Conditions: Diabetes Diabetes Mellitus, Type 2
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 788
Healthy volunteers: no

Brief summary:
This trial is conducted in Africa, Asia, Europe, North and South America. The aim of the trial is to compare the effect of once-weekly (OW) dosing of subcutaneous semaglutide (1.0 mg) versus once-daily dosing of oral canagliflozin (300 mg) on glycaemic control in subjects with type 2 diabetes (T2D) on a background treatment of metformin

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: Semaglutide intervention 2: Canagliflozin intervention 3: Placebo (canagliflozin) intervention 4: Placebo (semaglutide)
Intervention descriptions: intervention 1: Following a dose escalation phase of 8 weeks, semaglutide 1.0 mg once-weekly(administered subcutaneously, s.c., under the skin) and canagliflozin placebo once-daily (administered orally, as a tablet). Subjects will continue on their pre-trial daily dose of metformin. intervention 2: Following a dose escalation phase of 8 weeks, canagliflozin 300 mg once-daily (administered orally, as a tablet) and semaglutide placebo (administered subcutaneously, s.c., under the skin). Subjects will continue on their pre-trial daily dose of metformin. intervention 3: Following a dose escalation phase of 8 weeks, semaglutide 1.0 mg once-weekly(administered subcutaneously, s.c., under the skin) and canagliflozin placebo once-daily (administered orally, as a tablet). Subjects will continue on their pre-trial daily dose of metformin. intervention 4: Following a dose escalation phase of 8 weeks, canagliflozin 300 mg once-daily (administered orally, as a tablet) and semaglutide placebo (administered subcutaneously, s.c., under the skin). Subjects will continue on their pre-trial daily dose of metformin.

Protocol document:
Prot_000.pdf: 
Cover Page for Protocol 
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT03136484  
Sponsor trial ID: 
NN9535-4270 
Official title of study: 
Efficacy and Safety of Semaglutide Versus Canagliflozin as 
add-on to Metformin in Subjects With Type 2 Diabetes 
Document date: 
03 June 2019 
 


Link
Link
Link
Link
Link
List of contents
Protocol ...............................................................................................................................................
Appendix A .........................................................................................................................................
Appendix B..........................................................................................................................................
Protocol amendment 1 .......................................................................................................................
Attachment I and II............................................................................................................................
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
Semaglutide s.c.
Trial ID: NN9535-4270
Clinical Trial Report
Appendix 16.1.1
-XQH 
.
)LQDO
16.1.1 Protocol and protocol amendments
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Redacted protocol 
Includes redaction of personal identifiable information only. 
 
 
 
. 
 
 


Protocol
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Date:
17 October 2016
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Trial ID:NN9535-4270
Version:
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Protocol
Trial ID: NN9535-4270
SUSTAIN 8 – semaglutide versus canagliflozin
Efficacy and safety of semaglutide versus canagliflozin as add-on to 
metformin in subjects with type 2 diabetes
Trial phase: 3b
Protocol originator
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


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Version:
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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..................................................................................................................................................12
2
Flow chart ................................................................................................................................................15
3
Background information and rationale for the trial............................................................................18
Background information..............................................................................................................18
3.1
3.1.1
Type 2 diabetes..........................................................................................................18
3.1.2
Glucagon-like peptide-1 ............................................................................................18
3.1.3
Semaglutide ...............................................................................................................19
3.1.4
Non-clinical data........................................................................................................19
3.1.4.1
Semaglutide.........................................................................................19
3.1.5
Clinical data – semaglutide........................................................................................20
3.1.5.1
Pharmacokinetics ................................................................................20
3.1.5.2
Efficacy ...............................................................................................21
3.1.5.3
Safety...................................................................................................21
3.1.6
Canagliflozin..............................................................................................................22
Rationale for the trial...................................................................................................................22
3.2
4
Objective(s) and endpoint(s) ..................................................................................................................24
Objective(s)..................................................................................................................................24
4.1
Endpoint(s)...................................................................................................................................24
4.2
4.2.1
Primary endpoint........................................................................................................24
4.2.2
Secondary endpoints..................................................................................................24
4.2.2.1
Confirmatory secondary endpoints .....................................................24
4.2.2.2
Supportive secondary efficacy endpoints............................................24
4.2.2.3
Supportive secondary safety endpoints...............................................25
5
Trial design ..............................................................................................................................................27
Type of trial .................................................................................................................................27
5.1
Rationale for trial design..............................................................................................................28
5.2
Treatment of subjects...................................................................................................................28
5.3
5.3.1
Background medication.............................................................................................29
Injection site.................................................................................................................................29
5.4
Missed dose..................................................................................................................................29
5.5
Treatment after discontinuation of trial product ..........................................................................29
5.6
Rationale for treatment ................................................................................................................29
5.7
6
Trial population.......................................................................................................................................31
Number of subjects......................................................................................................................31
6.1
Inclusion criteria ..........................................................................................................................31
6.2
Exclusion criteria.........................................................................................................................31
6.3
Randomisation criteria (only applicable for the DXA scan sub-population)...............................33
6.4
Rescue criteria..............................................................................................................................33
6.5
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Criteria for premature discontinuation of trial product................................................................34
6.6
Withdrawal from trial ..................................................................................................................34
6.7
Subject replacement.....................................................................................................................35
6.8
Rationale for trial population.......................................................................................................35
6.9
7
Milestones.................................................................................................................................................36
8
Methods and assessments .......................................................................................................................37
Visit procedures...........................................................................................................................37
8.1
8.1.1
Investigator site log....................................................................................................37
8.1.2
Screening, Visit 1.......................................................................................................37
8.1.3
Screening failures ......................................................................................................37
8.1.4
Re-screening ..............................................................................................................38
8.1.5
Fasting visits ..............................................................................................................38
8.1.6
Unscheduled visits.....................................................................................................38
8.1.7
Phone contacts ...........................................................................................................38
8.1.8
Premature discontinuation of trial product ................................................................39
8.1.9
Withdrawal from trial ................................................................................................39
8.1.10
Investigator assessment..............................................................................................40
Subject related information/assessments .....................................................................................40
8.2
8.2.1
Demography...............................................................................................................40
8.2.2
Diabetes history and diabetes complications .............................................................41
8.2.3
Hypoglycaemia unawareness.....................................................................................41
8.2.4
Concomitant illness and medical history...................................................................41
8.2.5
Concomitant medication............................................................................................41
8.2.6
Childbearing potential................................................................................................42
8.2.7
Tobacco use ...............................................................................................................43
Efficacy assessments....................................................................................................................43
8.3
8.3.1
Height, body weight and BMI ...................................................................................43
8.3.2
Waist circumference ..................................................................................................43
8.3.3
Systolic and diastolic blood pressure.........................................................................44
8.3.4
Self-measured plasma glucose (SMPG) ....................................................................44
8.3.5
7-point profile ............................................................................................................44
8.3.6
DXA scan (sub-population only)...............................................................................45
Safety assessments.......................................................................................................................46
8.4
8.4.1
Physical examination.................................................................................................46
8.4.2
Pulse...........................................................................................................................46
8.4.3
Electrocardiogram – 12 lead......................................................................................46
8.4.4
Eye examination ........................................................................................................47
8.4.5
Adverse events...........................................................................................................47
8.4.5.1
Medication error..................................................................................47
8.4.5.2
Adverse events requiring additional data collection ...........................48
8.4.6
Hypoglycaemic episodes ...........................................................................................48
Laboratory assessments ...............................................................................................................51
8.5
8.5.1
Laboratory assessments for efficacy..........................................................................52
8.5.2
Laboratory assessments for safety .............................................................................52
Other assessments........................................................................................................................53
8.6
8.6.1
Subject diary ..............................................................................................................53
8.6.2
Electronic patient reported outcome questionnaires..................................................54
8.6.2.1
SF-36v2...............................................................................................54
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8.6.2.2
DTSQs.................................................................................................54
8.6.2.3
Control of Eating Questionnaire (CoEQ)............................................54
8.6.3
Training in the PDS290 pen-injector.........................................................................55
8.6.4
Training in blood glucose meter use..........................................................................55
Subject compliance......................................................................................................................55
8.7
9
Trial supplies ...........................................................................................................................................56
Trial products...............................................................................................................................56
9.1
Labelling......................................................................................................................................57
9.2
Storage .........................................................................................................................................57
9.3
Drug accountability and destruction............................................................................................58
9.4
Auxiliary supplies........................................................................................................................58
9.5
10 Interactive voice/web response system ..................................................................................................59
11 Randomisation procedure and breaking of blinded codes..................................................................60
Breaking of blinded codes ...........................................................................................................60
11.1
12 Adverse events, technical complaints and pregnancies .......................................................................61
Definitions ...................................................................................................................................61
12.1
12.1.1
Adverse event ............................................................................................................61
12.1.2
Serious adverse event.................................................................................................62
12.1.3
Non-serious adverse event.........................................................................................63
12.1.4
Medication errors.......................................................................................................63
12.1.5
Adverse events requiring additional data collection..................................................63
12.1.6
Technical complaints.................................................................................................64
Reporting of adverse events.........................................................................................................65
12.2
Follow-up of adverse events........................................................................................................67
12.3
Technical complaints and technical complaint samples ..............................................................68
12.4
12.4.1
Reporting of technical complaints .............................................................................68
12.4.2
Collection, storage and shipment of technical complaint samples ............................69
Pregnancies..................................................................................................................................69
12.5
12.5.1
Pregnancies in female subjects ..................................................................................69
Precautions and/or overdose ........................................................................................................71
12.6
Committees related to safety........................................................................................................71
12.7
12.7.1
Novo Nordisk safety committee ................................................................................71
12.7.2
Event adjudication committee....................................................................................71
13 Case report forms....................................................................................................................................74
Corrections to case report forms..................................................................................................74
13.1
Case report form flow..................................................................................................................75
13.2
Electronic collection of questionnaires........................................................................................75
13.3
14 Monitoring procedures ...........................................................................................................................76
15 Data management....................................................................................................................................78
16 Computerised systems.............................................................................................................................78
17 Statistical considerations ........................................................................................................................79
General considerations.................................................................................................................79
17.1
17.1.1
Data transformations..................................................................................................79
17.1.2
Definition of baseline.................................................................................................80
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17.1.3
Primary estimand.......................................................................................................80
17.1.4
Trial completion.........................................................................................................80
17.1.5
Missing data considerations at week 52.....................................................................80
Sample size calculation................................................................................................................81
17.2
17.2.1
Sample size for the sub-study (DXA scan)................................................................83
Definition of analysis sets............................................................................................................84
17.3
17.3.1
Data selections and observation periods....................................................................84
Primary endpoint..........................................................................................................................86
17.4
17.4.1
Primary analysis for the primary estimand ................................................................86
17.4.2
Primary hypotheses....................................................................................................87
17.4.3
Multiplicity and criteria for confirming hypotheses..................................................87
17.4.4
Statistical subgroup analyses of HbA1c......................................................................88
17.4.5
Sensitivity analyses....................................................................................................88
17.4.5.1
Sensitivity analyses for the primary estimand.....................................88
17.4.5.2
Other sensitivity analyses....................................................................89
Secondary endpoints....................................................................................................................89
17.5
17.5.1
Confirmatory secondary endpoints............................................................................89
17.5.2
Supportive secondary endpoints ................................................................................91
17.5.2.1
Efficacy endpoints...............................................................................91
17.5.2.2
Safety endpoints..................................................................................92
Health economics and/or patient reported outcomes (PROs) ......................................................97
17.6
18 Ethics........................................................................................................................................................98
Benefit-risk assessment of the trial..............................................................................................98
18.1
18.1.1
Risk and precautions..................................................................................................98
18.1.2
Identified risk.............................................................................................................98
18.1.3
Potential risks.............................................................................................................98
18.1.4
Other safety considerations........................................................................................99
18.1.5
Benefits....................................................................................................................101
Risk and benefit conclusion.......................................................................................................102
18.2
Informed consent .......................................................................................................................102
18.3
Data handling.............................................................................................................................103
18.4
Information to subjects during trial............................................................................................103
18.5
Premature termination of the trial and/or trial site.....................................................................103
18.6
19 Protocol compliance..............................................................................................................................104
Protocol deviations ....................................................................................................................104
19.1
Prevention of missing data.........................................................................................................104
19.2
20 Audits and inspections ..........................................................................................................................104
21 Critical documents ................................................................................................................................105
22 Responsibilities......................................................................................................................................107
23 Reports and publications......................................................................................................................108
Communication of results..........................................................................................................108
23.1
23.1.1
Authorship ...............................................................................................................109
23.1.2
Site-specific publication(s) by investigator(s) .........................................................109
Investigator access to data and review of results.......................................................................109
23.2
24 Retention of clinical trial documentation............................................................................................111
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Retention of clinical trial documentation...................................................................................111
24.1
25 Institutional Review Boards/Independent Ethics Committees and regulatory authorities............112
26 Indemnity statement .............................................................................................................................113
27 References..............................................................................................................................................114
Appendix A
Monitoring of Calcitonin
Appendix B 
Adverse events requiring additional data collection
Attachment I  Global list of key staff and relevant departments and suppliers 
Attachment II Country list of key staff and relevant departments
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Table of Figures
Page
Figure 5–1
Trial design.............................................................................................................................27
Figure 12–1
Reporting of AEs....................................................................................................................66
Figure 17–1
Graphical illustration of the closed testing procedure. ...........................................................83
Figure 17–2
Novo Nordisk classification of hypoglycaemia.....................................................................94
Figure 17–3
ADA classification of hypoglycaemia....................................................................................95
Table of Tables
Page
Table 9–1
Trial products..........................................................................................................................56
Table 9–2
Storage conditions ..................................................................................................................57
Table 12–1
Adverse events requiring completion of specific event forms and/or are subject to event 
adjudication ............................................................................................................................64
Table 12–2
Adverse events for adjudication ............................................................................................72
Table 17–1
Assumptions used in the sample size calculation...................................................................82
Table 17–2
Calculated powers for meeting individual hypotheses ...........................................................82
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List of abbreviations
ADA
American Diabetes Association
AACE
American Association of Clinical 
Endocrinologists
AE
adverse event
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
AUC
area under the curve
BG
blood glucose
BMI
body mass index
CKD-EPI
Chronic Kidney Disease 
Epidemiology Collaboration
CLAE
clinical laboratory adverse event
CoEQ
Control of Eating Questionnaire
CVOT
Cardio Vascular Outcome Trial
DFU
direction for use
DPP-4
ubiquitous dipeptidyl peptidase
DTSQs
Diabetes Treatment Satisfaction 
Questionnaire, short form
DKA
Diabetic Ketoacidosis
DUN
dispensing unit number
DXA
dual X-ray absorptiometry 
EAC
event adjudication committee
ECG
electrocardiogram
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
ePRO
electronic patient reported outcome
EMA
European Medicines Agency
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Exenatide ER
exenatide extended release 
FAS
full analysis set
FDA
U.S. Food and Drug Administration
FPFV
first patient first visit
FPG
fasting plasma glucose
GCP
Good Clinical Practice
GLP-1
glucagon-like peptide-1
GLP-1RA
glucagon-like peptide-1 receptor 
agonist
HbA1c
glycosylated haemoglobin
hCG
human chorionic gonadotrophin
HDL
high-density lipoprotein
IB
Investigator’s Brochure
ICH
International Conference on 
Harmonisation of Technical 
Requirements for Registration of 
Pharmaceuticals for Human Use
IEC
independent ethics committee
IgE
immunoglobulin E
IMP
investigational medicinal product
IRB
institutional review board
IWRS
interactive web response system
i.v.
Intravenous
LDL
low-density lipoprotein
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LLOQ
lower limit of qualification
LOCF 
Last observation carried forward
LPFV
last patient first visit
LPLV
last patient last visit
MACE
major adverse cardiac events
MAR
missing at random
MedDRA
Medical Dictionary for Regulatory 
Activities
MEN 2
Multipel endokrin neoplasi typ 2 
MI 
Myocardial infarction
MMRM
Mixed Model for Repeated 
Measurements
NIMP
non-investigational medicinal 
products
NOAEL
no observable adverse  event effect 
level
NYHA
New York Heart Association
OAD
oral antidiabetic drug
OW
Once weekly
P
phone contact
PG
plasma glucose
PK
Pharmacokinetics
PMM
Pattern mixture model
PP
per protocol
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PRO
patient reported outcome
SAE
serious adverse event
SAP
statistical analysis plan
SAS
statistical analysis set
s.c.
subcutaneous(ly)
SF-36v2TM
Short form healthy survey
SDV
source data verification
SIF
safety information form
SGLT-2
Sodium-glucose co-transporter-2
SmPC
summary of product characteristics
SMPG
self-measured plasma glucose
SUSAR
suspected unexpected serious adverse 
reaction
T2D
Type 2 diabetes mellitus
TMM
Trial Materials Manual
UNL
upper normal limit
UNR
upper normal range
UTN
Universal Trial Number
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1
Summary
Objective(s) and endpoint(s):
Primary objective
To compare the effect of once-weekly (OW) dosing of subcutaneous semaglutide (1.0 mg) versus 
once-daily dosing of oral canagliflozin (300 mg) on glycaemic control in subjects with type 2 
diabetes (T2D) on a background treatment of metformin.
Secondary objectives
To compare the effects of semaglutide s.c. 1.0 mg once-weekly versus canagliflozin 300 mg once-
daily after 52 weeks of treatment in subjects with T2D with regards to:
!
Weight management
!
Other parameters of effect, safety and Patient Reported Outcomes
Endpoint(s)
Primary endpoint
!
Change from baseline to week 52 in HbA1c
Supportive secondary efficacy endpoints
Change from baseline to week 52 in:
!
Fasting Plasma Glucose (FPG)*
!
Systolic and diastolic blood pressure*
!
Diabetes Treatment Satisfaction Questionnaire (DTSQ)*: Treatment satisfaction score (sum of 6 
of 8 items) and the 8 items separately
Trial design:
This is a 52-week, confirmatory, randomised, double-blind, double dummy, active-controlled, 
multicentre, multinational, two-arm, parallel-group trial.
Subjects with type 2 diabetes inadequately controlled with metformin alone will after approximately 
2 weeks screening period be randomised in a 1:1 manner to receive either a dose of 1.0 mg 
semaglutide once-weekly or 300 mg canagliflozin once-daily.
After a period of approximately 52 weeks in total, all subjects enter a follow up period of 5 weeks 
ended by a follow-up visit. Total trial duration for the individual subjects will be approximately 59 
weeks.
Trial population:
A planned total number of 784 subjects will be randomised in a 1:1 manner. 
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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. Diagnosed with type 2 diabetes mellitus (T2D).
4. HbA1c of 7.0-10.5% (53-91 mmol/mol, both inclusive).
5. Stable daily dose of metformin (≥1500 mg or maximum tolerated dose as documented in the 
subject medical record and in compliance with current local label) for at least 90 days prior 
to the day of screening.
Exclusion criteria
For an eligible subject, all exclusion criteria must be answered “no”. 
1. Known or suspected hypersensitivity to trial product(s) or related products. 
2. Previous participation in this trial. Participation is defined as signed informed consent.
3. Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing 
potential and not using an adequate contraceptive method (adequate contraceptive measure 
as required by local regulation or practice).
4. Participation in any clinical trial of an approved or non-approved investigational medicinal 
product within 90 days prior to the day of screening. 
5. Any disorder which in the investigator’s opinion might jeopardise subject’s safety or 
compliance with the protocol.
6. Subject with alanine aminotransferase (ALT) >2.5 x upper normal limit (UNL).
7. Family or personal history of multiple endocrine neoplasia type 2 or medullary thyroid 
carcinoma. Family is defined as a first degree relative.
8. History or presence of pancreatitis (acute or chronic).
9. History of diabetic ketoacidosis (DKA).
10. Any of the following: myocardial infarction (MI), stroke, hospitalization for unstable angina 
or transient ischaemic attack within the past 180 days prior to the day of screening.
11. Subjects presently classified as being in New York Heart Association (NYHA) Class IV.
12. Planned coronary, carotid or peripheral artery revascularisation known on the day of 
screening.
13. Renal impairment measured as eGFR <60 ml/min/1.73 m2 as defined by Kidney Disease 
Improving global outcomes (KDIGO 2012)1 classification using isotope dilution mass 
spectrometry (IDMS) for serum creatinine measured at screening. 
14. Treatment with any medication for the indication of diabetes or obesity other than stated in 
the inclusion criteria within the past 90 days prior to the day of screening. However, short 
term insulin treatment for a maximum of 14 days prior to the day of screening is allowed.
