        Invasive breast carcinoma
                                        Invasive ductal breast carcinoma
                                        Invasive lobular breast carcinoma
                                        Invasive papillary breast carcinoma
                                        Iris melanoma
                                        Juvenile chronic myelomonocytic leukaemia
                                        Kaposi's sarcoma
                                        Kaposi's sarcoma AIDS related
                                        Kaposi's sarcoma classical type
                                        Keratinising squamous cell carcinoma of nasopharynx
                                        Keratoacanthoma
                                        Langerhans cell sarcoma
                                        Large cell lung cancer
                                        Large cell lung cancer metastatic
                                        Large cell lung cancer recurrent
                                        Large cell lung cancer stage 0
                                        Large cell lung cancer stage I
                                        Large cell lung cancer stage II
                                        Large cell lung cancer stage III
                                        Large cell lung cancer stage IV
                                        Laryngeal cancer
                                        Laryngeal cancer metastatic
                                        Laryngeal cancer recurrent
                                        Laryngeal cancer stage 0
                                        Laryngeal cancer stage I
                                        Laryngeal cancer stage II
                                        Laryngeal cancer stage III
                                        Laryngeal cancer stage IV
                                        Laryngeal squamous cell carcinoma
                                        Leiomyosarcoma
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Clinical Trial Report
Section 16.1.9
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03 July 2019
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————————————————————————————————————————————————————————————————————————————————————————————————————
Malignant neoplasms                     Leiomyosarcoma metastatic
                                        Leiomyosarcoma recurrent
                                        Lentigo maligna
                                        Lentigo maligna recurrent
                                       Lentigo maligna stage I
                                        Lentigo maligna stage II
                                        Lentigo maligna stage III
                                        Lentigo maligna stage IV
                                        Leptomeningeal myelomatosis
                                        Leukaemia
                                        Leukaemia basophilic
                                        Leukaemia cutis
                                        Leukaemia granulocytic
                                        Leukaemia in remission
                                        Leukaemia monocytic
                                        Leukaemia recurrent
                                        Leukaemic cardiac infiltration
                                        Leukaemic infiltration
                                        Leukaemic infiltration extramedullary
                                        Leukaemic infiltration gingiva
                                        Leukaemic infiltration hepatic
                                        Leukaemic infiltration ovary
                                        Leukaemic infiltration pulmonary
                                        Leukaemic infiltration renal
                                        Leukaemic lymphoma
                                        Leukaemic retinopathy
                                        Leydig cell tumour of the testis
                                        Linitis plastica
                                        Lip and
                                        or oral cavity cancer
                                        Lip and
                                        or oral cavity cancer recurrent
                                        Lip and
                                        or oral cavity cancer stage 0
                                        Lip and
                                        or oral cavity cancer stage I
                                        Lip and
                                        or oral cavity cancer stage II
                                        Lip and
                                        or oral cavity cancer stage III
                                        Lip and
                                        or oral cavity cancer stage IV
                                        Lip neoplasm malignant stage unspecified
                                        Lip squamous cell carcinoma
                                        Liposarcoma
                                        Liposarcoma metastatic
                                        Liposarcoma recurrent
                                        Lobular breast carcinoma in situ
                                        Lung adenocarcinoma
                                        Lung adenocarcinoma recurrent
                                        Lung adenocarcinoma stage 0
                                        Lung adenocarcinoma stage I
                                        Lung adenocarcinoma stage II
                                        Lung adenocarcinoma stage III
                                        Lung adenocarcinoma stage IV
                                        Lung cancer metastatic
                                        Lung carcinoma cell type unspecified recurrent
                                        Lung carcinoma cell type unspecified stage 0
                                        Lung carcinoma cell type unspecified stage I
                                        Lung carcinoma cell type unspecified stage II
                                        Lung carcinoma cell type unspecified stage III
                                        Lung carcinoma cell type unspecified stage IV
                                        Lung infiltration malignant
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Clinical Trial Report
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03 July 2019
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————————————————————————————————————————————————————————————————————————————————————————————————————
Malignant neoplasms                     Lung neoplasm malignant
                                        Lung squamous cell carcinoma metastatic
                                        Lung squamous cell carcinoma recurrent
                                        Lung squamous cell carcinoma stage 0
                                        Lung squamous cell carcinoma stage I
                                        Lung squamous cell carcinoma stage II
                                        Lung squamous cell carcinoma stage III
                                        Lung squamous cell carcinoma stage IV
                                        Lymphangiosarcoma
                                        Lymphangiosis carcinomatosa
                                        Lymphocytic leukaemia
                                        Lymphocytic lymphoma
                                        Lymphoid leukaemia (in remission)
                                        Lymphoma
                                        Lymphoma AIDS related
                                        Lymphoma transformation
                                        Lymphoplasmacytoid lymphoma
                                        immunocytoma
                                        Lymphoplasmacytoid lymphoma
                                        immunocytoma recurrent
                                        Lymphoplasmacytoid lymphoma
                                        immunocytoma refractory
                                        Lymphoplasmacytoid lymphoma
                                        immunocytoma stage I
                                        Lymphoplasmacytoid lymphoma
                                        immunocytoma stage II
                                        Lymphoplasmacytoid lymphoma
                                        immunocytoma stage III
                                        Lymphoplasmacytoid lymphoma
                                        immunocytoma stage IV
                                       Malignant anorectal neoplasm
                                        Malignant blue naevus
                                        Malignant connective tissue neoplasm
                                        Malignant cranial nerve neoplasm
                                        Malignant fibrous histiocytoma
                                        Malignant fibrous histiocytoma metastatic
                                        Malignant fibrous histiocytoma of bone
                                        Malignant fibrous histiocytoma recurrent
                                        Malignant genitourinary tract neoplasm
                                        Malignant giant cell fibrous histiocytoma
                                        Malignant glioma
                                        Malignant haemangiopericytoma
                                        Malignant haemangiopericytoma metastatic
                                        Malignant haemangiopericytoma recurrent
                                        Malignant histiocytosis
                                        Malignant hydatidiform mole
                                        Malignant joint neoplasm
                                        Malignant lymphoid neoplasm
                                        Malignant lymphoma unclassifiable high grade
                                        Malignant lymphoma unclassifiable low grade
                                        Malignant mast cell neoplasm
                                        Malignant mediastinal neoplasm
                                        Malignant melanoma
                                        Malignant melanoma in situ
                                       Malignant melanoma of eyelid
                                        Malignant melanoma of sites other than skin
                                        Malignant melanoma stage I
                                        Malignant melanoma stage II
                                        Malignant melanoma stage III
                                        Malignant melanoma stage IV
                                        Malignant meningioma metastatic
                                        Malignant mesenchymoma
                                        Malignant mesenchymoma metastatic
————————————————————————————————————————————————————————————————————————————————————————————————————
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NN9535-4114
Clinical Trial Report
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03 July 2019
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————————————————————————————————————————————————————————————————————————————————————————————————————
Malignant neoplasms                     Malignant mesenchymoma recurrent
                                        Malignant mesenteric neoplasm
                                        Malignant middle ear neoplasm
                                        Malignant muscle neoplasm
                                        Malignant neoplasm of ampulla of Vater
                                        Malignant neoplasm of auricular cartilage
                                        Malignant neoplasm of choroid
                                        Malignant neoplasm of conjunctiva
                                        Malignant neoplasm of cornea
                                        Malignant neoplasm of eye
                                        Malignant neoplasm of eyelid
                                        Malignant neoplasm of islets of Langerhans
                                        Malignant neoplasm of lacrimal duct
                                        Malignant neoplasm of lacrimal gland
                                        Malignant neoplasm of orbit
                                        Malignant neoplasm of paraurethral glands
                                        Malignant neoplasm of placenta
                                        Malignant neoplasm of pleura
                                        Malignant neoplasm of pleura metastatic
                                        Malignant neoplasm of renal pelvis
                                        Malignant neoplasm of retina
                                        Malignant neoplasm of seminal vesicle
                                        Malignant neoplasm of spermatic cord
                                        Malignant neoplasm of spinal cord
                                        Malignant neoplasm of thorax
                                        Malignant neoplasm of thymus
                                        Malignant neoplasm of unknown primary site
                                        Malignant neoplasm of uterine adnexa
                                        Malignant neoplasm papilla of Vater
                                        Malignant nervous system neoplasm
                                        Malignant nipple neoplasm
                                        Malignant nipple neoplasm female
                                        Malignant nipple neoplasm male
                                        Malignant oligodendroglioma
                                        Malignant ovarian cyst
                                        Malignant palate neoplasm
                                        Malignant pericardial neoplasm
                                        Malignant peritoneal neoplasm
                                        Malignant pituitary tumour
                                        Malignant polyp
                                        Malignant respiratory tract neoplasm
                                        Malignant splenic neoplasm
                                        Malignant sweat gland neoplasm
                                        Malignant transformation
                                        Malignant urinary tract neoplasm
                                        Mantle cell lymphoma
                                        Mantle cell lymphoma recurrent
                                        Mantle cell lymphoma refractory
                                        Mantle cell lymphoma stage I
                                        Mantle cell lymphoma stage II
                                        Mantle cell lymphoma stage III
                                        Mantle cell lymphoma stage IV
                                        Marginal zone lymphoma
                                        Marginal zone lymphoma recurrent
                                        Marginal zone lymphoma refractory
                                        Marginal zone lymphoma stage I
                                        Marginal zone lymphoma stage II
                                        Marginal zone lymphoma stage III
                                        Marginal zone lymphoma stage IV
                                        Marjolin's ulcer
                                        Mastocytic leukaemia
                                        Maternal cancer in pregnancy
                                        Mature B-cell type acute leukaemia
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Malignant neoplasms                     Medullary carcinoma of breast
                                        Medullary thyroid cancer
                                        Medulloblastoma
                                        Medulloblastoma recurrent
                                        Melanoma recurrent
                                        Meningioma malignant
                                        Mesothelioma malignant
                                        Mesothelioma malignant recurrent
                                        Metaplastic breast carcinoma
                                        Metastases to Eustachian tube
                                        Metastases to abdominal cavity
                                        Metastases to abdominal wall
                                        Metastases to adrenals
                                        Metastases to biliary tract
                                        Metastases to bladder
                                        Metastases to bone
                                        Metastases to bone marrow
                                        Metastases to breast
                                        Metastases to central nervous system
                                        Metastases to chest wall
                                        Metastases to diaphragm
                                        Metastases to eye
                                        Metastases to fallopian tube
                                        Metastases to gallbladder
                                        Metastases to gastrointestinal tract
                                        Metastases to heart
                                        Metastases to kidney
                                        Metastases to larynx
                                        Metastases to liver
                                        Metastases to lung
                                        Metastases to lymph nodes
                                        Metastases to meninges
                                        Metastases to mouth
                                        Metastases to muscle
                                        Metastases to nasal sinuses
                                        Metastases to neck
                                        Metastases to nervous system
                                        Metastases to oesophagus
                                        Metastases to ovary
                                        Metastases to pancreas
                                        Metastases to pelvis
                                        Metastases to penis
                                        Metastases to perineum
                                        Metastases to peripheral nervous system
                                        Metastases to peripheral vascular system
                                        Metastases to peritoneum
                                        Metastases to pharynx
                                        Metastases to pituitary gland
                                        Metastases to placenta
                                        Metastases to pleura
                                        Metastases to prostate
                                        Metastases to rectum
                                        Metastases to reproductive organ
                                        Metastases to retroperitoneum
                                        Metastases to salivary gland
                                        Metastases to skin
                                        Metastases to soft tissue
                                        Metastases to spinal cord
                                        Metastases to spine
                                        Metastases to spleen
                                        Metastases to stomach
                                        Metastases to testicle
                                        Metastases to the mediastinum
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————————————————————————————————————————————————————————————————————————————————————————————————————
Malignant neoplasms                     Metastases to the respiratory system
                                        Metastases to thorax
                                        Metastases to thyroid
                                        Metastases to tonsils
                                        Metastases to trachea
                                        Metastases to urinary tract
                                        Metastases to uterus
                                        Metastases to vagina
                                        Metastasis
                                        Metastatic bronchial carcinoma
                                        Metastatic carcinoid tumour
                                        Metastatic carcinoma of the bladder
                                        Metastatic choriocarcinoma
                                        Metastatic gastric cancer
                                        Metastatic glioma
                                        Metastatic glucagonoma
                                        Metastatic lymphoma
                                        Metastatic malignant melanoma
                                        Metastatic neoplasm
                                        Metastatic nervous system neoplasm
                                        Metastatic ocular melanoma
                                        Metastatic renal cell carcinoma
                                        Metastatic salivary gland cancer
                                        Metastatic squamous cell carcinoma
                                        Metastatic uterine cancer
                                        Microsatellite instability cancer
                                        Minimal residual disease
                                        Mismatch repair cancer syndrome
                                        Mixed adenoneuroendocrine carcinoma
                                        Mixed hepatocellular cholangiocarcinoma
                                        Mixed-type liposarcoma
                                        Monocytic leukaemia in remission
                                        Mucinous adenocarcinoma of appendix
                                        Mucinous breast carcinoma
                                        Mucinous cystadenocarcinoma ovary
                                        Mucinous endometrial carcinoma
                                        Mucoepidermoid carcinoma
                                        Mucoepidermoid carcinoma of salivary gland
                                        Musculoskeletal cancer
                                        Mycosis fungoides
                                        Mycosis fungoides recurrent
                                        Mycosis fungoides refractory
                                        Mycosis fungoides stage I
                                        Mycosis fungoides stage II
                                        Mycosis fungoides stage III
                                        Mycosis fungoides stage IV
                                        Myeloblastoma
                                        Myeloid leukaemia
                                        Myeloid leukaemia in remission
                                        Myxofibrosarcoma
                                        Myxoid liposarcoma
                                        NUT midline carcinoma
                                        Naevoid melanoma
                                        Nasal cavity cancer
                                        Nasal sinus cancer
                                        Nasopharyngeal cancer
                                        Nasopharyngeal cancer metastatic
                                        Nasopharyngeal cancer recurrent
                                        Nasopharyngeal cancer stage 0
                                        Nasopharyngeal cancer stage I
                                        Nasopharyngeal cancer stage II
                                        Nasopharyngeal cancer stage III
                                        Nasopharyngeal cancer stage IV
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————————————————————————————————————————————————————————————————————————————————————————————————————
Malignant neoplasms                     Natural killer-cell leukaemia
                                        Natural killer-cell lymphoblastic lymphoma
                                        Neonatal leukaemia
                                        Neonatal neuroblastoma
                                        Neoplasm malignant
                                        Nephroblastoma
                                        Neuroblastoma
                                        Neuroblastoma recurrent
                                        Neuroendocrine breast tumour
                                        Neuroendocrine carcinoma
                                        Neuroendocrine carcinoma metastatic
                                        Neuroendocrine carcinoma of the bladder
                                        Neuroendocrine carcinoma of the skin
                                        Neuroendocrine tumour
                                        Neuroendocrine tumour of the lung
                                        Neuroendocrine tumour of the lung metastatic
                                        Neurofibrosarcoma
                                        Neurofibrosarcoma metastatic
                                        Neurofibrosarcoma recurrent
                                        Nodal marginal zone B-cell lymphoma
                                        Nodal marginal zone B-cell lymphoma recurrent
                                        Nodal marginal zone B-cell lymphoma refractory
                                        Nodal marginal zone B-cell lymphoma stage I
                                        Nodal marginal zone B-cell lymphoma stage II
                                        Nodal marginal zone B-cell lymphoma stage III
                                        Nodal marginal zone B-cell lymphoma stage IV
                                        Nodular lymphocyte predominant Hodgkin lymphoma
                                        Nodular melanoma
                                        Non-Hodgkin's lymphoma
                                        Non-Hodgkin's lymphoma metastatic
                                        Non-Hodgkin's lymphoma recurrent
                                        Non-Hodgkin's lymphoma refractory
                                        Non-Hodgkin's lymphoma stage I
                                        Non-Hodgkin's lymphoma stage II
                                        Non-Hodgkin's lymphoma stage III
                                        Non-Hodgkin's lymphoma stage IV
                                        Non-Hodgkin's lymphoma transformed recurrent
                                        Non-Hodgkin's lymphoma unspecified histology aggressive
                                        Non-Hodgkin's lymphoma unspecified histology aggressive
                                        recurrent
                                        Non-Hodgkin's lymphoma unspecified histology aggressive
                                        refractory
                                        Non-Hodgkin's lymphoma unspecified histology aggressive
                                        stage I
                                        Non-Hodgkin's lymphoma unspecified histology aggressive
                                        stage II
                                        Non-Hodgkin's lymphoma unspecified histology aggressive
                                        stage III
                                        Non-Hodgkin's lymphoma unspecified histology aggressive
                                        stage IV
                                        Non-Hodgkin's lymphoma unspecified histology indolent
                                        Non-Hodgkin's lymphoma unspecified histology indolent stage
                                        I
                                        Non-Hodgkin's lymphoma unspecified histology indolent stage
                                        II
                                        Non-Hodgkin's lymphoma unspecified histology indolent stage
                                        III
                                        Non-Hodgkin's lymphoma unspecified histology indolent stage
                                        IV
                                        Non-renal cell carcinoma of kidney
                                        Non-small cell lung cancer
                                        Non-small cell lung cancer metastatic
                                        Non-small cell lung cancer recurrent
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————————————————————————————————————————————————————————————————————————————————————————————————————
Malignant neoplasms                     Non-small cell lung cancer stage 0
                                        Non-small cell lung cancer stage I
                                        Non-small cell lung cancer stage II
                                        Non-small cell lung cancer stage III
                                        Non-small cell lung cancer stage IIIA
                                        Non-small cell lung cancer stage IIIB
                                        Non-small cell lung cancer stage IV
                                        Nongerminomatous germ cell tumour of the CNS
                                        Nonkeratinising carcinoma of nasopharynx
                                        Ocular cancer metastatic
                                        Ocular haemangiopericytoma
                                        Ocular lymphoma
                                        Oesophageal adenocarcinoma
                                        Oesophageal adenocarcinoma recurrent
                                        Oesophageal adenocarcinoma stage 0
                                        Oesophageal adenocarcinoma stage I
                                        Oesophageal adenocarcinoma stage II
                                        Oesophageal adenocarcinoma stage III
                                        Oesophageal adenocarcinoma stage IV
                                        Oesophageal cancer metastatic
                                        Oesophageal carcinoma
                                        Oesophageal carcinoma recurrent
                                        Oesophageal carcinoma stage 0
                                        Oesophageal squamous cell carcinoma
                                        Oesophageal squamous cell carcinoma metastatic
                                        Oesophageal squamous cell carcinoma recurrent
                                        Oesophageal squamous cell carcinoma stage 0
                                        Oesophageal squamous cell carcinoma stage I
                                        Oesophageal squamous cell carcinoma stage II
                                        Oesophageal squamous cell carcinoma stage III
                                        Oesophageal squamous cell carcinoma stage IV
                                        Oestrogen receptor positive breast cancer
                                        Oligoastrocytoma
                                        Oligodendroglioma
                                        Optic glioma
                                        Oral cavity cancer metastatic
                                        Oropharyngeal cancer
                                        Oropharyngeal cancer recurrent
                                        Oropharyngeal cancer stage 0
                                        Oropharyngeal cancer stage I
                                        Oropharyngeal cancer stage II
                                        Oropharyngeal cancer stage III
                                        Oropharyngeal cancer stage IV
                                        Oropharyngeal lymphoepithelioma
                                        Oropharyngeal squamous cell carcinoma
                                        Osteosarcoma
                                        Osteosarcoma metastatic
                                        Osteosarcoma recurrent
                                        Otic cancer metastatic
                                        Ovarian cancer
                                        Ovarian cancer metastatic
                                        Ovarian cancer recurrent
                                        Ovarian cancer stage I
                                        Ovarian cancer stage II
                                        Ovarian cancer stage III
                                        Ovarian cancer stage IV
                                        Ovarian clear cell carcinoma
                                        Ovarian dysgerminoma stage I
                                        Ovarian dysgerminoma stage II
                                        Ovarian dysgerminoma stage III
                                        Ovarian dysgerminoma stage IV
                                        Ovarian dysgerminoma stage unspecified
                                        Ovarian embryonal carcinoma
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————————————————————————————————————————————————————————————————————————————————————————————————————
Malignant neoplasms                     Ovarian endometrioid carcinoma
                                        Ovarian epithelial cancer
                                        Ovarian epithelial cancer metastatic
                                        Ovarian epithelial cancer recurrent
                                        Ovarian epithelial cancer stage I
                                        Ovarian epithelial cancer stage II
                                        Ovarian epithelial cancer stage III
                                        Ovarian epithelial cancer stage IV
                                        Ovarian germ cell cancer
                                        Ovarian germ cell cancer stage I
                                        Ovarian germ cell cancer stage II
                                        Ovarian germ cell cancer stage III
                                        Ovarian germ cell cancer stage IV
                                        Ovarian germ cell choriocarcinoma
                                        Ovarian germ cell choriocarcinoma stage I
                                        Ovarian germ cell choriocarcinoma stage II
                                        Ovarian germ cell choriocarcinoma stage III
                                        Ovarian germ cell choriocarcinoma stage IV
                                        Ovarian germ cell embryonal carcinoma stage I
                                        Ovarian germ cell embryonal carcinoma stage II
                                        Ovarian germ cell embryonal carcinoma stage III
                                        Ovarian germ cell embryonal carcinoma stage IV
                                        Ovarian germ cell endodermal sinus tumour
                                        Ovarian germ cell endodermal sinus tumour stage I
                                        Ovarian germ cell endodermal sinus tumour stage II
                                        Ovarian germ cell endodermal sinus tumour stage III
                                        Ovarian germ cell endodermal sinus tumour stage IV
                                        Ovarian germ cell polyembryoma
                                        Ovarian germ cell polyembryoma stage I
                                        Ovarian germ cell polyembryoma stage II
                                        Ovarian germ cell polyembryoma stage III
                                        Ovarian germ cell polyembryoma stage IV
                                        Ovarian germ cell teratoma
                                        Ovarian germ cell teratoma stage I
                                        Ovarian germ cell teratoma stage II
                                        Ovarian germ cell teratoma stage III
                                        Ovarian germ cell teratoma stage IV
                                        Ovarian germ cell tumour mixed
                                        Ovarian granulosa-theca cell tumour
                                        Ovarian low malignant potential tumour
                                        Ovarian stromal cancer
                                        Paget's disease of nipple
                                        Paget's disease of penis
                                        Paget's disease of the vulva
                                        Pancoast's tumour
                                        Pancreatic carcinoma
                                        Pancreatic carcinoma metastatic
                                        Pancreatic carcinoma recurrent
                                        Pancreatic carcinoma stage 0
                                        Pancreatic carcinoma stage I
                                        Pancreatic carcinoma stage II
                                        Pancreatic carcinoma stage III
                                        Pancreatic carcinoma stage IV
                                        Pancreatic neuroendocrine tumour
                                        Pancreatic neuroendocrine tumour metastatic
                                        Pancreatic sarcoma
                                        Pancreatoblastoma
                                        Papillary renal cell carcinoma
                                        Papillary serous endometrial carcinoma
                                        Papillary thyroid cancer
                                        Paraganglion neoplasm malignant
                                        Paranasal sinus and nasal cavity malignant neoplasm
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————————————————————————————————————————————————————————————————————————————————————————————————————
Malignant neoplasms                     Paranasal sinus and nasal cavity malignant neoplasm
                                        recurrent
                                        Paranasal sinus and nasal cavity malignant neoplasm stage 0
                                        Paranasal sinus and nasal cavity malignant neoplasm stage I
                                        Paranasal sinus and nasal cavity malignant neoplasm stage II
                                        Paranasal sinus and nasal cavity malignant neoplasm stage
                                        III
                                        Paranasal sinus and nasal cavity malignant neoplasm stage IV
                                        Parathyroid tumour malignant
                                        Penile cancer
                                        Penile squamous cell carcinoma
                                        Penis carcinoma metastatic
                                        Penis carcinoma recurrent
                                        Penis carcinoma stage I
                                        Penis carcinoma stage II
                                        Penis carcinoma stage III
                                        Penis carcinoma stage IV
                                        Pericardial mesothelioma malignant
                                        Pericardial mesothelioma malignant recurrent
                                        Peripheral T-cell lymphoma unspecified
                                        Peripheral T-cell lymphoma unspecified recurrent
                                        Peripheral T-cell lymphoma unspecified refractory
                                        Peripheral T-cell lymphoma unspecified stage I
                                        Peripheral T-cell lymphoma unspecified stage II
                                        Peripheral T-cell lymphoma unspecified stage III
                                        Peripheral T-cell lymphoma unspecified stage IV
                                        Peripheral neuroepithelioma of bone
                                        Peripheral neuroepithelioma of bone metastatic
                                        Peripheral neuroepithelioma of bone recurrent
                                        Peripheral neuroepithelioma of soft tissue
                                        Peripheral primitive neuroectodermal bone tumour
                                        Peripheral primitive neuroectodermal tumour of soft tissue
                                        Peritoneal carcinoma metastatic
                                        Peritoneal mesothelioma malignant
                                        Peritoneal mesothelioma malignant recurrent
                                        Peritoneal sarcoma
                                        Phaeochromocytoma malignant
                                        Pharyngeal cancer
                                        Pharyngeal cancer metastatic
                                        Pharyngeal cancer recurrent
                                        Pharyngeal cancer stage 0
                                        Pharyngeal cancer stage I
                                        Pharyngeal cancer stage II
                                        Pharyngeal cancer stage III
                                        Pharyngeal cancer stage IV
                                        Pilomatrix carcinoma
                                        Pineal germinoma
                                        Pineal parenchymal neoplasm malignant
                                        Pinealoblastoma
                                        Pituitary cancer metastatic
                                        Pituitary neoplasm malignant recurrent
                                        Plasma cell leukaemia
                                        Plasma cell leukaemia in remission
                                        Plasma cell myeloma
                                        Plasma cell myeloma in remission
                                        Plasma cell myeloma recurrent
                                        Plasmablastic lymphoma
                                        Plasmacytoma
                                        Pleomorphic liposarcoma
                                        Pleomorphic malignant fibrous histiocytoma
                                        Pleural mesothelioma
                                        Pleural mesothelioma malignant
                                        Pleural mesothelioma malignant recurrent
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Malignant neoplasms                     Pleural sarcoma
                                        Pleuropulmonary blastoma
                                        Poorly differentiated thyroid carcinoma
                                        Porocarcinoma
                                        Postcricoid cancer
                                        Precursor B-lymphoblastic lymphoma
                                        Precursor B-lymphoblastic lymphoma recurrent
                                        Precursor B-lymphoblastic lymphoma refractory
                                        Precursor B-lymphoblastic lymphoma stage I
                                        Precursor B-lymphoblastic lymphoma stage II
                                       Precursor B-lymphoblastic lymphoma stage III
                                        Precursor B-lymphoblastic lymphoma stage IV
                                        Precursor T-lymphoblastic lymphoma
                                        leukaemia
                                       Precursor T-lymphoblastic lymphoma
                                        leukaemia recurrent
                                        Precursor T-lymphoblastic lymphoma
                                        leukaemia refractory
                                        Precursor T-lymphoblastic lymphoma
                                        leukaemia stage I
                                        Precursor T-lymphoblastic lymphoma
                                        leukaemia stage II
                                        Precursor T-lymphoblastic lymphoma
                                        leukaemia stage III
                                        Precursor T-lymphoblastic lymphoma
                                        leukaemia stage IV
                                        Primary breast lymphoma
                                        Primary cardiac lymphoma
                                        Primary effusion lymphoma
                                        Primary gastrointestinal follicular lymphoma
                                        Primary mediastinal large B-cell lymphoma
                                        Primary mediastinal large B-cell lymphoma recurrent
                                        Primary mediastinal large B-cell lymphoma refractory
                                        Primary mediastinal large B-cell lymphoma stage I
                                        Primary mediastinal large B-cell lymphoma stage II
                                        Primary mediastinal large B-cell lymphoma stage III
                                        Primary mediastinal large B-cell lymphoma stage IV
                                        Primary pulmonary melanoma
                                        Primitive neuroectodermal tumour
                                        Primitive neuroectodermal tumour metastatic
                                        Prolymphocytic leukaemia
                                        Prostate cancer
                                        Prostate cancer metastatic
                                        Prostate cancer recurrent
                                        Prostate cancer stage 0
                                        Prostate cancer stage I
                                        Prostate cancer stage II
                                        Prostate cancer stage III
                                        Prostate cancer stage IV
                                        Pseudosarcoma
                                        Queyrat erythroplasia
                                        Rectal adenocarcinoma
                                        Rectal cancer
                                        Rectal cancer metastatic
                                        Rectal cancer recurrent
                                        Rectal cancer stage 0
                                        Rectal cancer stage I
                                        Rectal cancer stage II
                                        Rectal cancer stage III
                                        Rectal cancer stage IV
                                        Rectosigmoid cancer
                                        Rectosigmoid cancer metastatic
                                        Rectosigmoid cancer recurrent
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Malignant neoplasms                     Rectosigmoid cancer stage 0
                                        Rectosigmoid cancer stage I
                                        Rectosigmoid cancer stage II
                                        Rectosigmoid cancer stage III
                                        Rectosigmoid cancer stage IV
                                        Recurrent cancer
                                        Refractory cancer
                                        Renal cancer
                                        Renal cancer metastatic
                                        Renal cancer recurrent
                                        Renal cancer stage I
                                        Renal cancer stage II
                                        Renal cancer stage III
                                        Renal cancer stage IV
                                        Renal cell carcinoma
                                        Renal cell carcinoma recurrent
                                        Renal cell carcinoma stage I
                                        Renal cell carcinoma stage II
                                        Renal cell carcinoma stage III
                                        Renal cell carcinoma stage IV
                                        Respiratory tract carcinoma in situ
                                        Retinal melanoma
                                        Retinoblastoma
                                        Retroperitoneal cancer
                                        Retroperitoneal neoplasm metastatic
                                        Rhabdoid tumour
                                        Rhabdoid tumour of the kidney
                                        Rhabdomyosarcoma
                                        Rhabdomyosarcoma recurrent
                                        Richter's syndrome
                                        Round cell liposarcoma
                                        Salivary gland cancer
                                        Salivary gland cancer recurrent
                                        Salivary gland cancer stage 0
                                        Salivary gland cancer stage I
                                        Salivary gland cancer stage II
                                        Salivary gland cancer stage III
                                        Salivary gland cancer stage IV
                                        Sarcoma
                                        Sarcoma metastatic
                                        Sarcoma of skin
                                        Sarcoma uterus
                                        Sarcomatoid carcinoma
                                        Sarcomatoid carcinoma of the lung
                                        Sarcomatoid mesothelioma
                                        Sarcomatosis
                                        Scrotal cancer
                                        Sebaceous carcinoma
                                        Second primary malignancy
                                        Seminoma
                                        Serous cystadenocarcinoma ovary
                                        Signet-ring cell carcinoma
                                        Sinus cancer metastatic
                                        Skin angiosarcoma
                                        Skin cancer
                                        Skin cancer metastatic
                                        Skin squamous cell carcinoma metastatic
                                        Skin squamous cell carcinoma recurrent
                                        Small cell carcinoma
                                        Small cell carcinoma of the cervix
                                        Small cell lung cancer
                                        Small cell lung cancer extensive stage
                                        Small cell lung cancer limited stage
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————————————————————————————————————————————————————————————————————————————————————————————————————
Malignant neoplasms                     Small cell lung cancer metastatic
                                        Small cell lung cancer recurrent
                                        Small intestine adenocarcinoma
                                        Small intestine carcinoma
                                        Small intestine carcinoma metastatic
                                        Small intestine carcinoma recurrent
                                        Small intestine carcinoma stage 0
                                        Small intestine carcinoma stage I
                                        Small intestine carcinoma stage II
                                        Small intestine carcinoma stage III
                                        Small intestine carcinoma stage IV
                                        Small intestine leiomyosarcoma
                                        Soft tissue sarcoma
                                        Solid pseudopapillary tumour of the pancreas
                                        Spermatocytic seminoma
                                        Spinal meningioma malignant
                                        Spindle cell sarcoma
                                        Splenic marginal zone lymphoma
                                        Splenic marginal zone lymphoma recurrent
                                        Splenic marginal zone lymphoma refractory
                                        Splenic marginal zone lymphoma stage I
                                        Splenic marginal zone lymphoma stage II
                                        Splenic marginal zone lymphoma stage III
                                        Splenic marginal zone lymphoma stage IV
                                        Squamous cell breast carcinoma
                                       Squamous cell carcinoma
                                        Squamous cell carcinoma of head and neck
                                        Squamous cell carcinoma of lung
                                        Squamous cell carcinoma of pharynx
                                        Squamous cell carcinoma of skin
                                        Squamous cell carcinoma of the cervix
                                        Squamous cell carcinoma of the hypopharynx
                                        Squamous cell carcinoma of the oral cavity
                                        Squamous cell carcinoma of the tongue
                                        Squamous cell carcinoma of the vagina
                                        Squamous cell carcinoma of the vulva
                                        Squamous endometrial carcinoma
                                        Stewart-Treves syndrome
                                        Superficial spreading melanoma stage I
                                        Superficial spreading melanoma stage II
                                        Superficial spreading melanoma stage III
                                        Superficial spreading melanoma stage IV
                                        Superficial spreading melanoma stage unspecified
                                        Synovial sarcoma
                                        Synovial sarcoma metastatic
                                        Synovial sarcoma recurrent
                                        T-cell chronic lymphocytic leukaemia
                                        T-cell lymphoma
                                        T-cell lymphoma recurrent
                                        T-cell lymphoma refractory
                                        T-cell lymphoma stage I
                                        T-cell lymphoma stage II
                                        T-cell lymphoma stage III
                                        T-cell lymphoma stage IV
                                        T-cell prolymphocytic leukaemia
                                        T-cell type acute leukaemia
                                        T-cell unclassifiable lymphoma high grade
                                        T-cell unclassifiable lymphoma low grade
                                        Testicular cancer metastatic
                                        Testicular choriocarcinoma
                                        Testicular choriocarcinoma recurrent
                                        Testicular choriocarcinoma stage I
                                        Testicular choriocarcinoma stage II
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CONFIDENTIAL