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15. Proliferative retinopathy or maculopathy requiring acute treatment. Verified by fundus 
photography or dilated fundoscopy performed within the past 90 days prior to 
randomisation.
16. Presence or history of malignant neoplasms within the past 5 years prior to the day of 
screening. Basal and squamous cell skin cancer and any carcinoma in-situ is allowed.
Assessments:
!
Glucose metabolism (HbA1c, fasting plasma glucose)
!
Body measurements (weight (kg), body mass index (BMI), waist circumference, total fat 
mass (kg) and total lean mass measured by DXA in a sub-population)
!
Blood pressure
!
Fasting blood lipids (total cholesterol, LDL, HDL and triglycerides)
!
Self-measured plasma glucose (7-point profile)
!
Patient reported outcomes
!
Adverse events and serious adverse events
!
Hypoglycaemic episodes
!
Biochemistry and haematology
!
Pulse
!
Calcitonin and creatinine
!
Physical examination 
!
Electrocardiogram
!
Dilated fundoscopy/fundophotography
Trial product(s):
The following trial products will be provided by Novo Nordisk A/S, Denmark.
Investigational medicinal products:
!
Test product: Semaglutide 1.34mg/ml, solution for injection, 1.5 mL prefilled PDS290 pen-
injector
!
Reference therapy: Canagliflozin100 mg/300 mg, tablets
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Protocol
UTN:U1111-1180-3651 
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2
Flow chart
Trial Periods
Screening Randomisation
Treatment
End of 
Treatment
Follow-
up
End of 
treatment, 
Premature 
discontinuation
Follow-
up
Visit (V)/ phone contact (P)
V1
V2
V3
V4
P5
V6
V7
V8
V9
V10
P11
V10A
P11A
Timing of visit (weeks)
-2
0
4
8
10
12
16
28
40
52
57
Visit window (days)
±7
±3
±3
±3
±7
±7
±7
±7
±7
+7
SUBJECT RELATED
INFO/ASSESSMENTS
Section
Informed consent
18.3
x
In/exclusion criteria
6.2, 6.3
x
x
Randomisation
6.4
x
Withdrawal criteria
6.7
x
x
x
x
x
x
x
x
x
Concomitant illness
8.2.4
x
Concomitant medication
8.2.5
x
x
x
x
x
x
x
x
x
x
x
x
x
Demography
8.2.1
x
Hypoglycaemia unawareness
8.2.3
x
Diagnosis of diabetes
8.2.2
x
Diabetes history and diabetes 
complications 
8.2.2
x
Medical history
8.2.4
x
Tobacco use
8.2.7
x
EFFICACY
Height
8.3.1
x
Body weight
8.3.1
x
x
x
x
x
x
x
x
x
BMI
8.3.1
x
x
x
x
x
x
x
x
x
Waist circumference
8.3.1
x
x
x
x
PRO questionnaires
8.6.2
x
x
x
x


Protocol
UTN:U1111-1180-3651 
Date:
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Trial Periods
Screening Randomisation
Treatment
End of 
Treatment
Follow-
up
End of 
treatment, 
Premature 
discontinuation
Follow-
up
Visit (V)/ phone contact (P)
V1
V2
V3
V4
P5
V6
V7
V8
V9
V10
P11
V10A
P11A
Timing of visit (weeks)
-2
0
4
8
10
12
16
28
40
52
57
Visit window (days)
±7
±3
±3
±3
±7
±7
±7
±7
±7
+7
SUBJECT RELATED
INFO/ASSESSMENTS
EFFICACY cont.
Section
Systolic blood pressure
8.3.3
x
x
x
x
x
x
x
x
x
x
Diastolic blood pressure
8.3.3
x
x
x
x
x
x
x
x
x
x
Fasting plasma glucose
8.5.1
x
x
x
x
x
x
x
x
x
HbA1c
8.5.1
x
x
x
x
x
x
x
x
x
x
Lipids
8.5.1
x
x
x
x
7-point profile
8.3.5
x
x
x
x
DXA scan
8.3.6
x
x
x
SAFETY
Hypoglycaemic episodes
8.4.6
x
x
x
x
x
x
x
x
x
x
x
x
ECG
8.4.3
x
x
x
x
Eye examination
8.4.4
x
x
x
Physical examination
8.4.1
x
x
x
x
Pulse, sitting
8.4.2
x
x
x
x
x
x
x
x
x
x
Biochemistry
8.5.2
x
x
x
x
x
x
x
x
x
x
Creatinine (including eGFR)
8.5.2
x
x
x
x
x
x
x
x
x
x
Haematology
8.5.2
x
x
x
x
x
x
x
x
x
Pregnancy test
8.5.2
x
x
x
x
x
Adverse events
12.1.1
x
x
x
x
x
x
x
x
x
x
x
x
Calcitonin
8.5.2
x
x
x
x


Protocol
UTN:U1111-1180-3651 
Date:
17 October 2016
Status:
Final
1RYR1RUGLVN
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EudraCT no.:2016-000989-35
Version:
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Trial Periods
Screening Randomisation
Treatment
End of 
Treatment
Follow-
up
End of 
treatment, 
Premature 
discontinuation
Follow-
up
Visit (V)/ phone contact (P)
V1
V2
V3
V4
P5
V6
V7
V8
V9
V10
P11
V10A
P11A
Timing of visit (weeks)
-2
0
4
8
10
12
16
28
40
52
57
Visit window (days)
±7
±3
±3
±3
±7
±7
±7
±7
±7
+7
SUBJECT RELATED
INFO/ASSESSMENTS
TRIAL MATERIAL cont.
Section
Dispensing visit
x
x
x
x
x
x
x
Drug accountability
x
x
x
x
x
x
x
x
IWRS call
10
x
x
x
x
x
x
x
x
x
x
REMINDERS
Fasting visits
8.1.5
x
x
x
x
x
x
x
x
x
Hand-out direction for use 
(DFU)
x
End of treatment
x
x
End of trial
xa
Hand-out and instruct on BG 
meter use
x
Re-training on the BG meter use
x
Training in trial product and pen 
handling
x
x
Hand out ID card
x
Hand out and instruct in diary
8.6.1
x
x
x
x
x
x
x
x
Collect and review diary
x
x
x
x
x
x
x
x
x
a If premature discontinuation, End of Treatment form must be filled-in when the discontinuation happens and End of Trial form at scheduled visit P11. If a subject completes both the 
treatment and the trial at scheduled time, the End of Treatment form must be filled at V10 and End of Trial form to be filled in at P11. 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:
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Version:
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UTN:U1111-1180-3651 
Status:
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3
Background information and rationale for the trial
The trial will be conducted in compliance with this protocol, ICH GCP2 and applicable regulatory 
requirements, and in accordance with the Declaration of Helsinki3. 
For Mexico only: The above will include the following responsibilities for the head of the 
Institution/Health Care Establishment, Ethics, Research and, when applicable, Biosafety 
Committees and sponsor within their scope of responsibility: 
a) Investigation follow-up
b) Damages to health arising from the investigation development; as well as those arising from 
interruption or advanced suspension of treatment due to non-attributable reasons to the 
Subject;
c) Timely compliance of the terms in which the authorization of a research for health in human 
beings had been issued;
d) To present in a timely manner the information required by the Health Authority
In this document, the term investigator refers to the individual responsible for the overall conduct of 
the clinical trial at a trial site.
Background information
3.1
3.1.1
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 liver4.
Optimal glycaemic control is the treatment goal in subjects with T2D in order to prevent long-term 
complications associated with chronic hyperglycaemia5. Despite the availability of several 
antidiabetic drugs, a significant proportion of subjects with T2D do not achieve the recommended 
blood glucose (BG) target levels6, 7.
3.1.2
Glucagon-like peptide-1
Glucagon-like peptide-1 (GLP-1) is an incretin hormone with a glucose-dependent stimulatory 
effect on insulin and inhibitory effect on glucagon secretion from the pancreatic islets8, 9. Subjects 
with T2D have a decreased incretin effect10-13. However, the insulinotropic action of GLP-1 and 
thus, the ability to lower blood glucose (BG) levels, is preserved when GLP-1 is administered at 
supraphysiological levels14. In addition, supraphysiological levels of GLP-1 induce reduction in 
body weight15. 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 regulation16, 17. Physiologically, GLP-1 
also has a pronounced inhibitory effect on gastric emptying; however this effect seems to diminish 
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Date:
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upon chronic stimulation of the GLP-1 receptor15-17. These mechanisms of action make glucagon-
like peptide-1 receptor agonists (GLP-1RAs) an attractive pharmacological treatment for T2D18-20.
3.1.3
Semaglutide
Semaglutide is a potent human GLP-1 analogue with a pharmacokinetic (PK) profile suitable for 
once-weekly subcutaneous (s.c.) administration. It is structurally similar to liraglutide (Victoza®), a 
once-daily GLP-1RA developed by Novo Nordisk and approved worldwide for the treatment of 
T2D. The extended half-life of the semaglutide molecule is primarily obtained due to binding to 
albumin, which is 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 to increase stability against 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 di-acid with a terminal 
acidic group21, 22. The spacer and the fatty acid both contribute to increased albumin binding, which 
results in a prolonged half-life of approximately 1 week, making semaglutide suitable for once 
weekly (OW) s.c. administration.
3.1.4
Non-clinical data
3.1.4.1
Semaglutide
The nonclinical programme for semaglutide was designed according to the ICH M323 guideline to 
support the clinical development. The standard nonclinical data package required to support phase 3 
clinical trials has been completed. In addition, 2-year carcinogenicity studies and a pre- and 
postnatal development toxicity study have been completed. 
Semaglutide 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 and are detailed below.
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 low24.
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 
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Date:
17 October 2016
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Version:
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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  
event 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),25 or any updates hereof.
3.1.5
Clinical data – semaglutide
As of 1 August 2016, 16 clinical pharmacology trials (trials 1820, 3679, 3633, 3616, 3819, 4010, 
3789, 3652, 3685, 3634, 3687, 3817, 3818, 3684, 3651 and 3635) and 1 phase 2 trial (trial 1821) 
and 8 phase 3a trials (NN9535-3623, 3624, 3625,3626, 3627, 3744, 4091, 4092) have been 
completed with semaglutide s.c.OW.
Clinical pharmacology trials were conducted in healthy subjects, in subjects with T2D, in subjects 
with obesity and in subjects with renal- and hepatic impairment. 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 
antiglycaemic 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. 
3.1.5.1
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 36−60 hours post-dosing and an 
elimination half-life (t½) of approximately 1 week (149−165 hours). The absolute bioavailability of 
semaglutide s.c. was estimated to be 89%. 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.
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Date:
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3.1.5.2
Efficacy
Based on results from the clinical pharmacology trials, semaglutide treatment, compared to placebo, 
reduced both fasting and postprandial plasma glucose by improving multiple aspects of beta-cell 
function and by reducing both fasting and postprandial glucagon concentrations, all in a glucose 
dependent manner. The body 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.
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, exanatide extended release (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 ADA and AACE-
defined treatment targets 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 change in HbA1c were substantiated by improvements in secondary 
glycaemia-related supportive endpoints.26-29
3.1.5.3
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 reported adverse 
events (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 SU or insulin. In line with findings for other GLP-1RAs, 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. 
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Date:
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Version:
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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)30. 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 placebo30. 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 and non-fatal stroke by 13% versus placebo 31. A post-marketing 
cardiovascular outcomes trial on canagliflozin (CANVAS) is ongoing and results are expected in 
Q1 2017, see https://clinicaltrials.gov/ct2/show/NC01032629.
The overall safety profile of semaglutide in the SUSTAIN 6 trial (NN9535-3744) was consistent 
with previous 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 Section 18 for more details.
Please see the current edition of semaglutide s.c. (NN9535) IB or any updates hereof for further 
details25.
For an assessment of benefits and risks of the trial, see Section 18.1.
3.1.6
Canagliflozin
The selected active comparator in this trial is canagliflozin, a selective inhibitor of the sodium-
glucose co-transporter-2 (SGLT-2), which is the predominant transporter responsible for glucose 
reabsorption from the glomerular filtrate back into the circulation. Inhibition of SGLT-2 reduces 
BG levels by blocking renal glucose reabsorption, thereby increasing urinary glucose excretion. The 
amount of glucose removed by the kidney through this glucuretic mechanism is dependent on the 
BG concentration and renal function. Canagliflozin was developed by Janssen Pharmaceuticals and 
approved in 2013 in the US to improve glycaemic control in adults with T2D.
For further details, please see the current approved label for canagliflozin32.
For an assessment of benefits and risks of the trial, see section 18.1.
Rationale for the trial
3.2
The currently available treatment modalities for T2D are still not satisfactory and there is a 
significant proportion of patients not reaching the treatment targets 6. 
The aim for the present trial is to compare the effect of semaglutide versus canagliflozin, in subjects 
with T2D inadequately controlled with metformin, in terms of glycaemic control, weight 
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Protocol
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Date:
17 October 2016
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Version:
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Status:
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management and other efficacy parameters. This trial is also designed to compare safety profile, 
tolerability and patient satisfaction.
In order to further investigate the effects of semaglutide vs canagliflozin on body weight, a sub-
study on body composition has been implemented in this trial, which will allow collection of 
information on changes in body fat and lean mass.
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Protocol
CONFIDENTIAL
Date:
17 October 2016
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Version:
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Status:
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4
Objective(s) and endpoint(s)
Objective(s)
4.1
Primary objective
To compare the effect of once-weekly dosing of subcutaneous semaglutide (1.0 mg) versus once-
daily dosing of oral canagliflozin (300 mg) on glycaemic control in subjects with T2D on a 
background treatment of metformin.
Secondary objective
To compare the effect of semaglutide s.c. 1.0 mg once-weekly versus canagliflozin 300 mg once-
daily after 52 weeks of treatment in subjects with T2D with regards to:
!
Weight management
!
Other parameters of effect, safety and Patient Reported Outcomes (PRO)
Endpoint(s)
4.2
4.2.1
Primary endpoint
!
Change from baseline to week 52 in HbA1c
4.2.2
Secondary endpoints
4.2.2.1
Confirmatory secondary endpoints
Change from baseline to week 52 in 
!
body weight (kg)
In a sub-set of subjects assessed through dual X-ray absorptiometry (DXA):
!
Total fat mass (kg)
4.2.2.2
Supportive secondary efficacy endpoints
Change from baseline to week 52 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)
!
Fasting blood lipids (total cholesterol, low density lipoprotein cholesterol (LDL), high 
density lipoprotein cholesterol (HDL), triglycerides)
!
Systolic and diastolic blood pressure*
!
Body Mass Index (BMI) and waist circumference
!
Body weight (%)
!
Scores for selected patient reported outcomes:
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Date:
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o
SF-36v2TM Short Form health survey: Total scores (physical component and mental 
component) and scores from the 8 domains
o
Diabetes Treatment Satisfaction Questionnaire (DTSQ)*: Treatment satisfaction 
score (sum of 6 of 8 items) and the 8 items separately
o
Control of Eating Questionnaire (CoEQ): Scores from the 4 domains and scores from 
19 individual items
In a sub-set of subjects, assessed through DXA, change from baseline to week 52 in:
!
Total fat mass (%)
!
Total lean mass (kg)
!
Total lean mass (%)
!
Visceral fat mass (kg)a
!
Visceral fat mass (%)a
!
Ratio between total fat mass and total lean mass
aanalyses marked with an ‘a’ will be performed based on specific DXA equipment and software 
availability.
Subjects who after 52 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 ≥3%
!
Weight loss ≥5%
!
Weight loss ≥10%
!
HbA1c <7.0% (53 mmol/mol) without severe or blood glucose confirmed symptomatic 
hypoglycaemia episodes and no weight gain
!
HbA1c reduction ≥1%
!
HbA1c reduction ≥1% and weight loss ≥3%
!
HbA1c reduction ≥1% and weight loss ≥5%
!
HbA1c reduction ≥1% and weight loss ≥10%
4.2.2.3
Supportive secondary safety endpoints
!
Number of treatment emergent adverse events (TEAEs)
!
Number of treatment emergent severe or blood glucose confirmed symptomatic hypoglycaemic 
episodes
!
Treatment emergent severe or blood glucose confirmed symptomatic hypoglycaemia episodes 
(yes/no)
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Date:
17 October 2016
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Version:
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Change from baseline to week 52 in:
!
Haematology
!
Biochemistry
!
Calcitonin
!
Pulse
!
Electrocardiogram (ECG) category
!
Physical examination category
!
Eye examination category
Key supportive secondary endpoints prospectively selected for disclosure (e.g. clinicaltrials.gov and 
EudraCT) are marked with an asterisk (*).
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Date:
17 October 2016
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Trial ID:NN9535-4270
Version:
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Status:
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5
Trial design
Type of trial
5.1
This is a 52-week, confirmatory, randomised, double-blind, double dummy, active-controlled, 
multicentre, multinational, two-arm, parallel-group trial.
Subjects with T2D inadequately controlled on metformin alone, will after approximately 2 weeks 
screening period, be randomised in a 1:1 manner to receive either semaglutide 1.0 mg once-weekly 
and canagliflozin placebo once-daily, or canagliflozin 300 mg once-daily and semaglutide placebo 
once-weekly after a dose escalation phase of 8 weeks, see Figure 5–1.
Subjects continue participation in the trial regardless of premature discontinuation of trial product 
or the initiation of rescue medication. 
After the treatment period of approximately 52 weeks in total, all subjects enter a follow-up period 
of 5 weeks which ends by a follow-up visit. Total trial duration for the individual subjects is 
approximately 59 weeks.
The randomisation will be stratified according to the participation in the sub-study (yes or no) in 
order to ensure balanced treatment allocation within the sub-study.
The trial design is summarised schematically in Figure 5–1.
Figure 5–1
Trial design
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Date:
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Trial ID:NN9535-4270
Version:
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Rationale for trial design
5.2
This trial has been designed as a double-blind, two-arm, parallel-group trial to compare the effect of 
semaglutide s.c. 1.0 mg once-weekly versus canagliflozin 300 mg once-daily, as add-on to 
metformin, in terms of glycaemic control, weight management and other effect parameters. 
Furthermore, the trial is designed to address and compare safety, tolerability, patient well-being and 
treatment satisfaction. Body composition will be measured using dual energy x-ray absorptiometry 
(DXA) in a subset of 174 subjects (87 subjects per treatment arm) at V1 and V10 or V10A.
Semaglutide is administered as s.c. injections and canagliflozin as oral tablets. In order to fulfil 
blinding of the trial, a double-dummy design has been implemented. Accordingly, all subjects 
randomised to semaglutide s.c. will also receive canagliflozin placebo tablets, while subjects 
randomised to canagliflozin will also receive semaglutide placebo s.c. injections.
The treatment duration is 52 weeks, considered adequate for assessment of effect, safety, 
tolerability and patient satisfaction.
The follow-up period is 5 weeks to allow for wash-out of semaglutide. 
Treatment of subjects
5.3
Semaglutide treatment arm
Treatment with semaglutide, once-weekly must follow a fixed dose escalation. The maintenance 
dose of semaglutide 1.0 mg is reached after 4 doses (4 weeks) of 0.25 mg, followed by 4 doses (4 
weeks) of 0.5 mg. During the final maintenance period (V4-V10, see Table 5–1), doses must not be 
changed. . In addition, all subjects randomised to semaglutide will receive canagliflozin placebo 
once-daily.
Canagliflozin treatment arm
Treatment with canagliflozin, once-daily must follow a fixed dose escalation. The maintenance dose 
of canagaliflozin 300 mg is reached after 56 doses (8 weeks) of 100 mg. After the maintenance dose 
of 300 mg is reached the dose must not be changed during the course of the trial unless the eGFR 
falls <45mL/min/1.73 m2, see below. In addition, all subjects randomised to canagliflozin will 
receive semaglutide placebo once-weekly.
Treatment with canagliflozin must be in compliance with current local prescribing information. 
Canagliflozin should be taken orally once a day, preferably before the first meal of the day. Tablets 
should be swallowed whole. Treatment with canagliflozin or canagliflozin placebo should be 
temporarily stopped in subjects who are hospitalized for major surgical procedures or acute serious 
medical illnesses. In subjects whose eGFR falls persistently <60 mL/min/1.73 m2, the dose of 
canagliflozin or canagliflozin placebo should be reduced to 100 mg once-daily. The dose can be re-
escalated to 300 mg once-daily in case the renal function improves (eGFR ≥60 mL/min/1.73 m2) 
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Date:
17 October 2016
1RYR1RUGLVN
Trial ID:NN9535-4270
Version:
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UTN:U1111-1180-3651 
Status:
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during the trial. If the eGFR falls <45 mL/min/1.73 m2, treatment with all trial products should be 
discontinued (see section 6.6)1.
5.3.1
Background medication
The only allowed diabetes background medication is metformin. After signing the informed 
consent, subjects must continue pre-trial dose (≥1500 mg or maximum tolerated dose as 
documented in the subject medical record and in accordance with current local label) of metformin
throughout the entire treatment period, at the same dose level as given at trial entrance and with the 
same frequency, unless rescue criteria (see section 6.5) are met.
Metformin
Metformin is considered non-investigational medicinal product (NIMP) and will not be provided by 
Novo Nordisk, except if required by local regulations. Metformin should be used in accordance 
with standard of care in the individual country at the discretion of the investigator and in 
compliance to the current local label.
Injection site
5.4
Semaglutide (and semaglutide placebo) is administered subcutaneously by injections in the thigh, 
abdomen or upper arm, at any time of the day irrespective of meals. Injections should be 
administered on the same day of the week during the trial. Injections should not be administered 
intravenously or intramuscularly.
Missed dose 
5.5
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) away. 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 time of the week.
If a canagliflozin dose is missed it should be taken as soon as the subject remembers; however, a 
double dose should not be taken on the same day.
Treatment after discontinuation of trial product
5.6
When discontinuing trial products, either at the scheduled end of treatment visit or if trial product is 
discontinued prematurely, the subject should be switched to a suitable marketed product at the 
discretion of the investigator, while taking into consideration the long half-life of semaglutide.
For Brazil only: At the end of the trial, all participant subjects should be assured the access to the 
best proved prophylactic, diagnostic and therapeutic methods identified during the trial.
Rationale for treatment
5.7
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Date:
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Version:
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Semaglutide has been developed for s.c. administration. The dose of 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 subjects. Hence, the duration and the dose of the randomised treatments are 
considered adequate for obtaining meaningful information on effect and safety in accordance with 
the trial objectives. Subjects will be enrolled for a treatment period of 52 weeks in order to enable
evaluation of the full effect and durability of the primary and secondary endpoints as well as 
reasonable safety assessment.
For semaglutide, the three dose levels (0.25, 0.5 and 1.0 mg), have been chosen based on data from 
the phase 2 dose-finding trial. This regimen has shown the optimal benefit-risk profile for further 
development for treatment of T2D in the SUSTAIN programme25.
Canagliflozin has been chosen as active comparator since it is an established OAD within the drug 
class of SGLT-2 inhibitors and treatment will be initiated with 100 mg in accordance with the 
current approved EU-PI32.
Both s.c. semaglutide and oral canagliflozin will be dose escalated to their highest respective 
maintenance doses to investigate and compare the maximum efficacy of the two medications when 
added to metformin.
The duration of randomised treatments is considered adequate to collect sufficient data on effect 
and safety in accordance with the trial objectives.
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Date:
17 October 2016
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Trial ID:NN9535-4270
Version:
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UTN:U1111-1180-3651 
Status:
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6
Trial population
Number of subjects
6.1
Number of subjects planned to be screened (meaning the number of subjects providing 
informed consent): 
1307
Number of subjects planned to be randomised in a 1:1 manner: 
784
Number of subjects planned to be randomised in sub-study on body composition: 
174
Number of subjects planned to complete the trial on randomised trial product without 
rescue medication.
549
For Mexico only: Approximately 75 subjects are planned to be screened and 45 subject 
are planned to be randomised in Mexico.
Inclusion criteria
6.2
For an eligible subject, all inclusion criteria must be answered “yes”. 
1. Informed consent obtained before any trial-related activities. Trial-related activities are any 
procedures that are carried out as part of the trial, including activities to determine suitability 
for the trial.
2. Male or female, age above or equal to 18 years at the time of signing informed consent.
3. Diagnosed with type 2 diabetes mellitus (T2D).
4. HbA1c of 7.0-10.5% (53-91 mmol/mol, both inclusive).
5. Stable daily dose of metformin (≥1500 mg or maximum tolerated dose as documented in the 
subject medical record and in compliance with current local label) for at least 90 days prior 
to the day of screening.
Exclusion criteria
6.3
For an eligible subject, all exclusion criteria must be answered “no”. 
1. Known or suspected hypersensitivity to trial product(s) or related products. 
2. Previous participation in this trial. Participation is defined as signed informed consent.
For Brazil Only: Participation in other trials within one year prior to screening visit (Visit 
1) unless there is a direct benefit to the research subject at the investigator's discretion.
3. Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing 
potential and not using an adequate contraceptive method (adequate contraceptive measure 
as required by local regulation or practice).
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Date:
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Version:
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Status:
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For Brazil only: For women who expressly declare free of the risk of pregnancy, either by 
not engaging in sexual activity or by having sexual activity with no birth potential risk, use 
of contraceptive method will not be mandatory.
For EU countries only:
The following contraceptive measures are considered adequate:
!
Combined estrogen and progestogen containing hormonal contraception associated 
with inhibition of ovulation (oral, intravaginal, transdermal)
!
Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, 
injectable, implantable)
!
Placement of an intrauterine device (IUD) or intrauterine hormone-releasing system 
(IUS)
!
Bilateral tubal occlusion
!
Barrier methods of contraception (condom or occlusive cap with spermicidal 
foam/gel/film/cream/suppository). (Not applicable for Sweden and the UK). 
!
Vasectomised partner (where partner is sole partner of subject) and that the 
vasectomised partner has received medical assessment of the surgical success.
!
True sexual abstinence. Sexual abstinence is defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the trial treatments. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the subject.
4. Participation in any clinical trial of an approved or non-approved investigational medicinal 
product within 90 days prior to the day of screening.
5. Any disorder which in the investigator’s opinion might jeopardise subject’s safety or 
compliance with the protocol.
6. Subjects with ALT >2.5 x upper normal limit (UNL).
7. Family or personal history of multiple endocrine neoplasia type 2 or medullary thyroid 
carcinoma. Family is defined as a first degree relative.
8. History or presence of pancreatitis (acute or chronic).
9. History of diabetic ketoacidosis (DKA).
10. Any of the following: myocardial infarction (MI), stroke, hospitalization for unstable angina 
or transient ischaemic attack within the past 180 days prior to the day of screening.
11. Subjects presently classified as being in New York Heart Association (NYHA) Class IV.
12. Planned coronary, carotid or peripheral artery revascularisation known on the day of 
screening.
13. Renal impairment measured as eGFR <60 ml/min/1.73 m2 as defined by Kidney Disease 
Improving global outcomes (KDIGO 2012)1 classification using isotope dilution mass 
spectrometry (IDMS) for serum creatinine measured at screening. .
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Date:
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Version:
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Status:
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14. Treatment with any medication for the indication of diabetes or obesity other than stated in 
the inclusion criteria within the past 90 days prior to the day of screening. However, short 
term insulin treatment for a maximum of 14 days prior to the day of screening is allowed.
15. Proliferative retinopathy or maculopathy requiring acute treatment. Verified by fundus 
photography or dilated fundoscopy performed within the past 90 days prior to 
randomisation.
16. Presence or history of malignant neoplasms within the past 5 years prior to the day of 
screening. Basal and squamous cell skin cancer and any carcinoma in-situ are allowed.
Randomisation criteria (only applicable for the DXA scan sub-population)
6.4
To be randomised, all randomisation criteria must be answered “yes”.
1. The quality evaluation of the baseline DXA scan needs to be performed and found 
acceptable by the imaging laboratory prior to randomisation.
Rescue criteria
6.5
Subjects with persistent and unacceptable hyperglycaemia should be offered treatment 
intensification and the conclusion of the consideration to be documented in the medical records. If 
any of the FPG values (see section 8.5.1) (including protocol scheduled fasting SMPG, see section 
8.6.1) exceed the limits outlined below and no intercurrent cause of the hyperglycaemia can be 
identified, a confirmatory FPG (at central laboratory) should be obtained by calling the subject for a 
re-test. 
!
13.3 mmol/L (240 mg/dL) from week 8 to end of week 13
!
11.1 mmol/L (200 mg/dL) from week 14 to end of treatment
In addition, subject should be offered rescue medication if:
!
HbA1c (at central laboratory) >8.5 % (69.4 mmol/mol) from week 26 to end of 
treatment.
If the confirmatory FPG also exceeds the value described above, the subject should be offered 
rescue medication (i.e. intensification of anti-diabetic background medication and/or initiation of 
new anti-diabetic medication).
It is important for trial integrity that only subjects actually needing treatment intensification (as 
defined above) are started on rescue medication. Subjects that are started on rescue medication 
should continue to follow the protocol-specified visit schedule. Rescue medication should be 
prescribed at the investigator’s discretion as add-on to randomised treatment and according to 
American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) 
guidelines33, 34 (excluding GLP-1RAs, DPP-4 inhibitors, amylin analogues and SGLT-2). 
Rescue medication and any changes hereto should be captured on the concomitant medication form 
in the electronic case report form (eCRF), see Section 13. Rescue medication is considered to be 
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Date:
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Version:
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Status:
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NIMP and will not be provided by Novo Nordisk, unless required by the country’s Health Authority 
or IEC/IRB.
Criteria for premature discontinuation of trial product 
6.6
All efforts should be made to keep the subject on trial product. However, the subject might be 
prematurely discontinued from trial product at the discretion of the investigator due to a safety 
concern. 
If so, all efforts must be made to ensure the subjects attend and complete all scheduled visit 
procedures. Subjects should stay in the trial irrespective of lack of adherence to randomised 
treatment, lack of adherence to visit schedule or missing assessments. Only subjects who decline 
any further contact with the site in relation to the trial will be considered as withdrawn from the trial 
(see Section 6.7).
The subject must be prematurely discontinued from trial product, if the following applies:
1. Included in the trial in violation of the inclusion and/or exclusion criteria
2. Safety concern related to trial product or unacceptable intolerability at the discretion of the
investigator
3. Pregnancy*
4. Intention of becoming pregnant*
5. Simultaneous participation in another clinical trial of an approved or non-approved
investigational medicinal product.
6. If the eGFR falls persistently <45 mL/min/1.73m2, treatment with any trial product should
be discontinued (see section 5.3)
7. Calcitonin ≥100 ng/L(see appendix A)
*No DXA scans can be performed on these subjects.
See Section 8.1.8 for procedures to be performed for subjects discontinuing trial product 
prematurely.
The primary reason for discontinuation of trial product must be specified in the eCRF.
If a criterion for premature discontinuation of trial product is met, trial product should not be re-
initiated but subjects should continue with protocol-specified visit schedule.
Withdrawal from trial
6.7
The subject may withdraw consent at will at any time. The subject’s request to withdraw from the 
trial must always be respected. Only subjects who withdraw consent should be considered as 
withdrawn from trial.
See Section 8.1.9 for procedures to be performed for subjects withdrawing consent.
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Version:
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Status:
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For Mexico only: Should the subject his/her family members parents or legal representative decide 
to withdraw the consent for participation in the trial, the subject will be entitled to receive 
appropriate, free of charge medical care and/or trial drug during the follow up period of the 
protocol when it will be established with certainty that no untoward medical consequences of the 
subject´s participation in the research occurred.
Subject replacement
6.8
Subjects who discontinue trial product prematurely will not be replaced.
Rationale for trial population 
6.9
The trial population will include subjects with T2D treated with stable doses of metformin for at 
least 90 days prior to screening as changes in the background medication shortly before trial 
participation may potentially impact data interpretation. The HbA1c limits of 7.0-10.5% 
(53-91 mmol/mol) have been chosen to include subjects needing intensification of their 
anti-diabetic medication. FPG and HbA1c will be monitored throughout the trial and rescue 
medication should be initiated in subjects with persistent, unacceptable hyperglycaemia. No BMI or 
blood pressure restrictions are applied. Subjects with liver test abnormalities (ALT >2.5 x UNL) are
excluded to avoid potential confounding of liver safety assessments. In addition, subjects with mild, 
moderate, severe or end-stage renal impairment are excluded due to restrictions in the labels of 
canagliflozin and metformin. As SGLT-2 inhibitors have been associated with diabetic 
ketoacidosis, subjects with a history of diabetic ketoacidosis are also excluded from this trial. 
Overall, the eligibility criteria will allow for enrolment of a relatively broad trial population 
resembling the target population in common practice while taking relevant safety precautions.
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Date:
17 October 2016
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Trial ID:NN9535-4270
Version:
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UTN:U1111-1180-3651 
Status:
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7
Milestones
Planned duration of recruitment period 24 weeks.
Planned date for FPFV: 15-Mar-2017
Planned date for LPLV: 24-Oct-2018
End of trial (P11) is defined as LPLV.
Recruitment:
The screening and randomisation rate will be followed closely via the interactive web response 
system (IWRS) in order to estimate when to stop screening. All investigators will be notified 
immediately when the recruitment period ends, after which no further subjects may be screened and 
the IWRS will be closed for further screening. All subjects included in the screening period and 
eligible for randomisation can be randomised.
Trial registration:
Information of the trial will be disclosed at clinicaltrials.gov and novonordisk-trials.com. According 
to the Novo Nordisk Code of Conduct for Clinical Trial Disclosure35, it will also be disclosed 
according to other applicable requirements such as those of the International Committee of Medical 
Journal Editors (ICMJE)36, the Food and Drug Administration Amendment Act (FDAAA)37,
European Commission Requirements38, 39 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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Date:
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Version:
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8
Methods and assessments
Visit procedures
8.1
The following sections describe the assessments and procedures. These are also included in the flow 
chart (see Section 2) as well as visit numbers, timing of site and phone visits and windows during 
the trial period.
Informed consent must be obtained before any trial related activity, see Section 18.3.
For each Dispensing visit; interact with IWRS to obtain allocation of trial products, confirm 
dispensing of allocated trial products and, except for the randomisation visit, confirm trial products 
returned unused or lost.
A treatment completion session must be performed in the IWRS after completion of V10.
8.1.1
Investigator site log
The investigator must keep a subject screening log, a subject identification code list and a subject 
enrolment log. Only subjects who have signed the informed consent form should be included on the 
logs. The subject screening log and subject enrolment log may be combined in one log.
In addition, the investigator must keep a log of staff and a delegation of task(s) list at the trial site. 
Investigator must sign the log of staff and the delegation of task(s) at the trial site prior to the 
delegation of tasks.
8.1.2
Screening, Visit 1
At screening, subjects will be provided with a card stating that they are participating in a trial and 
giving contact address(es) and telephone number(s) of relevant trial site staff. Subjects should be 
instructed to return the card to the investigator at the last trial visit or to destroy the card after the 
last visit.
Each subject will be assigned a unique 6-digit subject number which will remain the same 
throughout the trial. 
8.1.3
Screening failures
For screening failures the screening failure form in the eCRF must be completed with the reason for 
not continuing in the trial. Serious adverse events (SAEs) from screening failures must be 
transcribed by the investigator into the eCRF. Follow-up on serious adverse events must be carried 
out according to Section 12.
A screening failure session must be made in the IWRS and the screening failure form completed in 
the eCRF. The case book must be signed. 
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8.1.4
Re-screening
Re-screening is NOT allowed if the subject has failed one of the inclusion or exclusion criteria or 
randomisation criteria; this includes re-sampling if the subject has failed one if the inclusion or 
exclusion criteria related to laboratory parameters.
8.1.5
Fasting visits
The subjects should attend site visits in a fasting state (see section 2 for details). Fasting is defined 
as having consumed only water within the last 6 hours prior to the visit. 
If the subject does not attend the visit in a fasting state, the subject should be asked to attend a re-
scheduled visit within the visit window to have the fasting assessments performed.
Glucose lowering agents and trial product should not be taken until after blood sampling has been 
performed but other prescribed medication should be taken according to prescription.
8.1.6
Unscheduled visits
Unscheduled visits can be performed at the investigators discretion if an AE requires additional 
follow-up or if required by the Novo Nordisk department responsible for safety. Unscheduled visits 
can take place at any time during the trial from screening until the last visit in the trial. Further, 
unscheduled visits for re-sampling can take place if laboratory samples are lost or damaged before 
arriving at the analysing laboratory. This re-sampling will be at the discretion of the Novo Nordisk 
medically responsible person in collaboration with the investigator.
All assessments performed at any time during the trial can be performed during unscheduled visits 
with the exception of DXA body composition scan (only permitted if required due to DXA 
technical reasons), waist circumference and ePROs. 
Visits/contacts to the site not related to the trial do not need to be reported as an unscheduled visit. 
Contacts for re-dispensing of trial drug as replacement for lost or damaged trial drug do not need to 
be recorded as unscheduled visits but need to be recorded in the IV/WRS.
8.1.7
Phone contacts
The phone contacts should be conducted as outlined in the flow chart (see Section 2).
At V2, and V3 the investigator should instruct the subject how to dose escalate 
semaglutide/semaglutide placebo up to 1.0 mg once-weekly and also how to dose escalate 
canagliflozin up to 300 mg daily. At the planned phone contact (P5), the investigator should follow-
up on any symptoms associated with diabetic ketoacidosis (DKA), any AEs as well as compliance 
and potential technical issues in regards to the dose escalation.
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At the phone contacts at P11 and P11A occurring at least 5 weeks after V10 or V10A the 
investigator should follow up on any new concomitant medication, hypoglycaemic episodes or any 
AEs. 
8.1.8
Premature discontinuation of trial product
If a subject prematurely discontinues trial product, the investigator must undertake procedures 
described for V10A as soon as possible (preferably the same day), which are similar to those at 
V10. P11A should be scheduled at least 5 weeks after the last date on trial product. 
If premature discontinuation of trial product is decided during a scheduled visit, the visit will be 
converted into a V10A and trial procedures must be performed accordingly.
Subjects should continue with the originally scheduled site contacts after P11A and up to and 
including P11. If necessary, in order to retain the subject in the trial, site visits can be replaced by 
phone contacts after P11A. However, all attempts should be made to ensure that V10 is performed 
as a site visit and includes all planned assessments.
In summary, subjects should stay in the trial irrespective of lack of adherence to randomised
treatment, lack of adherence to visit schedule, missing assessments or trial product discontinuation 
for any reason. Only subjects who decline any further contact with the site in relation to the trial 
should be considered as withdrawn from the trial (for withdrawal procedures see Section 8.1.9).
The primary reason for premature discontinuation of trial product must be specified in the end-of-
treatment form in the eCRF, and final drug accountability must be made. A treatment 
discontinuation session must be performed in the IWRS at V10A (see Section 10).
8.1.9
Withdrawal from trial
If a subject withdraws consent, the investigator must aim to undertake procedures similar to those 
for V10A (End of treatment) as soon as possible. If a subject has already prematurely discontinued 
from trial product and previously attended visit V10A and visit P11A, no further visits should be 
attended.
For withdrawn subjects the end-of-trial form and end-of-treatment form must be completed, 
including the primary reason for premature discontinuation of trial product, and final drug 
accountability must be performed even if the subject is not able to come to the trial site. 
A treatment discontinuation session must be made in the IWRS, however if a subject has already 
prematurely discontinued from trial product and a treatment discontinuation session in IWRS has 
been done, no IWRS session should be completed. The case book must be signed.
Although a subject is not obliged to give his/her reason(s) for withdrawing consent, the investigator 
must make a reasonable effort to ascertain the reason(s), while fully respecting the subject’s rights. 
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Where the reasons are obtained, the primary reason for withdrawing consent must be specified in 
the end-of-trial form in the eCRF.
8.1.10
Investigator assessment
Review of diaries, ePROs, laboratory reports, ECGs, dilated fundoscopy/fundus photography, 
physical examinations etc. must be documented with the investigator’s or delegate’s dated signature 
either on the front page of the documents and/or in the subjects medical record. The signed 
documents must be retained at the trial site as source documentation.
For ECGs, physical examinations and dilated fundoscopy/fundus photography the evaluations must 
follow the categories:
!
Normal
!
Abnormal
o
Was the result clinically significant (No/Yes)
The evaluation should be based on the investigator’s or delegate’s judgement.
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 visit 1 or assessments revealing baseline conditions at visit 2, the investigator must state a 
comment in the subject’s medical record and record this in the 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 trial site staff must review the diary to ensure that AEs, including overall changes in 
health and concomitant medication, are reported.
If clarification of entries or discrepancies in the diary 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.
Subject related information/assessments 
8.2
8.2.1
Demography
Demography will be recorded at screening and consists of:
!
Date of birth (according to local regulation)
!
Sex
!
Ethnicity (according to local regulation)
!