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NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
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Status:
Final
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Malignant neoplasms                     Testicular choriocarcinoma stage III
                                        Testicular embryonal carcinoma
                                        Testicular embryonal carcinoma stage I
                                        Testicular embryonal carcinoma stage II
                                        Testicular embryonal carcinoma stage III
                                        Testicular germ cell cancer
                                        Testicular germ cell cancer metastatic
                                        Testicular germ cell tumour mixed
                                        Testicular germ cell tumour mixed stage I
                                        Testicular germ cell tumour mixed stage II
                                        Testicular germ cell tumour mixed stage III
                                        Testicular leiomyosarcoma
                                        Testicular malignant teratoma
                                        Testicular malignant teratoma stage I
                                        Testicular malignant teratoma stage II
                                        Testicular malignant teratoma stage III
                                        Testicular seminoma (pure)
                                        Testicular seminoma (pure) stage I
                                        Testicular seminoma (pure) stage II
                                        Testicular seminoma (pure) stage III
                                        Testicular yolk sac tumour
                                        Testicular yolk sac tumour stage I
                                        Testicular yolk sac tumour stage II
                                        Testicular yolk sac tumour stage III
                                        Testis cancer
                                        Testis cancer recurrent
                                       Throat cancer
                                        Thymic cancer metastatic
                                        Thymoma malignant
                                        Thymoma malignant recurrent
                                        Thyroid B-cell lymphoma
                                        Thyroid cancer
                                        Thyroid cancer metastatic
                                        Thyroid cancer recurrent
                                        Thyroid cancer stage 0
                                        Thyroid cancer stage I
                                        Thyroid cancer stage II
                                        Thyroid cancer stage III
                                        Thyroid cancer stage IV
                                        Tongue cancer metastatic
                                        Tongue cancer recurrent
                                        Tongue carcinoma stage 0
                                        Tongue carcinoma stage I
                                        Tongue carcinoma stage II
                                        Tongue carcinoma stage III
                                        Tongue carcinoma stage IV
                                        Tongue neoplasm malignant stage unspecified
                                        Tonsil cancer
                                        Tonsil cancer metastatic
                                        Tracheal cancer
                                        Transformation to acute myeloid leukaemia
                                        Transitional cell cancer of renal pelvis and ureter
                                        metastatic
                                        Transitional cell cancer of the renal pelvis and ureter
                                        Transitional cell cancer of the renal pelvis and ureter
                                        localised
                                        Transitional cell cancer of the renal pelvis and ureter
                                        recurrent
                                        Transitional cell cancer of the renal pelvis and ureter
                                        regional
                                        Transitional cell carcinoma
                                        Transitional cell carcinoma metastatic
                                        Transitional cell carcinoma recurrent
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NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
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————————————————————————————————————————————————————————————————————————————————————————————————————
Malignant neoplasms                     Transitional cell carcinoma urethra
                                        Trichoblastic carcinoma
                                        Triple hit lymphoma
                                        Triple negative breast cancer
                                        Tubular breast carcinoma
                                        Tumour budding
                                        Undifferentiated carcinoma of colon
                                        Undifferentiated nasopharyngeal carcinoma
                                        Undifferentiated sarcoma
                                        Ureteric cancer
                                        Ureteric cancer local
                                        Ureteric cancer metastatic
                                        Ureteric cancer recurrent
                                        Ureteric cancer regional
                                        Urethral cancer
                                        Urethral cancer metastatic
                                        Urethral cancer recurrent
                                        Urethral melanoma metastatic
                                        Urinary bladder sarcoma
                                        Urinary tract carcinoma in situ
                                        Uterine cancer
                                        Uterine carcinoma in situ
                                        Uterine leiomyosarcoma
                                        Uveal melanoma
                                        Vaginal adenocarcinoma
                                        Vaginal cancer
                                        Vaginal cancer metastatic
                                        Vaginal cancer recurrent
                                        Vaginal cancer stage 0
                                        Vaginal cancer stage I
                                        Vaginal cancer stage II
                                        Vaginal cancer stage III
                                        Vaginal cancer stage IVA
                                        Vaginal cancer stage IVB
                                        Vulval cancer
                                        Vulval cancer metastatic
                                        Vulval cancer recurrent
                                        Vulval cancer stage 0
                                        Vulval cancer stage I
                                        Vulval cancer stage II
                                        Vulval cancer stage III
                                        Vulval cancer stage IV
                                        Vulvar adenocarcinoma
                                        Waldenstrom's macroglobulinaemia
                                        Waldenstrom's macroglobulinaemia recurrent
                                        Waldenstrom's macroglobulinaemia refractory
                                        Waldenstrom's macroglobulinaemia stage I
                                        Waldenstrom's macroglobulinaemia stage II
                                        Waldenstrom's macroglobulinaemia stage III
                                        Waldenstrom's macroglobulinaemia stage IV
Medication error and overdose           Accidental device ingestion
                                        Accidental device ingestion by a child
                                        Accidental exposure to product
                                        Accidental exposure to product by child
                                        Accidental exposure to product packaging
                                        Accidental exposure to product packaging by child
                                        Accidental overdose
                                        Accidental poisoning
                                        Accidental underdose
                                        Accidental use of placebo
                                        Assisted suicide
                                        Booster dose missed
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NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
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————————————————————————————————————————————————————————————————————————————————————————————————————
Medication error and overdose           Circumstance or information capable of leading to device
                                        use error
                                        Circumstance or information capable of leading to
                                        medication error
                                        Completed suicide
                                        Complication of device insertion
                                        Complication of device removal
                                        Complication of drug delivery system removal
                                        Contraindicated device used
                                        Contraindicated product administered
                                        Contraindicated product prescribed
                                        Contraindication to medical treatment
                                        Contraindication to vaccination
                                        Deprescribing error
                                        Device adhesion issue
                                        Device connection issue
                                        Device difficult to use
                                        Device dispensing error
                                        Device infusion issue
                                        Device malfunction
                                        Device monitoring procedure not performed
                                        Device programming error
                                        Device use error
                                        Device use issue
                                        Device used for unapproved schedule
                                        Device-device incompatibility
                                        Dietary supplement prescribing error
                                        Discontinued product administered
                                        Documented hypersensitivity to administered product
                                        Dopamine dysregulation syndrome
                                        Dose calculation error
                                        Drug abuse
                                        Drug abuser
                                        Drug administered in wrong device
                                        Drug dependence
                                        Drug dependence, antepartum
                                        Drug dependence, postpartum
                                        Drug dispensed to wrong patient
                                        Drug dose omission by device
                                        Drug dose titration not performed
                                        Drug monitoring procedure incorrectly performed
                                        Drug monitoring procedure not performed
                                        Drug titration error
                                        Drug use disorder
                                        Drug use disorder, antepartum
                                        Drug use disorder, postpartum
                                        Duplicate therapy error
                                        Expired device used
                                        Expired product administered
                                        Exposure to contaminated device
                                        Exposure via contaminated device
                                        Exposure via direct contact
                                        Exposure via eye contact
                                        Exposure via ingestion
                                        Exposure via inhalation
                                        Exposure via partner
                                        Exposure via skin contact
                                        Exposure via unknown route
                                        Extra dose administered
                                        Failure of child resistant mechanism for pharmaceutical
                                        product
                                        Failure to suspend medication
                                        Implantation complication
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NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
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Status:
Final
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Medication error and overdose           Inadequate aseptic technique in use of product
                                        Inappropriate schedule of product administration
                                        Incomplete course of vaccination
                                        Incorrect disposal of product
                                        Incorrect dosage administered
                                        Incorrect dose administered
                                        Incorrect dose administered by device
                                        Incorrect dose administered by product
                                        Incorrect drug administration rate
                                        Incorrect product administration duration
                                        Incorrect product dosage form administered
                                        Incorrect product formulation administered
                                        Incorrect route of product administration
                                        Injury associated with device
                                        Intentional device misuse
                                        Intentional dose omission
                                        Intentional misuse of drug delivery system
                                        Intentional overdose
                                        Intentional product misuse
                                        Intentional self-injury
                                        Intercepted accidental exposure to product by child
                                        Intercepted medication error
                                        Intercepted product administration error
                                        Intercepted product dispensing error
                                        Intercepted product monitoring error
                                        Intercepted product preparation error
                                        Intercepted product prescribing error
                                        Intercepted product selection error
                                        Intercepted product storage error
                                        Intercepted wrong patient selected
                                        Interchange of vaccine products
                                        Labelled drug-disease interaction medication error
                                        Labelled drug-drug interaction medication error
                                        Labelled drug-food interaction medication error
                                        Lack of administration site rotation
                                        Lack of application site rotation
                                        Lack of infusion site rotation
                                        Lack of injection site rotation
                                        Lack of vaccination site rotation
                                        Maternal use of illicit drugs
                                        Medical device monitoring error
                                        Medication error
                                        Multiple use of single-use product
                                        Needle issue
                                        Neonatal complications of substance abuse
                                        Occupational exposure to product
                                        Occupational exposure to radiation
                                        Overdose
                                        Paravenous drug administration
                                        Performance enhancing product use
                                        Poisoning deliberate
                                        Poor quality device used
                                        Poor quality product administered
                                        Prescribed overdose
                                        Prescribed underdose
                                        Product adhesion issue
                                        Product administered at inappropriate site
                                        Product administered to patient of inappropriate age
                                        Product administration error
                                        Product administration interrupted
                                        Product appearance confusion
                                        Product barcode issue
                                        Product commingling
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NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
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————————————————————————————————————————————————————————————————————————————————————————————————————
Medication error and overdose           Product communication issue
                                        Product compounding quality issue
                                        Product design confusion
                                        Product dispensing error
                                        Product dispensing issue
                                        Product dosage form confusion
                                        Product dosage form issue
                                        Product dose omission
                                        Product dropper issue
                                        Product expiration date issue
                                        Product identification number issue
                                        Product label confusion
                                        Product label issue
                                        Product label on wrong product
                                        Product lot number issue
                                        Product monitoring error
                                        Product name confusion
                                        Product packaging confusion
                                        Product packaging issue
                                        Product preparation error
                                        Product preparation issue
                                        Product prescribing error
                                        Product prescribing issue
                                        Product reconstitution quality issue
                                        Product selection error
                                        Product storage error
                                        Product substitution error
                                        Product use complaint
                                        Product use in unapproved indication
                                        Product use in unapproved therapeutic environment
                                        Product use issue
                                        Radiation overdose
                                        Radiation underdose
                                       Recalled product administered
                                        Single component of a two-component product administered
                                        Substance abuse
                                        Substance abuser
                                        Substance dependence
                                        Substance use disorder
                                        Suicide attempt
                                        Suspected suicide attempt
                                        Syringe issue
                                        Therapeutic drug monitoring analysis incorrectly performed
                                        Therapeutic drug monitoring analysis not performed
                                        Transcription medication error
                                        Transfusion with incompatible blood
                                        Treatment noncompliance
                                        Underdose
                                        Unintentional medical device removal
                                        Unintentional use for unapproved indication
                                        Vaccination error
                                        Wrong device used
                                        Wrong dosage form
                                        Wrong dosage formulation
                                        Wrong dose
                                        Wrong drug
                                        Wrong patient received product
                                        Wrong product administered
                                        Wrong product procured
                                        Wrong product stored
                                        Wrong rate
                                        Wrong schedule
                                        Wrong strength
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NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
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Final
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————————————————————————————————————————————————————————————————————————————————————————————————————
Medication error and overdose           Wrong technique in device usage process
                                        Wrong technique in product usage process
Neoplasm                                5q minus syndrome
                                        ACTH-producing pituitary tumour
                                        APUDoma
                                        Abdominal neoplasm
                                        Abdominal wall cyst
                                        Abdominal wall neoplasm
                                        Abdominal wall neoplasm benign
                                        Abdominal wall neoplasm malignant
                                        Acanthoma
                                        Acanthosis nigricans
                                        Acinar cell carcinoma of pancreas
                                        Acinic cell carcinoma of salivary gland
                                        Acoustic neuroma
                                        Acquired C1 inhibitor deficiency
                                        Acquired bronchial cyst
                                        Acquired thalassaemia
                                        Acral lentiginous melanoma
                                        Acral lentiginous melanoma stage I
                                        Acral lentiginous melanoma stage II
                                        Acral lentiginous melanoma stage III
                                        Acral lentiginous melanoma stage IV
                                        Acrochordon
                                        Acrokeratosis paraneoplastica
                                        Actinic keratosis
                                        Acute bilineal leukaemia
                                        Acute biphenotypic leukaemia
                                        Acute leukaemia
                                        Acute leukaemia in remission
                                        Acute lymphocytic leukaemia
                                        Acute lymphocytic leukaemia (in remission)
                                        Acute lymphocytic leukaemia recurrent
                                        Acute lymphocytic leukaemia refractory
                                        Acute megakaryocytic leukaemia
                                        Acute megakaryocytic leukaemia (in remission)
                                        Acute monocytic leukaemia
                                        Acute monocytic leukaemia (in remission)
                                        Acute myeloid leukaemia
                                        Acute myeloid leukaemia (in remission)
                                        Acute myeloid leukaemia recurrent
                                        Acute myeloid leukaemia refractory
                                        Acute myelomonocytic leukaemia
                                        Acute promyelocytic leukaemia
                                        Acute undifferentiated leukaemia
                                        Adenocarcinoma
                                        Adenocarcinoma gastric
                                        Adenocarcinoma of appendix
                                        Adenocarcinoma of colon
                                        Adenocarcinoma of salivary gland
                                        Adenocarcinoma of the cervix
                                        Adenocarcinoma pancreas
                                        Adenoid cystic carcinoma
                                        Adenoid cystic carcinoma of external auditory canal
                                        Adenoid cystic carcinoma of salivary gland
                                        Adenolipoma
                                        Adenolymphoma
                                        Adenoma benign
                                        Adenomatous polyposis coli
                                        Adenosquamous carcinoma of the cervix
                                        Adenosquamous carcinoma of vagina
                                        Adenosquamous cell carcinoma
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NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
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Status:
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————————————————————————————————————————————————————————————————————————————————————————————————————
Neoplasm                                Adenosquamous cell lung cancer
                                        Adenosquamous cell lung cancer recurrent
                                        Adenosquamous cell lung cancer stage 0
                                        Adenosquamous cell lung cancer stage I
                                        Adenosquamous cell lung cancer stage II
                                        Adenosquamous cell lung cancer stage III
                                        Adenosquamous cell lung cancer stage IV
                                        Administration site cyst
                                        Adnexa uteri cyst
                                        Adrenal adenoma
                                        Adrenal cyst
                                        Adrenal gland cancer
                                        Adrenal gland cancer metastatic
                                        Adrenal neoplasm
                                        Adrenocortical carcinoma
                                        Adult T-cell lymphoma
                                        leukaemia
                                        Adult T-cell lymphoma
                                        leukaemia recurrent
                                        Adult T-cell lymphoma
                                        leukaemia refractory
                                        Adult T-cell lymphoma
                                        leukaemia stage I
                                        Adult T-cell lymphoma
                                        leukaemia stage II
                                        Adult T-cell lymphoma
                                        leukaemia stage III
                                        Adult T-cell lymphoma
                                        leukaemia stage IV
                                        Aesthesioneuroblastoma
                                        Alcoholisation procedure
                                        Aleukaemic leukaemia
                                        Alpha 1 foetoprotein abnormal
                                        Alpha 1 foetoprotein increased
                                        Alpha interferon therapy
                                        Alpha-L-fucosidase increased
                                        Alveolar rhabdomyosarcoma
                                        Alveolar soft part sarcoma
                                        Alveolar soft part sarcoma metastatic
                                        Alveolar soft part sarcoma recurrent
                                        Ameloblastoma
                                        Ampullary polyp
                                        Amputation of penis
                                        Amyloidoma
                                        Anal cancer
                                        Anal cancer metastatic
                                        Anal cancer recurrent
                                        Anal cancer stage 0
                                        Anal cancer stage I
                                        Anal cancer stage II
                                        Anal cancer stage III
                                        Anal cancer stage IV
                                        Anal leukoplakia
                                        Anal neoplasm
                                        Anal polyp
                                        Anal polypectomy
                                        Anal squamous cell carcinoma
                                        Anaplastic astrocytoma
                                        Anaplastic large cell lymphoma T- and null-cell types
                                        Anaplastic large cell lymphoma T- and null-cell types
                                        recurrent
                                        Anaplastic large cell lymphoma T- and null-cell types
                                        refractory
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NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
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03 July 2019
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Final
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————————————————————————————————————————————————————————————————————————————————————————————————————
Neoplasm                                Anaplastic large cell lymphoma T- and null-cell types stage
                                        I
                                        Anaplastic large cell lymphoma T- and null-cell types stage
                                        II
                                        Anaplastic large cell lymphoma T- and null-cell types stage
                                        III
                                        Anaplastic large cell lymphoma T- and null-cell types stage
                                        IV
                                        Anaplastic large-cell lymphoma
                                        Anaplastic lymphoma kinase gene and nucleophosmin gene
                                        fusion overexpression
                                        Anaplastic meningioma
                                        Anaplastic oligodendroglioma
                                        Anaplastic thyroid cancer
                                        Androgen therapy
                                        Aneurysmal bone cyst
                                        Angiocentric glioma
                                        Angiocentric lymphoma
                                        Angiocentric lymphoma recurrent
                                        Angiocentric lymphoma refractory
                                        Angiocentric lymphoma stage I
                                       Angiocentric lymphoma stage II
                                        Angiocentric lymphoma stage III
                                        Angiocentric lymphoma stage IV
                                        Angiofibroma
                                        Angiogenesis biomarker increased
                                        Angioimmunoblastic T-cell lymphoma
                                        Angioimmunoblastic T-cell lymphoma recurrent
                                        Angioimmunoblastic T-cell lymphoma refractory
                                        Angioimmunoblastic T-cell lymphoma stage I
                                        Angioimmunoblastic T-cell lymphoma stage II
                                        Angioimmunoblastic T-cell lymphoma stage III
                                        Angioimmunoblastic T-cell lymphoma stage IV
                                        Angiolipoma
                                        Angiomyofibroblastoma
                                        Angiomyolipoma
                                        Angiomyxoma
                                        Angiosarcoma
                                        Angiosarcoma metastatic
                                        Angiosarcoma non-metastatic
                                        Angiosarcoma recurrent
                                        Anogenital dysplasia
                                        Anogenital warts
                                        Anorectal haemangioma
                                        Anti-NMDA antibody positive
                                        Anti-VGCC antibody positive
                                        Anti-androgen withdrawal syndrome
                                        Antiandrogen therapy
                                        Antioestrogen therapy
                                        Apocrine breast carcinoma
                                        Appendix adenoma
                                        Appendix cancer
                                        Application site cyst
                                        Arachnoid cyst
                                        Arsenical keratosis
                                        Aspiration bone marrow abnormal
                                        Astroblastoma
                                        Astrocytoma
                                        Astrocytoma malignant
                                        Astrocytoma, low grade
                                        Atypical fibroxanthoma
                                        Atypical teratoid
                                        rhabdoid tumour of CNS
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NN9535-4114
Clinical Trial Report
Section 16.1.9
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Date:
03 July 2019
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Status:
Final
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————————————————————————————————————————————————————————————————————————————————————————————————————
Neoplasm                                Aural cystadenoma
                                        Aural polyp
                                        Autologous bone marrow transplantation therapy
                                        Axillary lymphadenectomy
                                        B precursor type acute leukaemia
                                        B-cell depletion therapy
                                        B-cell lymphoma
                                        B-cell lymphoma recurrent
                                        B-cell lymphoma refractory
                                        B-cell lymphoma stage I
                                        B-cell lymphoma stage II
                                        B-cell lymphoma stage III
                                        B-cell lymphoma stage IV
                                        B-cell prolymphocytic leukaemia
                                        B-cell small lymphocytic lymphoma
                                        B-cell small lymphocytic lymphoma recurrent
                                        B-cell small lymphocytic lymphoma refractory
                                        B-cell small lymphocytic lymphoma stage I
                                        B-cell small lymphocytic lymphoma stage II
                                        B-cell small lymphocytic lymphoma stage III
                                        B-cell small lymphocytic lymphoma stage IV
                                        B-cell type acute leukaemia
                                        B-cell unclassifiable lymphoma high grade
                                        B-cell unclassifiable lymphoma low grade
                                        Bannayan-Riley-Ruvalcaba syndrome
                                        Barrett's oesophagus
                                        Bartholin's cyst
                                        Basal cell carcinoma
                                        Basal cell naevus syndrome
                                        Basosquamous carcinoma
                                        Basosquamous carcinoma of skin
                                        Becker's naevus
                                        Bence Jones proteinuria
                                        Benign abdominal neoplasm
                                        Benign anorectal neoplasm
                                        Benign biliary neoplasm
                                        Benign bone neoplasm
                                        Benign breast neoplasm
                                        Benign cardiac neoplasm
                                        Benign cartilage neoplasm
                                        Benign duodenal neoplasm
                                        Benign ear neoplasm
                                        Benign endocrine neoplasm
                                        Benign fallopian tube neoplasm
                                        Benign female reproductive tract neoplasm
                                        Benign gastric neoplasm
                                        Benign gastrointestinal neoplasm
                                        Benign genitourinary tract neoplasm
                                        Benign hepatic neoplasm
                                        Benign hepatobiliary neoplasm
                                        Benign hydatidiform mole
                                        Benign joint neoplasm
                                        Benign laryngeal neoplasm
                                        Benign lung neoplasm
                                        Benign lymph node neoplasm
                                        Benign male reproductive tract neoplasm
                                        Benign mediastinal neoplasm
                                        Benign mesenteric neoplasm
                                        Benign mesothelioma
                                        Benign middle ear neoplasm
                                        Benign muscle neoplasm
                                        Benign neoplasm
                                        Benign neoplasm of adrenal gland
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NN9535-4114
Clinical Trial Report
Section 16.1.9
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03 July 2019
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————————————————————————————————————————————————————————————————————————————————————————————————————
Neoplasm                                Benign neoplasm of ampulla of Vater
                                        Benign neoplasm of bladder
                                        Benign neoplasm of cervix uteri
                                        Benign neoplasm of choroid
                                        Benign neoplasm of conjunctiva
                                        Benign neoplasm of cornea
                                        Benign neoplasm of epididymis
                                        Benign neoplasm of eye
                                        Benign neoplasm of eyelid
                                        Benign neoplasm of islets of Langerhans
                                        Benign neoplasm of lacrimal duct
                                        Benign neoplasm of lacrimal gland
                                        Benign neoplasm of optic nerve
                                        Benign neoplasm of orbit
                                        Benign neoplasm of pineal gland
                                        Benign neoplasm of prostate
                                        Benign neoplasm of retina
                                        Benign neoplasm of scrotum
                                        Benign neoplasm of seminal vesicle
                                        Benign neoplasm of skin
                                        Benign neoplasm of spinal cord
                                        Benign neoplasm of testis
                                        Benign neoplasm of thymus
                                        Benign neoplasm of thyroid gland
                                        Benign neoplasm of ureter
                                        Benign neoplasm of urethra
                                        Benign nipple neoplasm
                                        Benign oesophageal neoplasm
                                        Benign ovarian tumour
                                        Benign pancreatic neoplasm
                                        Benign penile neoplasm
                                        Benign pericardium neoplasm
                                        Benign peritoneal neoplasm
                                        Benign pleural mesothelioma
                                        Benign pleural neoplasm
                                        Benign renal neoplasm
                                        Benign respiratory tract neoplasm
                                        Benign salivary gland neoplasm
                                        Benign small intestinal neoplasm
                                        Benign soft tissue neoplasm
                                        Benign spleen tumour
                                        Benign tracheal neoplasm
                                        Benign urinary tract neoplasm
                                        Benign uterine neoplasm
                                        Benign vaginal neoplasm
                                        Benign vascular neoplasm
                                        Benign vulval neoplasm
                                        Beta interferon therapy
                                        Bile duct adenocarcinoma
                                        Bile duct adenosquamous carcinoma
                                        Bile duct cancer
                                        Bile duct cancer recurrent
                                        Bile duct cancer stage 0
                                        Bile duct cancer stage I
                                        Bile duct cancer stage II
                                        Bile duct cancer stage III
                                        Bile duct cancer stage IV
                                        Bile duct squamous cell carcinoma
                                        Biliary adenoma
                                        Biliary cancer metastatic
                                        Biliary cyst
                                        Biliary hamartoma
                                        Biliary neoplasm
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Section 16.1.9
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03 July 2019
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Status:
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————————————————————————————————————————————————————————————————————————————————————————————————————
Neoplasm                                Biliary polyp
                                        Bing-Neel syndrome
                                        Biopsy abdominal wall abnormal
                                        Biopsy adrenal gland abnormal
                                        Biopsy anus abnormal
                                        Biopsy artery abnormal
                                        Biopsy bile duct abnormal
                                        Biopsy bladder abnormal
                                        Biopsy blood vessel abnormal
                                        Biopsy bone abnormal
                                        Biopsy bone marrow abnormal
                                        Biopsy brain abnormal
                                        Biopsy breast abnormal
                                        Biopsy bronchus abnormal
                                        Biopsy cartilage abnormal
                                        Biopsy cervix abnormal
                                        Biopsy chest wall abnormal
                                        Biopsy chorionic villous abnormal
                                        Biopsy colon abnormal
                                        Biopsy conjunctiva abnormal
                                        Biopsy cornea abnormal
                                        Biopsy diaphragm abnormal
                                        Biopsy ear abnormal
                                        Biopsy endometrium abnormal
                                        Biopsy epididymis abnormal
                                        Biopsy eyelid abnormal
                                        Biopsy fallopian tube abnormal
                                       Biopsy foetal abnormal
                                        Biopsy gallbladder abnormal
                                        Biopsy heart abnormal
                                        Biopsy intestine abnormal
                                        Biopsy kidney abnormal
                                        Biopsy larynx abnormal
                                        Biopsy ligament abnormal
                                        Biopsy lip abnormal
                                        Biopsy liver abnormal
                                        Biopsy lung abnormal
                                        Biopsy lymph gland abnormal
                                        Biopsy mucosa abnormal
                                        Biopsy muscle abnormal
                                        Biopsy oesophagus abnormal
                                        Biopsy ovary abnormal
                                        Biopsy palate abnormal
                                        Biopsy pancreas abnormal
                                        Biopsy parathyroid gland abnormal
                                        Biopsy penis abnormal
                                        Biopsy pericardium abnormal
                                        Biopsy peripheral nerve abnormal
                                        Biopsy peritoneum abnormal
                                        Biopsy pharynx abnormal
                                        Biopsy pleura abnormal
                                        Biopsy prostate abnormal
                                        Biopsy rectum abnormal
                                        Biopsy retina abnormal
                                        Biopsy salivary gland abnormal
                                        Biopsy sclera abnormal
                                        Biopsy seminal vesicle abnormal
                                        Biopsy site unspecified abnormal
                                        Biopsy skin abnormal
                                        Biopsy small intestine abnormal
                                        Biopsy spinal cord abnormal
                                        Biopsy spleen abnormal
                                        Biopsy stomach abnormal
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Clinical Trial Report
Section 16.1.9
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Final
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————————————————————————————————————————————————————————————————————————————————————————————————————
Neoplasm                                Biopsy tendon abnormal
                                        Biopsy testes abnormal
                                        Biopsy thymus gland abnormal
                                        Biopsy thyroid gland abnormal
                                        Biopsy tongue abnormal
                                        Biopsy trachea abnormal
                                        Biopsy urethra abnormal
                                        Biopsy uterus abnormal
                                        Biopsy vagina abnormal
                                        Biopsy vocal cord abnormal
                                        Biopsy vulva abnormal
                                        Biotherapy
                                        Biphasic mesothelioma
                                        Birt-Hogg-Dube syndrome
                                        Bladder adenocarcinoma recurrent
                                        Bladder adenocarcinoma stage 0
                                        Bladder adenocarcinoma stage I
                                        Bladder adenocarcinoma stage II
                                        Bladder adenocarcinoma stage III
                                        Bladder adenocarcinoma stage IV
                                        Bladder adenocarcinoma stage unspecified
                                        Bladder cancer
                                        Bladder cancer recurrent
                                        Bladder cancer stage 0, with cancer in situ
                                        Bladder cancer stage 0, without cancer in situ
                                        Bladder cancer stage I, with cancer in situ
                                       Bladder cancer stage I, without cancer in situ
                                        Bladder cancer stage II
                                        Bladder cancer stage III
                                        Bladder cancer stage IV
                                        Bladder cyst
                                        Bladder dysplasia
                                        Bladder leukoplakia
                                        Bladder mapping
                                        Bladder neck resection
                                        Bladder neoplasm
                                        Bladder neoplasm surgery
                                        Bladder papilloma
                                        Bladder polypectomy
                                        Bladder squamous cell carcinoma recurrent
                                        Bladder squamous cell carcinoma stage 0
                                        Bladder squamous cell carcinoma stage I
                                        Bladder squamous cell carcinoma stage II
                                        Bladder squamous cell carcinoma stage III
                                        Bladder squamous cell carcinoma stage IV
                                        Bladder squamous cell carcinoma stage unspecified
                                        Bladder transitional cell carcinoma
                                        Bladder transitional cell carcinoma metastatic
                                        Bladder transitional cell carcinoma recurrent
                                        Bladder transitional cell carcinoma stage 0
                                        Bladder transitional cell carcinoma stage I
                                        Bladder transitional cell carcinoma stage II
                                        Bladder transitional cell carcinoma stage III
                                        Bladder transitional cell carcinoma stage IV
                                        Blast cell count increased
                                        Blast cell crisis
                                        Blast cell proliferation
                                        Blast cells present
                                        Blast crisis in myelogenous leukaemia
                                        Blastic plasmacytoid dendritic cell neoplasia
                                        Blepharal papilloma
                                        Blood chromogranin A increased
                                        Bone cancer
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NN9535-4114
Clinical Trial Report
Section 16.1.9
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Date:
03 July 2019
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Final
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————————————————————————————————————————————————————————————————————————————————————————————————————
Neoplasm                                Bone cancer metastatic
                                        Bone cyst
                                        Bone giant cell tumour
                                        Bone giant cell tumour benign
                                        Bone giant cell tumour malignant
                                        Bone marrow infiltration
                                        Bone marrow leukaemic cell infiltration
                                        Bone marrow reticulin fibrosis
                                        Bone marrow tumour cell infiltration
                                        Bone neoplasm
                                       Bone sarcoma
                                        Bone scan abnormal
                                        Borderline mucinous tumour of ovary
                                        Borderline ovarian tumour
                                        Borderline serous tumour of ovary
                                        Bowen's disease
                                        Bowenoid papulosis
                                        Brachytherapy
                                        Brachytherapy to eye
                                        Brachytherapy to penis
                                        Brachytherapy to tongue
                                        Brachytherapy to tonsil
                                        Brain cancer metastatic
                                        Brain neoplasm
                                        Brain neoplasm benign
                                        Brain neoplasm malignant
                                        Brain sarcoma
                                        Brain scan abnormal
                                        Brain stem glioma
                                        Brain stem glioma benign
                                        Brain teratoma
                                        Brain tumour operation
                                        Branchial cyst
                                        Breakthrough pain
                                        Breast adenoma
                                        Breast angiosarcoma
                                        Breast angiosarcoma metastatic
                                        Breast calcifications
                                        Breast cancer
                                        Breast cancer female
                                        Breast cancer in situ
                                        Breast cancer male
                                        Breast cancer metastatic
                                        Breast cancer recurrent
                                        Breast cancer stage I
                                        Breast cancer stage II
                                        Breast cancer stage III
                                        Breast cancer stage IV
                                        Breast capsulotomy
                                        Breast conserving surgery
                                        Breast cyst
                                        Breast cyst rupture
                                        Breast dysplasia
                                        Breast fibroma
                                        Breast neoplasm
                                        Breast proliferative changes
                                        Breast prosthesis implantation
                                        Breast reconstruction
                                        Breast sarcoma
                                        Breast sarcoma metastatic
                                        Breast sarcoma recurrent
                                        Breast tumour excision
                                        Brenner tumour
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Clinical Trial Report
Section 16.1.9
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03 July 2019
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Final
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————————————————————————————————————————————————————————————————————————————————————————————————————
Neoplasm                                Bronchial carcinoma
                                        Bronchial neoplasm
                                        Bronchial neoplasm benign
                                        Bronchial polyp
                                        Bronchioloalveolar carcinoma
                                        Buccal polyp
                                        Burkitt's leukaemia
                                        Burkitt's lymphoma
                                        Burkitt's lymphoma recurrent
                                        Burkitt's lymphoma refractory
                                        Burkitt's lymphoma stage I
                                        Burkitt's lymphoma stage II
                                        Burkitt's lymphoma stage III
                                        Burkitt's lymphoma stage IV
                                        Buschke-Lowenstein's tumour
                                        C-kit gene negative
                                        CD20 antigen positive
                                        CD25 antigen positive
                                        CD30 expression
                                        CNS germinoma
                                        CSF lymphocyte count abnormal
                                        CSF lymphocyte count increased
                                       Cachexia
                                        Calcifying fibrous pseudotumour
                                        Cancer hormonal therapy
                                        Cancer in remission
                                        Cancer pain
                                        Cancer staging
                                        Cancer surgery
                                        Carbohydrate antigen 125 increased
                                        Carbohydrate antigen 15-3 increased
                                        Carbohydrate antigen 19-9 increased
                                        Carbohydrate antigen 27.29 increased
                                        Carbohydrate antigen 549 increased
                                        Carbohydrate antigen 72-4
                                        Carcinoembryonic antigen decreased
                                        Carcinoembryonic antigen increased
                                        Carcinogenic effect in offspring
                                        Carcinoid crisis
                                        Carcinoid heart disease
                                        Carcinoid syndrome
                                        Carcinoid tumour
                                        Carcinoid tumour of the appendix
                                        Carcinoid tumour of the caecum
                                        Carcinoid tumour of the duodenum
                                        Carcinoid tumour of the gastrointestinal tract
                                        Carcinoid tumour of the liver
                                        Carcinoid tumour of the ovary
                                        Carcinoid tumour of the pancreas
                                        Carcinoid tumour of the prostate
                                        Carcinoid tumour of the small bowel
                                        Carcinoid tumour of the stomach
                                        Carcinoid tumour pulmonary
                                        Carcinoma ex-pleomorphic adenoma
                                        Carcinoma in situ
                                        Carcinoma in situ of eye
                                        Carcinoma in situ of penis
                                        Carcinoma in situ of skin
                                        Carcinoma in situ of trachea
                                        Carcinomatous polyarthritis
                                        Cardiac fibroma
                                        Cardiac haemangioma benign
                                        Cardiac lymphangioma
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Clinical Trial Report
Section 16.1.9
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03 July 2019
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Final
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————————————————————————————————————————————————————————————————————————————————————————————————————
Neoplasm                                Cardiac myxoma
                                        Cardiac neoplasm malignant
                                        Cardiac neoplasm unspecified
                                        Cardiac neurofibroma
                                        Cardiac teratoma
                                        Cardiac valve fibroelastoma
                                       Carney complex
                                        Carotid body tumour
                                        Cartilage neoplasm
                                        Castleman's disease
                                        Cell marker increased
                                        Cell-free and concentrated ascites reinfusion therapy
                                        Cementoblastoma
                                        Cementoplasty
                                        Central nervous system dermoid tumour
                                        Central nervous system leukaemia
                                        Central nervous system lymphoma
                                        Central nervous system melanoma
                                        Central nervous system neoplasm
                                        Central nervous system neuroblastoma
                                        Cerebellar haemangioma
                                        Cerebellar tumour
                                        Cerebellopontine angle tumour
                                        Cerebral cyst
                                        Cerebral haemangioma
                                        Cervical cyst
                                        Cervical dysplasia
                                        Cervical polyp
                                        Cervix adenomatous polyp
                                        Cervix cancer metastatic
                                        Cervix carcinoma
                                        Cervix carcinoma recurrent
                                        Cervix carcinoma stage 0
                                        Cervix carcinoma stage I
                                        Cervix carcinoma stage II
                                        Cervix carcinoma stage III
                                        Cervix carcinoma stage IV
                                        Cervix neoplasm
                                        Cervix tumour excision
                                        Cervix warts
                                        Chemical peel of skin
                                        Chemodectoma
                                        Chemotherapy
                                        Chemotherapy cardiotoxicity attenuation
                                        Chemotherapy cytokine prophylaxis
                                        Chemotherapy extravasation management
                                        Chemotherapy multiple agents systemic
                                        Chemotherapy neurotoxicity attenuation
                                        Chemotherapy sensitivity and resistance assay
                                        Chemotherapy single agent systemic
                                        Chemotherapy urothelial toxicity attenuation
                                        Chest wall cyst
                                        Chest wall tumour
                                        Chiasma syndrome
                                        Chloroma
                                        Chloroma (in remission)
                                        Cholangioadenoma
                                        Cholangiocarcinoma
                                        Cholangiosarcoma
                                        Choledochal cyst
                                        Cholesteatoma
                                        Cholesterin granuloma of middle ear
                                        Cholesterol granuloma
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Section 16.1.9
CONFIDENTIAL
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03 July 2019
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Final
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————————————————————————————————————————————————————————————————————————————————————————————————————
Neoplasm                                Chondroblastoma
                                        Chondroma
                                        Chondromatosis
                                        Chondrosarcoma
                                        Chondrosarcoma metastatic
                                        Chondrosarcoma recurrent
                                        Chordoma
                                        Choriocarcinoma
                                        Choroid fissure cyst
                                        Choroid melanoma
                                        Choroid neoplasm
                                        Choroid plexus carcinoma
                                        Choroid plexus papilloma
                                        Choroid tumour excision
                                        Choroidal haemangioma
                                        Chromophobe renal cell carcinoma
                                        Chronic eosinophilic leukaemia
                                        Chronic leukaemia
                                        Chronic leukaemia in remission
                                        Chronic lymphocytic leukaemia
                                        Chronic lymphocytic leukaemia (in remission)
                                        Chronic lymphocytic leukaemia recurrent
                                        Chronic lymphocytic leukaemia refractory
                                        Chronic lymphocytic leukaemia stage 0
                                        Chronic lymphocytic leukaemia stage 1
                                        Chronic lymphocytic leukaemia stage 2
                                        Chronic lymphocytic leukaemia stage 3
                                        Chronic lymphocytic leukaemia stage 4
                                        Chronic lymphocytic leukaemia transformation
                                        Chronic myeloid leukaemia
                                        Chronic myeloid leukaemia (in remission)
                                        Chronic myeloid leukaemia recurrent
                                        Chronic myeloid leukaemia transformation
                                        Chronic myelomonocytic leukaemia
                                        Chronic myelomonocytic leukaemia (in remission)
                                        Chronic rhinosinusitis with nasal polyps
                                        Ciliary body melanoma
                                        Clear cell carcinoma of cervix
                                        Clear cell endometrial carcinoma
                                        Clear cell renal cell carcinoma
                                        Clear cell sarcoma of soft tissue
                                        Clear cell sarcoma of the kidney
                                        Clonal evolution
                                        Colectomy
                                        Colectomy total
                                        Colloid brain cyst
                                        Colon adenoma
                                        Colon cancer
                                        Colon cancer metastatic
                                        Colon cancer recurrent
                                        Colon cancer stage 0
                                        Colon cancer stage I
                                        Colon cancer stage II
                                        Colon cancer stage III
                                        Colon cancer stage IV
                                        Colon dysplasia
                                        Colon neoplasm
                                        Colony stimulating factor therapy
                                        Colorectal adenocarcinoma
                                        Colorectal cancer
                                        Colorectal cancer metastatic
                                        Colorectal cancer recurrent
                                        Colorectal cancer stage I
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Clinical Trial Report
Section 16.1.9
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Date:
03 July 2019
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————————————————————————————————————————————————————————————————————————————————————————————————————
Neoplasm                                Colorectal cancer stage II
                                        Colorectal cancer stage III
                                        Colorectal cancer stage IV
                                        Colorectal carcinoma stage 0
                                        Composite lymphoma
                                        Computerised tomogram breast abnormal
                                        Computerised tomogram liver abnormal
                                        Congenital acrochordon
                                        Congenital benign neoplasm
                                        Congenital cerebral cyst
                                        Congenital cerebral haemangioma
                                        Congenital choroid plexus cyst
                                        Congenital cyst
                                        Congenital cystic disease of liver
                                        Congenital cystic kidney disease
                                        Congenital eye naevus
                                        Congenital fibrosarcoma
                                        Congenital malignant neoplasm
                                        Congenital melanocytic naevus
                                        Congenital naevus
                                        Congenital neoplasm
                                        Congenital renal cyst
                                        Congenital retinoblastoma
                                        Congenital teratoma
                                        Congenital vaginal cyst
                                        Conjunctival cyst
                                        Conjunctival melanoma
                                        Conjunctival neoplasm
                                        Conjunctival primary acquired melanosis
                                        Connective tissue neoplasm
                                        Corneal cyst
                                        Corneoconjunctival intraepithelial neoplasia
                                        Cowden's disease
                                        Cranial nerve neoplasm benign
                                        Craniopharyngioma
                                        Craniopharyngioma benign
                                        Crohn's disease
                                        Cronkhite-Canada syndrome
                                        Cutaneous T-cell dyscrasia
                                        Cutaneous lymphoma
                                        Cyclotron therapy
                                        Cyst
                                        Cyst rupture
                                        Cystadenocarcinoma ovary
                                        Cystadenocarcinoma pancreas
                                        Cystadenofibroma of fallopian tube
                                        Cystic angiomatosis
                                        Cystic eyeball, congenital
                                        Cystic lymphangioma
                                        Cystoprostatectomy
                                        Cytokeratin 18 increased
                                        Dedifferentiated liposarcoma
                                        Dental cyst
                                        Denys-Drash syndrome
                                        Dermal cyst
                                        Dermatofibrosarcoma protuberans
                                        Dermatofibrosarcoma protuberans metastatic
                                        Dermoid cyst
                                        Desmoid tumour
                                        Desmoplastic melanoma
                                        Desmoplastic mesothelioma
                                        Desmoplastic small round cell tumour
                                        Diaphragm neoplasm
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NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
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Status:
Final
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————————————————————————————————————————————————————————————————————————————————————————————————————
Neoplasm                                Differentiation syndrome
                                        Diffuse large B-cell lymphoma
                                        Diffuse large B-cell lymphoma recurrent
                                       Diffuse large B-cell lymphoma refractory
                                        Diffuse large B-cell lymphoma stage I
                                        Diffuse large B-cell lymphoma stage II
                                        Diffuse large B-cell lymphoma stage III
                                        Diffuse large B-cell lymphoma stage IV
                                        Diffuse uveal melanocytic proliferation
                                        Disseminated large cell lymphoma
                                       Double hit lymphoma
                                        Ductal adenocarcinoma of pancreas
                                        Duodenal neoplasm
                                        Duodenal polyp
                                        Duodenectomy
                                        Dysplasia
                                        Dysplastic naevus
                                        Dysplastic naevus syndrome
                                        Ear neoplasm
                                        Ear neoplasm malignant
                                        Eastern Cooperative Oncology Group performance status
                                        improved
                                        Eastern Cooperative Oncology Group performance status
                                        worsened
                                        Eccrine carcinoma
                                        Ectopic ACTH syndrome
                                        Ectopic aldosterone secretion
                                        Ectopic antidiuretic hormone secretion
                                        Ectopic calcitonin production
                                        Ectopic chorionic gonadotrophin secretion
                                        Ectopic growth hormone secretion
                                        Ectopic hormone secretion
                                        Ectopic parathyroid hormone production
                                        Ectopic prolactin secretion
                                        Ectopic renin secretion
                                        Elastofibroma
                                        Electron radiation therapy
                                        Electron radiation therapy to bladder
                                        Electron radiation therapy to blood
                                        Electron radiation therapy to bone
                                        Electron radiation therapy to brain
                                        Electron radiation therapy to breast
                                        Electron radiation therapy to colon
                                        Electron radiation therapy to ear, nose, or throat
                                        Electron radiation therapy to liver
                                        Electron radiation therapy to lung
                                        Electron radiation therapy to pancreas
                                        Electron radiation therapy to prostate
                                        Electron radiation therapy to skin
                                        Electron radiation therapy to soft tissue
                                        Electron radiation therapy to uterus
                                        Elephantiasis nostras verrucosa
                                        Embryonal rhabdomyosarcoma
                                        Encephalitis autoimmune
                                        Enchondromatosis
                                        Endobronchial lipoma
                                        Endocrine neoplasm
                                        Endocrine neoplasm malignant
                                        Endometrial adenocarcinoma
                                        Endometrial adenoma
                                        Endometrial cancer
                                        Endometrial cancer metastatic
                                        Endometrial cancer recurrent
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NN9535-4114
Clinical Trial Report
Section 16.1.9
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Date:
03 July 2019
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Final
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————————————————————————————————————————————————————————————————————————————————————————————————————
Neoplasm                                Endometrial cancer stage 0
                                        Endometrial cancer stage I
                                        Endometrial cancer stage II
                                        Endometrial cancer stage III
                                        Endometrial cancer stage IV
                                        Endometrial dysplasia
                                        Endometrial hyperplasia
                                        Endometrial neoplasm
                                        Endometrial sarcoma
                                        Endometrial sarcoma metastatic
                                        Endometrial sarcoma recurrent
                                        Endometrial stromal sarcoma
                                        Endotheliomatosis
                                        Enteropathy-associated T-cell lymphoma
                                        Eosinophilic leukaemia
                                        Ependymoma
                                        Ependymoma benign
                                        Ependymoma malignant
                                        Epidermal naevus syndrome
                                        Epidermodysplasia verruciformis
                                        Epididymal cancer
                                        Epididymal cyst
                                        Epididymal neoplasm
                                        Epiglottic carcinoma
                                        Epiglottic cyst
                                        Epiglottic mass
                                        Epiglottidectomy
                                        Epithelioid mesothelioma
                                        Epithelioid sarcoma
                                        Epithelioid sarcoma metastatic
                                        Epithelioid sarcoma recurrent
                                        Epithelioma adenoides cysticum
                                        Epstein Barr virus positive mucocutaneous ulcer
                                        Epstein-Barr virus associated lymphoma
                                        Epstein-Barr virus associated lymphoproliferative disorder
                                        Epulis
                                        Erdheim-Chester disease
                                        Erythraemic myelosis (in remission)
                                        Erythroleukaemia
                                        Erythroplasia
                                        Erythroplasia of lip
                                        Erythroplasia of penis
                                        Erythroplasia of vulva
                                        Essential thrombocythaemia
                                        Ewing's sarcoma
                                        Ewing's sarcoma metastatic
                                        Ewing's sarcoma recurrent
                                        Ewing-like sarcoma
                                        Ex vivo gene therapy
                                        Exploratory operation
                                        Extended radical mastectomy
                                        Extra-osseous Ewing's sarcoma
                                        Extra-osseous Ewing's sarcoma metastatic
                                        Extra-osseous Ewing's sarcoma recurrent
                                        Extradural neoplasm
                                        Extragonadal primary embryonal carcinoma
                                        Extragonadal primary germ cell tumour
                                        Extragonadal primary germ cell tumour mixed
                                        Extragonadal primary germ cell tumour mixed stage I
                                        Extragonadal primary germ cell tumour mixed stage II
                                        Extragonadal primary germ cell tumour mixed stage III
                                        Extragonadal primary malignant teratoma
                                        Extragonadal primary non-seminoma
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NN9535-4114
Clinical Trial Report
Section 16.1.9
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03 July 2019
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Final
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————————————————————————————————————————————————————————————————————————————————————————————————————
Neoplasm                                Extragonadal primary non-seminoma stage I
                                        Extragonadal primary non-seminoma stage II
                                        Extragonadal primary non-seminoma stage III
                                        Extragonadal primary non-seminoma stage IV
                                        Extragonadal primary seminoma (pure)
                                        Extragonadal primary seminoma (pure) stage I
                                        Extragonadal primary seminoma (pure) stage II
                                        Extragonadal primary seminoma (pure) stage III
                                        Extragonadal primary seminoma (pure) stage IV
                                        Extramammary Paget's disease
                                       Extranodal marginal zone B-cell lymphoma (BALT type)
                                        Extranodal marginal zone B-cell lymphoma (MALT type)
                                        Extranodal marginal zone B-cell lymphoma (MALT type)
                                        recurrent
                                        Extranodal marginal zone B-cell lymphoma (MALT type)
                                        refractory
                                        Extranodal marginal zone B-cell lymphoma (MALT type) stage I
                                        Extranodal marginal zone B-cell lymphoma (MALT type) stage
                                        II
                                        Extranodal marginal zone B-cell lymphoma (MALT type) stage
                                        III
                                        Extranodal marginal zone B-cell lymphoma (MALT type) stage
                                        IV
                                        Extraocular retinoblastoma
                                        Extraskeletal chondrosarcoma metastatic
                                        Extraskeletal chondrosarcoma recurrent
                                        Extraskeletal myxoid chondrosarcoma
                                        Extraskeletal osteosarcoma
                                        Extraskeletal osteosarcoma metastatic
                                        Extraskeletal osteosarcoma recurrent
                                        Eye haemangioma
                                        Eye naevus
                                        Eyelid haemangioma
                                        Eyelid naevus
                                        Eyelid tumour
                                        Fallopian tube cancer
                                        Fallopian tube cancer metastatic
                                        Fallopian tube cancer stage I
                                        Fallopian tube cancer stage II
                                        Fallopian tube cancer stage III
                                        Fallopian tube cancer stage IV
                                        Fallopian tube cyst
                                        Fallopian tube leiomyoma
                                        Fallopian tube neoplasm
                                        Familial acromegaly
                                        Familial gigantiform cementoma
                                        Familial haemophagocytic lymphohistiocytosis
                                        Familial medullary thyroid cancer
                                        Familial multiple lipomatosis
                                        Female reproductive neoplasm
                                        Female reproductive tract carcinoma in situ
                                        Fibroadenoma of breast
                                        Fibrocystic breast disease
                                        Fibroma
                                        Fibromatosis
                                        Fibrosarcoma
                                        Fibrosarcoma excision
                                        Fibrosarcoma metastatic
                                        Fibrous cortical defect
                                        Fibrous histiocytoma
                                        Fiducial marker placement
                                        Fms-like tyrosine kinase 3 positive
                                        Focal nodular hyperplasia
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————————————————————————————————————————————————————————————————————————————————————————————————————
Neoplasm                                Foetal cystic hygroma
                                        Follicle centre lymphoma diffuse small cell lymphoma
                                        Follicle centre lymphoma diffuse small cell lymphoma
                                        recurrent
                                        Follicle centre lymphoma diffuse small cell lymphoma
                                        refractory
                                        Follicle centre lymphoma diffuse small cell lymphoma stage I
                                        Follicle centre lymphoma diffuse small cell lymphoma stage
                                        II
                                        Follicle centre lymphoma diffuse small cell lymphoma stage
                                        III
                                        Follicle centre lymphoma diffuse small cell lymphoma stage
                                        IV
                                        Follicle centre lymphoma, follicular grade I, II, III
                                        Follicle centre lymphoma, follicular grade I, II, III
                                        recurrent
                                        Follicle centre lymphoma, follicular grade I, II, III
                                        refractory
                                        Follicle centre lymphoma, follicular grade I, II, III stage
                                        I
                                        Follicle centre lymphoma, follicular grade I, II, III stage
                                        II
                                        Follicle centre lymphoma, follicular grade I, II, III stage
                                        III
                                        Follicle centre lymphoma, follicular grade I, II, III stage
                                        IV
                                        Follicular dendritic cell sarcoma
                                        Follicular thyroid cancer
                                        Frasier syndrome
                                        Free prostate-specific antigen increased
                                        Free prostate-specific antigen positive
                                        Fungating wound
                                        Gallbladder adenocarcinoma
                                        Gallbladder adenoma
                                        Gallbladder adenosquamous carcinoma
                                        Gallbladder cancer
                                        Gallbladder cancer metastatic
                                        Gallbladder cancer recurrent
                                        Gallbladder cancer stage 0
                                        Gallbladder cancer stage I
                                        Gallbladder cancer stage II
                                        Gallbladder cancer stage III
                                        Gallbladder cancer stage IV
                                        Gallbladder neoplasm
                                        Gallbladder papilloma
                                        Gallbladder polyp
                                        Gallbladder squamous cell carcinoma
                                        Gamma interferon therapy
                                        Gamma radiation therapy
                                        Gamma radiation therapy to bladder
                                        Gamma radiation therapy to blood
                                        Gamma radiation therapy to bone
                                        Gamma radiation therapy to brain
                                        Gamma radiation therapy to breast
                                        Gamma radiation therapy to colon
                                        Gamma radiation therapy to ear, nose, or throat
                                        Gamma radiation therapy to liver
                                        Gamma radiation therapy to lung
                                        Gamma radiation therapy to pancreas
                                        Gamma radiation therapy to pleura
                                        Gamma radiation therapy to prostate
                                        Gamma radiation therapy to skin
                                        Gamma radiation therapy to soft tissue
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Section 16.1.9
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————————————————————————————————————————————————————————————————————————————————————————————————————
Neoplasm                                Gamma radiation therapy to thyroid
                                        Gamma radiation therapy to uterus
                                        Gammopathy
                                        Ganglioglioma
                                        Ganglioneuroblastoma
                                        Ganglioneuroma
                                        Garcin syndrome
                                        Gastrectomy
                                        Gastric adenoma
                                        Gastric cancer
                                        Gastric cancer recurrent
                                        Gastric cancer stage 0
                                        Gastric cancer stage I
                                        Gastric cancer stage II
                                        Gastric cancer stage III
                                        Gastric cancer stage IV
                                        Gastric cyst
                                        Gastric dysplasia
                                        Gastric haemangioma
                                        Gastric leiomyoma
                                        Gastric neoplasm
                                        Gastric polypectomy
                                        Gastric polyps
                                        Gastric sarcoma
                                        Gastric stent insertion
                                        Gastrinoma
                                        Gastrinoma malignant
                                        Gastroenteropancreatic neuroendocrine tumour disease
                                        Gastrointestinal adenocarcinoma
                                        Gastrointestinal cancer metastatic
                                        Gastrointestinal carcinoma
                                        Gastrointestinal carcinoma in situ
                                        Gastrointestinal dysplasia
                                        Gastrointestinal lymphoma
                                        Gastrointestinal melanoma
                                        Gastrointestinal neoplasm
                                        Gastrointestinal polyp
                                        Gastrointestinal polyp haemorrhage
                                        Gastrointestinal stromal cancer
                                        Gastrointestinal stromal tumour
                                        Gastrointestinal submucosal tumour
                                        Gastrointestinal tract adenoma
                                        Gastrooesophageal cancer
                                        Gastrooesophageal cancer recurrent
                                        Genital cancer male
                                        Genital cancer male in situ
                                        Genital cyst
                                        Genital neoplasm malignant female
                                        Genitourinary melanoma
                                        Genitourinary tract neoplasm
                                        Germ cell cancer
                                        Germ cell cancer metastatic
                                        Germ cell neoplasm
                                       Gestational trophoblastic tumour
                                        Giant cell epulis
                                        Giant cell tumour of tendon sheath
                                        Gingival cancer
                                        Gingival cyst
                                        Gingival polyp
                                        Glioblastoma
                                        Glioblastoma multiforme
                                        Glioma
                                        Gliomatosis cerebri
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03 July 2019
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————————————————————————————————————————————————————————————————————————————————————————————————————
Neoplasm                                Glioneuronal tumour
                                        Gliosarcoma
                                        Glomus jugulare tumour
                                        Glomus tumour
                                        Glomus tympanicum tumour
                                        Glossectomy
                                        Glottis carcinoma
                                        Glucagonoma
                                        Good syndrome
                                       Gorham's disease
                                        Granular cell tumour
                                        Granulosa cell tumour of the testis
                                        Growth hormone-producing pituitary tumour
                                        HER-2 positive breast cancer
                                        HER-2 positive gastric cancer
                                        Haemangioblastoma
                                        Haemangioma
                                        Haemangioma congenital
                                        Haemangioma of bone
                                        Haemangioma of breast
                                        Haemangioma of liver
                                        Haemangioma of retina
                                        Haemangioma of skin
                                        Haemangioma of spleen
                                        Haemangioma-thrombocytopenia syndrome
                                        Haemangiopericytoma
                                        Haemangiopericytoma of meninges
                                        Haematological malignancy
                                        Haematopoietic neoplasm
                                        Haemophagocytic lymphohistiocytosis
                                        Haemophilic pseudotumour
                                        Haemorrhagic breast cyst
                                        Haemorrhagic cyst
                                        Haemorrhagic hepatic cyst
                                        Haemorrhagic ovarian cyst
                                        Haemorrhagic thyroid cyst
                                        Haemorrhagic tumour necrosis
                                        Hair follicle tumour benign
                                        Hairy cell leukaemia
                                        Hairy cell leukaemia recurrent
                                        Hamartoma
                                        Hamartoma vascular
                                        Head and neck cancer
                                        Head and neck cancer metastatic
                                        Head and neck cancer stage I
                                        Head and neck cancer stage II
                                        Head and neck cancer stage III
                                        Head and neck cancer stage IV
                                        Heavy chain disease
                                        Hemicorporectomy
                                        Hemipelvectomy
                                        Hepatectomy
                                        Hepatic adenoma
                                        Hepatic angiosarcoma
                                        Hepatic cancer
                                        Hepatic cancer metastatic
                                        Hepatic cancer recurrent
                                        Hepatic cancer stage I
                                        Hepatic cancer stage II
                                        Hepatic cancer stage III
                                        Hepatic cancer stage IV
                                        Hepatic cyst
                                        Hepatic cyst infection
————————————————————————————————————————————————————————————————————————————————————————————————————
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Clinical Trial Report
Section 16.1.9
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————————————————————————————————————————————————————————————————————————————————————————————————————
Neoplasm                                Hepatic cyst ruptured
                                        Hepatic haemangioma rupture
                                        Hepatic hamartoma
                                        Hepatic neoplasm
                                        Hepatobiliary cancer
                                        Hepatobiliary cancer in situ
                                        Hepatobiliary cyst
                                        Hepatobiliary neoplasm
                                        Hepatoblastoma
                                        Hepatoblastoma recurrent
                                        Hepatocellular carcinoma
                                        Hepatosplenic T-cell lymphoma
                                        Hereditary leiomyomatosis renal cell carcinoma
                                        Hereditary multiple osteochondromas
                                        Hereditary non-polyposis colorectal cancer syndrome
                                        Hereditary papillary renal carcinoma
                                        Hidradenocarcinoma
                                        High frequency ablation
                                        High grade B-cell lymphoma Burkitt-like lymphoma
                                        High grade B-cell lymphoma Burkitt-like lymphoma recurrent
                                        High grade B-cell lymphoma Burkitt-like lymphoma refractory
                                        High grade B-cell lymphoma Burkitt-like lymphoma stage I
                                        High grade B-cell lymphoma Burkitt-like lymphoma stage II
                                        High grade B-cell lymphoma Burkitt-like lymphoma stage III
                                        High grade B-cell lymphoma Burkitt-like lymphoma stage IV
                                        High intensity focused ultrasound
                                       High-grade B-cell lymphoma
                                        Histiocytic medullary reticulosis
                                        Histiocytic necrotising lymphadenitis
                                        Histiocytic sarcoma
                                        Histiocytosis
                                        Hodgkin's disease
                                        Hodgkin's disease lymphocyte depletion stage I site
                                        unspecified
                                        Hodgkin's disease lymphocyte depletion stage I subdiaphragm
                                        Hodgkin's disease lymphocyte depletion stage I
                                        supradiaphragm
                                        Hodgkin's disease lymphocyte depletion stage II site
                                        unspecified
                                        Hodgkin's disease lymphocyte depletion stage II subdiaphragm
                                        Hodgkin's disease lymphocyte depletion stage II
                                        supradiaphragm
                                        Hodgkin's disease lymphocyte depletion type recurrent
                                        Hodgkin's disease lymphocyte depletion type refractory
                                        Hodgkin's disease lymphocyte depletion type stage III
                                        Hodgkin's disease lymphocyte depletion type stage IV
                                        Hodgkin's disease lymphocyte depletion type stage
                                        unspecified
                                        Hodgkin's disease lymphocyte predominance stage I site
                                        unspec
                                        Hodgkin's disease lymphocyte predominance stage I
                                        subdiaphragm
                                        Hodgkin's disease lymphocyte predominance stage I
                                        supradiaphragm
                                        Hodgkin's disease lymphocyte predominance stage II site
                                        unspec
                                        Hodgkin's disease lymphocyte predominance stage II
                                        subdiaphragm
                                        Hodgkin's disease lymphocyte predominance stage II
                                        supradiaphragm
                                        Hodgkin's disease lymphocyte predominance type recurrent
                                        Hodgkin's disease lymphocyte predominance type refractory
                                        Hodgkin's disease lymphocyte predominance type stage III
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03 July 2019
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————————————————————————————————————————————————————————————————————————————————————————————————————
Neoplasm                                Hodgkin's disease lymphocyte predominance type stage IV
                                        Hodgkin's disease lymphocyte predominance type stage
                                        unspecified
                                        Hodgkin's disease mixed cellularity recurrent
                                        Hodgkin's disease mixed cellularity refractory
                                        Hodgkin's disease mixed cellularity stage I site unspecified
                                        Hodgkin's disease mixed cellularity stage I subdiaphragmatic
                                        Hodgkin's disease mixed cellularity stage I
                                        supradiaphragmatic
                                        Hodgkin's disease mixed cellularity stage II
                                        subdiaphragmatic
                                        Hodgkin's disease mixed cellularity stage II
                                        supradiaphragmatic
                                        Hodgkin's disease mixed cellularity stage III
                                        Hodgkin's disease mixed cellularity stage IV
                                        Hodgkin's disease mixed cellularity stage unspecified
                                        Hodgkin's disease nodular sclerosis
                                        Hodgkin's disease nodular sclerosis recurrent
                                        Hodgkin's disease nodular sclerosis refractory
                                        Hodgkin's disease nodular sclerosis stage I
                                        Hodgkin's disease nodular sclerosis stage II
                                        Hodgkin's disease nodular sclerosis stage III
                                        Hodgkin's disease nodular sclerosis stage IV
                                        Hodgkin's disease recurrent
                                        Hodgkin's disease refractory
                                        Hodgkin's disease stage I
                                        Hodgkin's disease stage II
                                        Hodgkin's disease stage III
                                        Hodgkin's disease stage IV
                                        Hodgkin's disease unclassifiable
                                        Hormone refractory breast cancer
                                        Hormone suppression therapy
                                        Hormone therapy
                                        Hormone-dependent prostate cancer
                                        Hormone-refractory prostate cancer
                                        Hormone-secreting ovarian tumour
                                        Horner's syndrome
                                        Huerthle cell carcinoma
                                        Human chorionic gonadotropin increased
                                        Human chorionic gonadotropin positive
                                        Human epidermal growth factor receptor increased
                                        Hygroma colli
                                        Hypercalcaemia of malignancy
                                        Hypercalcitoninaemia
                                        Hypergammaglobulinaemia benign monoclonal
                                        Hyperleukocytosis
                                        Hyperreactio luteinalis
                                        Hyperthermia therapy
                                        Hyperthermic chemotherapy
                                        Hypertrophic osteoarthropathy
                                        Hypopharyngeal cancer
                                        Hypopharyngeal cancer recurrent
                                        Hypopharyngeal cancer stage 0
                                        Hypopharyngeal cancer stage I
                                        Hypopharyngeal cancer stage II
                                        Hypopharyngeal cancer stage III
                                        Hypopharyngeal cancer stage IV
                                        Hypopharyngeal neoplasm
                                        Hypopharyngeal neoplasm benign
                                        Hypophosphataemic osteomalacia
                                        Hypophysectomy
                                        Hypothalamic hamartoma
                                        Hysterectomy
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Clinical Trial Report
Section 16.1.9
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03 July 2019
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Neoplasm                                Hysterosalpingectomy
                                        Hysterosalpingo-oophorectomy
                                        Ileectomy
                                        Ileocolectomy
                                        Imaging procedure abnormal
                                        Immune enhancement therapy
                                        Immune reconstitution inflammatory syndrome associated
                                        Kaposi's sarcoma
                                        Immunoblastic lymphoma
                                        Immunochemotherapy
                                        Immunoglobulin clonality assay
                                        Implant site cyst
                                        In vivo gene therapy
                                        Infantile fibromatosis
                                        Infantile haemangioma
                                        Infantile septic granulomatosis
                                        Infected cyst
                                        Infected dermal cyst
                                        Infected lymphocele
                                        Infected naevus
                                        Infected neoplasm
                                        Inferior vena cava syndrome
                                        Inflammatory carcinoma of breast recurrent
                                        Inflammatory carcinoma of breast stage III
                                        Inflammatory carcinoma of breast stage IV
                                        Inflammatory carcinoma of the breast
                                        Inflammatory malignant fibrous histiocytoma
                                        Inflammatory myofibroblastic tumour
                                        Inflammatory pseudotumour
                                        Infusion site cyst
                                        Injection site cyst
                                        Insulinoma
                                        Interleukin therapy
                                        Intestinal T-cell lymphoma recurrent
                                        Intestinal T-cell lymphoma refractory
                                        Intestinal T-cell lymphoma stage I
                                        Intestinal T-cell lymphoma stage II
                                        Intestinal T-cell lymphoma stage III
                                        Intestinal T-cell lymphoma stage IV
                                        Intestinal adenocarcinoma
                                        Intestinal angioma
                                        Intestinal cyst
                                        Intestinal metastasis
                                        Intestinal polyp
                                        Intestinal polypectomy
                                        Intestinal resection
                                        Intra-abdominal haemangioma
                                        Intracranial germ cell tumour
                                        Intracranial haemangioma
                                        Intracranial meningioma malignant
                                        Intracranial tumour haemorrhage
                                        Intracystic breast papilloma
                                        Intraductal papillary breast neoplasm
                                        Intraductal papillary mucinous neoplasm
                                        Intraductal papillary-mucinous carcinoma of pancreas
                                        Intraductal papilloma of breast
                                       Intraductal proliferative breast lesion
                                        Intraneural cyst
                                        Intraocular melanoma
                                        Intraosseous angioma
                                        Intratumoural aneurysm
                                        Intravascular lipoma
                                        Intravascular papillary endothelial hyperplasia
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Section 16.1.9
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03 July 2019
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Final
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Neoplasm                                Intravenous leiomyomatosis
                                        Intravesical immunotherapy
                                        Invasive breast carcinoma
                                       Invasive ductal breast carcinoma
                                        Invasive lobular breast carcinoma
                                        Invasive papillary breast carcinoma
                                        Iris cyst
                                        Iris hamartoma
                                        Iris melanoma
                                        Iris neoplasm
                                        Irreversible electroporation
                                        Isocitrate dehydrogenase gene mutation
                                        Jaw cyst
                                        Jejunectomy
                                        Joint neoplasm
                                        Juvenile angiofibroma
                                        Juvenile chronic myelomonocytic leukaemia
                                        Juvenile melanoma benign
                                        Kaposi's sarcoma
                                        Kaposi's sarcoma AIDS related
                                        Kaposi's sarcoma classical type
                                        Keratinising squamous cell carcinoma of nasopharynx
                                        Keratoacanthoma
                                        Kidney angiomyolipoma
                                        Knuckle pads
                                        Lacrimal cyst
                                        Lacrimal duct neoplasm
                                        Langerhans cell sarcoma
                                        Langerhans' cell histiocytosis
                                        Large cell lung cancer
                                        Large cell lung cancer metastatic
                                        Large cell lung cancer recurrent
                                        Large cell lung cancer stage 0
                                        Large cell lung cancer stage I
                                        Large cell lung cancer stage II
                                        Large cell lung cancer stage III
                                        Large cell lung cancer stage IV
                                        Large granular lymphocytosis
                                        Large intestinal polypectomy
                                        Large intestine benign neoplasm
                                        Large intestine fibroma
                                        Large intestine polyp
                                        Laryngeal cancer
                                        Laryngeal cancer metastatic
                                        Laryngeal cancer recurrent
                                        Laryngeal cancer stage 0
                                        Laryngeal cancer stage I
                                        Laryngeal cancer stage II
                                        Laryngeal cancer stage III
                                        Laryngeal cancer stage IV
                                        Laryngeal cyst
                                        Laryngeal dysplasia
                                        Laryngeal leukoplakia
                                        Laryngeal neoplasm
                                        Laryngeal papilloma
                                        Laryngeal polyp
                                        Laryngeal polypectomy
                                        Laryngeal squamous cell carcinoma
                                        Laryngectomy
                                        Laryngopharyngectomy
                                        Laser brain ablation
                                        Leiomyoma
                                        Leiomyosarcoma
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03 July 2019
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————————————————————————————————————————————————————————————————————————————————————————————————————
Neoplasm                                Leiomyosarcoma metastatic
                                        Leiomyosarcoma recurrent
                                        Lentigo maligna
                                        Lentigo maligna recurrent
                                        Lentigo maligna stage I
                                        Lentigo maligna stage II
                                        Lentigo maligna stage III
                                        Lentigo maligna stage IV
                                        Leptomeningeal myelomatosis
                                        Leser-Trelat sign
                                        Leukaemia
                                        Leukaemia basophilic
                                        Leukaemia cutis
                                        Leukaemia granulocytic
                                        Leukaemia in remission
                                        Leukaemia monocytic
                                        Leukaemia recurrent
                                        Leukaemic cardiac infiltration
                                        Leukaemic infiltration
                                        Leukaemic infiltration extramedullary
                                        Leukaemic infiltration gingiva
                                        Leukaemic infiltration hepatic
                                        Leukaemic infiltration ovary
                                        Leukaemic infiltration pulmonary
                                        Leukaemic infiltration renal
                                        Leukaemic lymphoma
                                        Leukaemic retinopathy
                                        Leukoerythroblastosis
                                        Leukoplakia
                                        Leukoplakia oesophageal
                                        Leukoplakia of penis
                                       Leukoplakia oral
                                        Leukostasis syndrome
                                        Leydig cell tumour of the testis
                                        Light chain disease
                                        Limbic encephalitis
                                        Linitis plastica
                                        Lip and
                                        or oral cavity cancer
                                        Lip and
                                        or oral cavity cancer recurrent
                                        Lip and
                                        or oral cavity cancer stage 0
                                        Lip and
                                        or oral cavity cancer stage I
                                        Lip and
                                        or oral cavity cancer stage II
                                        Lip and
                                        or oral cavity cancer stage III
                                        Lip and
                                        or oral cavity cancer stage IV
                                        Lip neoplasm
                                        Lip neoplasm benign
                                        Lip neoplasm malignant stage unspecified
                                        Lip squamous cell carcinoma
                                        Lipoblastoma
                                        Lipodermoid tumour
                                        Lipofibroma
                                        Lipoma
                                        Lipoma of breast
                                        Liposarcoma
                                        Liposarcoma metastatic
                                        Liposarcoma recurrent
————————————————————————————————————————————————————————————————————————————————————————————————————
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NN9535-4114
Clinical Trial Report
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03 July 2019
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Neoplasm                                Liver ablation
                                        Liver carcinoma ruptured
                                        Liver scan abnormal
                                        Lobular breast carcinoma in situ
                                       Lung adenocarcinoma
                                        Lung adenocarcinoma recurrent
                                        Lung adenocarcinoma stage 0
                                        Lung adenocarcinoma stage I
                                        Lung adenocarcinoma stage II
                                        Lung adenocarcinoma stage III
                                        Lung adenocarcinoma stage IV
                                       Lung cancer metastatic
                                        Lung carcinoma cell type unspecified recurrent
                                        Lung carcinoma cell type unspecified stage 0
                                        Lung carcinoma cell type unspecified stage I
                                        Lung carcinoma cell type unspecified stage II
                                        Lung carcinoma cell type unspecified stage III
                                        Lung carcinoma cell type unspecified stage IV
                                        Lung cyst
                                        Lung infiltration malignant
                                        Lung lobectomy
                                        Lung neoplasm
                                        Lung neoplasm malignant
                                        Lung neoplasm surgery
                                        Lung squamous cell carcinoma metastatic
                                        Lung squamous cell carcinoma recurrent
                                        Lung squamous cell carcinoma stage 0
                                        Lung squamous cell carcinoma stage I
                                        Lung squamous cell carcinoma stage II
                                        Lung squamous cell carcinoma stage III
                                        Lung squamous cell carcinoma stage IV
                                        Lymph nodes scan abnormal
                                        Lymphadenectomy
                                        Lymphangioma
                                        Lymphangiosarcoma
                                        Lymphangiosis carcinomatosa
                                        Lymphatic mapping
                                        Lymphatic system neoplasm
                                        Lymphocele
                                        Lymphocyte adoptive therapy
                                        Lymphocyte morphology abnormal
                                        Lymphocytic leukaemia
                                        Lymphocytic lymphoma
                                        Lymphoid leukaemia (in remission)
                                        Lymphoid tissue operation
                                        Lymphoma
                                        Lymphoma AIDS related
                                        Lymphoma operation
                                        Lymphoma transformation
                                        Lymphoplasmacytoid lymphoma
                                        immunocytoma
                                        Lymphoplasmacytoid lymphoma
                                        immunocytoma recurrent
                                        Lymphoplasmacytoid lymphoma
                                        immunocytoma refractory
                                        Lymphoplasmacytoid lymphoma
                                        immunocytoma stage I
                                        Lymphoplasmacytoid lymphoma
                                        immunocytoma stage II
                                        Lymphoplasmacytoid lymphoma
                                        immunocytoma stage III
                                        Lymphoplasmacytoid lymphoma
                                        immunocytoma stage IV
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NN9535-4114
Clinical Trial Report
Section 16.1.9
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Date:
03 July 2019
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————————————————————————————————————————————————————————————————————————————————————————————————————
Neoplasm                                Lymphoproliferative disorder
                                        Lymphoproliferative disorder in remission
                                        Male reproductive tract neoplasm
                                        Malignant anorectal neoplasm
                                        Malignant ascites
                                        Malignant biliary obstruction
                                        Malignant blue naevus
                                        Malignant connective tissue neoplasm
                                        Malignant cranial nerve neoplasm
                                        Malignant dysphagia
                                        Malignant exophthalmos
                                        Malignant fibrous histiocytoma
                                        Malignant fibrous histiocytoma metastatic
                                        Malignant fibrous histiocytoma of bone
                                        Malignant fibrous histiocytoma recurrent
                                        Malignant gastrointestinal obstruction
                                        Malignant genitourinary tract neoplasm
                                        Malignant giant cell fibrous histiocytoma
                                        Malignant glioma
                                        Malignant haemangiopericytoma
                                        Malignant haemangiopericytoma metastatic
                                        Malignant haemangiopericytoma recurrent
                                        Malignant histiocytosis
                                        Malignant hydatidiform mole
                                        Malignant joint neoplasm
                                        Malignant lymphoid neoplasm
                                        Malignant lymphoma unclassifiable high grade
                                        Malignant lymphoma unclassifiable low grade
                                        Malignant mast cell neoplasm
                                        Malignant mediastinal neoplasm
                                        Malignant melanoma
                                        Malignant melanoma in situ
                                        Malignant melanoma of eyelid
                                        Malignant melanoma of sites other than skin
                                        Malignant melanoma stage I
                                        Malignant melanoma stage II
                                        Malignant melanoma stage III
                                        Malignant melanoma stage IV
                                        Malignant meningioma metastatic
                                        Malignant mesenchymoma
                                        Malignant mesenchymoma metastatic
                                        Malignant mesenchymoma recurrent
                                        Malignant mesenteric neoplasm
                                        Malignant middle ear neoplasm
                                        Malignant muscle neoplasm
                                        Malignant neoplasm of ampulla of Vater
                                        Malignant neoplasm of auricular cartilage
                                        Malignant neoplasm of choroid
                                        Malignant neoplasm of conjunctiva
                                        Malignant neoplasm of cornea
                                        Malignant neoplasm of eye
                                        Malignant neoplasm of eyelid
                                        Malignant neoplasm of islets of Langerhans
                                        Malignant neoplasm of lacrimal duct
                                        Malignant neoplasm of lacrimal gland
                                        Malignant neoplasm of orbit
                                        Malignant neoplasm of paraurethral glands
                                        Malignant neoplasm of placenta
                                        Malignant neoplasm of pleura
                                        Malignant neoplasm of pleura metastatic
                                        Malignant neoplasm of renal pelvis
                                        Malignant neoplasm of retina
                                        Malignant neoplasm of seminal vesicle
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————————————————————————————————————————————————————————————————————————————————————————————————————
Neoplasm                                Malignant neoplasm of spermatic cord
                                        Malignant neoplasm of spinal cord
                                        Malignant neoplasm of thorax
                                        Malignant neoplasm of thymus
                                        Malignant neoplasm of unknown primary site
                                        Malignant neoplasm of uterine adnexa
                                        Malignant neoplasm papilla of Vater
                                        Malignant neoplasm progression
                                        Malignant nervous system neoplasm
                                        Malignant nipple neoplasm
                                        Malignant nipple neoplasm female
                                        Malignant nipple neoplasm male
                                        Malignant oligodendroglioma
                                        Malignant ovarian cyst
                                        Malignant palate neoplasm
                                        Malignant pericardial neoplasm
                                        Malignant peritoneal neoplasm
                                        Malignant pituitary tumour
                                        Malignant pleural effusion
                                        Malignant polyp
                                        Malignant psoas syndrome
                                        Malignant respiratory tract neoplasm
                                        Malignant splenic neoplasm
                                        Malignant sweat gland neoplasm
                                        Malignant transformation
                                        Malignant urinary tract neoplasm
                                        Malignant urinary tract obstruction
                                        Mantle cell lymphoma
                                        Mantle cell lymphoma recurrent
                                       Mantle cell lymphoma refractory
                                        Mantle cell lymphoma stage I
                                        Mantle cell lymphoma stage II
                                        Mantle cell lymphoma stage III
                                        Mantle cell lymphoma stage IV
                                        Marginal zone lymphoma
                                        Marginal zone lymphoma recurrent
                                        Marginal zone lymphoma refractory
                                        Marginal zone lymphoma stage I
                                        Marginal zone lymphoma stage II
                                        Marginal zone lymphoma stage III
                                        Marginal zone lymphoma stage IV
                                        Marjolin's ulcer
                                        Marrow hyperplasia
                                        Mastectomy
                                        Mastocytic leukaemia
                                        Mastocytoma
                                        Mastoid cyst
                                       Mastoidectomy
                                        Maternal cancer in pregnancy
                                        Mature B-cell type acute leukaemia
                                        Maxillofacial sinus neoplasm
                                        Mazabraud's syndrome
                                        Mediastinal biopsy abnormal
                                        Mediastinal cyst
                                        Mediastinum neoplasm
                                        Medical device site cyst
                                        Medullary carcinoma of breast
                                        Medullary thyroid cancer
                                        Medulloblastoma
                                        Medulloblastoma recurrent
                                        Megaloblasts increased
                                        Meigs' syndrome
                                        Melanocytic naevus
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————————————————————————————————————————————————————————————————————————————————————————————————————
Neoplasm                                Melanoma recurrent
                                        Melanoplakia oral
                                        Meningeal neoplasm
                                        Meningioma
                                        Meningioma benign
                                        Meningioma malignant
                                        Meniscus cyst
                                        Mesenteric cyst
                                        Mesenteric neoplasm
                                        Mesoblastic nephroma
                                        Mesonephric duct cyst
                                        Mesothelioma
                                        Mesothelioma malignant
                                        Mesothelioma malignant recurrent
                                        Metaplastic breast carcinoma
                                        Metastases to Eustachian tube
                                        Metastases to abdominal cavity
                                        Metastases to abdominal wall
                                        Metastases to adrenals
                                        Metastases to biliary tract
                                        Metastases to bladder
                                        Metastases to bone
                                        Metastases to bone marrow
                                        Metastases to breast
                                        Metastases to central nervous system
                                        Metastases to chest wall
                                        Metastases to diaphragm
                                        Metastases to eye
                                        Metastases to fallopian tube
                                        Metastases to gallbladder
                                        Metastases to gastrointestinal tract
                                        Metastases to heart
                                        Metastases to kidney
                                        Metastases to larynx
                                        Metastases to liver
                                        Metastases to lung
                                        Metastases to lymph nodes
                                        Metastases to meninges
                                        Metastases to mouth
                                        Metastases to muscle
                                        Metastases to nasal sinuses
                                        Metastases to neck
                                        Metastases to nervous system
                                        Metastases to oesophagus
                                        Metastases to ovary
                                        Metastases to pancreas
                                        Metastases to pelvis
                                        Metastases to penis
                                        Metastases to perineum
                                        Metastases to peripheral nervous system
                                        Metastases to peripheral vascular system
                                        Metastases to peritoneum
                                        Metastases to pharynx
                                        Metastases to pituitary gland
                                        Metastases to placenta
                                        Metastases to pleura
                                        Metastases to prostate
                                        Metastases to rectum
                                        Metastases to reproductive organ
                                        Metastases to retroperitoneum
                                        Metastases to salivary gland
                                        Metastases to skin
                                        Metastases to soft tissue
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Neoplasm                                Metastases to spinal cord
                                        Metastases to spine
                                        Metastases to spleen
                                        Metastases to stomach
                                        Metastases to testicle
                                        Metastases to the mediastinum
                                        Metastases to the respiratory system
                                        Metastases to thorax
                                        Metastases to thyroid
                                        Metastases to tonsils
                                        Metastases to trachea
                                        Metastases to urinary tract
                                        Metastases to uterus
                                        Metastases to vagina
                                        Metastasis
                                        Metastatic bronchial carcinoma
                                        Metastatic carcinoid tumour
                                        Metastatic carcinoma of the bladder
                                        Metastatic choriocarcinoma
                                        Metastatic gastric cancer
                                        Metastatic glioma
                                        Metastatic glucagonoma
                                        Metastatic lymphoma
                                        Metastatic malignant melanoma
                                        Metastatic neoplasm
                                        Metastatic nervous system neoplasm
                                        Metastatic ocular melanoma
                                        Metastatic pulmonary embolism
                                        Metastatic renal cell carcinoma
                                        Metastatic salivary gland cancer
                                        Metastatic squamous cell carcinoma
                                        Metastatic uterine cancer
                                        Micrographic skin surgery
                                        Microsatellite instability cancer
                                        Minimal residual disease
                                        Mismatch repair cancer syndrome
                                        Mixed adenoneuroendocrine carcinoma
                                        Mixed hepatocellular cholangiocarcinoma
                                        Mixed-type liposarcoma
                                        Modified radical mastectomy
                                        Monoclonal gammopathy
                                        Monocytic leukaemia in remission
                                        Mouth cyst
                                        Mucinous adenocarcinoma of appendix
                                        Mucinous breast carcinoma
                                        Mucinous cystadenocarcinoma ovary
                                        Mucinous endometrial carcinoma
                                        Mucoepidermoid carcinoma
                                        Mucoepidermoid carcinoma of salivary gland
                                        Mucosal cyst of postmastoidectomy cavity
                                        Mueller's mixed tumour
                                        Muir-Torre syndrome
                                        Multicentric reticulohistiocytosis
                                        Multinucleate cell angiohistiocytoma
                                        Multiple cutaneous and uterine leiomyomatosis
                                        Multiple endocrine neoplasia
                                        Multiple endocrine neoplasia Type 1
                                        Multiple endocrine neoplasia Type 2
                                        Multiple endocrine neoplasia Type 2A
                                        Multiple endocrine neoplasia Type 2B
                                        Multiple gated acquisition scan abnormal
                                        Muscle neoplasm
                                        Musculoskeletal cancer
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————————————————————————————————————————————————————————————————————————————————————————————————————
Neoplasm                                Myasthenic syndrome
                                        Mycosis fungoides
                                        Mycosis fungoides recurrent
                                        Mycosis fungoides refractory
                                        Mycosis fungoides stage I
                                        Mycosis fungoides stage II
                                        Mycosis fungoides stage III
                                        Mycosis fungoides stage IV
                                        Myectomy
                                        Myeloblast present
                                        Myeloblastoma
                                        Myelodysplastic syndrome
                                        Myelodysplastic syndrome transformation
                                        Myelodysplastic syndrome unclassifiable
                                        Myelofibrosis
                                        Myeloid leukaemia
                                       Myeloid leukaemia in remission
                                        Myeloid metaplasia
                                        Myelolipoma
                                        Myeloma cast nephropathy
                                        Myeloproliferative neoplasm
                                        Myolipoma
                                        Myxofibrosarcoma
                                        Myxoid liposarcoma
                                        NMP22 test abnormal
                                        NUT midline carcinoma
                                        Naevoid melanoma
                                        Naevus haemorrhage
                                        Naevus lipomatosus cutaneous superficialis
                                        Nasal cavity cancer
                                        Nasal cyst
                                        Nasal neoplasm
                                        Nasal neoplasm benign
                                        Nasal polyps
                                        Nasal sinus cancer
                                        Nasopharyngeal cancer
                                        Nasopharyngeal cancer metastatic
                                        Nasopharyngeal cancer recurrent
                                        Nasopharyngeal cancer stage 0
                                        Nasopharyngeal cancer stage I
                                        Nasopharyngeal cancer stage II
                                        Nasopharyngeal cancer stage III
                                        Nasopharyngeal cancer stage IV
                                        Nasopharyngeal neoplasm benign
                                        Nasopharyngeal polyp
                                        Natural killer-cell leukaemia
                                        Natural killer-cell lymphoblastic lymphoma
                                        Neck dissection
                                        Necrolytic migratory erythema
                                        Needle biopsy site unspecified abnormal
                                        Neoadjuvant therapy
                                        Neobladder surgery
                                        Neonatal leukaemia
                                        Neonatal neuroblastoma
                                        Neoplasm
                                        Neoplasm malignant
                                        Neoplasm of appendix
                                        Neoplasm of cornea unspecified malignancy
                                        Neoplasm of orbit
                                        Neoplasm of thymus
                                        Neoplasm progression
                                        Neoplasm prostate
                                        Neoplasm recurrence
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————————————————————————————————————————————————————————————————————————————————————————————————————
Neoplasm                                Neoplasm skin
                                        Neoplasm swelling
                                        Nephrectomy
                                        Nephroblastoma
                                        Nephroureterectomy
                                        Nervous system cyst
                                        Nervous system neoplasm
                                        Nervous system neoplasm benign
                                        Nervous system neoplasm surgery
                                        Neurilemmoma benign
                                        Neuroblastoma
                                        Neuroblastoma recurrent
                                        Neuroectodermal neoplasm
                                        Neuroendocrine breast tumour
                                        Neuroendocrine carcinoma
                                        Neuroendocrine carcinoma metastatic
                                        Neuroendocrine carcinoma of the bladder
                                       Neuroendocrine carcinoma of the skin
                                        Neuroendocrine tumour
                                        Neuroendocrine tumour of the lung
                                        Neuroendocrine tumour of the lung metastatic
                                        Neuroendoscopy
                                        Neurofibroma
                                        Neurofibromatosis
                                        Neurofibrosarcoma
                                        Neurofibrosarcoma metastatic
                                        Neurofibrosarcoma recurrent
                                        Neurogenic tumour
                                        Neuroma
                                        Neuromyotonia
                                        Neurotensinoma
                                        Nipple neoplasm
                                        Nipple resection
                                        Nodal marginal zone B-cell lymphoma
                                        Nodal marginal zone B-cell lymphoma recurrent
                                        Nodal marginal zone B-cell lymphoma refractory
                                        Nodal marginal zone B-cell lymphoma stage I
                                        Nodal marginal zone B-cell lymphoma stage II
                                        Nodal marginal zone B-cell lymphoma stage III
                                        Nodal marginal zone B-cell lymphoma stage IV
                                        Nodular fasciitis
                                        Nodular lymphocyte predominant Hodgkin lymphoma
                                        Nodular melanoma
                                        Non-Hodgkin's lymphoma
                                        Non-Hodgkin's lymphoma metastatic
                                        Non-Hodgkin's lymphoma recurrent
                                        Non-Hodgkin's lymphoma refractory
                                        Non-Hodgkin's lymphoma stage I
                                        Non-Hodgkin's lymphoma stage II
                                        Non-Hodgkin's lymphoma stage III
                                        Non-Hodgkin's lymphoma stage IV
                                        Non-Hodgkin's lymphoma transformed recurrent
                                        Non-Hodgkin's lymphoma unspecified histology aggressive
                                        Non-Hodgkin's lymphoma unspecified histology aggressive
                                        recurrent
                                        Non-Hodgkin's lymphoma unspecified histology aggressive
                                        refractory
                                        Non-Hodgkin's lymphoma unspecified histology aggressive
                                        stage I
                                        Non-Hodgkin's lymphoma unspecified histology aggressive
                                        stage II
                                        Non-Hodgkin's lymphoma unspecified histology aggressive
                                        stage III
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————————————————————————————————————————————————————————————————————————————————————————————————————
Neoplasm                                Non-Hodgkin's lymphoma unspecified histology aggressive
                                        stage IV
                                        Non-Hodgkin's lymphoma unspecified histology indolent
                                        Non-Hodgkin's lymphoma unspecified histology indolent stage
                                        I
                                        Non-Hodgkin's lymphoma unspecified histology indolent stage
                                        II
                                        Non-Hodgkin's lymphoma unspecified histology indolent stage
                                        III
                                        Non-Hodgkin's lymphoma unspecified histology indolent stage
                                        IV
                                        Non-renal cell carcinoma of kidney
                                        Non-secretory adenoma of pituitary
                                        Non-small cell lung cancer
                                        Non-small cell lung cancer metastatic
                                        Non-small cell lung cancer recurrent
                                        Non-small cell lung cancer stage 0
                                        Non-small cell lung cancer stage I
                                        Non-small cell lung cancer stage II
                                        Non-small cell lung cancer stage III
                                        Non-small cell lung cancer stage IIIA
                                        Non-small cell lung cancer stage IIIB
                                        Non-small cell lung cancer stage IV
                                        Nongerminomatous germ cell tumour of the CNS
                                        Nonkeratinising carcinoma of nasopharynx
                                        Numb chin syndrome
                                        Ocular cancer metastatic
                                        Ocular haemangiopericytoma
                                        Ocular lymphoma
                                        Ocular neoplasm
                                        Odontogenic cyst
                                        Oesophageal adenocarcinoma
                                        Oesophageal adenocarcinoma recurrent
                                        Oesophageal adenocarcinoma stage 0
                                        Oesophageal adenocarcinoma stage I
                                        Oesophageal adenocarcinoma stage II
                                        Oesophageal adenocarcinoma stage III
                                        Oesophageal adenocarcinoma stage IV
                                        Oesophageal cancer metastatic
                                        Oesophageal carcinoma
                                        Oesophageal carcinoma recurrent
                                        Oesophageal carcinoma stage 0
                                        Oesophageal cyst
                                        Oesophageal dysplasia
                                        Oesophageal neoplasm
                                        Oesophageal papilloma
                                        Oesophageal polyp
                                        Oesophageal polypectomy
                                        Oesophageal prosthesis insertion
                                        Oesophageal squamous cell carcinoma
                                        Oesophageal squamous cell carcinoma metastatic
                                        Oesophageal squamous cell carcinoma recurrent
                                        Oesophageal squamous cell carcinoma stage 0
                                        Oesophageal squamous cell carcinoma stage I
                                        Oesophageal squamous cell carcinoma stage II
                                        Oesophageal squamous cell carcinoma stage III
                                        Oesophageal squamous cell carcinoma stage IV
                                        Oesophagectomy
                                        Oesophagogastrectomy
                                        Oestrogen receptor assay positive
                                        Oestrogen receptor positive breast cancer
                                        Oligoastrocytoma
                                        Oligodendroglioma
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Neoplasm                                Oligodendroglioma benign
                                        Omenn syndrome
                                        Omentectomy
                                        Oncocytoma
                                        Oncologic complication
                                        Oophorectomy
                                        Oophorectomy bilateral
                                        Optic glioma
                                        Optic nerve neoplasm
                                        Oral cavity cancer metastatic
                                        Oral cavity neoplasm surgery
                                        Oral fibroma
                                        Oral haemangioma
                                        Oral hairy leukoplakia
                                        Oral neoplasm
                                        Oral neoplasm benign
                                        Oral papilloma
                                        Oral polypectomy
                                        Orbital exenteration
                                        Orchidectomy
                                        Orchidotomy
                                        Oropharyngeal cancer
                                        Oropharyngeal cancer recurrent
                                        Oropharyngeal cancer stage 0
                                        Oropharyngeal cancer stage I
                                        Oropharyngeal cancer stage II
                                        Oropharyngeal cancer stage III
                                        Oropharyngeal cancer stage IV
                                        Oropharyngeal dysplasia
                                        Oropharyngeal lymphoepithelioma
                                        Oropharyngeal neoplasm
                                        Oropharyngeal neoplasm benign
                                        Oropharyngeal squamous cell carcinoma
                                        Ostectomy
                                        Osteochondroma
                                        Osteofibroma
                                        Osteoma
                                        Osteoma cutis
                                        Osteosarcoma
                                        Osteosarcoma metastatic
                                        Osteosarcoma recurrent
                                        Ota's naevus
                                        Otic cancer metastatic
                                        Ovarian Sertoli-Leydig cell tumour
                                        Ovarian adenoma
                                        Ovarian cancer
                                        Ovarian cancer metastatic
                                        Ovarian cancer recurrent
                                        Ovarian cancer stage I
                                        Ovarian cancer stage II
                                        Ovarian cancer stage III
                                        Ovarian cancer stage IV
                                        Ovarian clear cell carcinoma
                                        Ovarian cyst
                                        Ovarian cyst ruptured
                                        Ovarian cyst torsion
                                        Ovarian dysgerminoma stage I
                                        Ovarian dysgerminoma stage II
                                        Ovarian dysgerminoma stage III
                                        Ovarian dysgerminoma stage IV
                                        Ovarian dysgerminoma stage unspecified
                                        Ovarian dysplasia
                                        Ovarian embryonal carcinoma
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Neoplasm                                Ovarian endometrioid carcinoma
                                        Ovarian epithelial cancer
                                        Ovarian epithelial cancer metastatic
                                        Ovarian epithelial cancer recurrent
                                        Ovarian epithelial cancer stage I
                                        Ovarian epithelial cancer stage II
                                        Ovarian epithelial cancer stage III
                                        Ovarian epithelial cancer stage IV
                                        Ovarian fibroma
                                        Ovarian germ cell cancer
                                        Ovarian germ cell cancer stage I
                                        Ovarian germ cell cancer stage II
                                        Ovarian germ cell cancer stage III
                                        Ovarian germ cell cancer stage IV
                                        Ovarian germ cell choriocarcinoma
                                        Ovarian germ cell choriocarcinoma stage I
                                        Ovarian germ cell choriocarcinoma stage II
                                        Ovarian germ cell choriocarcinoma stage III
                                        Ovarian germ cell choriocarcinoma stage IV
                                        Ovarian germ cell embryonal carcinoma stage I
                                        Ovarian germ cell embryonal carcinoma stage II
                                        Ovarian germ cell embryonal carcinoma stage III
                                        Ovarian germ cell embryonal carcinoma stage IV
                                        Ovarian germ cell endodermal sinus tumour
                                        Ovarian germ cell endodermal sinus tumour stage I
                                        Ovarian germ cell endodermal sinus tumour stage II
                                        Ovarian germ cell endodermal sinus tumour stage III
                                        Ovarian germ cell endodermal sinus tumour stage IV
                                        Ovarian germ cell polyembryoma
                                        Ovarian germ cell polyembryoma stage I
                                        Ovarian germ cell polyembryoma stage II
                                        Ovarian germ cell polyembryoma stage III
                                        Ovarian germ cell polyembryoma stage IV
                                        Ovarian germ cell teratoma
                                        Ovarian germ cell teratoma benign
                                        Ovarian germ cell teratoma stage I
                                        Ovarian germ cell teratoma stage II
                                        Ovarian germ cell teratoma stage III
                                        Ovarian germ cell teratoma stage IV
                                        Ovarian germ cell tumour
                                        Ovarian germ cell tumour mixed
                                        Ovarian granulosa cell tumour
                                        Ovarian granulosa-theca cell tumour
                                        Ovarian low malignant potential tumour
                                        Ovarian neoplasm
                                        Ovarian stromal cancer
                                        Ovarian stromal hyperplasia
                                        Ovarian theca cell tumour
                                        PHACES syndrome
                                        PML
                                        RAR alpha expression
                                        POEMS syndrome
                                        Paget's disease of nipple
                                        Paget's disease of penis
                                        Paget's disease of the vulva
                                        Palliative care
                                        Palmar fasciitis
                                        Pancoast's syndrome
                                        Pancoast's tumour
                                        Pancreastatin abnormal
                                        Pancreastatin increased
                                        Pancreatectomy
                                        Pancreatic carcinoma
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————————————————————————————————————————————————————————————————————————————————————————————————————
Neoplasm                                Pancreatic carcinoma metastatic
                                        Pancreatic carcinoma recurrent
                                        Pancreatic carcinoma stage 0
                                        Pancreatic carcinoma stage I
                                        Pancreatic carcinoma stage II
                                        Pancreatic carcinoma stage III
                                        Pancreatic carcinoma stage IV
                                        Pancreatic cyst
                                        Pancreatic cyst rupture
                                        Pancreatic neoplasm
                                        Pancreatic neuroendocrine tumour
                                        Pancreatic neuroendocrine tumour metastatic
                                        Pancreatic sarcoma
                                        Pancreaticoduodenectomy
                                        Pancreaticosplenectomy
                                        Pancreatoblastoma
                                        Papillary cystadenoma lymphomatosum
                                        Papillary renal cell carcinoma
                                        Papillary serous endometrial carcinoma
                                        Papillary thyroid cancer
                                        Papillary tumour of renal pelvis
                                        Papilloma
                                        Papilloma conjunctival
                                        Paracancerous pneumonia
                                        Paraganglion neoplasm
                                        Paraganglion neoplasm benign
                                        Paraganglion neoplasm malignant
                                        Paranasal biopsy abnormal
                                        Paranasal cyst
                                        Paranasal sinus and nasal cavity malignant neoplasm
                                        Paranasal sinus and nasal cavity malignant neoplasm
                                        recurrent
                                        Paranasal sinus and nasal cavity malignant neoplasm stage 0
                                        Paranasal sinus and nasal cavity malignant neoplasm stage I
                                        Paranasal sinus and nasal cavity malignant neoplasm stage II
                                        Paranasal sinus and nasal cavity malignant neoplasm stage
                                        III
                                        Paranasal sinus and nasal cavity malignant neoplasm stage IV
                                        Paranasal sinus benign neoplasm
                                        Paranasal sinus neoplasm
                                        Paraneoplastic arthritis
                                        Paraneoplastic dermatomyositis
                                        Paraneoplastic dermatosis
                                        Paraneoplastic encephalomyelitis
                                        Paraneoplastic glomerulonephritis
                                       Paraneoplastic myelopathy
                                        Paraneoplastic nephrotic syndrome
                                        Paraneoplastic neurological syndrome
                                        Paraneoplastic pemphigus
                                        Paraneoplastic pleural effusion
                                        Paraneoplastic rash
                                        Paraneoplastic retinopathy
                                        Paraneoplastic syndrome
                                        Paraneoplastic thrombosis
                                        Paraproteinaemia
                                        Parapsoriasis
                                        Parathyroid cyst
                                        Parathyroid scan abnormal
                                        Parathyroid tumour
                                        Parathyroid tumour benign
                                        Parathyroid tumour malignant
                                        Parathyroidectomy
                                        Parotidectomy
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NN9535
NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
114 of 152
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Neoplasm                                Pathological fracture
                                        Pearly penile papules
                                        Pelvic cyst
                                        Pelvic neoplasm
                                        Penile cancer
                                        Penile dysplasia
                                        Penile neoplasm
                                        Penile operation
                                        Penile squamous cell carcinoma
                                        Penile wart
                                        Penile warts excision
                                        Penis carcinoma metastatic
                                        Penis carcinoma recurrent
                                        Penis carcinoma stage I
                                        Penis carcinoma stage II
                                        Penis carcinoma stage III
                                        Penis carcinoma stage IV
                                        Pepsinogen test positive
                                        Percutaneous ethanol injection therapy
                                        Pericardial cyst
                                        Pericardial effusion malignant
                                        Pericardial mesothelioma malignant
                                        Pericardial mesothelioma malignant recurrent
                                        Pericardial neoplasm
                                        Pericarditis malignant
                                        Perineal cyst
                                        Perineurial cyst
                                        Peripheral T-cell lymphoma unspecified
                                        Peripheral T-cell lymphoma unspecified recurrent
                                        Peripheral T-cell lymphoma unspecified refractory
                                        Peripheral T-cell lymphoma unspecified stage I
                                        Peripheral T-cell lymphoma unspecified stage II
                                        Peripheral T-cell lymphoma unspecified stage III
                                        Peripheral T-cell lymphoma unspecified stage IV
                                        Peripheral nervous system neoplasm
                                        Peripheral neuroepithelioma of bone
                                        Peripheral neuroepithelioma of bone metastatic
                                        Peripheral neuroepithelioma of bone recurrent
                                        Peripheral neuroepithelioma of soft tissue
                                        Peripheral primitive neuroectodermal bone tumour
                                        Peripheral primitive neuroectodermal tumour of soft tissue
                                        Peritoneal carcinoma metastatic
                                       Peritoneal cyst
                                        Peritoneal fluid protein increased
                                        Peritoneal gliomatosis
                                        Peritoneal mesothelioma malignant
                                        Peritoneal mesothelioma malignant recurrent
                                        Peritoneal neoplasm
                                        Peritoneal sarcoma
                                        Peritonectomy
                                        Peritumoural oedema
                                        Peutz-Jeghers syndrome
                                        Phaeochromocytoma
                                        Phaeochromocytoma crisis
                                        Phaeochromocytoma excision
                                        Phaeochromocytoma malignant
                                        Phakomatosis
                                        Pharyngeal cancer
                                        Pharyngeal cancer metastatic
                                        Pharyngeal cancer recurrent
                                        Pharyngeal cancer stage 0
                                        Pharyngeal cancer stage I
                                        Pharyngeal cancer stage II
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CONFIDENTIAL


NN9535
NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
115 of 152
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————————————————————————————————————————————————————————————————————————————————————————————————————
Neoplasm                                Pharyngeal cancer stage III
                                        Pharyngeal cancer stage IV
                                        Pharyngeal cyst
                                        Pharyngeal leukoplakia
                                        Pharyngeal mass
                                        Pharyngeal neoplasm
                                        Pharyngeal neoplasm benign
                                        Pharyngeal polyp
                                        Pharyngectomy
                                        Philadelphia chromosome positive
                                        Phosphaturic mesenchymal tumour
                                        Photodynamic diagnostic procedure
                                        Photon radiation therapy
                                        Photon radiation therapy to bladder
                                        Photon radiation therapy to blood
                                        Photon radiation therapy to bone
                                        Photon radiation therapy to brain
                                        Photon radiation therapy to breast
                                        Photon radiation therapy to colon
                                        Photon radiation therapy to ear, nose, or throat
                                        Photon radiation therapy to liver
                                        Photon radiation therapy to lung
                                        Photon radiation therapy to pancreas
                                        Photon radiation therapy to pleura
                                        Photon radiation therapy to prostate
                                        Photon radiation therapy to skin
                                        Photon radiation therapy to soft tissue
                                        Photon radiation therapy to thyroid
                                        Photon radiation therapy to uterus
                                        Phyllodes tumour
                                        Pilomatrix carcinoma
                                        Pineal germinoma
                                        Pineal gland cyst
                                        Pineal neoplasm
                                        Pineal parenchymal neoplasm malignant
                                        Pinealoblastoma
                                        Pinealoma
                                        Pineocytoma
                                        Pituitary cancer metastatic
                                        Pituitary cyst
                                        Pituitary gland radiotherapy
                                        Pituitary neoplasm malignant recurrent
                                        Pituitary tumour
                                        Pituitary tumour benign
                                        Pituitary tumour recurrent
                                        Placental chorioangioma
                                        Placental neoplasm
                                        Placental polyp
                                        Plasma cell leukaemia
                                        Plasma cell leukaemia in remission
                                        Plasma cell myeloma
                                        Plasma cell myeloma in remission
                                        Plasma cell myeloma recurrent
                                        Plasmablastic lymphoma
                                        Plasmacytoma
                                        Pleomorphic adenoma
                                        Pleomorphic liposarcoma
                                        Pleomorphic malignant fibrous histiocytoma
                                        Pleural cyst
                                        Pleural mesothelioma
                                        Pleural mesothelioma malignant
                                        Pleural mesothelioma malignant recurrent
                                        Pleural neoplasm
————————————————————————————————————————————————————————————————————————————————————————————————————
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CONFIDENTIAL