Race (according to local regulation)
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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
–
Diabetic retinopathy
–
Diabetic neuropathy
–
Diabetic nephropathy
–
Macroangiopathy (including peripheral vascular disease)
8.2.3
Hypoglycaemia unawareness 
Information on hypoglycaemia unawareness will be recorded at screening according to Clarke’s 
questionnaire, question 840.
The investigator must ask the subject in the following way: “To what extent can you tell by your 
symptoms that your blood glucose is low?” The subject can answer never, rarely, sometimes, often 
or always. Subjects answering ‘never, rarely or sometimes’ are considered as having impaired 
awareness of hypoglycaemia.
8.2.4
Concomitant illness and medical history
A concomitant illness is any illness that is present at the start of the trial as described in section 
8.1.10.
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. 
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 investigator’s own practice; the investigator must make 
reasonable effort to obtain a copy of subject’s medical record from relevant party e.g. primary 
physician. The investigator must document any attempt to obtain external medical information by 
noting the date(s) when information was requested and who has been contacted.
8.2.5
Concomitant medication
A concomitant medication is any medication, other than the trial product(s) which is taken during 
the trial, including the screening and follow-up periods.
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Details of any concomitant medication must be recorded at the first visit (screening visit). Changes 
in concomitant medication must be recorded at each visit as they occur. 
The information collected for each concomitant medication includes:
!
trade name or generic name, 
!
indication, start date (only start year is applicable if more than one year) and stop date or 
continuation. 
!
total daily dose (only applicable for anti-diabetic medication) 
If a change is due to an AE, then this must be reported according to Section 12. If the change 
influences the subject’s eligibility to continue in the trial, the monitor must be informed.
8.2.6
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. 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 Argentina only: Birth control methods will be reimbursed by Novo Nordisk Pharma Argentina 
S.A.
For Brazil only: For women who expressly declare free of the risk of pregnancy, either by not 
engaging in sexual activity or by having sexual activity with no birth potential risk, use of 
contraceptive method will not be mandatory.
For EU countries only:
The following contraceptive measures are considered adequate:
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!
Combined estrogen and progestogen containing hormonal contraception associated with 
inhibition of ovulation (oral, intravaginal, transdermal)
!
Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, 
injectable, implantable)
!
Placement of an intrauterine device (IUD) or intrauterine hormone-releasing system (IUS)
!
Bilateral tubal occlusion
!
Barrier methods of contraception (condom or occlusive cap with spermicidal 
foam/gel/film/cream/suppository). (Not applicable for the Sweden and UK). 
!
Vasectomised partner (where partner is sole partner of subject) and that the vasectomised 
partner has received medical assessment of the surgical success.
!
True sexual abstinence. Sexual abstinence is defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the trial treatments. The reliability 
of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and 
the preferred and usual lifestyle of the subject.
8.2.7
Tobacco use 
Details of tobacco use must be recorded at the screening visit. 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.
Smoking status:
!
Never smoked
!
Previous smoker, smoking stop date
!
Current smoker
Efficacy assessments
8.3
8.3.1
Height, body weight and BMI
Height is measured without shoes in cm or inches and recorded to nearest ½ cm or ¼ inch.
Body weight should be measured and recorded in the eCRF in kilogram or pound (kg or lb), with 
one decimal, without shoes and only wearing light clothing.
BMI will be calculated in the eCRF every time the weight is measured using the equation:
BMI = body weight (kg)/(height (m) x height (m)) or [kg/m2 = lb/in2 x 703]
8.3.2
Waist circumference
The waist circumference is defined as the minimal abdominal circumference located midway 
between the lower rib margin and the iliac crest.
The measurement of waist circumference should be performed and recorded in the eCRF. The 
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waist circumference will be measured using a non-stretchable measuring tape. It should be 
recorded to the nearest ½ cm or ¼ inch using the same measuring tape throughout the trial.
The waist circumference 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. The subject 
should be asked to breathe normally and the measurement should be taken when the subject is 
breathing out gently.
8.3.3
Systolic and diastolic blood pressure
Systolic and diastolic blood pressure should be measured in a sitting position after the subject has 
been resting for at least 5 minutes and by using standard clinical practice at the trial site.
8.3.4
Self-measured plasma glucose (SMPG)
At the screening visit, subjects will be provided with a blood glucose meter including lancets, 
plasma-calibrated test strips and control solutions as well as instructions for use. The blood glucose 
meters use test strips calibrated to plasma values. Therefore, all measurements performed with 
capillary blood are automatically calibrated to plasma equivalent glucose values, which will be 
shown on the display. 
Only the blood glucose meter provided by Novo Nordisk should be used for the measurements 
required in the protocol.
Subjects should be instructed in how to record the results of the SMPG values in the diaries. The 
record of each SMPG value should include date, time and value. All data from the diary must be 
transcribed into the eCRF during or following the contact. If obtained via phone and a discrepancy 
is later detected, the values in the eCRF must be corrected.
Occasional review by the investigator of the values stored in the memory of the blood glucose meter 
and correct reporting of these in the diary is advised in order to ensure adequacy of the data reported 
in the trial database.
8.3.5
7-point profile
The subject will be asked to perform a 7-point SMPG profile, preferably within one week prior to 
site visit according to the flow chart, on days 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
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!
before lunch
!
90 min after start of lunch
!
before dinner
!
90 min after start of dinner
!
at bed time
8.3.6
DXA scan (sub-population only)
Body composition will be measured using dual energy x-ray absorptiometry (DXA) whole body 
scans. These scans will be performed in a sub-set of 174 randomised subjects (approximately 87 
subjects per treatment arm). The overall process of image acquisition, transfer, central analysis, 
reporting of results and arching is described in an Imaging Charter prepared by the laboratory. The 
baseline DXA scan will be performed at screening (V1+5 days), this to allow the imaging 
laboratory to confirm the quality of the scan, prior randomisation. It is recommended the site 
confirms patient eligibility prior performing the DXA scans. At the end of treatment visit (V10 or
V10A), the scans must be performed ± 5 calendar days.
The quality of the baseline DXA scan obtained at V1 must be confirmed by the imaging laboratory 
before the subject can be randomised. The quality of the DXA scans will be evaluated by the 
imaging laboratory designated by Novo Nordisk for reading in a blinded manner. If a subject 
withdraws prematurely from the trial, an end of trial DXA scan should preferably be performed.
Process for image acquisition is outlined in an Image acquisition guideline (IAG). Besides the two 
scans per subject described in this protocol a limited number of repeat scans might be acquired if 
required due to technical reasons. Repeated scans should not be performed if the subject has 
prematurely discontinued trial medication due to pregnancy or intention of becoming pregnant.
A cross calibration using cross calibration phantom will be performed at least once at each site prior 
to the database lock (DBL) of the trial.
Each trial site participating in the sub-study will receive an imaging manual prepared and 
distributed by the imaging laboratory which will include machine specific instructions for acquiring 
DXA scans. The manual will serve as reference tool for use during the trial and when training 
technologists. DXA technologist training will occur at the start of the trial and at any time deemed 
necessary to assure proper scan acquisition.
Following DXA scan acquisition each trial site will be responsible for transferring each DXA scan 
to the imaging laboratory for quality review and analysis. DXA analysis data will include:
!
Total fat mass (kg)
!
Total fat mass (%)
!
Total lean mass (kg)
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!
Total lean mass (%)
!
Visceral fat mass (kg)*
!
Visceral fat mass (%)*
!
Ratio between total fat mass and total lean mass
*analyses marked with an asterisk will be performed based on specific DXA equipment and 
software availability.
DXA analysis data will be transferred from the imaging laboratory to Novo Nordisk immediately 
prior to the DBL of the trial. The investigators will receive the results from the analysis only after 
LPLV in order to avoid un-blinding.
Safety assessments
8.4
8.4.1
Physical examination
A physical examination must be performed at V1, V8 and V10/V10A and include the following:
!
General appearance 
!
Skin
!
Thyroid gland
!
Respiratory system 
!
Cardiovascular system 
!
Gastrointestinal system including mouth
!
Central and peripheral nervous system
!
Lymph node palpation
8.4.2
Pulse
Pulse (beats per minute) should be recorded at the site of visits after resting for 5 minutes in a 
sitting position.
8.4.3
Electrocardiogram – 12 lead 
A 12-lead ECG must be performed and interpreted locally by the investigator as described in 
section 8.1.10
It is allowed to perform the baseline ECG between the screening visit and the randomisation visit. 
The result should be available prior to randomisation. An ECG performed for any reason unrelated 
to this trial within 7 days prior to the screening visit is acceptable provided no clinical symptoms 
suggestive of cardiac disease have occurred in the meantime.
If the ECG was performed as part of a routine clinical practice on/before the date when the subject 
has signed the informed consent, it must be documented in the medical records that the reason for 
performing the procedure is not related to this trial.
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8.4.4
Eye examination
The eye examination will be performed as per flowchart (see section 2). 
It is allowed to perform the baseline fundus photography or dilated fundoscopy between the 
screening visit and the randomisation visit.Results of the baseline 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, dilated fundoscopy/fundus photography must be performed at V10. In the case of 
premature discontinuation, the assessments must be performed both at V10A and at V10. The 
assessments at V10A and V10 can be performed in the period between V10A and P11A, and 
between V10 and P11, respectively but the results should be available no later than at P11A and 
P11, 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 concomitant illness/medical history in accordance 
with section 8.2.4.
8.4.5
Adverse events
AEs must be reported at each visit in accordance with the procedures outlined in Section 12. 
8.4.5.1
Medication error
If a medication error is observed during the trial, the following information is required and a 
specific event form must be completed in the eCRF in addition to the AE form: 
!
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
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For definition of medication errors, see Section 12.1.4.
8.4.5.2
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. 
8.4.6
Hypoglycaemic episodes
Plasma 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) occurring in conjunction with hypoglycaemic symptoms
should be reported in the diary according to the instructions below in section 8.6.1 throughout the 
trial from visit 1 to visit 10/10A. For the follow-up visit (P11/P11A) the hypoglycaemic episode(s) 
should be documented in the subject’s medical record.
All information must be transcribed into the eCRF (hypoglycaemic episode form) throughout the 
trial from visit 1 to visit 11/11A.
Upon onset of a hypoglycaemic episode the subject is recommended to measure plasma glucose 
every 15 minutes until the SMPG value is >3.9 mmol/L (70 mg/dL) and/or symptoms have been 
resolved in accordance to current guidelines41.
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An SMPG value ≤3.9 mmol/L (70 mg/dL) or hypoglycaemic symptoms will be recorded in the 
diary in 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/dL (70 mg/dL) and/or symptoms have been resolved. One hypoglycaemic 
episode form is to cover these measurement 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 plasma glucose 
value is >3.9 mmol/L (70 mg/dL) and/or symptoms have been resolved). 
!
If a stop date and time is not reported, a hypoglycaemic episode will cover a period of 60 
minutes.
!
The 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 plasma 
glucose value for the episode, the remaining values will be kept as source data in the diary.
!
Whether the episode was symptomatic (Yes/No)
!
A hypoglycaemic episode starting without symptoms should be updated to symptomatic if the 
subject experiences symptoms later during the episode.
!
Whether the subject was able to treat him/herself 
!
If the severity of a hypoglycaemic episode aggravates, only one hypoglycaemic episode should 
be reported, reflecting the most severe degree of hypoglycaemia. 
!
Date-and time of last trial product administration and 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 plasma glucose to normal is considered sufficient 
evidence that the event was induced by a low plasma glucose concentration41.
Oral carbohydrates must not be given if the subject is unconscious.
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If the question "Was the subject able to treat him/herself?" is answered "No", the following 
information should be recorded by the subject:
!
Who assisted in the treatment of the hypoglycaemic episode (i.e. medical person or non-medical 
person)?
!
Where the treatment was administered (in clinic/emergency room/hospital or other. If the 
subject was treated in clinic/emergency room/hospital, whether they were transported in an 
ambulance or not)
!
Type of treatment provided by 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 symptoms (layman term used in the diary is 
specified in brackets if different from the protocol term)?41
–
Autonomic: sweating, trembling, hunger or palpitations (rapid or irregular heart beat)
–
Neuroglycopenic: confusion, drowsiness, speech difficulty, visual disturbances, odd 
behaviour, impaired balance or incoordination (reduced ability to coordinate movement)
–
General malaise: headache or malaise (feeling discomfort/unease)
!
Other symptoms 
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 data42, 43.
The subject must be re-trained in how to report hypoglycaemic episodes if the investigator identifies 
low SMPG values not reported as hypoglycaemic episodes.
If the hypoglycaemic episode fulfils the criteria for an SAE then an AE form and a safety 
information form must also be filled in, see section 12.
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Laboratory assessments
8.5
The laboratory assessments will be performed by a central laboratory. If collected, anti-semaglutide 
IgE antibody samples will be analysed by Novo Nordisk (for further details see Section 18.1.1). The 
central laboratory may utilise sub-contractors.
In the events described in section 8.4.5.2, a local laboratory must be used.
Descriptions of assay methods, laboratory supplies and procedures for collecting, handling, storage 
and shipping of samples, will be described in the laboratory manual provided by the central 
laboratory.
For Mexico only: Descriptions of assay methods, laboratory supplies and procedures for obtaining 
samples, handling, transportation and storage of biological samples and information regarding 
who will perform the assessments , will be described in a trial specific laboratory manual, provided 
by the central laboratory (for central laboratory details, see attachment 1).
Laboratory samples not drawn on the day of the actual visit should preferably be drawn on another 
day within the visit window stated in the flow chart. For some of the samples drawn during the trial, 
subjects will be asked to attend the relevant site visits fasting (see section 8.1.5).
Laboratory results will be sent by the central laboratory 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 this protocol (see section 12).
The laboratory provides results to the trial sites in the units preferred by the trial sites while the 
results that are transferred to the trial database will always be in SI units.
The laboratory equipment may provide analyses not requested in the protocol but produced 
automatically in connection with the requested analyses according to specifications in the laboratory 
standard operating procedures. Such data will not be transferred to the trial database, but abnormal 
values will be reported to the investigator. The investigator must review all laboratory results for 
concomitant illnesses and AEs and report these according to Section 8.2.4and Section 12.
For Brazil only: All laboratory results will be communicated to the investigators.
Only laboratory samples specified in the protocol must be sent to the central laboratory for analysis; 
if additional laboratory sampling is needed, e.g. to follow up on AEs, this must be done at a local 
laboratory.
All laboratory samples will be destroyed at the latest at the completion of the clinical trial report or 
according to local regulations.
For Brazil only: Biological samples from Brazil will be destroyed at the end of the trial.
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8.5.1
Laboratory assessments for efficacy
Blood samples will be drawn according to flow chart and analysed at the central laboratory to 
determine levels of the following efficacy laboratory parameters:
!
Glucose metabolism:
!
HbA1c
!
FPG 
!
Lipids (all fasting):
o
Total cholesterol
o
LDL cholesterol
o
HDL cholesterol
o
Triglycerides
Fasting plasma glucose 
FPG is measured at central laboratory in order to evaluate glycaemic control. The subject must 
attend these visits fasting (see Section 8.1.5).
A central FPG result obtained at the central laboratory of ≤3.9 mmol/L (70 mg/dL) in relation to 
planned fasting visits should not be reported as a hypoglycaemic episode but as a clinical laboratory 
adverse event (CLAE) at the discretion of the investigator (see Section 12.1.1). 
8.5.2
Laboratory assessments for safety
Blood samples will be drawn and analysed at the central laboratory to determine levels of the 
following laboratory parameters: 
Biochemistry:
!
Alanine aminotransferase (ALT)
!
Aspartate aminotransferase (AST)
!
Albumin, bilirubin (total)
!
Alkaline phosphatase,
!
Potassium, 
!
Sodium 
!
Calcium (total) 
!
Amylase
!
Lipase 
!
Calcitonin
!
Creatinine, including eGFR (per CKD-EPI)1
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Haematology:
!
Haemoglobin
!
Haematocrit
!
Erythrocytes
!
Thrombocytes
!
Leucocytes
Pregnancy test (females of child bearing potential):
!
Serum beta-human chorionic gonadotropin (V1, V8, V10/V10A)
!
Urine dip stick (V2)
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.
Pregnancy testing
Females of childbearing potential will have a serum pregnancy test performed. At the randomisation 
visit, a urine pregnancy test must be performed prior to randomisation.
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), see section 8.2.6.
Other assessments
8.6
8.6.1
Subject diary
The subject must be provided with paper diaries at visits described in the flow chart. If a subject 
prematurely discontinues trial product, diaries, should be not be dispensed and completed by the 
subject after follow-up-premature discontinuation visit (P11A). Entries in the diaries are only to be 
made by the subject, unless otherwise specified.
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The investigator should instruct the subject in recording the following data in the diary:
!
Date, time and dose of first dose of trial product
!
Date and last dose of trial product prior to each visit
!
SMPG 7-point profile
!
Hypoglycaemic episodes
!
Concomitant medication
!
AEs
The diaries should be handed out/collected as indicated in the flow chart. The subject should bring 
the diary for review at every clinic visit up until end of treatment visit (V10). The recordings must 
be reviewed as described in section 8.1.10 and transcribed to the eCRF.
If any hypoglycaemic events are reported at P11 or P11A, the information related to the 
hypoglycaemic event(s) should be documented in the subject’s medical record and the entry in the 
medical record will be considered source data.
8.6.2
Electronic patient reported outcome questionnaires
The following PRO questionnaire will be used in the trial:
SF-36v2TM
DTSQ
CoEQ
The questionnaires should be completed by the subject as specified in the flow chart, see section 2, 
preferably after conclusion of all fasting related activities but before any other visit-related 
activities. It takes approximately 15 minutes to complete the questionnaires, see Section 13.3. 
Subjects should be given the opportunity to complete the questionnaires by themselves without 
interruption. The assessments must be reviewed as described in Section 8.1.10.
8.6.2.1
SF-36v2
The SF-36v2™ 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. This questionnaire contains 36 items and measures the individual overall 
health related quality of life on 8 domains; physical functioning, role functioning, body pain, 
general health, vitality, social functioning, role emotional and mental health.
8.6.2.2
DTSQs
The DTSQs questionnaire will be used to assess subject’s treatment satisfaction. This questionnaire 
consists of 8 items and measures the subject’s diabetes treatment (including insulin, tablets and/or 
diet in terms of convenience, flexibility and general feelings regarding treatment).
8.6.2.3
Control of Eating Questionnaire (CoEQ)
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The CoEQ has its origin in the Food Craving Record. It comprises of 21-items designed to assess
the intensity of food cravings, as well as subjective sensation of appetite and mood. For this trial a 
version with only 19 items will be included.
8.6.3
Training in the PDS290 pen-injector
The subjects must be trained in how to handle the PDS290 pen-injector when handed out the first 
time. Training should be repeated during the trial at regular intervals at the discretion of the 
investigator in order to ensure correct use of the device. The training should be done in accordance 
with the directions for use.
8.6.4
Training in blood glucose meter use
The subjects must be provided with a BG meter at visit 1 and instructed in how to use and handle 
the BG meter, in accordance with the flow chart (see section 2). The subjects will be instructed in 
how to use the device and the instruction will be repeated at visit 2 and thereafter as necessary 
during the trial. 
Subject compliance
8.7
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.
Treatment compliance: will be assessed by monitoring of drug accountability. Prior to visits 
where drug accountability is performed the subject will be asked to return all used, partly used and 
unused trial products. The investigator must assess the amount of trial products returned compared 
to what was dispensed at the last dispensing visit and, in case of discrepancies, question the subject.
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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). 
The trial products will be dispensed to each subject as required according to treatment group. The 
IWRS will allocate trial product Dispensing Unit Number (DUN) to the subject at each dispensing 
or randomisation visit. The correct DUN must be dispensed to the subject.
If additional medication is needed, the IWRS must be contacted in order to have correct medication 
allocated.
Trial products must not be dispensed to any person not included in the trial. 
Semaglutide must not be used, if it does not appear clear, colourless, or almost colourless.
Trial products
9.1
The following trial products will be provided by Novo Nordisk A/S, Denmark:
Table 9–1
Trial products
Trial product
Strength
Dosage form
Route of 
administration
Container/
delivery device
Semaglutide 1.34 mg/mL
1.34 mg/mL
Solution for 
injection
Subcutaneous
1.5 mL PDS290 
pre-filled pen-
injector
Semaglutide placebo
N/A
Canagliflozin 100 mg
100 mg
Tablet
Oral
Blister pack
Canagliflozin placebo 
N/A
Canagliflozin 300 mg
300 mg
Canagliflozin placebo 
N/A
Background medication is defined as antidiabetic treatment with metformin. All randomised 
subjects must continue their antidiabetic pre-trial background medication throughout the entire 
duration of the trial, unless rescue criteria are met or a safety concern arises. As metformin is 
considered background medication (non-investigational medicinal product), it will not be provided 
by Novo Nordisk. However, metformin will be reimbursed if required by the country’s Health 
Authority or IEC/IRB.