NN9535
NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
116 of 152
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————————————————————————————————————————————————————————————————————————————————————————————————————
Neoplasm                                Pleural sarcoma
                                        Pleurectomy
                                        Pleuropulmonary blastoma
                                        Pneumonectomy
                                        Polycythaemia vera
                                        Polyneuropathy in malignant disease
                                        Polyp
                                        Poorly differentiated thyroid carcinoma
                                        Porocarcinoma
                                        Portal vein embolisation
                                        Post breast therapy pain syndrome
                                        Post transplant lymphoproliferative disorder
                                        Postcricoid cancer
                                        Posterior fossa syndrome
                                        Postmastectomy lymphoedema syndrome
                                        Precancerous lesion excision
                                        Precancerous mucosal lesion
                                        Precancerous skin lesion
                                        Precursor B-lymphoblastic lymphoma
                                        Precursor B-lymphoblastic lymphoma recurrent
                                        Precursor B-lymphoblastic lymphoma refractory
                                        Precursor B-lymphoblastic lymphoma stage I
                                        Precursor B-lymphoblastic lymphoma stage II
                                        Precursor B-lymphoblastic lymphoma stage III
                                        Precursor B-lymphoblastic lymphoma stage IV
                                        Precursor T-lymphoblastic lymphoma
                                        leukaemia
                                        Precursor T-lymphoblastic lymphoma
                                        leukaemia recurrent
                                        Precursor T-lymphoblastic lymphoma
                                        leukaemia refractory
                                        Precursor T-lymphoblastic lymphoma
                                        leukaemia stage I
                                        Precursor T-lymphoblastic lymphoma
                                        leukaemia stage II
                                        Precursor T-lymphoblastic lymphoma
                                        leukaemia stage III
                                        Precursor T-lymphoblastic lymphoma
                                        leukaemia stage IV
                                        Primary breast lymphoma
                                        Primary cardiac lymphoma
                                        Primary effusion lymphoma
                                        Primary gastrointestinal follicular lymphoma
                                        Primary mediastinal large B-cell lymphoma
                                        Primary mediastinal large B-cell lymphoma recurrent
                                        Primary mediastinal large B-cell lymphoma refractory
                                        Primary mediastinal large B-cell lymphoma stage I
                                        Primary mediastinal large B-cell lymphoma stage II
                                        Primary mediastinal large B-cell lymphoma stage III
                                        Primary mediastinal large B-cell lymphoma stage IV
                                        Primary myelofibrosis
                                        Primary pulmonary melanoma
                                        Primitive neuroectodermal tumour
                                        Primitive neuroectodermal tumour metastatic
                                        Proctectomy
                                        Proctocolectomy
                                        Progesterone receptor assay positive
                                        Prolactin-producing pituitary tumour
                                        Prolymphocytic leukaemia
                                        Prophylactic chemotherapy
                                        Prostate ablation
                                        Prostate cancer
                                        Prostate cancer metastatic
————————————————————————————————————————————————————————————————————————————————————————————————————
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CONFIDENTIAL