Semaglutide 1.34 mg/mL and semaglutide placebo are visually identical and will be packed 
blinded.
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Canagliflozin 100/300 mg drug and corresponding placebo will be packed blinded. There are 2 
different placebos: 1 for each of the respective doses of canagliflozin (100 mg and 300 mg).
Labelling
9.2
The trial products will be labelled in accordance with Annex 1344, local regulations and trial 
requirements. Each box will be labelled with a unique (DUN).
Each trial site will be supplied with sufficient trial products for the trial on an on-going basis 
controlled by the IWRS. Trial product will be distributed to the trial sites according to enrolment 
and randomisation. 
The investigator must document that directions for use (DFU) is given to the subject orally and in 
writing at the first dispensing visit (randomisation visit, V2).
For Argentina only: Glucose-lowering background medication and rescue medication, if 
applicable, will be reimbursed by Novo Nordisk Pharma Argentina S.A.
Storage 
9.3
Table 9–2
Storage conditions
Trial product
Storage conditions
(not-in-use)
In-use conditions
In-use timea
Semaglutide 1.34 mg/mL
Store in refrigerator (2–8°C)
Do not freeze
Protect from light
Store below 30°C
Do not freeze
Protect from light
8 weeks
Semaglutide placebo
Canagliflozin 100 mg
Do not store above 30°C
Do not freeze
Protect from light
N/A
N/A
Canagliflozin placebo 
Canagliflozin 300 mg
Canagliflozin placebo 
a In-use time starts in the subjects home when the product is taken out of the refrigerator.
The investigator must ensure that trial product is kept under proper storage conditions and record 
and evaluate the temperature. The investigator must inform Novo Nordisk immediately if any trial 
product has been stored outside specified conditions (e.g. outside temperature range). Additional 
details regarding handling of temperature deviations can be found in the TMM.
Trial product that has been stored improperly must not be dispensed to any subject before it has 
been evaluated and approved for further use by Novo Nordisk. The investigator must take 
appropriate action to ensure correct storage.
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Drug accountability and destruction
9.4
Drug accountability of all trial products received at site is the responsibility of the investigator.
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 (please see flow chart, 
section 2).
Returned trial product (used/partly used and/or unused), expired or damaged trial product can be 
stored at room temperature and must be stored separately from non-allocated trial product.
Non-allocated trial products including expired or damaged products must be accounted as unused at 
the latest at closure of the trial site.
Drug accountability should be performed at pen level for semaglutide/placebo, and at tablet level 
for Canagliflozin/placebo.
Destruction of trial products can be performed on an on-going basis and will be done according to 
local procedures after accountability is finalised and reconciled by the monitor. Destruction of 
products must be documented in the IWRS.
Auxiliary supplies
9.5
The following auxiliary supplies will be supplied by Novo Nordisk in accordance with the TMM:
!
DFU for PDS290 pen-injector
!
Needles for PDS290 pen-injector
!
BG-meter and BG-meter related auxiliaries
Only needles provided by Novo Nordisk must be used for administration of trial product.
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10
Interactive voice/web response system
A trial-specific IWRS will be set up which can be accessed at any time via the internet or telephone. 
Access to the IWRS must be restricted to and controlled by authorised persons. 
IWRS is used for:
!
Screening
!
Screening failure
!
Randomisation
!
Medication arrival
!
Dispensing
!
Dispensing Verification (when barcode scanner is used)
!
Treatment discontinuation 
!
Completion
!
Code break
!
Drug accountability
!
Data change
IWRS user guides and worksheets will be provided to each trial site.
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11 Randomisation procedure and breaking of blinded codes
This is a double-blind, two-arm parallel-group trial. A randomisation session will be performed for 
all eligible subjects by using IWRS.
At the randomisation visit (V2), eligible subjects will be randomised to one of the two parallel 
treatment groups in a 1:1 manner:
!
semaglutide 1.0 mg once-weekly + canagliflozin placebo
!
canagliflozin 300 mg once-daily + semaglutide placebo
The randomisation will be stratified according to the participation in the DXA scan sub-study (yes 
or no) in order to ensure balanced treatment allocation within the sub-study.
When a subject is randomised he/she must be assigned the lowest available randomisation number.
Breaking of blinded codes
11.1
The IWRS will notify Novo Nordisk (monitor and the Global Safety department) immediately after 
the code is broken. However, if the code is broken by Global Safety, the monitor will not be 
notified.
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,
and sign and date the document. The reason for code break should be documented in the medical 
record.
When the code is broken, the treatment allocation will be accessible to the investigator and the 
Novo Nordisk Global Safety department. If IWRS is not accessible at the time of code break the 
IWRS helpdesk should be contacted. Contact details are listed in attachment 1.
If the code has been broken by the investigator, the subject must discontinue treatment with trial 
product and a treatment discontinuation session must be completed in IWRS.
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12 Adverse events, technical complaints and pregnancies
Definitions
12.1
12.1.1
Adverse event 
An adverse event (AE) is any untoward medical occurrence in a subject administered a medicinal 
product, and which does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom or disease temporally associated with the use of a product, whether or not 
considered related to the product. 
An AE includes:
!
A clinically significant worsening of a concomitant illness.
!
A clinical laboratory adverse event (CLAE): a clinical laboratory abnormality which is 
clinically significant, i.e. an abnormality that suggests a disease and/or organ toxicity and is of a 
severity that requires active management. Active management includes active treatment or 
further investigations, for example change of medicine dose or more frequent follow-up due to 
the abnormality.
The following should not be reported as AEs:
!
Pre-existing conditions, including those found as a result of screening or other trial procedures 
performed before exposure to trial product (pre-existing conditions should be reported as 
medical history or concomitant illness).
!
Pre-planned procedures unless the condition for which the procedure was planned has worsened 
from the first trial related activity after the subject has signed the informed consent.
!
Non-serious hypoglycaemia is an AE, but is reported on a hypoglycaemic episode form instead 
of on an AE form, see Section 8.4.6
The following three definitions are used when assessing an AE:
!
Severity 
–
Mild – no or transient symptoms, no interference with the subject’s daily activities.
–
Moderate – marked symptoms, moderate interference with the subject’s daily activities.
–
Severe – considerable interference with the subject’s daily activities; unacceptable.
!
Causality 
Relationship between an AE and the relevant trial products): 
–
Probable - Good reason and sufficient documentation to assume a causal relationship.
–
Possible - A causal relationship is conceivable and cannot be dismissed.
–
Unlikely - The event is most likely related to aetiology other than the trial product.
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!
Final outcome
o
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.
o
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.
o
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.
o
Not recovered/not resolved - The condition of the subject has not improved and the 
symptoms are unchanged, or the outcome is not known.
o
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.
o
Unknown - This term is only applicable if the subject is lost to follow-up.
12.1.2
Serious adverse event
A serious adverse event (SAE) is an experience that at any dose results in any of the following:
!
Death.
!
A life-threateninga experience.
!
In-patient hospitalisationb or prolongation of existing hospitalisation.
!
A persistent or significant disability or incapacityc.
!
A congenital anomaly or birth defect.
!
Important medical events that may not result in death, be life threateninga or require 
hospitalisationb may be considered an SAE when - based on appropriate medical judgement -
they may jeopardise the subject and may require medical or surgical intervention to prevent one 
of the outcomes listed in the definition of SAEd. 
a
The term “life threatening” in the definition of SAE refers to an event in which the subject was 
at risk of death at the time of the event. It does not refer to an event which hypothetically might 
have caused death if it was more severe.
b
The term “hospitalisation” is used when a subject:
o
Is admitted to a hospital or in-patient, irrespective of the duration of physical stay, or 
o
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 
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purposes do not constitute AEs and should therefore not be reported as AEs or SAEs. Hospital 
admissions for surgical procedures, planned before trial inclusion, are not considered AEs or 
SAEs.
c
A substantial disruption of a subject’s ability to conduct normal life functions (e.g. following the 
event or clinical investigation the subject has significant, persistent or permanent change, 
impairment, damage or disruption in his/her body function or structure, physical activity and/or 
quality of life).
d
For example intensive treatment in an emergency room or at home of allergic bronchospasm, 
blood dyscrasia or convulsions that do not result in hospitalisation, or development of drug 
dependency or drug abuse.
The following adverse events must always be reported as an SAE using the important medical event 
criterion if no other seriousness criteria are applicable:
!
suspicion of transmission of infectious agents via the trial product 
!
risk of liver injury defined as ALT or AST >3 x UNL and total bilirubin >2 x UNL, where no 
alternative aetiology exists (Hy's law).
Additional assessments should be made for events meeting the criterion of Hy’s law as stated above 
(see appendix B).
12.1.3
Non-serious adverse event
A non-serious AE is any AE which does not fulfil the definition of an SAE.
12.1.4
Medication errors
A medication error concerning trial products is defined as:
!
Administration of wrong drug.
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 (e.g. 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 extent where clinical consequences for the trial subject 
were likely to happen as judged by the investigator, although they did not necessarily occur.
Medication errors must be reported on an AE form and a specific event form, see Section 8.4.5.1.
12.1.5
Adverse events requiring additional data collection
AEs requiring additional data collection are AEs where the additional data will benefit the 
evaluation of the safety of the trial product.
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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
For details about specific event forms, see appendix B
12.1.6
Technical complaints
A technical complaint is any written, electronic, or oral communication that alleges product 
(medicine or device) defects. The technical complaint may be associated with an AE, but does not 
concern the AE itself.
Examples of technical complaints:
!
The physical or chemical appearance of trial products (e.g. discoloration, particles or 
contamination)
!
All packaging material including labelling
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
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!
Problems related to devices (e.g. to the injection mechanism, dose setting mechanism, push
button or interface between the pen and the needle).
Reporting of adverse events
12.2
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 (V1) until the
end of the post-treatment follow-up period (P11). 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, 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 SIF must be completed in addition to the AE form. If several symptoms or diagnoses 
occur as part of the same clinical picture, one SIF 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.
Timelines for initial reporting of AEs:
The investigator must complete the following forms in the eCRF within the specified timelines:
!
SAEs:The AE form within 24 hours and the SIFwithin 5 calendardays of the investigator’s
first knowledge of the SAE.
!
For SAEs requiring reporting on a specific event form:In addition to the above the specific
event form within 14 calendar daysfrom the investigator’s first knowledge of the AE.
!
Events for adjudication:The adjudication form should be completed within 14 calendar days
of investigator’s first knowledge of the AE, see Section 12.7.2. The investigator should
preferably provide the medical documentation within 4 weeks of event identification according
to instructions in the event adjudication site manual.
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If the eCRF is unavailable, the concerned AE information must be reported on a paper AE form and 
sent to Novo Nordisk fax, e-mail or courier within the same timelines as stated above. When the 
eCRF becomes available again, the investigator must enter the information on the form into the 
eCRF.
Contact details (fax, telephone, e-mail and address) are provided in the investigator trial master file. 
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 IB25 current version and any updates thereto
!
Canagliflozin: Current version of the EU PI32 and U.S. Food and Drug Administration (FDA) 
prescribing information and any updates thereto.
Reporting of trial product-related SUSARs by Novo Nordisk:
Novo Nordisk will notify the investigator of trial product-related suspected unexpected serious 
adverse reactions (SUSARs) in accordance with local requirements and ICH GCP2. In addition, the 
investigator will be informed of any trial-related SAEs that may warrant a change in any trial 
procedure.
In accordance with regulatory requirements, Novo Nordisk will inform the regulatory authorities, 
including EMA, of trial product-related SUSARs. In addition, Novo Nordisk will inform the 
IRBs/IECs of trial product-related SUSARs in accordance with local requirement and ICH GCP2,
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.
Follow-up of adverse events
12.3
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 (e.g. corrections or additional) 
information and must be reported within 24 hours of the investigator’s first knowledge of the 
information. This is also the case for previously non-serious AEs which subsequently become 
SAEs. 
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!
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. 
Technical complaints and technical complaint samples
12.4
12.4.1
Reporting of technical complaints 
All technical complaints on any of the following products:
!
Semaglutide 1.34 mg/mL or placebo, 1.5 mL pen-injector
!
Canagliflozin 100 mg or placebo tablets (blister pack)
!
Canagliflozin 300 mg or placebo tablets (blister pack)
!
Novo Nordisk needles for prefilled PDS290 pen-injector
which occur from the time of first usage of the product until the time of the last usage of the 
product, must be collected and reported to Customer Complaint Centre, Novo Nordisk.
Contact details (fax, e-mail and address) are provided in attachment 1 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: 
!
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 
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The investigator must complete and forward the technical complaint form by fax, e-mail or courier 
to Customer Complaint Center, Novo Nordisk, 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 1) and ensure 
that the sample is sent as soon as possible. A copy of the technical complaint form must be included 
in the shipment of the sample. If several samples are returned in one shipment, the individual 
sample and the corresponding technical complaint form must be clearly separated.
The investigator must ensure that the technical complaint sample contains the code 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.
Pregnancies
12.5
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 
(e.g. in PDF format), or by fax or courier:
1. Reporting of pregnancy information
Information about the pregnancy and pregnancy outcome/health of the newborn infant(s) has to 
be reported on Maternal Form 1A and 1B, respectively. 
When the pregnancy outcome is abnormal (i.e. congenital anomalies, foetal death including 
spontaneous abortion and/or any anomalies of the foetus observed at gross examination or 
during autopsy), and/or when a congenital anomaly is diagnosed within the first month, further 
information has to be reported for the female subject on Maternal Form 2. In addition, 
information from the male partner has to be reported on the Paternal Form, after an informed 
consent has been obtained from the male partner. 
Initial reporting and follow-up information must be reported within 14 calendar days of the 
investigator’s first knowledge of initial or follow-up information.
2. Reporting of AE information
The investigator has to report AEs in connection with the pregnancy as well as in the foetus and 
newborn infant(s). The SAEs that must be reported include abnormal outcome, such as foetal 
death (including spontaneous abortion), and congenital anomalies (including those observed at 
gross examination or during autopsy of the foetus), as well as other pregnancy complications 
fulfilling the criteria of an SAE.
Forms and timelines for reporting AEs:
Non-serious AEs: 
!
AE forma within 14 calendar days of the investigator’s first knowledge of the initial or follow-
up information to the non-serious AE.
SAEs: 
!
AE forma within 24 hours of the investigator’s first knowledge of the SAE.
!
SIF within 5 calendar days of the investigator’s first knowledge of the SAE.
!
SAE follow-up information to the AE form and/or safety information form within 24 hours of 
the investigator’s first knowledge of the follow-up information.
a 
It must be clearly stated in the AE diagnosis field on the AE form if the event occurred in 
the subject, foetus or newborn infant. If the AE occurred in the foetus or newborn infant, the AE 
can only be reported on paper AE and safety information form.
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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.
Precautions and/or overdose
12.6
Events of nausea, vomiting and headache have been reported in connection with accidental 
administration of semaglutide doses up to 4 mg. No symptoms of hypoglycaemia have been 
reported in connection with overdose of semaglutide. In the event of overdosage, appropriate 
supportive treatment should be initiated according to subject’s clinical signs and symptoms.
Committees related to safety
12.7
12.7.1
Novo Nordisk safety committee
Novo Nordisk will constitute 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 EAC is established to perform validation of selected AEs according to pre-
defined diagnostic criteria. The validation is based on review of pre-defined clinical data related to 
the specific AE. Pre-defined clinical data consist of copies of source documents collected and 
delivered by the investigational sites.
The EAC is composed of permanent members covering required medical specialities. EAC 
members must disclose any potential conflicts of interest and must be independent of Novo 
Nordisk. 
The events are reviewed by the EAC in a blinded manner. The EAC will have no authorisations to 
impact on trial conduct, trial protocol or amendments.
The EAC works in accordance with written guidelines included in the EAC Charter describing in 
details the composition, tasks, responsibilities and work processes of the committee.
The events outlined in Section 12.1.5 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 Definitions45.
The EAC will review copies in English (translated if necessary) of medical documentation received 
in the adjudication packages (e.g. x-ray, ECGs, ultrasound images, discharge summaries, pathology 
reports and death certificates). The investigator must provide medical documentation as soon as 
possible, when they receive the request from Novo Nordisk or the event adjudication vendor.
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The AEs for adjudication are listed in Table 12–2
Table 12–2
Adverse events for adjudication
*Death is not a separate event, but an outcome
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 ischemia, 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 through the blood and lymph systems
!
C-cell hyperplasia, defined as hyperplasia of the 
parafollicular C-cells of the thyroid gland
!
Malignant thyroid neoplasm
!
C-cell hyperplasia
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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.
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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 provided by an external supplier.
Ensure that all relevant questions are answered, and that no empty data field exists. If a test or an 
assessment has not been done and will not be available, or if the question is irrelevant (e.g. is not 
applicable), indicate this according to the data entry instructions.
The following will be provided as paper CRFs:
!
Pregnancy forms
The following will be provided as paper CRFs to be used when access to the eCRF is revoked or if 
the eCRF is unavailable:
!
AE forms 
!
Safety information forms
!
Technical complaint forms (also to be used to report complaints that are not subject related (e.g. 
discovered at trial site before allocation)
On the paper CRF forms print legibly, using a ballpoint pen. Ensure that all questions are answered, 
and that no empty data blocks exist. Ensure that no information is recorded outside the data blocks. 
If a test/assessment has not been done and will not be available, indicate this by writing “ND” (not 
done) in the appropriate answer field in the paper CRF. If the question is irrelevant (e.g. is not 
applicable) indicate this by writing “NA” (not applicable) in the appropriate answer field. Further 
guidance can be obtained from the instructions in the paper CRF.
The investigator must ensure that all information is consistent with the source documentation. By 
electronically signing the case book in the eCRF, the investigator confirms that the information in 
the eCRF and related forms is complete and correct.
Corrections to case report forms 
13.1
Corrections to the eCRF data may be made by the investigator or the investigator’s delegated staff. 
An audit trail will be maintained in the eCRF application containing as a minimum: the old and the 
new data, identification of the person entering the data, date and time of the entry and reason for the 
correction.
If corrections are made by the investigator’s delegated staff after the date the investigator has signed 
the case book, the case book must be signed and dated again by the investigator.
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Case report form flow 
13.2
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.
The pregnancy forms are paper based CRFs. Also, the AE forms, technical complaint forms, and 
safety information forms 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 is recorded in these forms as soon as possible after the visit.
At the end of the trial the investigator must ensure that all remaining data have been entered into the
eCRF no later than 3 days after Last Patient Last Visit (LPLV) at the site in order to ensure the 
planned lock of the database.
Site specific eCRF data (in an electronic readable format) will be provided to the trial site before 
access to the eCRF is revoked. This data must be retained at the trial site.
Electronic collection of questionnaires
13.3
Novo Nordisk will use a tablet computer at sites for electronic recording of PRO questionnaires (see 
Section 8.6.2). The tablet computer and related support services will be supplied by an external 
vendor.
Subjects will be instructed in the use of the tablet computer before entering any data. The tablet 
computer will contain built-in edit checks, to ensure that all relevant questions are answered. The 
tablet computer is not intended to support the subsequent review and modification of completed 
entries. In case of need for corrections to the transferred data, a query flow must be initiated by the 
investigator or delegate. An audit trail will be maintained.
All data entered will be transferred automatically from the tablet computer to a database hosted by 
the supplier which is considered source data. Data entered on the devices will upon confirmation of 
successful backup be deleted from the devices.
Data in this database will be viewable to relevant site and Novo Nordisk personnel through a secure 
and password-protected web portal. Data will be transferred to the Novo Nordisk clinical database 
at defined intervals.
Site-specific electronic questionnaire data (in an electronic readable format) will be provided to the 
trial site before access to the supplier database is revoked. This data must be retained at the trial site.
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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 at 
the trial site and no later than 4 weeks after, this will include a visit at the DXA radiology unit as 
well. The monitoring visit intervals will depend on the outcome of the remote monitoring of the 
eCRFs, the trial site's recruitment rate and the compliance of the trial site to the protocol and GCP, 
but will not exceed 12 weeks until LPLV at the trial site. The on-site monitoring visit interval to the 
DXA radiology unit must not exceed 6 months at sites with active subjects.