NN9535
NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
117 of 152
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————————————————————————————————————————————————————————————————————————————————————————————————————
Neoplasm                                Prostate cancer recurrent
                                        Prostate cancer stage 0
                                        Prostate cancer stage I
                                        Prostate cancer stage II
                                        Prostate cancer stage III
                                        Prostate cancer stage IV
                                        Prostate cryoablation
                                        Prostate interstitial hyperthermia therapy
                                        Prostatectomy
                                        Prostatic adenoma
                                        Prostatic cyst
                                        Prostatic dysplasia
                                        Prostatic polyp
                                        Prostatic specific antigen abnormal
                                        Prostatic specific antigen increased
                                        Pseudoachalasia
                                        Pseudocirrhosis
                                        Pseudomyxoma peritonei
                                        Pseudosarcoma
                                        Pulmonary resection
                                        Pulmonary tumour thrombotic microangiopathy
                                        Pylorectomy
                                        Pyoderma gangrenosum
                                        Pyogenic granuloma
                                        Queyrat erythroplasia
                                        Radiation therapy to ear, nose, or throat
                                        Radical cystectomy
                                        Radical hysterectomy
                                        Radical mastectomy
                                        Radical parametrectomy
                                        Radical prostatectomy
                                        Radioactive iodine therapy
                                        Radioembolisation
                                        Radiofrequency ablation of oesophagus
                                        Radiofrequency-induced thermochemotherapeutic effect
                                        Radioisotope scan abnormal
                                        Radiosensitisation therapy
                                        Radiotherapy
                                        Radiotherapy to abdomen
                                        Radiotherapy to adrenal gland
                                        Radiotherapy to blood
                                        Radiotherapy to bone
                                        Radiotherapy to brain
                                        Radiotherapy to breast
                                        Radiotherapy to colon
                                        Radiotherapy to ear
                                        Radiotherapy to eye
                                        Radiotherapy to gallbladder
                                        Radiotherapy to gastrointestinal tract
                                        Radiotherapy to head and neck
                                        Radiotherapy to joint
                                        Radiotherapy to kidney
                                        Radiotherapy to liver
                                        Radiotherapy to lung
                                        Radiotherapy to lymph nodes
                                        Radiotherapy to mediastinum
                                        Radiotherapy to nose
                                        Radiotherapy to oesophagus
                                        Radiotherapy to oral cavity
                                        Radiotherapy to ovary
                                        Radiotherapy to pancreas
                                        Radiotherapy to pleura
                                        Radiotherapy to prostate
————————————————————————————————————————————————————————————————————————————————————————————————————
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CONFIDENTIAL


NN9535
NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
118 of 152
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————————————————————————————————————————————————————————————————————————————————————————————————————
Neoplasm                                Radiotherapy to rectum
                                        Radiotherapy to skin
                                        Radiotherapy to soft tissue
                                        Radiotherapy to spleen
                                        Radiotherapy to stomach
                                        Radiotherapy to throat
                                        Radiotherapy to thymus
                                        Radiotherapy to thyroid
                                        Radiotherapy to urinary bladder
                                        Radiotherapy to uterus
                                        Radiotherapy to vagina
                                        Rectal adenocarcinoma
                                        Rectal adenoma
                                        Rectal cancer
                                        Rectal cancer metastatic
                                        Rectal cancer recurrent
                                        Rectal cancer stage 0
                                        Rectal cancer stage I
                                        Rectal cancer stage II
                                        Rectal cancer stage III
                                        Rectal cancer stage IV
                                        Rectal neoplasm
                                        Rectal polyp
                                        Rectal polypectomy
                                        Rectosigmoid cancer
                                        Rectosigmoid cancer metastatic
                                        Rectosigmoid cancer recurrent
                                        Rectosigmoid cancer stage 0
                                        Rectosigmoid cancer stage I
                                        Rectosigmoid cancer stage II
                                        Rectosigmoid cancer stage III
                                        Rectosigmoid cancer stage IV
                                        Recurrent cancer
                                        Refractory anaemia with an excess of blasts
                                        Refractory anaemia with ringed sideroblasts
                                        Refractory cancer
                                        Refractory cytopenia with multilineage dysplasia
                                        Refractory cytopenia with unilineage dysplasia
                                        Regional chemotherapy
                                        Renal adenoma
                                        Renal cancer
                                        Renal cancer metastatic
                                        Renal cancer recurrent
                                        Renal cancer stage I
                                        Renal cancer stage II
                                        Renal cancer stage III
                                        Renal cancer stage IV
                                        Renal cell carcinoma
                                        Renal cell carcinoma recurrent
                                        Renal cell carcinoma stage I
                                        Renal cell carcinoma stage II
                                        Renal cell carcinoma stage III
                                        Renal cell carcinoma stage IV
                                        Renal cell dysplasia
                                        Renal cyst
                                        Renal cyst haemorrhage
                                        Renal cyst infection
                                        Renal cyst ruptured
                                        Renal haemangioma
                                        Renal neoplasm
                                        Renal oncocytoma
                                        Renal scan abnormal
                                        Renal tumour excision
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CONFIDENTIAL


NN9535
NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
119 of 152
Pre-defined MedDRA search - list of preferred terms
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Neoplasm                                Respiratory papilloma
                                        Respiratory tract carcinoma in situ
                                        Respiratory tract neoplasm
                                        Retention cyst
                                        Retinal melanocytoma
                                        Retinal melanoma
                                        Retinal neoplasm
                                        Retinal tumour excision
                                        Retinoblastoma
                                        Retro-orbital neoplasm
                                        Retro-pubic prostatectomy
                                        Retroperitoneal cancer
                                        Retroperitoneal neoplasm
                                        Retroperitoneal neoplasm metastatic
                                        Retroperitoneum cyst
                                        Rhabdoid tumour
                                        Rhabdoid tumour of the kidney
                                        Rhabdomyoma
                                        Rhabdomyosarcoma
                                        Rhabdomyosarcoma recurrent
                                        Richter's syndrome
                                        Rosai-Dorfman syndrome
                                        Round cell liposarcoma
                                        Sacrectomy
                                        Salivary bypass tube insertion
                                        Salivary gland adenoma
                                        Salivary gland cancer
                                        Salivary gland cancer recurrent
                                        Salivary gland cancer stage 0
                                        Salivary gland cancer stage I
                                        Salivary gland cancer stage II
                                        Salivary gland cancer stage III
                                        Salivary gland cancer stage IV
                                        Salivary gland cyst
                                        Salivary gland induration
                                        Salivary gland neoplasm
                                        Salivary gland resection
                                        Salivary gland scan abnormal
                                        Salpingectomy
                                        Salpingo-oophorectomy
                                        Salpingo-oophorectomy bilateral
                                        Salpingo-oophorectomy unilateral
                                        Sarcoma
                                        Sarcoma excision
                                        Sarcoma metastatic
                                        Sarcoma of skin
                                        Sarcoma uterus
                                        Sarcomatoid carcinoma
                                        Sarcomatoid carcinoma of the lung
                                        Sarcomatoid mesothelioma
                                        Sarcomatosis
                                        Scan abdomen abnormal
                                        Scan abnormal
                                        Scan adrenal gland abnormal
                                        Scan bone marrow abnormal
                                        Scan gallium abnormal
                                        Scan myocardial perfusion abnormal
                                        Scan with contrast abnormal
                                        Schwannoma
                                        Sclerosing pneumocytoma
                                        Scrotal cancer
                                        Scrotal cyst
                                        Sebaceous adenoma
————————————————————————————————————————————————————————————————————————————————————————————————————
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CONFIDENTIAL


NN9535
NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
120 of 152
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Neoplasm                                Sebaceous carcinoma
                                        Sebaceous naevus
                                        Seborrhoeic keratosis
                                        Second primary malignancy
                                        Secondary cerebellar degeneration
                                        Secretory adenoma of pituitary
                                        Seminal vesicular cyst
                                        Seminoma
                                        Serous cystadenocarcinoma ovary
                                        Sertoli cell testicular tumour
                                       Sezary cells increased
                                        Sigmoidectomy
                                        Signet-ring cell carcinoma
                                        Silicon granuloma
                                        Simple mastectomy
                                        Sinonasal papilloma
                                        Sinus cancer metastatic
                                        Sinus polyp
                                        Sinus polyp degeneration
                                        Skin angiosarcoma
                                        Skin cancer
                                        Skin cancer metastatic
                                        Skin cryotherapy
                                        Skin neoplasm bleeding
                                        Skin neoplasm excision
                                        Skin papilloma
                                        Skin squamous cell carcinoma metastatic
                                        Skin squamous cell carcinoma recurrent
                                        Small cell carcinoma
                                        Small cell carcinoma of the cervix
                                        Small cell lung cancer
                                        Small cell lung cancer extensive stage
                                        Small cell lung cancer limited stage
                                        Small cell lung cancer metastatic
                                        Small cell lung cancer recurrent
                                        Small intestinal polypectomy
                                        Small intestinal resection
                                        Small intestine adenocarcinoma
                                        Small intestine carcinoma
                                        Small intestine carcinoma metastatic
                                        Small intestine carcinoma recurrent
                                        Small intestine carcinoma stage 0
                                        Small intestine carcinoma stage I
                                        Small intestine carcinoma stage II
                                        Small intestine carcinoma stage III
                                        Small intestine carcinoma stage IV
                                        Small intestine leiomyosarcoma
                                        Small intestine polyp
                                        Smooth muscle cell neoplasm
                                        Soft tissue neoplasm
                                        Soft tissue sarcoma
                                        Solid pseudopapillary tumour of the pancreas
                                        Solitary epithelioid histiocytoma
                                        Somatostatin receptor scan abnormal
                                        Somatostatinoma
                                        Spermatocele
                                        Spermatocytic seminoma
                                        Spinal cord lipoma
                                        Spinal cord neoplasm
                                        Spinal meningeal cyst
                                        Spinal meningioma benign
                                        Spinal meningioma malignant
                                        Spinal synovial cyst
————————————————————————————————————————————————————————————————————————————————————————————————————
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CONFIDENTIAL


NN9535
NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
121 of 152
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Neoplasm                                Spindle cell sarcoma
                                        Spleen scan abnormal
                                        Splenectomy
                                        Splenic cyst
                                        Splenic hamartoma
                                        Splenic marginal zone lymphoma
                                        Splenic marginal zone lymphoma recurrent
                                        Splenic marginal zone lymphoma refractory
                                        Splenic marginal zone lymphoma stage I
                                        Splenic marginal zone lymphoma stage II
                                        Splenic marginal zone lymphoma stage III
                                        Splenic marginal zone lymphoma stage IV
                                        Splenic neoplasm malignancy unspecified
                                        Squamous cell breast carcinoma
                                        Squamous cell carcinoma
                                        Squamous cell carcinoma of head and neck
                                        Squamous cell carcinoma of lung
                                        Squamous cell carcinoma of pharynx
                                        Squamous cell carcinoma of skin
                                        Squamous cell carcinoma of the cervix
                                        Squamous cell carcinoma of the hypopharynx
                                        Squamous cell carcinoma of the oral cavity
                                        Squamous cell carcinoma of the tongue
                                        Squamous cell carcinoma of the vagina
                                        Squamous cell carcinoma of the vulva
                                        Squamous endometrial carcinoma
                                        Stauffer's syndrome
                                        Steatocystoma multiplex
                                        Stem cell therapy
                                        Stem cell transplant
                                        Stewart-Treves syndrome
                                        Stoma site polyp
                                        Stomach scan abnormal
                                        Superficial spreading melanoma stage I
                                        Superficial spreading melanoma stage II
                                        Superficial spreading melanoma stage III
                                        Superficial spreading melanoma stage IV
                                        Superficial spreading melanoma stage unspecified
                                        Superior vena cava occlusion
                                        Superior vena cava syndrome
                                        Suprapubic prostatectomy
                                        Sweat gland tumour
                                        Synovial cyst
                                        Synovial sarcoma
                                        Synovial sarcoma metastatic
                                        Synovial sarcoma recurrent
                                        Systemic mastocytosis
                                        T-cell chronic lymphocytic leukaemia
                                        T-cell lymphoma
                                        T-cell lymphoma recurrent
                                        T-cell lymphoma refractory
                                        T-cell lymphoma stage I
                                        T-cell lymphoma stage II
                                        T-cell lymphoma stage III
                                        T-cell lymphoma stage IV
                                        T-cell prolymphocytic leukaemia
                                        T-cell type acute leukaemia
                                        T-cell unclassifiable lymphoma high grade
                                        T-cell unclassifiable lymphoma low grade
                                        TEMPI syndrome
                                        Targeted cancer therapy
                                        Tendon neoplasm
                                        Teratoma
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CONFIDENTIAL


NN9535
NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
122 of 152
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Neoplasm                                Teratoma benign
                                        Testicle adenoma
                                        Testicular cancer metastatic
                                        Testicular choriocarcinoma
                                        Testicular choriocarcinoma recurrent
                                        Testicular choriocarcinoma stage I
                                        Testicular choriocarcinoma stage II
                                        Testicular choriocarcinoma stage III
                                        Testicular cyst
                                        Testicular embryonal carcinoma
                                        Testicular embryonal carcinoma stage I
                                        Testicular embryonal carcinoma stage II
                                        Testicular embryonal carcinoma stage III
                                        Testicular germ cell cancer
                                        Testicular germ cell cancer metastatic
                                        Testicular germ cell tumour
                                        Testicular germ cell tumour mixed
                                        Testicular germ cell tumour mixed stage I
                                        Testicular germ cell tumour mixed stage II
                                        Testicular germ cell tumour mixed stage III
                                        Testicular leiomyosarcoma
                                        Testicular malignant teratoma
                                        Testicular malignant teratoma stage I
                                        Testicular malignant teratoma stage II
                                        Testicular malignant teratoma stage III
                                        Testicular neoplasm
                                        Testicular papilloma
                                        Testicular scan abnormal
                                        Testicular seminoma (pure)
                                        Testicular seminoma (pure) stage I
                                        Testicular seminoma (pure) stage II
                                        Testicular seminoma (pure) stage III
                                        Testicular teratoma benign
                                        Testicular yolk sac tumour
                                        Testicular yolk sac tumour stage I
                                        Testicular yolk sac tumour stage II
                                        Testicular yolk sac tumour stage III
                                        Testis cancer
                                        Testis cancer recurrent
                                        Therapeutic ovarian suppression
                                        Throat cancer
                                        Thymic cancer metastatic
                                        Thymic cyst
                                        Thymoma
                                        Thymoma malignant
                                        Thymoma malignant recurrent
                                        Thyroglossal cyst
                                        Thyroid B-cell lymphoma
                                        Thyroid C-cell hyperplasia
                                        Thyroid adenoma
                                        Thyroid cancer
                                        Thyroid cancer metastatic
                                        Thyroid cancer recurrent
                                        Thyroid cancer stage 0
                                        Thyroid cancer stage I
                                        Thyroid cancer stage II
                                        Thyroid cancer stage III
                                        Thyroid cancer stage IV
                                        Thyroid cyst
                                        Thyroid electron radiation therapy
                                        Thyroid gland scan abnormal
                                        Thyroid neoplasm
                                        Thyroid stimulating hormone-producing pituitary tumour
————————————————————————————————————————————————————————————————————————————————————————————————————
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CONFIDENTIAL


NN9535
NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
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123 of 152
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Neoplasm                                Thyroidectomy
                                        Tissue polypeptide antigen increased
                                        Tongue cancer metastatic
                                        Tongue cancer recurrent
                                        Tongue carcinoma stage 0
                                        Tongue carcinoma stage I
                                        Tongue carcinoma stage II
                                        Tongue carcinoma stage III
                                        Tongue carcinoma stage IV
                                        Tongue cyst
                                        Tongue dysplasia
                                        Tongue neoplasm
                                        Tongue neoplasm benign
                                        Tongue neoplasm malignant stage unspecified
                                        Tongue polyp
                                        Tonsil cancer
                                        Tonsil cancer metastatic
                                        Tonsillar cyst
                                        Tonsillar neoplasm
                                        Tonsillar neoplasm benign
                                        Tornwaldt cyst
                                        Total adrenalectomy
                                        Tracheal cancer
                                        Tracheal neoplasm
                                        Tracheal papilloma
                                        Tracheal resection
                                        Transcatheter arterial chemoembolisation
                                        Transcranial electrical motor evoked potential monitoring
                                        abnormal
                                        Transdifferentiation of neoplasm
                                        Transformation to acute myeloid leukaemia
                                        Transitional cell cancer of renal pelvis and ureter
                                        metastatic
                                        Transitional cell cancer of the renal pelvis and ureter
                                        Transitional cell cancer of the renal pelvis and ureter
                                        localised
                                        Transitional cell cancer of the renal pelvis and ureter
                                        recurrent
                                        Transitional cell cancer of the renal pelvis and ureter
                                        regional
                                        Transitional cell carcinoma
                                        Transitional cell carcinoma metastatic
                                        Transitional cell carcinoma recurrent
                                        Transitional cell carcinoma urethra
                                        Transurethral bladder resection
                                        Transurethral prostatectomy
                                        Trichoblastic carcinoma
                                        Triple hit lymphoma
                                        Triple negative breast cancer
                                        Trisomy 12
                                        Trousseau's syndrome
                                        Tuberous sclerosis complex
                                        Tubular breast carcinoma
                                        Tumour associated fever
                                        Tumour budding
                                        Tumour cavitation
                                        Tumour cell mobilisation
                                        Tumour compression
                                        Tumour embolism
                                        Tumour excision
                                        Tumour exudation
                                        Tumour fistulisation
                                        Tumour flare
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CONFIDENTIAL


NN9535
NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
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————————————————————————————————————————————————————————————————————————————————————————————————————
Neoplasm                                Tumour haemorrhage
                                        Tumour hyperprogression
                                        Tumour inflammation
                                        Tumour invasion
                                        Tumour lysis syndrome
                                        Tumour marker abnormal
                                        Tumour marker decreased
                                        Tumour marker increased
                                        Tumour necrosis
                                        Tumour obstruction
                                        Tumour of ampulla of Vater
                                        Tumour pain
                                        Tumour perforation
                                        Tumour pruritus
                                        Tumour pseudoprogression
                                        Tumour rupture
                                        Tumour thrombosis
                                        Tumour treating fields therapy
                                        Tumour ulceration
                                        Tumour vaccine therapy
                                        Ulcerated haemangioma
                                        Ultrasound pancreas abnormal
                                        Ultrasound scan abnormal
                                        Ultrasound scan vagina abnormal
                                        Umbilical cord cyst
                                        Undifferentiated carcinoma of colon
                                        Undifferentiated nasopharyngeal carcinoma
                                        Undifferentiated sarcoma
                                        Ureteral cyst
                                        Ureteral neoplasm
                                        Ureteral polyp
                                        Ureteric cancer
                                        Ureteric cancer local
                                        Ureteric cancer metastatic
                                        Ureteric cancer recurrent
                                        Ureteric cancer regional
                                        Ureteric papilloma
                                        Urethral adenoma
                                        Urethral cancer
                                        Urethral cancer metastatic
                                        Urethral cancer recurrent
                                        Urethral cyst
                                        Urethral melanoma metastatic
                                        Urethral neoplasm
                                        Urethral papilloma
                                        Urethral polyp
                                        Urethrectomy
                                        Urinary bladder adenoma
                                        Urinary bladder polyp
                                        Urinary bladder sarcoma
                                        Urinary cystectomy
                                        Urinary tract carcinoma in situ
                                        Urinary tract neoplasm
                                        Urinary tract polyp
                                        Uterine cancer
                                        Uterine carcinoma in situ
                                        Uterine cyst
                                        Uterine leiomyoma
                                        Uterine leiomyosarcoma
                                        Uterine myoma expulsion
                                        Uterine neoplasm
                                        Uterine polyp
                                        Uterine tumour excision
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CONFIDENTIAL


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Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
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Status:
Final
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————————————————————————————————————————————————————————————————————————————————————————————————————
Neoplasm                                Uveal melanoma
                                        Uvulectomy
                                        Vaccination site cyst
                                        Vaginal adenocarcinoma
                                        Vaginal cancer
                                        Vaginal cancer metastatic
                                        Vaginal cancer recurrent
                                        Vaginal cancer stage 0
                                        Vaginal cancer stage I
                                        Vaginal cancer stage II
                                        Vaginal cancer stage III
                                        Vaginal cancer stage IVA
                                        Vaginal cancer stage IVB
                                        Vaginal cyst
                                        Vaginal dysplasia
                                        Vaginal neoplasm
                                        Vaginal polyp
                                        Vaginectomy
                                        Vascular neoplasm
                                        Venous angioma of brain
                                        Vipoma
                                        Viral acanthoma
                                        Vitreous cyst
                                        Vocal cord cyst
                                        Vocal cord leukoplakia
                                        Vocal cord neoplasm
                                        Vocal cord polyp
                                        Vocal cordectomy
                                        Vulva cyst
                                        Vulval cancer
                                        Vulval cancer metastatic
                                        Vulval cancer recurrent
                                        Vulval cancer stage 0
                                        Vulval cancer stage I
                                        Vulval cancer stage II
                                        Vulval cancer stage III
                                        Vulval cancer stage IV
                                        Vulval neoplasm
                                        Vulval operation
                                        Vulval polyp
                                        Vulval warts removal
                                        Vulvar adenocarcinoma
                                        Vulvar dysplasia
                                        Vulvectomy
                                        Vulvovaginal adenosis
                                        Vulvovaginal warts
                                        Waldenstrom's macroglobulinaemia
                                        Waldenstrom's macroglobulinaemia recurrent
                                        Waldenstrom's macroglobulinaemia refractory
                                        Waldenstrom's macroglobulinaemia stage I
                                        Waldenstrom's macroglobulinaemia stage II
                                        Waldenstrom's macroglobulinaemia stage III
                                        Waldenstrom's macroglobulinaemia stage IV
                                        Warty dyskeratoma
                                        White sponge naevus
                                        X-linked lymphoproliferative syndrome
                                        X-ray therapy to bladder
                                        X-ray therapy to blood
                                        X-ray therapy to bone
                                        X-ray therapy to brain
                                        X-ray therapy to breast
                                        X-ray therapy to colon
                                        X-ray therapy to ear, nose, or throat
————————————————————————————————————————————————————————————————————————————————————————————————————
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CONFIDENTIAL


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NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
126 of 152
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————————————————————————————————————————————————————————————————————————————————————————————————————
Neoplasm                                X-ray therapy to joint
                                        X-ray therapy to liver
                                        X-ray therapy to lung
                                        X-ray therapy to pancreas
                                        X-ray therapy to pleura
                                        X-ray therapy to prostate
                                        X-ray therapy to skin
                                        X-ray therapy to soft tissue
                                        X-ray therapy to thyroid
                                        X-ray therapy to uterus
                                        X-ray treatment
                                        Xanthogranuloma
                                        Yolk sac tumour site unspecified
Pancreatitis                            Alcoholic pancreatitis
                                        Alcoholic pancreopathy
                                        Autoimmune pancreatitis
                                        Cullen's sign
                                        Cytomegalovirus pancreatitis
                                        Grey Turner's sign
                                        Haemorrhagic necrotic pancreatitis
                                        Hereditary pancreatitis
                                        Ischaemic pancreatitis
                                        Lupus pancreatitis
                                        Obstructive pancreatitis
                                        Oedematous pancreatitis
                                        Pancreas infection
                                        Pancreatic abscess
                                        Pancreatic haemorrhage
                                        Pancreatic necrosis
                                        Pancreatic phlegmon
                                        Pancreatic pseudoaneurysm
                                        Pancreatic pseudocyst
                                        Pancreatic pseudocyst drainage
                                        Pancreatitis
                                        Pancreatitis acute
                                        Pancreatitis bacterial
                                        Pancreatitis chronic
                                        Pancreatitis fungal
                                        Pancreatitis haemorrhagic
                                        Pancreatitis helminthic
                                        Pancreatitis mumps
                                        Pancreatitis necrotising
                                        Pancreatitis relapsing
                                        Pancreatitis viral
                                        Pancreatorenal syndrome
                                        Radiation pancreatitis
                                        Traumatic pancreatitis
Rare                                    11-beta-hydroxylase deficiency
                                        17,20-desmolase deficiency
                                        17-alpha-hydroxylase deficiency
                                        18q minus syndrome
                                        2-Hydroxyglutaric aciduria
                                        20,22-desmolase deficiency
                                        21-hydroxylase deficiency
                                        3-hydroxyacetyl-coenzyme A dehydrogenase deficiency
                                        3M syndrome
                                        5-alpha-reductase deficiency
                                        ABO haemolytic disease of newborn
                                        ACAD9 deficiency
                                        Aase syndrome
                                        Abdominal transposition
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CONFIDENTIAL


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NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
127 of 152
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————————————————————————————————————————————————————————————————————————————————————————————————————
Rare                                    Abdominal wall anomaly
                                        Abnormal palmar
                                        plantar creases
                                        Acardia
                                        Accessory auricle
                                        Accessory breast
                                        Accessory carpal bone
                                        Accessory kidney
                                        Accessory liver lobe
                                        Accessory muscle
                                        Accessory navicular syndrome
                                        Accessory salivary gland
                                        Accessory spleen
                                        Acetylcholinesterase deficiency
                                        Achromotrichia congenital
                                        Acquired amegakaryocytic thrombocytopenia
                                        Acral peeling skin syndrome
                                        Acrodermatitis enteropathica
                                        Acrodysostosis
                                        Acrokeratosis verruciformis
                                        Activated PI3 kinase delta syndrome
                                        Acute focal bacterial nephritis
                                        Adactyly
                                        Adams-Oliver syndrome
                                        Adenine phosphoribosyl transferase deficiency
                                        Adenylosuccinate lyase deficiency
                                        Adrenal insufficiency neonatal
                                        Adrenogenital syndrome
                                        Adrenoleukodystrophy
                                        Adult polyglucosan body disease
                                        Aglossia
                                        Agranulocytosis
                                        Aicardi's syndrome
                                        Alagille syndrome
                                        Albinism
                                        Albright's disease
                                        Alkaptonuria
                                        Allan-Herndon-Dudley syndrome
                                        Alpers' disease
                                        Alpha-1 anti-trypsin deficiency
                                        Alport's syndrome
                                        Alstroem syndrome
                                        Alternating hemiplegia of childhood
                                        Alveolar capillary dysplasia
                                        Amblyopia congenital
                                        Amegakaryocytic thrombocytopenia
                                        Amelogenesis imperfecta
                                        Aminoaciduria
                                        Amniotic band syndrome
                                        Amyotrophic lateral sclerosis gene carrier
                                        Anal atresia
                                        Androgen insensitivity syndrome
                                        Anencephaly
                                        Angelman's syndrome
                                        Angiotensin converting enzyme inhibitor foetopathy
                                        Aniridia
                                        Ankyloglossia congenital
                                        Annular pancreas
                                        Anodontia
                                        Anomalous arrangement of pancreaticobiliary duct
                                        Anomalous pulmonary venous connection
                                        Anomaly of external ear congenital
                                        Anomaly of middle ear congenital
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MedDRA version 21.1
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CONFIDENTIAL


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NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
128 of 152
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————————————————————————————————————————————————————————————————————————————————————————————————————
Rare                                    Anomaly of orbit, congenital
                                        Anophthalmos
                                        Anorchism
                                        Anorectal agenesis
                                        Anotia
                                        Anterior chamber cleavage syndrome
                                        Anterior displaced anus
                                        Antithrombin III deficiency
                                        Aorta hypoplasia
                                        Aortic valve atresia
                                        Aorticopulmonary septal defect
                                        Apert's syndrome
                                        Aphakia congenital
                                        Aplasia
                                        Aplasia cutis congenita
                                        Aplastic anaemia
                                        Apparent mineralocorticoid excess
                                        Arachnodactyly
                                        Arcuate foramen
                                        Arginase deficiency
                                        Argininosuccinate lyase deficiency
                                        Argininosuccinate synthetase deficiency
                                        Arnold-Chiari malformation
                                        Arterial tortuosity syndrome
                                        Arteriovenous malformation
                                        Ash leaf macule
                                        Aspartate-glutamate-transporter deficiency
                                        Aspartylglucosaminuria
                                        Asphyxiating thoracic dystrophy
                                        Asplenia
                                        Asymptomatic gene carrier
                                        Ataxia telangiectasia
                                        Atrial septal defect
                                        Atrioventricular septal defect
                                        Auditory neuropathy spectrum disorder
                                        Autoimmune aplastic anaemia
                                        Autoimmune lymphoproliferative syndrome
                                        Autoimmune nephritis
                                        Autosomal chromosome anomaly
                                        Azygos lobe
                                        B-lymphocyte abnormalities
                                        B-lymphocyte count abnormal
                                        B-lymphocyte count decreased
                                        BPES syndrome
                                        Baltic myoclonic epilepsy
                                        Band neutrophil count decreased
                                        Band neutrophil percentage decreased
                                        Baraitser Rodeck Garner syndrome
                                        Barakat syndrome
                                        Barth syndrome
                                        Bartter's syndrome
                                        Basophil count abnormal
                                        Basophil count decreased
                                        Basophil percentage decreased
                                        Basophilopenia
                                        Becker's muscular dystrophy
                                        Beckwith-Wiedemann syndrome
                                        Benign congenital hypotonia
                                        Benign familial haematuria
                                        Benign familial neonatal convulsions
                                        Benign familial pemphigus
                                        Benjamin syndrome
                                        Berdon's syndrome
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CONFIDENTIAL