The monitor must be given direct access to all source documents (original documents, data and 
records). Direct access includes permission to examine, analyse, verify and reproduce any record(s) 
and report(s) that are important to the evaluation of the trial. If the electronic medical record does 
not have a visible audit trail, the investigator must provide the monitor with signed and dated 
printouts. In addition the relevant trial site staff should be available for discussions at monitoring 
visits and between monitoring visits (e.g. by telephone).
All data must be verifiable in source documentation other than the eCRF.
For all data recorded the source document must be defined in a source document agreement at each 
trial site. There must only be one source defined at any time for any data element.
Source data generated by the trial site can be corrected by another person than the person entering 
the source data if accepted by local regulations; any correction must be explained, signed and dated 
by the person making the correction.
The original of the completed diaries and ePROs (tablets) must not be removed from the trial site, 
unless they form part of the CRF/eCRF and a copy is kept at the site.
All data entered will be automatically transferred from the device to the ePRO database, hosted by 
the supplier. This database is considered as the source. The monitor will ensure that the eCRFs are 
completed and that paper CRFs are collected.
The following data will be source data verified for screening failures: 
!
Date for obtaining informed consent. 
!
Reason for screening failure
Monitors will review the subject’s medical records and other source data (e.g. the diaries and ensure 
ePROs are completed) to ensure consistency and/or identify omissions compared to the eCRF. If 
discrepancies are found, the investigator must be questioned about these.
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A follow-up letter (paper or electronic) will be sent to the investigator following each monitoring 
visit. This should address any action to be taken.
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15 Data management
Data management is the responsibility of Novo Nordisk. Data management may be delegated under 
an agreement of transfer of responsibilities to a CRO. 
In cases where data management activities are delegated to external vendors, there will be regular 
transfer of data during the trial.
Appropriate measures, including encryption of data files containing person identifiable data, will be 
used to ensure confidentiality of subject data, when they are transmitted over open networks. 
Data from central laboratories will be transferred electronically. In cases where data is transferred 
via non-secure electronic networks, data will be encrypted during transfer.
The subject and any biological material obtained from the subject will be identified by subject 
number and trial ID. Appropriate measures such as encryption or leaving out certain identifiers will 
be enforced to protect the identity of subjects in all presentations and publications as required by 
local, regional and national requirements.
16 Computerised systems
Novo Nordisk will capture and process clinical data using computerised systems that are described 
in Novo Nordisk Standard Operating Procedures and IT architecture documentation. The use and 
control of these systems are documented.
Investigators working on the trial may use their own electronic systems to capture source data.
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17 Statistical considerations
General considerations
17.1
No interim analyses or other analyses of un-blinded or between group data will be performed 
before the database is locked.
If necessary, a statistical analysis plan (SAP) may be written in addition to the protocol, including a 
more technical and detailed elaboration of the statistical analyses. The SAP will be finalised before 
database lock.
Laboratory values below the lower limit of quantification (LLOQ) will be set to ½LLOQ. 
Results from a statistical analysis will be presented by the estimated treatment contrasts at week 52 
with associated two-sided 95% confidence intervals and p-values corresponding to two-sided tests 
of no difference if not otherwise specified.
The comparison presented from a statistical analysis will be semaglutide 1.0 mg versus 
canagliflozin 300 mg
If no statistical analysis is specified, data will be presented using relevant summary statistics.
Data from all trial sites will be analysed and reported together. 
The regions used in the statistical analyses are defined as:
!
North America (USA and Canada)
!
Region Europe (UK, Ireland, Italy and Sweden)
!
International Operations (Lebanon, Malaysia, Argentina, Mexico, Brazil, India)
17.1.1
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).
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17.1.2
Definition of baseline
For each assessment, the baseline assessment is defined as the latest available measurement at or 
prior to the randomisation visit. This specifically implies that if a visit 2 assessment is missing 
(whether it was planned or not planned) then the screening assessment (from visit 1), if available, 
will be used as the baseline assessment.
17.1.3
Primary estimand
To further detail the trial objective an estimand is defined which is a de-jure (efficacy) estimand: 
1. Primary estimand
!
The treatment difference between semaglutide and canagliflozin at week 52 for all 
randomised subjects if all subjects completed treatment and did not initiate rescue 
medication
This primary de-jure estimand is considered clinically relevant as it assesses the glycaemic benefit a 
person with T2D is expected to achieve if initiating and continuing treatment with semaglutide 
compared to canagliflozin. Accordingly, only data collected prior to discontinuation of trial product 
or initiation of rescue medication will be used to draw inference. This will avoid confounding from 
rescue medication.
17.1.4
Trial completion
Unless subjects withdraw their informed consent, data collection will continue for the full duration 
of the trial. The full duration of the trial is defined as up to and including the follow-up visit (P11). 
Subjects completing the follow-up visit (P11) will be considered trial completers.
17.1.5
Missing data considerations at week 52
The actual rate of missing data at week 52 is expected to be maximum 10% based on the rate of trial 
completers from the subcutaneous semaglutide phase 3a clinical development program. The 
frequency of missing data is expected to be similar in the semaglutide and the canagliflozin groups.
When estimating the primary estimand, the combined rate of missing data, subjects discontinuing 
treatment prematurely or initiating rescue medication on top of trial product, is expected to be 
maximum 30%. This is based on the results from the subcutaneous semaglutide phase 3a clinical 
development program. Based on these data, premature treatment discontinuation due to 
gastrointestinal adverse events is expected to be low but more frequent in semaglutide compared to 
canagliflozin. Other reasons for discontinuing treatment are assumed to be unrelated to treatment 
and therefore occur with similar rates, so overall the frequency of missing data or data not used at 
week 52 in the primary analysis is expected to be slightly larger in semaglutide as compared to 
canagliflozin.
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To document the extent and reason(s) for missing data, descriptive summaries and graphical 
representation of extent, reason(s) for and pattern of missing data will be presented by treatment 
group.
Sample size calculation
17.2
The primary endpoint, change from baseline to week 52 in HbA1c (%) will be tested for non-
inferiority and superiority of semaglutide vs. canagliflozin. The confirmatory secondary endpoints, 
change from baseline to week 52 in body weight (kg) and change from baseline to week 52 in total 
fat mass (kg) are planned to be tested for superiority of semaglutide vs. canagliflozin.
The sample size calculation is made to ensure a power of at least 90% for meeting HbA1c
superiority of semaglutide vs. canagliflozin out of the four pre-specified confirmatory hypotheses 
shown in Table 17–1. The closed testing procedure described in Bretz et.al. 201146 combined with a
hierarchical approach is used to control the overall type-1 error at a nominal two-sided 5% level. 
The statistical testing strategy is built on the following principle:
!
Glycaemic efficacy must be established by HbA1c non-inferiority before testing for added 
benefits in terms of superiority in terms of HbA1c or body weight.
!
HbA1c and body weight superiority must be established before testing for added benefits in 
terms of superiority in terms of total fat mass.
The sample size is calculated using the calcPower function in the R package, gMCP47 using 10,000 
simulations. All of the four pre-specified confirmatory tests are assumed to be independent. Since 
some of these tests are positively correlated, the assumption of independence is viewed as 
conservative. The four hypotheses are:
!
HbA1c non-inferiority of semaglutide 1.0 mg vs. canagliflozin 300 mg with a non-inferiority 
margin of 0.3
!
HbA1c superiority of semaglutide 1.0 mg vs. canagliflozin 300 mg
!
Body weight superiority of semaglutide 1.0 mg vs. canagliflozin 300 mg
!
Total fat mass superiority of semaglutide 1.0 mg vs. canagliflozin 300 mg
The sample size assumptions for efficacy based on on-treatment data without rescue medication, a 
treatment effect based on in-trial data (see Section 17.3.1) and the standard deviations (SD) are 
given in Table 17–1. The HbA1c and body weight assumptions are based on the efficacy results and 
an observed reduction of approximately 20% and 15% respectively in in-trial treatment effect 
compare to efficacy in the subcutaneous semaglutide phase 3a clinical development programme28, 
48-52.
A similar reduction in the in-trial treatment effect compared to efficacy is assumed with 
canagliflozin as comparator. The total fat mass assumption is based on the relevant literature 
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focusing on fat mass53-55, which indicates a smaller SD for total fat mass as compared to body 
weight.
Table 17–1
Assumptions used in the sample size calculation
Semaglutide vs. canagliflozin 
HbA1c
Body weight
Total fat mass
Efficacy 
-0.32%
-2.4 kg
-1.8 kg
In-trial treatment effect 
-0.256%
-2.04 kg
-1.53 kg
Standard deviation 
1.1%
4.0 kg
3.5 kg
With the above assumptions, allocating 392 subjects to the semaglutide arm and the canagliflozin 
arm provides 90% power to confirm HbA1c superiority of semaglutide vs. canagliflozin across 
plausible assumptions.
Table 17–2
Calculated powers for meeting individual hypotheses
Statistical test
HbA1c
non-
inferiority
HbA1c
superiority
Body weight 
superiority
Total fat 
mass 
superiority
Efficacy Power (%)
>99%
90%
>99%
91%
In-trial effect power (%)
>99%
90%
>99%
74%
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Figure 17–1
Graphical illustration of the closed testing procedure. 
The overall significance level of α = 0.05 (two-sided) is initially allocated to the 
HbA1c non-inferiority test. The local significance level (α-local) will be reallocated if 
a hypothesis is confirmed according to the weight given by the directed edges 
between nodes (hypotheses). The total fat mass superiority test will receive the 
overall significance of α = 0.05 (two-sided) if and only if both HbA1c and body 
weight superiority are confirmed at their respective local significance levels.
The overall significance level of α = 0.05 (two-sided) is initially allocated to the HbA1c non-
inferiority test. The local significance level (α-local) will be reallocated if a hypothesis is confirmed 
according to the weight given by the directed edges between nodes (hypotheses). The total fat mass 
superiority test will receive the overall significance of α = 0.05 (two-sided) if and only if both 
HbA1c and body weight superiority are confirmed at their respective local significance levels. 
17.2.1
Sample size for the sub-study (DXA scan)
For the sub-study on body composition assuming an efficacy treatment difference of 1.8 kg and a 
SD of 3.5 kg, 174 subjects (87 subjects in each arm) will provide 92% power to establish a 
statistical significant difference resulting in 91% power for confirming superiority in the testing 
strategy in terms of fat mass loss (kg) at week 52 using a two-sided significance level of 5%. 
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Definition of analysis sets
17.3
The following analysis sets will be defined:
Full analysis set (FAS): includes all randomised subjects. Subjects in the FAS will contribute to 
evaluation “as randomised”.
Safety analysis set (SAS): includes all subjects exposed to at least one dose of trial product. 
Subjects in the SAS will contribute to the evaluation based on the trial product received for the 
majority of the period they were on treatment. This will be referred to as contributing to the 
evaluation “as treated”.
Per protocol (PP) analysis set: includes all subjects in the 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
!
Is on trial product at week 28 and have at least one non-missing HbA1c measurement at or 
after week 28
Subjects in the PP analysis set will contribute to the analysis “as treated” as defined for the SAS.
17.3.1
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
!
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 period starts at the date of 
first dose of trial product
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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 (P11)
!
the follow-up prematurely discontinuation visit (P11A)
!
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. 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.
Data points collected outside an observation period will be treated as missing in the analysis. 
Baseline data will always be included in an observation period. For adjudicated events, the onset 
date will be the EAC adjudicated onset date.
Before data are locked for statistical analysis, a review of all data will take place. Any decision to 
exclude either a subject or single observations from the statistical analysis is the joint responsibility
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of the members of the Novo Nordisk study group.
Exclusion of data from analyses will be used restrictively and normally no data should be excluded 
from the FAS. The subjects or observations to be excluded, and the reasons for their exclusion will 
be documented and signed by those responsible before database lock. The subjects and observations 
excluded from analysis sets, and the reason for this, will be described in the clinical trial report.
Primary endpoint
17.4
The primary endpoint is change from baseline to week 52 in HbA1c.
17.4.1
Primary analysis for the primary estimand 
The primary estimand will be estimated based on the FAS using post-baseline measurements up to 
and including week 52 from the ’on-treatment without rescue medication’ observation period. 
Imputation of missing data will be handled using multiple imputation assuming that missing data is 
missing at random (MAR). Missing data will be imputed using observed data within the same group 
defined by the randomised treatment (semaglutide/canagliflozin). It is hereby assumed that the 
likely values of what the missing data would have been if available are best described by 
information from subjects who receive the same treatment. 
Technically missing values will be imputed as follows:
!
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 200 copies of the dataset will be generated
!
A sequential regression approach for imputing monotone missing values at planned visits will 
be implemented starting with the first visit after baseline and sequentially continuing to the last 
planned visit at week 52. 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 (sub-study, non-sub-study) and region as categorical effects and baseline and post-
baseline HbA1c values observed prior to the visit in question as covariates. 
!
An ANCOVA with treatment, stratification factor (sub-study, non-sub-study) and region as 
categorical effects and baseline HbA1c as a covariate will be used to analyse HbA1c values at 
week 52 for each of the 200 complete data sets generated as part of the imputation of missing 
values. Rubin’s rule will be used to combine the analysis results in order to draw inference.
From this analysis, the estimated treatment difference between semaglutide and canagliflozin at 
week 52 will be presented together with the associated two-sided 95% confidence interval and 
unadjusted two sided p-values for testing non-inferiority and superiority.
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17.4.2
Primary hypotheses 
For the primary HbA1c endpoint the following confirmatory one-sided hypotheses are planned to be 
tested for semaglutide versus canagliflozin. Let the mean treatment difference be defined as μ = 
(semaglutide minus canagliflozin):
!
Non-inferiority, using a non-inferiority margin of 0.3%
o
H0: μ ≥0.3% against Ha: μ <0.3%
!
Superiority
o
H0: μ ≥0.0% against Ha: μ <0.0%
Operationally the hypotheses will be evaluated by two-sided tests.
The non-inferiority margin of 0.3 is chosen based on the diabetes guideline56, 57 and the effect of 
canagliflozin on glycaemic effect seen in a similar trial (DIA3006) where canagliflozin was used as 
add on to metformin. In this trial canagliflozin showed an HbA1c treatment difference to placebo of 
-0.77% Hence, based on this trial, the chosen margin of 0.3 provides assurance that semaglutide has 
an effect compared to placebo greater than 0 with a clinically relevant size. With regards to the 
constancy assumption, controlled clinical trials have consistently established that canagliflozin is an 
effective anti-diabetic drug. Therefore, lack of trial sensitivity with canagliflozin as comparator is 
not anticipated to be an issue in this trial.
17.4.3
Multiplicity and criteria for confirming hypotheses
The Type-I error for testing the four confirmatory hypotheses related to the HbA1c, body weight, 
and fat mass endpoints will be preserved in the strong sense at 5% (two-sided) using the weighted 
Bonferroni-based closed testing procedure described in Bretz et. al.46 and outlined in Figure 17–1. 
The first hypothesis to be tested is non-inferiority of HbA1c. It will be tested at the overall 
significance level (5%) while allocating 0% local significance level to the remaining three 
hypotheses. For this hypothesis, and in general, if a hypothesis is confirmed the significance level 
will be reallocated according to the weight and the direction of the edges going from the confirmed 
hypothesis to the next hypotheses as specified in Figure 17–1. Total fat mass will be tested at the 
overall significance level if each of the other 3 hypotheses is confirmed, otherwise its local 
significance level will remain 0%. Each of the following hypotheses will be tested at their local 
significance level (α-local). This process will be repeated until no further hypotheses can be 
confirmed. 
Non-inferiority and subsequent superiority will be considered confirmed if the mean treatment 
difference is supporting the corresponding alternative hypothesis and the two-sided p-value from 
the primary analysis of the primary estimand is strictly below its local two-sided significance level 
as defined by the closed testing procedure in Figure 17–1. This is equivalent to using a one-sided p-
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value (nominal alpha = 0.025) and a one-sided 2.5% overall significance level in the closed testing 
procedure.
17.4.4
Statistical subgroup analyses of HbA1c
Five subgroups based on baseline Hba1c values are defined as follows:
1. ≤ 7.5%
2. > 7.5% to 8.0% (inclusive)
3. > 8.0% to 8.5% (inclusive)
4. > 8.5% to 9.0% (inclusive)
5. > 9.0%
Change from baseline in Hba1c at week 52 for subgroups based on baseline Hba1c values will be 
analysed for the primary estimand using a similar multiple imputation approach as described in 
section 17.4.1. The complete data sets from the primary analysis will be reused. However the 
ANCOVA model used to analyse the 200 complete data sets will additionally include the 
interaction effect of subgroup and treatment as a categorical effect. Rubin’s rule will then be used to 
combine the results and the p-value for the interaction effect and estimated treatment differences at 
52 weeks with corresponding two-sided 95% confidence intervals for each subgroup will be 
presented.
17.4.5
Sensitivity analyses
In order to investigate the robustness of the conclusions from the primary analysis and to stress test 
the MAR assumption for missing data tipping point sensitivity analyses will be performed for the 
primary estimand both for the sensitivity of the non-inferiority and the superiority HbA1c
hypotheses.  
17.4.5.1
Sensitivity analyses for the primary estimand
The estimation of the primary estimand will be repeated using the following sensitivity analysis:
!
Tipping-point analysis (pattern mixture model based) based on the FAS using the ’on-treatment 
without rescue medication’ observation period. In this analysis, subjects from the semaglutide 
group 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 conclusion of the analyses in 
terms of statistical significance is changed. 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 canagliflozin to being 
non-statistically significantly better for the superiority test and similarly for the non-inferiority 
test. Technically, this analysis will be implemented by replicating the primary analysis including 
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the assumption of MAR but subsequently adding increasing penalty values at week 52 to
imputed observations in the semaglutide group before applying ANCOVA on the 200 complete 
data sets.
17.4.5.2
Other sensitivity analyses
The following additional sensitivity analyses are specified:
!
In-trial treatment policy analysis based on the FAS using post-baseline measurements up to and 
including week 52 from the in-trial observation period. Missing data will be imputed using the 
same approach as described for the primary analysis of the primary estimand. However the 
imputation will be done within the same group defined not only by the randomised treatment  
(semaglutide/canagliflozin) but also by the status of treatment completion (still on randomised 
treatment at week 52 yes/no) (4 groups in total). It is hereby assumed that the likely values of 
what the missing data would have been if available are best described by information from 
subjects who at week 52 are similar in terms of randomised treatment and treatment completion 
status. In addition in the imputation step stratification factor and region is not included in the 
model in order to avoid potential issues with sparse data. This analysis could be considered 
addressing an effectiveness estimand.
!
PP analysis based on the PP data set using the ‘on-treatment without rescue’ observation period. 
This analysis will be carried out for non-inferiority testing only. The statistical analysis will be 
the same as the primary analysis for the primary estimand.
Secondary endpoints
17.5
17.5.1
Confirmatory secondary endpoints 
Change from baseline to week 52 in body weight (kg) and change from baseline to week 52 in total 
fat mass (kg) will be confirmatory secondary endpoints. 
The primary estimand will be estimated using the same approach as described for the primary
HbA1c endpoint. Body weight and total fat mass will be tested for superiority. Baseline and post-
baseline body weight or total fat mass will be used as covariates instead of HbA1c for their 
respective analyses.
Superiority will be considered confirmed if the mean treatment difference is supporting the 
corresponding hypothesis and the two-sided p-value from the primary analysis of the primary 
estimand is strictly below its local two-sided significance level resulting from the closed testing 
procedure in Figure 17–1.
The tipping point sensitivity analysis pre-specified to evaluate the robustness of the conclusions 
from the primary analysis of HbA1c will also be performed to evaluate the robustness of the 
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conclusions from the body weight and total fat mass superiority tests. In addition, the in-trial 
sensitivity analysis will also be performed for both body weight and total fat mass.
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17.5.2
Supportive secondary endpoints
No sensitivity analyses are planned for the supportive secondary endpoints. 
17.5.2.1
Efficacy endpoints
Continuous endpoints
The continuous endpoints are change from baseline to week 52 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)
!
Fasting blood lipids (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides)
!
Body Mass Index (BMI) and waist circumference
!
Systolic and diastolic blood pressure
!
Body weight (%)
!
Total fat mass (%)
!
Total lean mass (kg)
!
Total lean mass (%)
!
Visceral fat mass (kg)
!
Visceral fat mass (%)
!
Ratio between total fat mass and total lean mass
The above continuous endpoints will be analysed for the primary estimand separately using a 
similar model approach as for the primary endpoint with the associated baseline and post-baseline 
responses as covariates instead of HbA1c for their respective analyses.