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NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
129 of 152
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————————————————————————————————————————————————————————————————————————————————————————————————————
Rare                                    Bergmeister's papilla
                                        Beta ketothiolase deficiency
                                        Bicuspid aortic valve
                                        Bicuspid pulmonary valve
                                        Bicytopenia
                                        Biotinidase deficiency
                                        Birth mark
                                        Bladder agenesis
                                        Blau syndrome
                                        Blepharophimosis congenital
                                        Blindness congenital
                                        Bloch-Sulzberger syndrome
                                        Blood count abnormal
                                        Blood disorder
                                        Blood incompatibility haemolytic anaemia of newborn
                                        Bloom syndrome
                                        Bone marrow disorder
                                        Bone marrow failure
                                       Bone marrow myelogram abnormal
                                        Bone marrow necrosis
                                        Bone marrow toxicity
                                        Brachycephaly
                                        Brachydactyly
                                        Brachymetatarsia
                                        Brain malformation
                                        Branchial cleft sinus
                                        Branchio-oto-renal syndrome
                                        Branchiogenic syndrome
                                        Breast malformation
                                        Bronchial atresia
                                        Bronchogenic cyst
                                        Brunner syndrome
                                        Bruton's agammaglobulinaemia
                                        Bulbospinal muscular atrophy congenital
                                        Buried penis syndrome
                                        C1q nephropathy
                                        C3 glomerulopathy
                                        CANDLE syndrome
                                        CHARGE syndrome
                                        CTLA4 deficiency
                                        Camptodactyly congenital
                                        Camptomelia
                                        Canavan disease
                                        Cancer gene carrier
                                        Carbamoyl phosphate synthetase deficiency
                                        Carbohydrate metabolism disorder
                                        Cardiac malposition
                                        Cardiac septal defect
                                        Carnitine palmitoyltransferase deficiency
                                        Carnitine-acylcarnitine translocase deficiency
                                        Carpenter syndrome
                                        Carpus curvus
                                        Cartilage-hair hypoplasia
                                        Cataract congenital
                                        Caudal regression syndrome
                                        Central core disease
                                        Cerebellar dysplasia
                                        Cerebellar hypoplasia
                                        Cerebral atrophy congenital
                                        Cerebral dysgenesis
                                        Cerebral palsy
                                        Cerebrohepatorenal syndrome
                                        Cervical auricle
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MedDRA version 21.1
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CONFIDENTIAL


NN9535
NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
130 of 152
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————————————————————————————————————————————————————————————————————————————————————————————————————
Rare                                    Cervical rib
                                        Chediak-Higashi syndrome
                                        Chiari network
                                        Chimerism
                                        Choanal atresia
                                        Choanal stenosis
                                        Cholangiectasis congenital
                                        Chondrodystrophy
                                        Chondroectodermal dysplasia
                                        Chordee
                                        Chorea-acanthocytosis
                                        Chorioretinal degeneration congenital
                                        Choroidal coloboma
                                        Chromosomal deletion
                                        Chromosomal mutation
                                        Chronic autoimmune glomerulonephritis
                                        Chronic granulomatous disease
                                        Chronic infantile neurological cutaneous and articular
                                        syndrome
                                        Citrate transporter deficiency
                                        Cleft lip
                                        Cleft lip and palate
                                        Cleft palate
                                        Cleft uvula
                                        Cleidocranial dysostosis
                                        Clinodactyly
                                        Cloacal exstrophy
                                        Clostridial infection
                                        Clostridial sepsis
                                        Clostridium bacteraemia
                                        Clostridium colitis
                                        Clostridium difficile colitis
                                        Clostridium difficile infection
                                        Clostridium test positive
                                        Coagulation factor mutation
                                        Coarctation of the aorta
                                        Cobb syndrome
                                        Cockayne's syndrome
                                        Cohen syndrome
                                        Collodion baby
                                        Coloboma
                                        Colour blindness
                                        Combined immunodeficiency
                                        Complement deficiency disease
                                        Congenital Eustachian tube anomaly
                                        Congenital HIV infection
                                        Congenital Horner's syndrome
                                        Congenital Zika syndrome
                                        Congenital abdominal hernia
                                        Congenital absence of bile ducts
                                        Congenital absence of cranial vault
                                        Congenital absence of vertebra
                                        Congenital adrenal gland hypoplasia
                                        Congenital amputation
                                        Congenital anaemia
                                        Congenital androgen deficiency
                                        Congenital anomalies of ear ossicles
                                        Congenital anomaly
                                        Congenital anomaly in offspring
                                        Congenital anomaly of adrenal gland
                                        Congenital anomaly of inner ear
                                        Congenital anosmia
                                        Congenital aortic anomaly
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CONFIDENTIAL


NN9535
NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
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131 of 152
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Rare                                    Congenital aortic atresia
                                        Congenital aortic dilatation
                                        Congenital aortic stenosis
                                        Congenital aortic valve incompetence
                                        Congenital aortic valve stenosis
                                        Congenital aplastic anaemia
                                        Congenital aqueductal stenosis
                                        Congenital arterial malformation
                                        Congenital arteriovenous fistula
                                       Congenital astigmatism
                                        Congenital aural fistula
                                        Congenital bladder anomaly
                                        Congenital bladder diverticulum
                                        Congenital bladder neck obstruction
                                        Congenital bowing of long bones
                                        Congenital brain damage
                                        Congenital bronchiectasis
                                        Congenital bronchomalacia
                                        Congenital calyceal diverticulum
                                        Congenital cardiovascular anomaly
                                        Congenital carnitine deficiency
                                        Congenital central diabetes insipidus
                                        Congenital central hypoventilation syndrome
                                        Congenital central nervous system anomaly
                                        Congenital cerebellar agenesis
                                        Congenital choroidal anomaly
                                        Congenital chylothorax
                                        Congenital clavicular agenesis
                                        Congenital claw toe
                                        Congenital coagulopathy
                                        Congenital condyloma
                                        Congenital corneal anomaly
                                        Congenital coronary artery malformation
                                        Congenital cranial nerve paralysis
                                        Congenital cutis laxa
                                        Congenital cystic lung
                                        Congenital cytomegalovirus infection
                                        Congenital deformity of clavicle
                                        Congenital dermal sinus
                                        Congenital diaphragmatic anomaly
                                        Congenital diaphragmatic eventration
                                        Congenital diaphragmatic hernia
                                        Congenital disorder of glycosylation
                                        Congenital dyserythropoietic anaemia
                                        Congenital dysfibrinogenaemia
                                        Congenital dyskeratosis
                                        Congenital ectodermal dysplasia
                                        Congenital ectopic bladder
                                        Congenital ectopic pancreas
                                        Congenital elevation of scapula
                                        Congenital emphysema
                                        Congenital endocrine anomaly
                                        Congenital epiblepharon
                                        Congenital epiglottal anomaly
                                        Congenital eye disorder
                                        Congenital eyelid malformation
                                        Congenital facial nerve hypoplasia
                                        Congenital fallopian tube anomaly
                                        Congenital flaccid paralysis
                                        Congenital flat feet
                                        Congenital floppy infant
                                        Congenital foot malformation
                                        Congenital gastric anomaly
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CONFIDENTIAL


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NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
132 of 152
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Rare                                    Congenital gastrointestinal vessel anomaly
                                        Congenital generalised lipodystrophy
                                        Congenital genital malformation
                                        Congenital genital malformation female
                                        Congenital genital malformation male
                                        Congenital genitourinary abnormality
                                        Congenital great vessel anomaly
                                        Congenital haematological disorder
                                        Congenital hair disorder
                                        Congenital hand malformation
                                        Congenital hearing disorder
                                        Congenital heart valve disorder
                                        Congenital heart valve incompetence
                                        Congenital hepatic fibrosis
                                        Congenital hepatitis B infection
                                        Congenital hepatobiliary anomaly
                                        Congenital hepatomegaly
                                        Congenital herpes simplex infection
                                        Congenital hiatus hernia
                                        Congenital high airway obstruction syndrome
                                        Congenital hydrocele renalis
                                        Congenital hydrocephalus
                                        Congenital hydronephrosis
                                        Congenital hypercoagulation
                                        Congenital hyperextension of knee
                                        Congenital hyperextension of spine
                                        Congenital hypertrichosis
                                        Congenital hypogammaglobulinaemia
                                        Congenital hypoparathyroidism
                                        Congenital hypoplasia of depressor angularis oris muscle
                                        Congenital infection
                                        Congenital inguinal hernia
                                        Congenital intestinal malformation
                                        Congenital intestinal obstruction
                                        Congenital intrinsic factor deficiency
                                        Congenital iris anomaly
                                        Congenital jaw malformation
                                        Congenital joint malformation
                                        Congenital knee deformity
                                       Congenital knee dislocation
                                        Congenital kyphoscoliosis
                                        Congenital labia pudendi adhesions
                                        Congenital lacrimal gland anomaly
                                        Congenital lacrimal passage anomaly
                                        Congenital large intestinal atresia
                                        Congenital laryngeal stridor
                                        Congenital lenticonus
                                        Congenital limb hyperextension
                                        Congenital lip fistula
                                        Congenital lymphoedema
                                        Congenital malaria
                                        Congenital megacolon
                                        Congenital megaureter
                                        Congenital melanosis
                                        Congenital methaemoglobinaemia
                                        Congenital midline defect
                                        Congenital mitochondrial cytopathy
                                        Congenital mitral valve incompetence
                                        Congenital mitral valve stenosis
                                        Congenital monorchidism
                                        Congenital multiplex arthrogryposis
                                        Congenital muscle absence
                                        Congenital musculoskeletal anomaly
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CONFIDENTIAL


NN9535
NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
133 of 152
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————————————————————————————————————————————————————————————————————————————————————————————————————
Rare                                    Congenital myopathy
                                        Congenital myopia
                                        Congenital nail disorder
                                        Congenital nephrogenic diabetes insipidus
                                        Congenital nephrotic syndrome
                                        Congenital neurological degeneration
                                        Congenital neurological disorder
                                        Congenital neuropathy
                                        Congenital night blindness
                                        Congenital nipple anomaly
                                        Congenital nipple inversion
                                        Congenital nose malformation
                                        Congenital nystagmus
                                        Congenital oculomotor apraxia
                                        Congenital oesophageal anomaly
                                        Congenital oesophageal stenosis
                                        Congenital oesophageal web
                                        Congenital optic nerve anomaly
                                        Congenital oral malformation
                                        Congenital osteodystrophy
                                        Congenital ovarian anomaly
                                        Congenital oxalosis
                                        Congenital pancreatic anomaly
                                        Congenital perforated nasal septum
                                        Congenital pharyngeal anomaly
                                        Congenital pigmentation disorder
                                        Congenital pneumonia
                                        Congenital poikiloderma
                                        Congenital pseudarthrosis
                                        Congenital pulmonary artery anomaly
                                        Congenital pulmonary hypertension
                                        Congenital pulmonary valve atresia
                                        Congenital pulmonary valve disorder
                                        Congenital pyelocaliectasis
                                        Congenital renal disorder
                                        Congenital rubella infection
                                        Congenital salivary gland anomaly
                                        Congenital scleral disorder
                                        Congenital scoliosis
                                        Congenital scrotal hypertrophy
                                        Congenital skin dimples
                                        Congenital skin disorder
                                        Congenital small intestinal atresia
                                        Congenital spinal cord anomaly
                                        Congenital spinal fusion
                                        Congenital spinal stenosis
                                        Congenital spondylolisthesis
                                        Congenital spondylolysis
                                        Congenital syphilis
                                        Congenital syphilitic encephalitis
                                        Congenital syphilitic meningitis
                                        Congenital syphilitic osteochondritis
                                        Congenital thrombocyte disorder
                                        Congenital thrombocytopenia
                                        Congenital thymus absence
                                        Congenital tongue anomaly
                                        Congenital torticollis
                                        Congenital toxoplasmosis
                                        Congenital tracheomalacia
                                        Congenital trichomegaly
                                        Congenital tricuspid valve atresia
                                        Congenital tricuspid valve incompetence
                                        Congenital tricuspid valve stenosis
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CONFIDENTIAL


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NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
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Status:
Final
Page:
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————————————————————————————————————————————————————————————————————————————————————————————————————
Rare                                    Congenital tuberculosis
                                        Congenital umbilical hernia
                                        Congenital ureteric anomaly
                                        Congenital ureterocele
                                        Congenital ureterovesical junction anomaly
                                        Congenital urethral anomaly
                                        Congenital urinary tract obstruction
                                        Congenital uterine anomaly
                                        Congenital varicella infection
                                        Congenital varicocele
                                        Congenital vas deferens absence
                                        Congenital vesicoureteric reflux
                                        Congenital visual acuity reduced
                                        Congenital vitreous anomaly
                                        Congenital white blood cell disorder
                                        Conjoined twins
                                        Conjunctivitis gonococcal neonatal
                                        Constricted ear deformity
                                        Cor biloculare
                                        Cor triatriatum
                                        Corneal dystrophy
                                        Corneal opacity congenital
                                        Cornelia de Lange syndrome
                                        Corrected transposition of great vessels
                                        Cortical dysplasia
                                        Costello syndrome
                                        Craniofacial deformity
                                        Craniofacial dysostosis
                                        Craniolacunia
                                        Craniorachischisis
                                        Craniosynostosis
                                        Craniotabes
                                        Cri du Chat syndrome
                                        Crigler-Najjar syndrome
                                        Cryopyrin associated periodic syndrome
                                        Cryptophthalmos
                                        Cryptorchism
                                        Currarino syndrome
                                        Cutaneovisceral angiomatosis with thrombocytopenia
                                        Cyclic neutropenia
                                        Cyclopia
                                        Cystathionine beta-synthase deficiency
                                        Cystic fibrosis
                                        Cystic fibrosis carrier
                                        Cystic fibrosis gastrointestinal disease
                                        Cystic fibrosis hepatic disease
                                       Cystic fibrosis lung
                                        Cystic fibrosis pancreatic
                                        Cystic fibrosis related diabetes
                                        Cystinosis
                                        Cystinuria
                                        Cytogenetic abnormality
                                        Cytomegalovirus nephritis
                                        Cytopenia
                                        DNA mismatch repair protein gene mutation
                                        DOOR syndrome
                                        Dacryostenosis congenital
                                        Dandy-Walker syndrome
                                        Deaf mutism
                                        Deafness congenital
                                        Deficiency of the interleukin-1 receptor antagonist
                                        Deficiency of the interleukin-36 receptor antagonist
                                        Delayed foetal renal development
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CONFIDENTIAL


NN9535
NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
135 of 152
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Rare                                    Delta-beta thalassaemia
                                        Dent's disease
                                        Dentatorubral-pallidoluysian atrophy
                                        Dentinogenesis imperfecta
                                        Dentofacial anomaly
                                        Dermatofibrosis lenticularis disseminata
                                        Dermatoglyphic anomaly
                                        Developmental glaucoma
                                        Developmental hip dysplasia
                                        Dextrocardia
                                        DiGeorge's syndrome
                                        Diabetic foetopathy
                                        Diaphragmatic aplasia
                                        Diastematomyelia
                                        Diastrophic dysplasia
                                        Diencephalic syndrome of infancy
                                        Diethylstilboestrol syndrome
                                        Differential white blood cell count abnormal
                                        Dihydropyrimidine dehydrogenase deficiency
                                        Dilatation intrahepatic duct congenital
                                        Disorder of sex development
                                        Distichiasis
                                        Diverticulitis Meckel's
                                        Diverticulum of pharynx, congenital
                                        Dolichocolon
                                        Dopa-responsive dystonia
                                        Double cortex syndrome
                                        Double heterozygous sickling disorders
                                        Double outlet left ventricle
                                        Double outlet right ventricle
                                        Double ureter
                                        Dowling-Degos disease
                                        Duane's syndrome
                                        Dubin-Johnson syndrome
                                        Dubowitz syndrome
                                        Duchenne muscular dystrophy
                                        Duchenne muscular dystrophy gene carrier
                                        Ductus arteriosus premature closure
                                        Ductus arteriosus stenosis foetal
                                        Ductus venosus agenesis
                                        Duodenal atresia
                                        Duplex appendix
                                        Duplication of inferior vena cava
                                        Dyke-Davidoff-Masson syndrome
                                        Dyschondrosteosis
                                        Dyschromatosis
                                        Dysgnathia
                                        Dysmorphism
                                        Dysmyelination
                                        Eagle Barrett syndrome
                                        Ear malformation
                                        Early onset familial Alzheimer's disease
                                        Early onset primary dystonia
                                        Ebstein's anomaly
                                        Ectopia cordis
                                        Ectopic kidney
                                        Ectopic ovary
                                        Ectopic posterior pituitary gland
                                        Ectopic ureter
                                        Ectrodactyly
                                        Ehlers-Danlos syndrome
                                        Elliptocytosis hereditary
                                        Ellis-van Creveld syndrome
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NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
136 of 152
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Rare                                    Emanuel syndrome
                                        Emery-Dreifuss muscular dystrophy
                                        Encephalocele
                                        Encephalocutaneous angiomatosis
                                        Enteric duplication
                                        Entropion congenital
                                        Eosinopenia
                                        Eosinophil count abnormal
                                        Eosinophil count decreased
                                        Eosinophil percentage decreased
                                        Epidermal naevus
                                        Epilepsy congenital
                                        Epilepsy with myoclonic-atonic seizures
                                        Epispadias
                                        Erythroblastosis foetalis
                                        Erythrokeratodermia variabilis
                                        Essential fructosuria
                                        Exomphalos
                                        Exophthalmos congenital
                                        External auditory canal atresia
                                        Extrarenal pelvis
                                        Eye anterior chamber congenital anomaly
                                        Eyelid ptosis congenital
                                        Fabry's disease
                                        Faciodigitogenital dysplasia
                                        Facioscapulohumeral muscular dystrophy
                                        Factor I deficiency
                                        Factor II deficiency
                                        Factor II mutation
                                        Factor III deficiency
                                        Factor IX deficiency
                                        Factor V Leiden carrier
                                        Factor V Leiden mutation
                                        Factor V deficiency
                                        Factor VII deficiency
                                        Factor VIII deficiency
                                        Factor X deficiency
                                        Factor XI deficiency
                                        Factor XII deficiency
                                        Factor XIII deficiency
                                        Fallot's pentalogy
                                        Fallot's tetralogy
                                        Fallot's trilogy
                                        Familial amyloidosis
                                        Familial amyotrophic lateral sclerosis
                                        Familial cold autoinflammatory syndrome
                                        Familial hemiplegic migraine
                                        Familial high density lipoprotein deficiency
                                        Familial hypertriglyceridaemia
                                        Familial hypocalciuric hypercalcaemia
                                        Familial infantile bilateral striatal necrosis
                                        Familial isolated hyperparathyroidism
                                        Familial mediterranean fever
                                        Familial periodic paralysis
                                        Familial polycythaemia
                                        Familial renal glycosuria
                                        Familial scaphocephaly syndrome
                                        Familial tremor
                                        Fanconi syndrome
                                        Fatal familial insomnia
                                        Fatty acid oxidation disorder
                                        Febrile bone marrow aplasia
                                        Febrile neutropenia
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CONFIDENTIAL


NN9535
NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
137 of 152
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Rare                                    Femoral anteversion
                                        Femoral retroversion
                                        Femur-fibula-ulna complex
                                        Fibrillary glomerulonephritis
                                        Fibrodysplasia ossificans progressiva
                                        Fibrous dysplasia of bone
                                        Fibrous dysplasia of jaw
                                        Fibula agenesis
                                        Fissure of tongue, congenital
                                        Floating-Harbor syndrome
                                        Focal segmental glomerulosclerosis
                                        Foetal alcohol syndrome
                                        Foetal anticonvulsant syndrome
                                        Foetal chromosome abnormality
                                        Foetal malformation
                                        Foetal megacystis
                                        Foetal methotrexate syndrome
                                        Foetal retinoid syndrome
                                        Foetal warfarin syndrome
                                        Foramen magnum stenosis
                                        Fragile X carrier
                                        Fragile X syndrome
                                        Fraser syndrome
                                        Freeman-Sheldon syndrome
                                        Frenulum breve
                                        Friedreich's ataxia
                                        Fructose-1,6-bisphosphatase deficiency
                                        Fryns syndrome
                                        Full blood count abnormal
                                        Full blood count decreased
                                        GNE myopathy
                                        GRACILE syndrome
                                        Galactosaemia
                                        Gallbladder agenesis
                                        Gallbladder anomaly congenital
                                        Gastroenteritis clostridial
                                        Gastrointestinal arteriovenous malformation
                                        Gastrointestinal disorder congenital
                                        Gastrointestinal malformation
                                        Gastroschisis
                                        Gatad2b associated neurodevelopmental disorder
                                        Gaucher's disease
                                        Gaucher's disease type I
                                        Gaucher's disease type II
                                        Gaucher's disease type III
                                        Gelatinous transformation of the bone marrow
                                        Gene mutation
                                        Genitalia external ambiguous
                                        Gilbert's syndrome
                                        Gitelman's syndrome
                                        Glomerulonephritis
                                        Glomerulonephritis acute
                                        Glomerulonephritis chronic
                                        Glomerulonephritis membranoproliferative
                                        Glomerulonephritis membranous
                                        Glomerulonephritis minimal lesion
                                        Glomerulonephritis proliferative
                                        Glomerulonephritis rapidly progressive
                                        Glucose transporter type 1 deficiency syndrome
                                        Glucose-6-phosphate dehydrogenase deficiency
                                        Glucose-galactose malabsorption
                                        Glutathione synthetase deficiency
                                        Glycogen storage disease type I
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NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
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Status:
Final
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Rare                                    Glycogen storage disease type II
                                        Glycogen storage disease type III
                                        Glycogen storage disease type IV
                                        Glycogen storage disease type V
                                        Glycogen storage disease type VI
                                        Glycogen storage disease type VII
                                        Glycogen storage disease type VIII
                                        Glycogen storage disorder
                                        Gnathoschisis
                                        Gollop-Wolfgang complex
                                        Gonadal dysgenesis
                                        Granulocyte count decreased
                                        Granulocytes abnormal
                                        Granulocytes maturation arrest
                                        Granulocytopenia
                                        Granulocytopenia neonatal
                                        Gray matter heterotopia
                                       Greig's syndrome
                                        Griscelli syndrome
                                        HIV associated nephropathy
                                        Haematotoxicity
                                        Haemochromatosis trait
                                        Haemoglobin C disease
                                        Haemoglobin C trait
                                        Haemoglobin D disease
                                        Haemoglobin D trait
                                        Haemoglobin E disease
                                        Haemoglobin E trait
                                        Haemoglobin E-thalassaemia disease
                                        Haemoglobinopathy
                                        Haemophilia
                                        Haemophilia A with anti factor VIII
                                        Haemophilia A without inhibitors
                                        Haemophilia B with anti factor IX
                                        Haemophilia B without inhibitors
                                        Haemophilia carrier
                                        Haemorrhagic arteriovenous malformation
                                        Hand-foot-genital syndrome
                                        Harlequin foetus
                                        Hartnup disease
                                        Heart disease congenital
                                        Hemihypertrophy
                                        Hemimegalencephaly
                                        Hemivertebra
                                        Hepatic arteriovenous malformation
                                        Hepatitis virus-associated nephropathy
                                        Hepato-lenticular degeneration
                                        Hereditary angioedema with normal C1 esterase inhibitor
                                        Hereditary areflexic dystasia
                                        Hereditary cerebral degeneration
                                        Hereditary choroidal dystrophy
                                        Hereditary disorder
                                        Hereditary fructose intolerance
                                        Hereditary haemochromatosis
                                        Hereditary haemolytic anaemia
                                        Hereditary haemorrhagic telangiectasia
                                        Hereditary hypophosphataemic rickets
                                        Hereditary motor and sensory neuropathy
                                        Hereditary motor neurone disease
                                        Hereditary neuropathic amyloidosis
                                        Hereditary neuropathy with liability to pressure palsies
                                        Hereditary optic atrophy
                                        Hereditary palmoplantar keratoderma
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CONFIDENTIAL


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NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
139 of 152
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Rare                                    Hereditary renal microhaematuria
                                        Hereditary retinal dystrophy
                                        Hereditary sideroblastic anaemia
                                       Hereditary spastic paraplegia
                                        Hereditary spherocytosis
                                        Hereditary stomatocytosis
                                        Hermansky-Pudlak syndrome
                                        Hermaphroditism
                                        Hernia congenital
                                        Heterochromia iridis
                                        Heterotaxia
                                        Hexokinase deficiency anaemia
                                        High arched palate
                                        Hollow visceral myopathy
                                        Holoprosencephaly
                                        Holt-Oram syndrome
                                        Homocystinaemia
                                        Homocystinuria
                                        Hooded prepuce
                                        Huntington's disease
                                        Hydranencephaly
                                        Hydrocele
                                        Hydronephrosis
                                        Hydroureter
                                        Hydroxyprolinaemia
                                        Hyper IgD syndrome
                                        Hyper IgE syndrome
                                        Hyper IgM syndrome
                                        Hyperexplexia
                                        Hyperglycinaemia
                                        Hyperinsulinism syndrome
                                        Hyperlysinaemia
                                        Hypermethioninaemia
                                        Hypermethioniuria
                                        Hyperprolinaemia
                                        Hypersplenism congenital
                                        Hypertelorism of orbit
                                        Hyperthermia malignant
                                        Hypocalvaria
                                        Hypochondroplasia
                                        Hypodontia
                                        Hypomelanosis of Ito
                                        Hypophosphatasia
                                        Hypopituitarism foetal
                                        Hypoplastic left heart syndrome
                                        Hypoplastic nasal cartilage
                                        Hypoplastic right heart syndrome
                                        Hypospadias
                                        Hypotelorism of orbit
                                        Hypoxanthine-guanine phosphoribosyl transferase deficiency
                                        IPEX syndrome
                                        Ichthyosis
                                        Idiopathic neutropenia
                                        IgA nephropathy
                                        IgM nephropathy
                                        Ileal atresia
                                        Immunodeficiency congenital
                                        Immunotactoid glomerulonephritis
                                        Imperforate hymen
                                        Imperforate oesophagus
                                        Inborn error in primary bile acid synthesis
                                        Inborn error of bilirubin metabolism
                                        Inborn error of lipid metabolism
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NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
140 of 152
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Rare                                    Inborn error of metabolism
                                        Infantile cortical hyperostosis
                                        Infantile genetic agranulocytosis
                                        Inherited cardiac conduction disorder
                                        Iniencephaly
                                        Interferon gamma receptor deficiency
                                        Interruption of aortic arch
                                        Intestinal atresia
                                        Intestinal malrotation
                                        Intestinal neuronal dysplasia
                                        Intestinal sepsis
                                        Intestinal transposition
                                        Intracranial arterial fenestration
                                        Intracranial lipoma
                                        Iris coloboma
                                        Isodicentric chromosome 15 syndrome
                                        Johanson-Blizzard syndrome
                                        Joubert syndrome
                                        Juvenile Paget's disease
                                        Kabuki make-up syndrome
                                        Kaufman-McKusick syndrome
                                        Kearns-Sayre syndrome
                                        Kenny-Caffey syndrome
                                       Keratitis-ichthyosis-deafness syndrome
                                        Keratolysis exfoliativa congenital
                                        Keratosis follicular
                                        Kidney duplex
                                        Kidney malformation
                                        Kidney malrotation
                                        Kimmerle's anomaly
                                        Kinematic imbalances due to suboccipital strain
                                        Kleefstra syndrome
                                        Klinefelter's syndrome
                                        Klippel-Feil syndrome
                                        Klippel-Trenaunay syndrome
                                        Kniest dysplasia
                                        Kommerell's diverticulum
                                        Kosaki overgrowth syndrome
                                        Krabbe's disease
                                        Kyphosis congenital
                                        LDLR mutation
                                        Labial tie
                                        Lacrimal punctum agenesis
                                        Laevocardia
                                        Lafora's myoclonic epilepsy
                                        Lamin A
                                        C gene mutation
                                        Langer-Giedion syndrome
                                        Laron syndrome
                                        Larsen syndrome
                                        Laryngeal cleft
                                        Laryngeal web
                                        Laryngo-onycho-cutaneous syndrome
                                        Laryngocele
                                        Laryngomalacia
                                        Laurence-Moon-Bardet-Biedl syndrome
                                        Leber's congenital amaurosis
                                        Lecithin-cholesterol acyltransferase deficiency
                                        Left ventricle outflow tract obstruction
                                        Left ventricular false tendon
                                        Left-to-right cardiac shunt
                                        Lens abnormality, congenital
                                        Leukodystrophy
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CONFIDENTIAL


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NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
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141 of 152
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Rare                                    Leukopenia
                                        Leukopenia neonatal
                                        Li-Fraumeni syndrome
                                        Lichen spinulosus
                                        Liddle's syndrome
                                        Limb hypoplasia congenital
                                        Limb malformation
                                        Limb reduction defect
                                        Lipid proteinosis
                                        Lipidosis
                                        Lipomeningocele
                                        Lissencephaly
                                        Loeys-Dietz syndrome
                                        Long-chain acyl-coenzyme A dehydrogenase deficiency
                                        Low set ears
                                        Lowry-Wood syndrome
                                        Lumbarisation
                                        Lupus nephritis
                                        Lymphangiectasia intestinal congenital
                                        Lymphocyte count abnormal
                                        Lymphocyte count decreased
                                        Lymphocyte percentage abnormal
                                        Lymphocyte percentage decreased
                                        Lymphocytopenia neonatal
                                        Lymphopenia
                                        Lysinuric protein intolerance
                                        Lysosomal acid lipase deficiency
                                        MELAS syndrome
                                        MLASA syndrome
                                        MYH9-related disease
                                        Macrocephaly
                                        Macrocheilia
                                        Macrocornea
                                        Macrodactyly
                                        Macrogenia
                                        Macroglossia
                                        Macrognathia
                                        Macrostomia
                                        Macrotia
                                        Macular dystrophy congenital
                                        Majeed's syndrome
                                        Malformation biliary
                                        Malformation venous
                                        Mandibulofacial dysostosis
                                        Maple syrup disease
                                        Marcus Gunn syndrome
                                        Marfan's syndrome
                                        Maxillonasal dysplasia
                                        Mayer-Rokitansky-Kuster-Hauser syndrome
                                        McLeod neuroacanthocytosis syndrome
                                        Medium-chain acyl-coenzyme A dehydrogenase deficiency
                                        Megakaryocytes decreased
                                        Meier-Gorlin syndrome
                                        Melkersson-Rosenthal syndrome
                                        Membranous lipodystrophy
                                        Meningocele
                                        Meningomyelocele
                                        Menkes' syndrome
                                        Mesangioproliferative glomerulonephritis
                                        Metabolic myopathy
                                        Metachromatic leukodystrophy
                                        Metamyelocyte count decreased
                                        Metaphyseal dysplasia
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NN9535-4114
Clinical Trial Report
Section 16.1.9
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Date:
03 July 2019
Novo Nordisk
Version:
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Status:
Final
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Rare                                    Metatarsus primus varus
                                        Methylenetetrahydrofolate reductase deficiency
                                        Methylenetetrahydrofolate reductase gene mutation
                                        Methylmalonic aciduria
                                        Mevalonate kinase deficiency
                                        Mevalonic aciduria
                                        Microcephaly
                                        Microcheilia
                                        Microcolon
                                        Microcornea
                                        Microencephaly
                                        Microgenia
                                        Microglossia
                                        Micrognathia
                                        Microorchidism
                                        Micropenis
                                        Microphthalmos
                                        Microstomia
                                        Microtia
                                        Microvillous inclusion disease
                                        Mitochondrial DNA deletion
                                        Mitochondrial DNA depletion
                                        Mitochondrial DNA duplication
                                        Mitochondrial DNA mutation
                                        Mitochondrial encephalomyopathy
                                        Mitochondrial enzyme deficiency
                                        Mitochondrial hepatopathy
                                        Mitochondrial myopathy
                                        Mitochondrial neurogastrointestinal encephalopathy
                                        Mitral valve atresia
                                        Mitral valve hypoplasia
                                        Mittendorf dot
                                        Mobile caecum syndrome
                                        Moebius II syndrome
                                        Molybdenum cofactor deficiency
                                        Monoblast count decreased
                                        Monocyte count abnormal
                                        Monocyte count decreased
                                        Monocyte percentage decreased
                                        Monocytopenia
                                        Monolid eyes
                                        Monopodia
                                        Morgagni-Stewart-Morel syndrome
                                        Morning glory syndrome
                                        Morton's syndrome
                                        Mosaicism
                                        Mount-Reback syndrome
                                        Muckle-Wells syndrome
                                        Mucolipidosis
                                        Mucolipidosis type I
                                        Mucolipidosis type II
                                        Mucolipidosis type III
                                        Mucolipidosis type IV
                                        Mucopolysaccharidosis
                                        Mucopolysaccharidosis I
                                        Mucopolysaccharidosis II
                                        Mucopolysaccharidosis III
                                        Mucopolysaccharidosis IV
                                        Mucopolysaccharidosis IX
                                        Mucopolysaccharidosis V
                                        Mucopolysaccharidosis VI
                                        Mucopolysaccharidosis VII
                                        Multiple carboxylase deficiency
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NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
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03 July 2019
Novo Nordisk
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Rare                                    Multiple cardiac defects
                                        Multiple congenital abnormalities
                                        Multiple epiphyseal dysplasia
                                        Multiple gastrointestinal atresias
                                        Multiple lentigines syndrome
                                        Muscular dystrophy
                                        Mutagenic effect
                                        Myeloblast count decreased
                                        Myeloblast percentage decreased
                                        Myelocyte count decreased
                                        Myelocyte percentage decreased
                                        Myeloid maturation arrest
                                        Myeloperoxidase deficiency
                                        Myocardial bridging
                                        Myoclonic epilepsy and ragged-red fibres
                                        Myotonia congenita
                                        Myotonic dystrophy
                                        N-acetylglutamate synthase deficiency
                                        Naevus anaemicus
                                        Naevus flammeus
                                        Naevus spider congenital
                                        Nail aplasia
                                        Nail-patella syndrome
                                        Nasopharyngeal atresia
                                        Neonatal alloimmune thrombocytopenia
                                        Neonatal haemochromatosis
                                        Neonatal lupus erythematosus
                                        Nephritic syndrome
                                        Nephritis haemorrhagic
                                        Nephritis radiation
                                        Nephrotic syndrome
                                        Netherton's syndrome
                                        Neural tube defect
                                        Neuroacanthocytosis
                                        Neuroleptic malignant syndrome
                                       Neuronal ceroid lipofuscinosis
                                        Neuronal migration disorder
                                        Neuropathy, ataxia, retinitis pigmentosa syndrome
                                        Neutropenia
                                        Neutropenia neonatal
                                        Neutropenic infection
                                        Neutropenic sepsis
                                        Neutrophil count abnormal
                                        Neutrophil count decreased
                                        Neutrophil percentage decreased
                                        Niemann-Pick disease
                                        Nijmegen breakage syndrome
                                        Non-compaction cardiomyopathy
                                        Noonan syndrome
                                        Norrie's disease
                                        Ocular albinism
                                        Oculoauriculovertebral dysplasia
                                        Oculocerebrorenal syndrome
                                        Oculodentodigital dysplasia
                                        Oculopharyngeal dystrophy
                                        Oesophageal atresia
                                        Olfacto genital dysplasia
                                        Olfactory nerve agenesis
                                        Olmsted syndrome
                                        Opitz-G
                                        BBB syndrome
                                        Optic disc pit
                                        Optic nerve hypoplasia
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CONFIDENTIAL


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NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
144 of 152
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Rare                                    Oral-facial-digital syndrome type II
                                        Ornithine transcarbamoylase deficiency
                                        Oroticaciduria congenital
                                        Os trigonum
                                        Osteogenesis imperfecta
                                        Osteopathia striata
                                        Osteopetrosis
                                        Osteopoikilosis
                                        Osteoporosis-pseudoglioma syndrome
                                        Otocephaly
                                        Ovarian agenesis
                                        Ovarian hypoplasia
                                        Oxycephaly
                                        PIK3CA related overgrowth spectrum
                                        Pachydermoperiostosis
                                        Pachygyria
                                        Pachyonychia congenita
                                        Pallister-Killian syndrome
                                        Pancreas divisum
                                        Pancytopenia
                                        Panmyelopathy
                                        Parachute mitral valve
                                        Paranasal sinus aplasia
                                        Parkes-Weber syndrome
                                        Patent ductus arteriosus
                                        Pearson's syndrome
                                        Pectus carinatum
                                        Pectus excavatum
                                        Pelizaeus-Merzbacher disease
                                        Pelvi-ureteric obstruction
                                        Pelvic fibrosis
                                        Pelvic kidney
                                        Penile torsion
                                        Penoscrotal fusion
                                        Penoscrotal transposition
                                        Perinephritis
                                        Periodontal congenital anomaly
                                        Perry syndrome
                                        Persistent Muellerian duct syndrome
                                        Persistent cloaca
                                        Persistent foetal circulation
                                        Persistent left superior vena cava
                                        Persistent pupillary membrane
                                        Persistent urogenital sinus
                                        Phalangeal agenesis
                                        Phalangeal hypoplasia
                                        Phenylketonuria
                                        Phimosis
                                        Phytosterolaemia
                                        Pierre Robin syndrome
                                        Pilonidal cyst congenital
                                        Plagiocephaly
                                        Plasma cell disorder
                                        Plasma cells absent
                                        Plasmablast count decreased
                                        Platelet count decreased
                                        Platelet glycoprotein gene mutation
                                        Platelet maturation arrest
                                        Platelet production decreased
                                        Platelet toxicity
                                        Platonychia
                                        Platybasia
                                        Platyspondylia
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CONFIDENTIAL


NN9535
NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
145 of 152
Pre-defined MedDRA search - list of preferred terms
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Rare                                    Poland's syndrome
                                        Polycystic liver disease
                                        Polydactyly
                                        Polymicrogyria
                                        Polyorchidism
                                        Popliteal pterygium syndrome
                                        Porencephaly
                                        Porokeratosis
                                        Porphyria
                                        Porphyria acute
                                        Porphyria non-acute
                                        Porphyrin metabolism disorder
                                        Porphyrinuria
                                        Portal venous system anomaly
                                        Post infection glomerulonephritis
                                        Post streptococcal glomerulonephritis
                                        Postauricular fistula
                                        Posterior segment of eye anomaly congenital
                                        Potter's syndrome
                                        Prader-Willi syndrome
                                        Preauricular cyst
                                        Preduodenal portal vein
                                        Preternatural anus
                                        Primary cerebellar degeneration
                                        Primary ciliary dyskinesia
                                        Primary familial hypomagnesaemia
                                        Primary hypercholesterolaemia
                                        Primary immunodeficiency syndrome
                                        Primary insulin like growth factor-1 deficiency
                                        Progeria
                                        Progressive cerebellar degeneration
                                        Progressive external ophthalmoplegia
                                        Progressive familial intrahepatic cholestasis
                                        Prominent epicanthal folds
                                        Promyelocyte count decreased
                                        Protein C deficiency
                                        Protein S deficiency
                                        Proteus syndrome
                                        Protuberant ear
                                        Proximal focal femoral deficiency
                                        Pseudocholinesterase deficiency
                                        Pseudohermaphroditism
                                        Pseudohermaphroditism female
                                        Pseudohermaphroditism male
                                        Pseudohypoaldosteronism
                                        Pseudohypoparathyroidism
                                        Pseudomembranous colitis
                                        Pseudotruncus arteriosus
                                        Pseudoxanthoma elasticum
                                        Pterygium colli
                                        Pulmonary aplasia
                                        Pulmonary arteriovenous fistula
                                        Pulmonary artery atresia
                                        Pulmonary artery stenosis congenital
                                        Pulmonary hypoplasia
                                        Pulmonary lymphangiectasia
                                        Pulmonary malformation
                                        Pulmonary renal syndrome
                                        Pulmonary sequestration
                                        Pulmonary valve stenosis congenital
                                        Pure white cell aplasia
                                        Pyloric stenosis
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CONFIDENTIAL


NN9535
NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
146 of 152
Pre-defined MedDRA search - list of preferred terms
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Rare                                    Pyogenic sterile arthritis pyoderma gangrenosum and acne
                                        syndrome
                                        Pyruvate carboxylase deficiency
                                        Pyruvate kinase deficiency anaemia
                                        Radiation leukopenia
                                        Radioulnar synostosis
                                        Rathke's cleft cyst
                                        Rectal atresia
                                        Red blood cell enzymes abnormal
                                        Refsum's disease
                                        Renal aplasia
                                        Renal arteriovenous malformation
                                        Renal dysplasia
                                        Renal fusion anomaly
                                        Renal hypoplasia
                                        Renal malposition
                                        Renal vessel congenital anomaly
                                        Reproductive tract hypoplasia, male
                                        Respiratory tract malformation
                                        Retinal anomaly congenital
                                        Retinal arteriovenous malformation
                                        Retinal coloboma
                                        Retinitis pigmentosa
                                        Retinopathy congenital
                                        Retinoschisis congenital
                                        Retroperitonitis
                                        Rett syndrome
                                        Rhesus haemolytic disease of newborn
                                        Rib hypoplasia
                                        Rib synostosis
                                        Right aortic arch
                                        Right ventricular false tendon
                                        Right-to-left cardiac shunt
                                        Riley-Day syndrome
                                        Rippling muscle disease
                                        Rotor's syndrome
                                        Rubinstein-Taybi syndrome
                                        Sacral hypoplasia
                                        Sacralisation
                                        Sandhoff disease
                                        Sarcosinaemia
                                        Scaphocephaly
                                        Schimke immunoosseous dysplasia
                                        Schinzel-Giedion syndrome
                                        Schizencephaly
                                        Scimitar syndrome
                                        Sclerotylosis
                                        Sensory neuropathy hereditary
                                        Septate hymen
                                        Septo-optic dysplasia
                                        Septum pellucidum agenesis
                                        Serotonin syndrome
                                        Sertoli-cell-only syndrome
                                        Severe myoclonic epilepsy of infancy
                                        Sex chromosome abnormality
                                        Shawl scrotum
                                        Shigella sepsis
                                        Shone complex
                                        Short-chain acyl-coenzyme A dehydrogenase deficiency
                                        Shwachman-Diamond syndrome
                                        Sickle cell anaemia
                                        Sickle cell disease
                                       Sickle cell trait
————————————————————————————————————————————————————————————————————————————————————————————————————
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CONFIDENTIAL


NN9535
NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
147 of 152
Pre-defined MedDRA search - list of preferred terms
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Rare                                    Silver-Russell syndrome
                                        Single umbilical artery
                                        Sirenomelia
                                        Sjogren-Larsson syndrome
                                        Skeletal dysplasia
                                        Skin hypoplasia
                                        Skin malformation
                                        Skull malformation
                                        Smith-Lemli-Opitz syndrome
                                        Smith-Magenis syndrome
                                        Sotos' syndrome
                                        Special senses congenital anomaly
                                        Spherophakia
                                        Spina bifida
                                        Spina bifida cystica
                                        Spina bifida occulta
                                        Spinal muscular atrophy
                                        Spine malformation
                                        Spinocerebellar ataxia
                                        Spleen malformation
                                        Spondyloepiphyseal dysplasia
                                        Stargardt's disease
                                        Stickler's syndrome
                                        Sticky platelet syndrome
                                        Strabismus congenital
                                        Sturge-Weber syndrome
                                        Sucrase-isomaltase deficiency
                                        Supernumerary nipple
                                        Supernumerary vertebra
                                        Syndactyly
                                        Synostosis
                                        Syringomyelia
                                        T-lymphocyte count abnormal
                                        T-lymphocyte count decreased
                                        Talipes
                                        Tangier disease
                                        Tay-Sachs disease
                                        Telangiectasia congenital
                                        Teratogenicity
                                        Testicular dysplasia
                                        Testotoxicosis
                                        Tetrahydrobiopterin deficiency
                                        Thalassaemia
                                        Thalassaemia alpha
                                        Thalassaemia beta
                                        Thalassaemia sickle cell
                                        Thalidomide embryopathy
                                        Thanatophoric dwarfism
                                        Thrombocytopenia
                                        Thrombocytopenia-absent radius syndrome
                                        Thymus hypoplasia
                                        Tibial agenesis
                                        Tibial torsion
                                        Tilted disc syndrome
                                        Timothy syndrome
                                        Tooth discolouration congenital
                                        Tooth hypoplasia
                                        Tooth malformation hereditary
                                        Tourette's disorder
                                        Tracheal atresia
                                        Tracheal web
                                        Tracheo-oesophageal fistula
                                        Transitional vertebrae
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CONFIDENTIAL


NN9535
NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
148 of 152
Pre-defined MedDRA search - list of preferred terms
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Rare                                    Transposition of the great vessels
                                        Trichorhinophalangeal syndrome
                                        Trifunctional protein deficiency
                                        Trimethylaminuria
                                        Triple A syndrome
                                        Trisomy 11
                                        Trisomy 13
                                        Trisomy 14
                                        Trisomy 15
                                        Trisomy 17
                                        Trisomy 18
                                        Trisomy 21
                                        Trisomy 22
                                        Trisomy 4p
                                        Trisomy 8
                                        Trisomy 9
                                        Truncus arteriosus persistent
                                        Tubulointerstitial nephritis and uveitis syndrome
                                        Tumour necrosis factor receptor-associated periodic syndrome
                                        Turner's syndrome
                                        Twin reversed arterial perfusion sequence malformation
                                        Type I hyperlipidaemia
                                        Type II hyperlipidaemia
                                        Type III hyperlipidaemia
                                        Type IIa hyperlipidaemia
                                        Type IIb hyperlipidaemia
                                        Type IV hyperlipidaemia
                                        Type V hyperlipidaemia
                                        Tyrosinaemia
                                        Uhl's anomaly
                                        Umbilical artery hypoplasia
                                        Umbilical malformation
                                        Unicuspid aortic valve
                                        Univentricular heart
                                        Urachal abnormality
                                        Urea cycle disorder
                                        Ureteric atresia
                                        Ureteric compression
                                        Ureteric dilatation
                                        Ureteric obstruction
                                        Ureteric stenosis
                                        Urethral atresia
                                        Urethral valves
                                        Urinary tract malformation
                                        Urinary tract obstruction
                                        Usher's syndrome
                                        Uterine aplasia
                                        Uterine cervix hypoplasia
                                        Uterine hypoplasia
                                        Uvula aplasia
                                        VACTERL syndrome
                                        Vaginal atresia
                                        Vaginal hypoplasia
                                        Vaginal septum
                                        Vascular malformation
                                        Velo-cardio-facial syndrome
                                        Venolymphatic malformation
                                        Ventricular hypoplasia
                                        Ventricular septal defect
                                        Vertebral artery hypoplasia
                                        Vertical talus
                                        Very long-chain acyl-coenzyme A dehydrogenase deficiency
                                        Vestibulocerebellar syndrome
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CONFIDENTIAL


NN9535
NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
149 of 152
Pre-defined MedDRA search - list of preferred terms
————————————————————————————————————————————————————————————————————————————————————————————————————
Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Rare                                    Virilism foetal
                                        Vitello-intestinal duct remnant
                                        Von Hippel-Lindau disease
                                        Von Willebrand's disease
                                        Von Willebrand's disease gene carrier
                                        Waardenburg syndrome
                                        Wagner's disease
                                        Weill-Marchesani syndrome
                                        Welander distal myopathy
                                        Werner's syndrome
                                        White blood cell analysis abnormal
                                        White blood cell count abnormal
                                        White blood cell count decreased
                                        White blood cell disorder
                                        Wildervanck syndrome
                                        Williams syndrome
                                        Winchester syndrome
                                        Wiskott-Aldrich syndrome
                                        Wolf-Hirschhorn syndrome
                                        Wolfram syndrome
                                        Wyburn Mason's syndrome
                                        X-linked chromosomal disorder
                                        XXX syndrome
                                        XXXY syndrome
                                        XXYY syndrome
                                        XYY syndrome
                                        Xeroderma pigmentosum
                                        Y-linked chromosomal disorder
                                        Young's syndrome
                                        Zhu-Tokita-Takenouchi-Kim syndrome
                                        Zika virus associated birth defect
                                        Zika virus associated microencephaly
                                        Zika virus associated ocular birth defect
Suspicion of transmission of            Air-borne transmission
infectious disease
                                        Arthropod-borne disease
                                        Bacterial disease carrier
                                        Community acquired infection
                                        Diphtheria carrier
                                        Direct infection transmission
                                        Faecal-oral transmission of infection
                                        Fungal disease carrier
                                        HIV carrier
                                        HTLV-1 carrier
                                        Human immunodeficiency virus transmission
                                        Iatrogenic infection
                                        Indirect infection transmission
                                        Infection transmission via personal contact
                                        Infection via vaccinee
                                        Infectious disease carrier
                                        Mycobacterial disease carrier
                                        Nosocomial infection
                                        Primary transmission
                                        Secondary transmission
                                        Sexual transmission of infection
                                        Sexually transmitted disease
                                        Sexually transmitted disease carrier
                                        Suspected transmission of an infectious agent via product
                                        Transmission of an infectious agent via product
                                        Transmission of an infectious agent via transplant
                                        Typhoid carrier
                                        Vaccine virus shedding
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CONFIDENTIAL


NN9535
NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
150 of 152
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Suspicion of transmission of            Vector-borne transmission of infection
infectious disease
                                       Vertical infection transmission
                                        Viral disease carrier
                                        Viral hepatitis carrier
Thyroid disorders                       Anaplastic thyroid cancer
                                        Anti-thyroid antibody
                                        Anti-thyroid antibody positive
                                        Antithyroid arthritis syndrome
                                        Atrophic thyroiditis
                                        Autoimmune hypothyroidism
                                        Autoimmune thyroid disorder
                                        Autoimmune thyroiditis
                                        Bannayan-Riley-Ruvalcaba syndrome
                                        Basedow's disease
                                        Benign neoplasm of thyroid gland
                                        Biopsy thyroid gland
                                        Biopsy thyroid gland abnormal
                                        Blood thyroid stimulating hormone abnormal
                                        Blood thyroid stimulating hormone decreased
                                        Blood thyroid stimulating hormone increased
                                        Butanol-extractable iodine decreased
                                        Butanol-extractable iodine increased
                                        Congenital hyperthyroidism
                                        Congenital hypothyroidism
                                        Congenital thyroid disorder
                                        Ectopic thyroid
                                        Endocrine ophthalmopathy
                                        Euthyroid sick syndrome
                                        Exophthalmos
                                        Familial medullary thyroid cancer
                                        Follicular thyroid cancer
                                        Free thyroxine index abnormal
                                        Free thyroxine index decreased
                                        Free thyroxine index increased
                                        Gamma radiation therapy to thyroid
                                        Generalised resistance to thyroid hormone
                                        Goitre
                                        Goitre congenital
                                        Haemorrhagic thyroid cyst
                                        Hashimoto's encephalopathy
                                        Hashitoxicosis
                                        Huerthle cell carcinoma
                                        Hyperthyroidism
                                        Hypothyroidic goitre
                                        Hypothyroidism
                                        Inappropriate thyroid stimulating hormone secretion
                                        Infectious thyroiditis
                                        Iodine uptake abnormal
                                        Iodine uptake decreased
                                        Iodine uptake increased
                                        Lid lag
                                        Malignant exophthalmos
                                        Marine Lenhart syndrome
                                        Medullary thyroid cancer
                                        Metastases to thyroid
                                        Myxoedema
                                        Myxoedema coma
                                        Orbital decompression
                                        Papillary thyroid cancer
                                        Pendred syndrome
                                        Photon radiation therapy to thyroid
————————————————————————————————————————————————————————————————————————————————————————————————————
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                                                      02JUL2019:18:22:33 - l_meddra.sas/l_meddra.txt
CONFIDENTIAL


NN9535
NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
151 of 152
Pre-defined MedDRA search - list of preferred terms
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Thyroid disorders                       Polyglandular autoimmune syndrome type II
                                        Polyglandular autoimmune syndrome type III
                                       Poorly differentiated thyroid carcinoma
                                        Post procedural hypothyroidism
                                        Primary hyperthyroidism
                                        Primary hypothyroidism
                                        Protein bound iodine decreased
                                        Protein bound iodine increased
                                        Radiation thyroiditis
                                        Radioactive iodine therapy
                                        Radiotherapy to thyroid
                                        Reverse tri-iodothyronine decreased
                                        Reverse tri-iodothyronine increased
                                        Secondary hyperthyroidism
                                        Secondary hypothyroidism
                                        Silent thyroiditis
                                        Tertiary hypothyroidism
                                        Thyreostatic therapy
                                        Thyroglobulin absent
                                        Thyroglobulin decreased
                                        Thyroglobulin increased
                                        Thyroglobulin present
                                        Thyroglossal cyst infection
                                        Thyroglossal fistula
                                        Thyroid B-cell lymphoma
                                        Thyroid C-cell hyperplasia
                                        Thyroid adenoma
                                        Thyroid atrophy
                                        Thyroid calcification
                                        Thyroid cancer
                                        Thyroid cancer metastatic
                                        Thyroid cancer recurrent
                                        Thyroid cancer stage 0
                                        Thyroid cancer stage I
                                        Thyroid cancer stage II
                                        Thyroid cancer stage III
                                       Thyroid cancer stage IV
                                        Thyroid cyst
                                        Thyroid dermatopathy
                                        Thyroid disorder
                                        Thyroid dysfunction in pregnancy
                                        Thyroid echinococciasis
                                        Thyroid electron radiation therapy
                                        Thyroid fibrosis
                                        Thyroid function test abnormal
                                        Thyroid gland abscess
                                        Thyroid gland injury
                                        Thyroid gland scan abnormal
                                        Thyroid haemorrhage
                                        Thyroid hemiagenesis
                                        Thyroid hormone replacement therapy
                                        Thyroid hormones increased
                                        Thyroid infarction
                                        Thyroid malformation
                                        Thyroid mass
                                        Thyroid neoplasm
                                        Thyroid operation
                                        Thyroid pain
                                        Thyroid releasing hormone challenge test abnormal
                                        Thyroid size decreased
                                        Thyroid steatosis
                                        Thyroid stimulating hormone deficiency
                                        Thyroid stimulating immunoglobulin increased
————————————————————————————————————————————————————————————————————————————————————————————————————
MedDRA version 21.1
                                                                   nn9535/nn9535-4114/20190704_rm_er
                                                      02JUL2019:18:22:33 - l_meddra.sas/l_meddra.txt
CONFIDENTIAL


NN9535
NN9535-4114
Clinical Trial Report
Section 16.1.9
CONFIDENTIAL
Date:
03 July 2019
Novo Nordisk
Version:
1.0
Status:
Final
Page:
152 of 152
Pre-defined MedDRA search - list of preferred terms
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Pre-defined MedDRA search               Preferred term
————————————————————————————————————————————————————————————————————————————————————————————————————
Thyroid disorders                       Thyroid therapy
                                        Thyroid tuberculosis
                                        Thyroidectomy
                                        Thyroiditis
                                        Thyroiditis acute
                                        Thyroiditis chronic
                                        Thyroiditis fibrous chronic
                                        Thyroiditis subacute
                                        Thyrotoxic cardiomyopathy
                                        Thyrotoxic crisis
                                        Thyrotoxic myopathy
                                        Thyrotoxic periodic paralysis
                                        Thyroxin binding globulin abnormal
                                        Thyroxin binding globulin decreased
                                        Thyroxin binding globulin increased
                                        Thyroxine abnormal
                                        Thyroxine decreased
                                        Thyroxine free abnormal
                                        Thyroxine free decreased
                                        Thyroxine free increased
                                        Thyroxine increased
                                        Thyroxine therapy
                                        Toxic goitre
                                        Toxic nodular goitre
                                        Transient hypothyroxinaemia of prematurity
                                        Tri-iodothyronine abnormal
                                        Tri-iodothyronine decreased
                                        Tri-iodothyronine free abnormal
                                        Tri-iodothyronine free decreased
                                        Tri-iodothyronine free increased
                                        Tri-iodothyronine free normal
                                        Tri-iodothyronine increased
                                        Tri-iodothyronine uptake abnormal
                                        Tri-iodothyronine uptake decreased
                                        Tri-iodothyronine uptake increased
                                        Ultrasound thyroid abnormal
                                        X-ray therapy to thyroid
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CONFIDENTIAL