Fasting lipid profile endpoints will be log-transformed prior to analysis with the associated log-
transformed baseline value as a covariate.
Mean 7-point profile (SMPG) definition
Subjects will be asked to perform SMPG measurements before and 90 minutes after breakfast, 
lunch, dinner, and at bedtime. 
Mean of the 7-point profile is defined as the area under the profile, calculated using the trapezoidal 
method, divided by the measurement time.
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Binary endpoints
The binary endpoints are subjects who after 52 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 ≥3%
!
Weight loss ≥5%
!
Weight loss ≥10%
!
HbA1c <7.0% (53 mmol/mol) without severe or blood glucose confirmed symptomatic 
hypoglycaemia episodes and no weight gain
!
HbA1c reduction ≥1%
!
HbA1c reduction ≥1% and weight loss ≥3%
!
HbA1c reduction ≥1% and weight loss ≥5%
!
HbA1c reduction ≥1% and weight loss ≥10%
The above 10 endpoints will be analysed for the primary estimand. The analyses for the primary 
estimand for all 10 endpoints will be based on the ’on-treatment without rescue medication’ 
observation period. They will be analysed separately using the same type of logistic regression 
model with treatment, stratification factor (sub-study, non- sub-study), region and associated 
baseline and post-baseline response(s) (i.e. HbA1c responses for HbA1c endpoints, body weight 
responses for weight endpoints and both HbA1c and body weight responses for the binary endpoints 
that combine both parameters) as covariates. To account for missing data, the analysis will be made 
using a sequential multiple imputation approach as described below: 
!
Multiple imputed data sets (200) will be created in which missing values for the underlying 
continuous assessments are imputed by treatment group assuming MAR similar to the approach 
described for the primary analysis in section 17.4.1.
!
The binary endpoint will be created for each of the 200 complete data sets
!
Each of the created complete data sets will be analysed with the logistic regression model. 
Estimated odds ratios will be log transformed and inference will be drawn using Rubin’s rule58.
The results after applying Rubin’s rule will be back-transformed and described by the odds ratio 
between treatments and the associated 95% confidence interval and p-value for no treatment 
difference.
17.5.2.2
Safety endpoints
The safety endpoints will be evaluated based on SAS using the on-treatment observation period and 
the in-trial observation period unless otherwise stated. 
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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.
Hypoglycaemic episodes
The following two endpoints related to hypoglycaemic episodes are used to support the safety 
objective:
!
Number of treatment-emergent severe or BG-confirmed symptomatic hypoglycaemic 
episodes 
!
Treatment-emergent severe or BG-confirmed symptomatic hypoglycaemic episodes 
(yes/no)
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 episode 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. 
Classification of Hypoglycaemia: 
Treatment emergent: hypoglycaemic episodes will be defined as treatment emergent if the onset is 
in the on-treatment period (see definition of observation period in section 17.3.1)
Nocturnal hypoglycaemic episodes: are episodes occurring between 00:01 and 05.59 both inclusive.
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Hypoglycaemic episodes are classified according to the Novo Nordisk classification of 
hypoglycaemia (see Figure 17–2) and the ADA classification of hypoglycaemia (see Figure 17–3).
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)59. Therefore, Novo Nordisk has included hypoglycaemia with plasma glucose 
levels below this cut-off point in the definition of BG confirmed hypoglycaemia.
Novo Nordisk uses the following classification (see Figure 17–2) in addition to the ADA 
classification:
!
Severe or BG confirmed symptomatic hypoglycaemia: An episode that is severe according to 
the ADA classification60 or BG confirmed by a plasma glucose value <3.1 mmol/L (56 mg/dL) 
with symptoms consistent with hypoglycaemia. 
Figure 17–2
Novo Nordisk classification of hypoglycaemia 
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ADA classification60 of hypoglycaemia 
– Severe hypoglycaemia: An episode requiring assistance of another person to actively administer 
carbohydrate, glucagon, or take other corrective actions. Plasma glucose concentrations may 
not be available during an event, but neurological recovery following the return of plasma 
glucose to normal is considered sufficient evidence that the event was induced by a low plasma 
glucose concentration.
– Asymptomatic hypoglycaemia: An episode not accompanied by typical symptoms of 
hypoglycaemia, but with a measured plasma glucose concentration ≤ 3.9 mmol/L (70 mg/dL).
– Documented symptomatic hypoglycaemia: An episode during which typical symptoms of 
hypoglycaemia are accompanied by a measured plasma glucose concentration ≤ 3.9 mmol/L 
(70 mg/dL).
– Pseudo-hypoglycaemia: An episode during which the person with diabetes reports any of the 
typical symptoms of hypoglycaemia with a measured plasma glucose concentration 
> 3.9 mmol/L (70 mg/dL) but approaching that level.
– Probable symptomatic hypoglycaemia: An episode during which symptoms of hypoglycaemia 
are not accompanied by a plasma glucose determination but that was presumably caused by a 
plasma glucose concentration ≤3.9 mmol/L (70 mg/dL).
Figure 17–3
ADA classification of hypoglycaemia
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Number of treatment emergent severe or blood glucose (BG) confirmed symptomatic 
hypoglycaemic episodes
Number of treatment emergent severe or BG confirmed symptomatic hypoglycaemic episodes 
during 56 weeks 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 and stratification factor (sub-study, 
non- sub-study) as categorical factors and baseline HbA1c as covariate. The SAS will be used for the 
analysis.
The results will be described by the rate ratio between treatments and the associated 95% 
confidence interval and p-value for no treatment difference.
Treatment emergent severe or blood glucose confirmed symptomatic hypoglycaemia 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. The model will include factors for treatment and stratification factor (sub-study, 
non- sub-study) as categorical factors and baseline HbA1c as covariate. The SAS will be used for the 
analysis.
The results will be described by the odds ratio between treatments and the associated 95% 
confidence interval and p-value for no treatment difference.
Laboratory assessments
The laboratory assessments supporting the safety objective are change from baseline to week 52 in:
!
Haematology
!
Biochemistry
!
Calcitonin
The above continuous laboratory assessments will be summarised and evaluated by descriptive 
statistics.
In addition amylase and lipase 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 on-
treatment observation period.
Both analyses will use the associated baseline and post-baseline responses as covariates instead of 
HbA1c. Lipase and amylase values will be log-transformed prior to the analysis.
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Pulse
Change from baseline to week 52 in pulse will be analysed separately with the same model 
approach as for amylase and lipase but with the pulse value at baseline and post-baseline as 
covariates instead of HbA1c.
Categorical safety assessments
The categorical assessments supporting the safety objective are change from baseline to week 52 in:
!
Electrocardiogram (ECG) category
!
Physical examination
!
Eye examination category
The above assessments will be summarised descriptively
Health economics and/or patient reported outcomes (PROs)
17.6
Change from baseline to week 52 in:
!
Scores for selected patient reported outcomes:
o
SF-36v2TM Short Form health survey: Total scores (physical component and mental 
component) and scores from the 8 domains
o
Diabetes Treatment Satisfaction Questionnaire (DTSQ): Treatment satisfaction score 
(sum of 6 of 8 items) and the 8 items separately
o
Control of Eating Questionnaire (CoEQ): Scores from the 4 domains and scores from 
19 individual items
The PRO questionnaires, SF-36v2™, DTSQ and CoEQ will be used to evaluate the objective 
regarding Quality of Life. Each of the PRO endpoints will be analysed separately as the other 
continuous efficacy endpoints for the primary estimand using a similar model approach as for the 
primary endpoint with the associated baseline and post-baseline responses as covariates.
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18 Ethics
Benefit-risk assessment of the trial
18.1
18.1.1
Risk 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-1RAs. For each of these risks and precautions, mitigating 
actions have been implemented to minimise the risks for subjects enrolled in this trial.
18.1.2
Identified risk
Gastrointestinal adverse events
Consistent with findings with other GLP-1RAs, 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.
18.1.3
Potential risks
Medullary thyroid cancer
The human relevance of the proliferative C-cell changes found in rodents treated with GLP-1RAs is 
unknown, but data suggest that rodents are more sensitive to the mode of action of GLP-1RAs for 
induction of C-cell tumours. However, as a precaution, subjects with a family or personal history of 
Multipel Endokrin Neoplasi type 2 (MEN 2) or Medullary thyroid cancer will not be enrolled in the 
trial. During the trial, calcitonin will be measured at randomistion visit, visit 8 and at V10/V10A, 
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-1RAs 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.
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 
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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-1RAs 
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, 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-1RA drug class, there is a risk of hypoglycaemic 
episodes. Hypoglycaemic episodes have mainly been observed when semaglutide is combined with 
SU or insulin. 
Acute kidney injury
In subjects treated with GLP-1RAs, including semaglutide, gastrointestinal AEs such as nausea, 
vomiting and diarrhoea may lead to significant dehydration and secondary acute kidney injury. 
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 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-
1RAs 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.
18.1.4
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 
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or intend to become pregnant or are of childbearing potential and not using an adequate 
contraceptive method will not be enrolled in the trial. In addition, pregnancy tests will be performed 
at all visits, including screening and follow-up and at any time during the trial if a menstrual period 
is missed, or as required by local law.
Diabetic retinopathy
A transient worsening of diabetic retinopathy is a recognised complication in selected patients with 
diabetes after initiation of intensive anti-diabetic treatment61-63. Risk factors for these events include 
long-standing poor glycaemic control and presence of proliferative retinopathy, and initial large 
improvements in blood glucose may be an additional aggravating factor. Several studies have, 
however, documented long-term beneficial effects of intensive glycaemic treatment in reducing 
retinopathy progression5, 64 even in intensively treated patients who experienced early worsening62. 
In a cardiovascular outcomes trial with s.c. semaglutide, results indicate an increased risk of events 
related to diabetic retinopathy in subjects treated with semaglutide compared to placebo. As a 
precaution in this trial, all subjects are required to have a fundus photography or dilated fundoscopy 
performed before enrolment into the trial; moreover, subjects with proliferative retinopathy or 
maculopathy requiring acute treatment will be excluded. As part of good diabetes management the
investigator is encouraged to ensure adequate monitoring and treatment of diabetic retinopathy in 
subjects enrolled into the trial65.
General precautions 
All subjects will be included after a thorough evaluation with regards to in- and exclusion criteria 
defined in order to ensure that subjects are eligible for trial treatment.
There are also strict glycaemic rescue criteria in place to ensure acceptable glycaemic control 
during the trial. If rescue medication is required, it should be in accordance with ADA/European 
Association for the Study of Diabetes33, 34 (excluding GLP-1RAs, DPP-4 inhibitors, amylin 
analogues and SGLT-2).
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 Diabetes65.
Further details with regards to safety of trial product are described in the current edition of the IB 
for semaglutide (NN9535)25 or any updates thereto or in the current approved label of the relevant 
SGLT-inhibitors.
Canagliflozin
Subjects should be considered suitable for treatment with canagliflozin and the use of canagliflozin 
should be in accordance with the current, approved label. It is important to monitor renal function 
and for signs and symptoms of volume depletion during therapy. Serum creatinine will be measured 
regularly for monitoring of renal function.
The most common adverse reactions reported with canagliflozin are female genital mycotic 
infections, urinary tract infections and increased urination. Other events include hypoglycaemia 
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(with concomitant use of insulin or insulin secretagogues), hypotension, hyperkalemia, increased 
LDL-C levels and bone fracture. Canagliflozin and other SGLT-2 inhibitors have also been 
associated with a risk of urinary tract infections and ketoacidosis. Symptoms of ketoacidosis include 
nausea, vomiting, abdominal pain, tiredness, general malaise and shortness of breath. Ketoacidosis 
associated with the use of SGLT-2 inhibitors can occur even if blood sugar levels are only relatively 
elevated or non-elevated. If ketoacidosis is suspected, canagliflozin or canagliflozin placebo should 
be discontinued and appropriate treatment should be instituted promptly.
18.1.5
Benefits
In this trial, subjects will be randomised in a 1:1 manner to one of two treatment arms involving an 
active add-on treatment regimen anticipated to be more efficacious than the treatment they receive 
at the time of entry into the trial (metformin only).
Based on the results of the completed clinical trials, semaglutide is expected to provide clinically 
relevant improvements in glycaemic control and body weight in subjects with type 2 diabetes.
In addition, it is expected that all subjects, will benefit from participation through close contact with 
the trial site, with close follow-up of their T2D and a careful medical examination, all of which will 
most likely result in an intensified management of their T2D.
Finally, data from two cardiovascular outcomes trials investigating treatment with GLP-1RAs 
compared to placebo have indicated that there might be a potential 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 3.1.5.3).
All subjects in this trial will receive trial products and auxiliary supplies free of charge. 
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Risk and benefit conclusion
18.2
The safety profile for semaglutide generated from the clinical and nonclinical development 
programme has not revealed any safety issues that would prohibit administration of semaglutide in 
accordance with the planned clinical trial. Completed clinical trials with semaglutide provided 
clinically relevant improvements in glycaemic control and body weight.
Safety and efficacy will be monitored regularly and acceptable glycaemic control will be reinforced 
at all times during the trial.
In conclusion, the potential risk to the subjects in this trial is considered low and acceptable in view 
of the anticipated benefits semaglutide would provide to patients with T2D.
Informed consent 
18.3
In seeking and documenting informed consent, the investigator must comply with applicable 
regulatory requirement(s) and adhere to ICH GCP2 and the requirements in the Declaration of 
Helsinki3.
Before any trial-related activity, the investigator must give the subject verbal and written 
information about the trial and the procedures involved in a form that the subject can read and 
understand.
The subjects must be fully informed of their rights and responsibilities while participating in the 
trial as well as possible disadvantages of being treated with the trial products.
The investigator must ensure the subject ample time to come to a decision whether or not to 
participate in the trial. 
A voluntary, signed and personally dated informed consent must be obtained from the subject 
before any trial-related activity.
The responsibility for seeking informed consent must remain with the investigator, but the 
investigator may delegate the task to a medically qualified person, in accordance with local 
requirements. The written informed consent must be signed and personally dated by the person who 
seeks the informed consent before any trial-related activity.
If information becomes available that may be relevant to the subject’s willingness to continue 
participating in the trial, the investigator must inform the subject in a timely manner, and a revised 
written subject information must be provided and a new informed consent must be obtained.
In order to avoid missing data, the subjects will be informed about the importance of completing the 
trial also if the subjects discontinue treatment with trial product.
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Data handling
18.4
If the subject withdraws from the trial or is lost to follow up, then the subject’s data will be handled 
as follows:
!
Data already collected and any data collected at the end-of-trial visit including follow up visits
will be retained by Novo Nordisk, entered into the database and used for the clinical trial report. 
!
Safety events will be reported to Novo Nordisk and regulatory authorities according to 
local/national requirements.
If data is used, it will always be in accordance with local regulations and IRBs/IECs.
Information to subjects during trial
18.5
All written information to subjects must be sent to IRB/IEC for approval/favourable opinion and to 
regulatory authorities for approval or notification according to local regulations.
Premature termination of the trial and/or trial site
18.6
Novo Nordisk, the IRBs/IECs or a regulatory authority may decide to stop the trial, part of the trial 
or a trial site at any time, but agreement on procedures to be followed must be obtained.
If the trial is suspended or prematurely terminated, the investigator must inform the subjects 
promptly and ensure appropriate therapy and follow-up. The investigator and/or Novo Nordisk must 
also promptly inform the regulatory authorities and IRBs/IECs and provide a detailed written 
explanation. 
If, after the termination of the trial, the benefit-risk analysis changes, the new evaluation must be 
provided to the IRBs/IECs in case it has an impact on the planned follow-up of subjects who have 
participated in the trial. If it has an impact, the actions needed to inform and protect the subjects 
should be described.
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19 Protocol compliance
Protocol deviations
19.1
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. 
Documentation on protocol deviations must be kept in the investigator trial master file and sponsor 
trial master file.
Prevention of missing data
19.2
The importance of subject retention will be addressed by Novo Nordisk in the training and 
communication with the trial sites. 
The subjects will be carefully informed about the trial procedures before signing informed consent, 
so that they know the implications of participating in the trial. 
Close surveillance of subject retention will be performed throughout the trial by Novo Nordisk with 
focus on reasons for premature discontinuation of trial product or withdrawal of consent to secure 
early mitigations in collaboration with the trial sites. 
The investigator will make every effort to ensure that all assessments are performed and data is 
collected. If missing data does occur the reason will be collected via the protocol deviation process, 
see Section 19.1. Novo Nordisk will monitor protocol deviations on an on-going basis throughout 
the trial followed by appropriate actions (e.g. re-training of site staff).
20 Audits and inspections
Any aspect of the clinical trial may be subject to audits conducted by Novo Nordisk or inspections 
from domestic or foreign regulatory authorities or from IRBs/IECs. Audits and inspections may 
take place during or after the trial. The investigator and the site staff as well as Novo Nordisk staff 
have an obligation to cooperate and assist in audits and inspections. This includes giving auditors 
and inspectors direct access to all source documents and other documents at the trial site relevant to 
the clinical trial. This includes permission to examine, analyse, verify and reproduce any record(s) 
and report(s) that are relevant to the evaluation of the trial.
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21 Critical documents
Before a trial site is allowed to start screening subjects, written notification from Novo Nordisk 
must be received and the following documents must be available to Novo Nordisk:
!
Regulatory approval and/or acknowledgement of notification as required 
!
Approval/favourable opinion from IRBs/IECs clearly identifying the documents reviewed as 
follows: protocol, any protocol amendments, subject information/informed consent form, any 
other written information to be provided to the subject and subject recruitment materials
!
List of IRB/IEC members and/or constitution (or a general assurance number/statement of 
compliance)
!
Curricula vitae of investigator and sub-investigator(s) (current, dated and signed - must include 
documented GCP training or a certificate)
!
Signed receipt of Investigator’s Brochure SmPC or similar labelling 
!
Signed and dated Agreement on Protocol
!
Signed and dated Agreement on Protocol Amendment, if applicable
!
Contract, signed by the investigator and/or appropriate parties on behalf of the investigator’s site 
and Novo Nordisk
!
Source document agreement
!
Central laboratory certification and normal ranges
!
Insurance statement, if applicable
!
Financial disclosure form from investigator and sub-investigator(s)
Only applicable for US trial sites: 
!
For US trial sites: verification under disclosures per Code of Federal Regulations (CFR) of 
Financial Conflict of Interest
!
For US trial sites: FDA form 1572 must be completed and signed by the investigator at each site
FDA form 1572:
For US sites:
!
Intended for US sites
!
Conducted under the IND
!
All US investigators, as described above, will sign FDA Form 1572
For sites outside the US:
!
Intended for participating sites outside of the US
!
Not conducted under the IND
!
All investigators outside of the US will not sign FDA form 1572
Novo Nordisk will analyse and report data from all sites together if more than one site is involved in 
the trial.
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By signing the protocol agreement, each investigator agrees to comply fully with ICH GCP2
applicable regulatory requirements and the Declaration of Helsinki3. 
By signing the protocol agreement, each investigator also agrees to allow Novo Nordisk to make 
investigator’s name and information about site name and address publically available if this is 
required by national or international regulations.
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22 Responsibilities
The investigator is accountable for the conduct of the trial at his/her site and must ensure adequate 
supervision of the conduct of the trial at the trial site. If any tasks are delegated, the investigator 
must maintain a log of appropriately qualified persons to whom he/she has delegated specified trial-
related duties. The investigator must ensure that there is adequate and documented training for all 
staff participating in the conduct of the trial. It is the investigator’s responsibility to supervise the 
conduct of the trial and to protect the rights, safety, and well-being of the subjects.
A qualified physician, who is an investigator or a sub-investigator for the trial, must be responsible 
for all trial-related medical decisions.
The investigator will follow instructions from Novo Nordisk when processing data.
The investigator is responsible for filing essential documents (i.e. those documents which 
individually and collectively permit evaluation of the conduct of a trial and the quality of the data 
produced) in the investigator trial master file. The documents including the subject identification 
code list must be kept in a secure locked facility, so no unauthorized persons can get access to the 
data. 
The investigator will take all necessary technical and organisational safety measures to prevent 
accidental or wrongful destruction, loss or deterioration of data. The investigator will prevent any 
unauthorised access to data or any other processing of data against applicable law. The investigator 
must be able to provide the necessary information or otherwise demonstrate to Novo Nordisk that 
such technical and organisational safety measures have been taken.
During any period of unavailability, the investigator must delegate responsibility for medical care of 
subjects to a specific qualified physician who will be readily available to subjects during that time.
If the investigator is no longer able to fulfil the role as investigator (e.g. if he/she moves or retires), 
a new investigator will be appointed in consultation with Novo Nordisk. 
The investigator and other site personnel must have sufficient English skills according to their 
assigned task(s).
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23 Reports and publications
The information obtained during the conduct of this trial is considered confidential, and may be 
used by or on behalf of Novo Nordisk for regulatory purposes as well as for the general 
development of the trial product. All information supplied by Novo Nordisk in connection with this 
trial shall remain the sole property of Novo Nordisk and is to be considered confidential 
information. 
No confidential information shall be disclosed to others without prior written consent from Novo 
Nordisk. Such information shall not be used except in the performance of this trial. The information 
obtained during this trial may be made available to other physicians who are conducting other 
clinical trials with the trial product, if deemed necessary by Novo Nordisk. Provided that certain 
conditions are fulfilled, Novo Nordisk may grant access to information obtained during this trial to 
researchers who require access for research projects studying the same disease and/or trial product 
studied in this trial.
Novo Nordisk may publish on its clinical trials website a redacted clinical trial report for this trial.
One or two investigators will be appointed by Novo Nordisk to review and sign the clinical trial 
report (signatory investigator) on behalf of all participating investigators. The signatory investigator 
will be appointed based upon the criteria defined by the International Committee of Medical Journal 
Editors for research publications66.
Communication of results
23.1
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 Disclosure35.
Novo Nordisk reserves the right to defer the release of data until specified milestones are reached, 
for example when the clinical trial report is available. This includes the right not to release the 
results of interim analyses, because the release of such information may influence the results of the 
entire trial.
At the end of the trial, one or more scientific publications may be prepared collaboratively by the 
investigator(s) and Novo Nordisk. Novo Nordisk reserves the right to postpone publication and/or 
communication for up to 60 days to protect intellectual property.
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In all cases the trial results will be reported in an objective, accurate, balanced and complete 
manner, with a discussion of the strengths and limitations. All authors will be given the relevant 
statistical tables, figures, and reports needed to evaluate the planned publication. In the event of any 
disagreement on the content of any publication, both the investigators’ and Novo Nordisk opinions 
will be fairly and sufficiently represented in the publication.
Where required by the journal, the investigator from each trial site will be named in an 
acknowledgement or in the supplementary material, as specified by the journal. 
Novo Nordisk maintains the right to be informed of plans by any investigator to publish and to 
review any scientific paper, presentation, communication or other information concerning the 
investigation described in this protocol. Any such communication must be submitted in writing to 
Novo Nordisk before submission for comments. Comments will be given within four weeks from 
receipt of the planned communication. 
23.1.1
Authorship
Authorship of publications should be in accordance with the Uniform Requirements of the 
International Committee of Medical Journal Editors66 (sometimes referred to as the Vancouver 
Criteria).
Novo Nordisk will appoint investigator(s) to prepare publications in collaboration with Novo 
Nordisk.
23.1.2
Site-specific publication(s) by investigator(s)
For a multi-centre clinical trial, analyses based on single-site data usually have significant statistical 
limitations and frequently do not provide meaningful information for healthcare professionals or 
subjects, and therefore may not be supported by Novo Nordisk. It is a Novo Nordisk policy that 
such individual reports do not precede the primary manuscript and should always reference the 
primary manuscript of the trial.
Novo Nordisk reserves the right to prior review of such publications. Further to allow for the 
primary manuscript to be published as the first, Novo Nordisk asks for deferment of publication of 
individual site results until the primary manuscript is accepted for publication. As Novo Nordisk
wants to live up to the industry publication policy, submission of a primary publication will take 
place no later than 18 months after trial completion. 
Investigator access to data and review of results
23.2
As owner of the trial database, Novo Nordisk has the discretion to determine who will have access 
to the database. 
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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
Retention of clinical trial documentation
24.1
Subject’s medical records must be kept for the maximum period permitted by the hospital, 
institution or private practice.
The investigator must agree to archive the documentation (this includes both electronic and paper-
based records) pertaining to the trial in an archive after completion or discontinuation of the trial if 
not otherwise notified. The investigator should not destroy any documents without prior permission 
from Novo Nordisk. If the investigator cannot archive the documents at the trial site, Novo Nordisk 
can refer the investigator to an independent archive provider that has a system in place to allow only 
the investigator to access the files.
The investigator must be able to access his/her trial documents without involving Novo Nordisk in 
any way. Site-specific CRFs and other subject data (in an electronic readable format or as paper 
copies or prints) will be provided to the investigator before access is revoked to the systems and/or 
electronic devices supplied by Novo Nordisk. These data must be retained by the trial site. If the 
provided data (e.g. the CD-ROM) is not readable during the entire storage period, the investigator 
can request a new copy. A copy of all data will be stored by Novo Nordisk.
Novo Nordisk will maintain Novo Nordisk documentation pertaining to the trial for at least 20 years 
after discontinuation of the marketing authorisation, termination of the trial or cancellation of the 
research project whichever is longest.
The files from the trial site/institution must be retained for 15 years after end of  trial as defined in 
section 7, or longer if required by local regulations or Novo Nordisk. In any case trial files cannot 
be destroyed until the trial site/institution is notified by Novo Nordisk. The deletion process must 
ensure confidentiality of data and must be done in accordance with local regulatory requirements.  
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25 Institutional Review Boards/Independent Ethics Committees and 
regulatory authorities
IRB/IEC:
Written approval or favourable opinion must be obtained from IRB/IEC prior to commencement of 
the trial.
During the trial, the investigator or Novo Nordisk, as applicable, must promptly report the 
following to the IRB/IEC, in accordance with local requirements: updates to Investigator’s 
Brochure, unexpected SAEs where a causal relationship cannot be ruled out, protocol amendments 
according to local requirements, deviations to the protocol implemented to eliminate immediate 
hazards to the subjects, new information that may affect adversely the safety of the subjects or the 
conduct of the trial (including new benefit-risk analysis in case it will have an impact on the 
planned follow-up of the subjects), annually written summaries of the trial status, and other 
documents as required by the local IRB/IEC.
The investigator must ensure submission of the clinical trial report synopsis to the IRB/IEC.
Protocol amendments must not be implemented before approval or favourable opinion according to 
local regulations, unless necessary to eliminate immediate hazards to the subjects.
The investigator must maintain an accurate and complete record of all submissions made to the 
IRB/IEC. The records must be filed in the investigator trial master file and copies must be sent to 
Novo Nordisk.
Regulatory Authorities:
Regulatory authorities will receive the clinical trial application, protocol amendments, reports on 
SAEs, and the clinical trial report according to national requirements.
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UTN:U1111-1180-3651 
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26 Indemnity statement
Novo Nordisk carries product liability for its products, and liability as assumed under the special 
laws, acts and/or guidelines for conducting clinical trials in any country, unless others have shown 
negligence.
Novo Nordisk assumes no liability in the event of negligence, or any other liability of the sites or 
investigators conducting the trial, or by persons for whom the said site or investigator are 
responsible.
Novo Nordisk accepts liability in accordance with: 
For Mexico only:
a) Novo Nordisk carries product liability for its products assumed under the special laws, 
acts/and/or guidelines for conducting trials in any country, including those applicable 
provisions on the Mexican United States. If the subject feels that something goes wrong 
during the course of this trial, the subject should contact the trial staff in the first instance.
b) If during their participation in the trial the subject experiences a disease or injury that, 
according to the trial doctor and the sponsor, is directly caused by the trial medication 
and/or a trial procedure that otherwise would not have been part of his/her regular care, 
the subject will receive from the Institution or Medical Care Establishment and free of 
charge, the appropriate medical treatment as required.
c) In this case, the costs resulting from such treatment  as well as the costs of any 
indemnification established by law will be covered by the trial sponsor in accordance with 
the terms provided by all applicable regulations; even if the  subject discontinues his/her 
participation in the trial by his own will or by a decision from the investigator.
d) By signing the informed consent, the subject will not renounce to any compensation or 
indemnification he/she may be entitled to by law, nor will he/she will incur any additional 
expense as a result of his/her participation in the trial; any additional expense resulting 
from the subject’s participation in the trial will be covered by the trial sponsor.
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Date:
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27 References
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CONFIDENTIAL
Date:
17 October 2016
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Version:
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UTN:U1111-1180-3651 
Status:
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Lau J, Bloch P, Schäffer L, Pettersson I, Spetzler J, Kofoed J, et al. Discovery of the Once-
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Investigator's Brochure for s.c. Semaglutide (NN9535), Edition 11 or any updates hereof. 
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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 
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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). 
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Ahmann A CM, Charpentier G, Dotta F, Henkel E, Lingvay I, Gaarsdal Holst A, Chang D, 
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Weeks in Subjects With Type 2 Diabetes (SUSTAIN 3). Diabetes. 2016.
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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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Novo Nordisk A/S. Company Announcement: SUSTAIN 6. 2016.
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Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, et al. 
Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016.
32.
Janssen-Cilag International N.V. Invokana (canagliflozin) EU prescribing information 
(SmPC). January 2016.
33.
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.
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Protocol
CONFIDENTIAL
Date:
17 October 2016
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Version:
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UTN:U1111-1180-3651 
Status:
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34.
Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. 
Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update 
to a position statement of the American Diabetes Association and the European Association 
for the Study of Diabetes. Diabetes Care. 2015;38(1):140-9.
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Novo Nordisk A/S. http://www.novonordisk-trials.com/website/content/how-we-disclose-
trial-information.aspx.
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registration: a statement from the International Committee of Medical Journal Editors. N 
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awareness of hypoglycemia in adults with IDDM. A prospective study of hypoglycemic 
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Outcome Measures: Use in Medical Product Development to Support Labeling Claims. 
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version 0.8-8. 3 Oct 2014.
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48.
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type 2 diabetes. Company official announcement, Dec. 2015. Available at 
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type 2 diabetes. Company official announcement, Sept. 2015. Available at 
http://www.novonordisk.com/content/Denmark/HQ/www-novonordisk-
com/en_gb/home/media/news-details.1954507.html.
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type 2 diabetes. Company official announcement, July 2015. Available at 
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com/en_gb/home/media/news-details.1934243.html.
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Results from the SUSTAIN 4 trial comparing once-weekly subcutaneous administration of 
the GLP-1 analogue semaglutide with once-daily insulin glargine. In 'Highlights to be 
presented at Novo Nordisk's Capital Markets Day 2015' - Company official announcement, 
Nov. 2015. Available at http://www.novonordisk.com/content/Denmark/HQ/www-
novonordisk-com/en_gb/home/media/news-details.1967802.html.
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type 2 diabetes. Company official announcement, Feb 2016. Available at 
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Bolinder J, Ljunggren O, Kullberg J, Johansson L, Wilding J, Langkilde AM, et al. Effects 
of dapagliflozin on body weight, total fat mass, and regional adipose tissue distribution in 
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Bolinder J, Ljunggren O, Johansson L, Wilding J, Langkilde AM, Sjostrom CD, et al. 
Dapagliflozin maintains glycaemic control while reducing weight and body fat mass over 2 
years in patients with type 2 diabetes mellitus inadequately controlled on metformin. 
Diabetes Obes Metab. 2014;16(2):159-69.
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Cefalu WT, Leiter LA, Yoon KH, Arias P, Niskanen L, Xie J, et al. Efficacy and safety of 
canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled 
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Administration FaD. Guidence for Industry. Diabetes Mellitus - Evaluating Cardiovascular 
Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. 12/1/2008 2008.
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U.S. Department of Health and Human Services, Food and Drug Administration. Guidance 
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Little RJA, Rubin DB. Statistical analysis with missing data: New York: John Wiley & 
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Schwartz NS, Clutter WE, Shah SD, Cryer PE. Glycemic thresholds for activation of 
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Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, et al. Hypoglycemia 
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Endocrine Society. Diabetes Care. 2013;36(5):1384-95.
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Protocol
CONFIDENTIAL
Date:
17 October 2016
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Version:
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Status:
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61.
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-
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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.
63.
Varadhan L, Humphreys T, Walker AB, Varughese GI. The impact of improved glycaemic 
control with GLP-1 receptor agonist therapy on diabetic retinopathy. Diabetes Res Clin 
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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.
65.
American Diabetes Association. Standards of medical care in diabetes -2016. Diabetes Care. 
2016;39 (Suppl. 1):S1-S109.
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International Committee of Medical Journal Editors. Recommendations for the Conduct, 
Reporting, Editing and Publication of Scholarly Work in Medical Journals; current version 
available at www.icmje.org.
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Protocol - Appendix A
CONFIDENTIAL
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Appendix A
Monitoring of Calcitonin
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol - Appendix A
CONFIDENTIAL
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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.
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Protocol - Appendix A
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2
Calcitonin monitoring
A blood sample will be drawn at pre-specified trial visits for measurement of calcitonin.
In case a subject has a calcitonin value ≥10 ng/L, the algorithm outlined in Figure 1 and described 
below should be followed. The algorithm applies for all calcitonin values in the trial.
Calcitonin < 10ng/L
Calcitonin  ≥ 10 ng/L and 
< 50 ng/L
Calcitonin  ≥ 50 ng/L and 
< 100 ng/L
Calcitonin  ≥ 100 ng/L
Evaluation of 
calcitonin results
Calcitonin  ≥ 10 ng/L and 
last measurement in the 
trial
No action
●Investigate potential confounding 
factors
●Continue sampling of calcitonin 
according to protocol
●Refer to thyroid specialist
●Discontinue trial product
●Refer to thyroid specialist
●Refer to thyroid specialist
Figure 1
Flow of calcitonin monitoring
2.1
Calcitonin ≥100 ng/L
Action: The subject must immediately be referred to a thyroid specialist for further evaluation and 
the trial product must be discontinued (see protocol section 6.5 premature discontinuation of trial 
CONFIDENTIAL


Protocol - Appendix A
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Date:
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Version:
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UTN: U1111-1180-3651
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product). The subject should remain in the trial; however, all medications suspected to relate to this 
condition must be discontinued until diagnosis has been established.
Background: These values were found in 9 (0.15%) of a population of 5817 patients with thyroid 
nodular disease 1. All of these patients were diagnosed with MTC, resulting in a positive predictive 
value of 100%.
Diagnostic evaluation should include:
!
thyroid ultrasound examination
!
fine needle aspiration of any nodules >1 cm 
!
potentially, surgery with neck dissection
In case a subject is diagnosed with MTC, it is common clinical practice to explore the family 
history of MTC or MEN2 and perform a genetic test for RET proto-oncogene mutation.
2.2
Calcitonin ≥50 and <100 ng/L
Action: The subject should be referred to a thyroid specialist for further evaluation. The subject 
should remain in the trial and continuation on trial product should be based on the evaluation done 
by the thyroid specialist. 
Background: These values were found in 8 (0.14%) of the population of 5817 patients with thyroid 
nodular 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.
CONFIDENTIAL


Protocol - Appendix A
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Background: Calcitonin values from 20–50 ng/L were found in up to 1% of subjects of the
population of 5817 patients with thyroid nodular disease 1. The predictive value of a C-cell anomaly 
for this calcitonin level was 8.3%. However, the likelihood of having a medullary carcinoma >1 cm 
with calcitonin in this range is extremely low.
For calcitonin values between 10-20 ng/L Costante et 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:
21 September 2016
1RYR1RUGLVN
Trial ID: NN9535-4270
Version:
1.0
UTN: U1111-1180-3651
Status:
Final
EudraCT No.: 2016-000989-35
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 B
CONFIDENTIAL
Date:
21 September 2016
1RYR1RUGLVN
Trial ID: NN9535-4270
Version:
1.0
UTN: U1111-1180-3651
Status:
Final
EudraCT no.: 2016-000989-35
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:
21 September 2016
1RYR1RUGLVN
Trial ID: NN9535-4270
Version:
1.0
UTN: U1111-1180-3651
Status:
Final
EudraCT no.: 2016-000989-35
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) ..........................................................................................4
1.3
Heart failure...................................................................................................................................4
1.4
Hypersensitivity reactions..............................................................................................................4
1.5
Neoplasm .......................................................................................................................................5
1.6
Pancreatitis.....................................................................................................................................5
1.7
Renal event ....................................................................................................................................6
1.8
Thyroid disease..............................................................................................................................7
1.9
Hepatic event .................................................................................................................................7
1.10
Diabetic retinopathy.......................................................................................................................8
1.11
Laboratory outlier ..........................................................................................................................8
2
References..................................................................................................................................................9
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
21 September 2016
1RYR1RUGLVN
Trial ID: NN9535-4270
Version:
1.0
UTN: U1111-1180-3651
Status:
Final
EudraCT no.: 2016-000989-35
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 12.1.2.
!
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 8.4.6 and medication 
errors are described in protocol section 8.4.5.1. and 12.1.4.
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
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
21 September 2016
1RYR1RUGLVN
Trial ID: NN9535-4270
Version:
1.0
UTN: U1111-1180-3651
Status:
Final
EudraCT no.: 2016-000989-35
Page:
4 of 9
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:
!
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
If an event of heart failure is observed during the trial, the following additional information must be 
reported if available:
!
Signs and symptoms of heart failure
!
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 and 8.1.6).
If suspicion of a hypersensitivity reaction occurs, the subjects should be instructed to contact the 
site staff as soon as possible for further guidance.
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
21 September 2016
1RYR1RUGLVN
Trial ID: NN9535-4270
Version:
1.0
UTN: U1111-1180-3651
Status:
Final
EudraCT no.: 2016-000989-35
Page:
5 of 9
To assist in the diagnostic evaluation it is recommended to draw a blood sample for measurement of 
tryptase (total and/or mature tryptase, local assessment) within 3 hours of onset of the 
hypersensitivity reaction, and if this is achieved, a tryptase sample should also be drawn 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 and 8.1.6). It is recommended to draw a 
blood sample for local assessment of complement levels (C3 and C4) to assist in the diagnostic 
evaluation. Complement level results should be included in the specific event form when reporting 
the AE.
1.5
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
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
21 September 2016
1RYR1RUGLVN
Trial ID: NN9535-4270
Version:
1.0
UTN: U1111-1180-3651
Status:
Final
EudraCT no.: 2016-000989-35
Page:
6 of 9
Assessments in case of suspicion of acute pancreatitis
Most patients with acute pancreatitis experience severe abdominal pain that is located generally in 
the epigastrium and radiates to the back. The onset of the pain may be swift, reaching maximum 
intensity within 30 min, 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 and 8.1.6).
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
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
21 September 2016
1RYR1RUGLVN
Trial ID: NN9535-4270
Version:
1.0
UTN: U1111-1180-3651
Status:
Final
EudraCT no.: 2016-000989-35
Page:
7 of 9
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:
!
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 12.1.2).
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
21 September 2016
1RYR1RUGLVN
Trial ID: NN9535-4270
Version:
1.0
UTN: U1111-1180-3651
Status:
Final
EudraCT no.: 2016-000989-35
Page:
8 of 9
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: 
!
Signs and symptoms of diabetic retinopathy
!
Fundoscopy/fundus photography supporting the diagnosis
!
Verification of diagnosis
!
Treatment given for the event
!
Relevant risk factors associated with the event
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. Furthermore, repeated 
laboratory assessments should be obtained at the central laboratory until the value is within the 
normal range or back to baseline values. 
!
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
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
21 September 2016
1RYR1RUGLVN
Trial ID: NN9535-4270
Version:
1.0
UTN: U1111-1180-3651
Status:
Final
EudraCT no.: 2016-000989-35
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 Amendment No 1
CONFIDENTIAL
Date:
16 December 2016
1RYR1RUGLVN
Trial ID: NN9535-4270
Version:
1.0
UTN:U1111-1180-3651
Status:
Final
EudraCT No.:2016-000989
Page:
1 of 12
Protocol Amendment
no 1
to Protocol, final version 2
dated 17 Oct 2016
Trial ID:NN9535-4270
SUSTAIN 8 – semaglutide versus canagliflozin
Efficacy and safety of semaglutide versus canagliflozin as add-on to
metformin in subject with type 2 diabetes
Trial phase: 3b
Applicable to all countries
Amendment originator:
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol Amendment No 1
CONFIDENTIAL
Date:
16 December 2016
1RYR1RUGLVN
Trial ID: NN9535-4270
Version:
1.0
UTN:U1111-1180-3651
Status:
Final
EudraCT No.:2016-000989
Page:
2 of 12
Table of Contents   
Page
Table of Contents..............................................................................................................................................2
Table of Figures  (N/A) ....................................................................................................................................2
Table of Tables (N/A).......................................................................................................................................2
1
Introduction including rationale for the protocol amendment.............................................................3
1.1
Risk-mitigation strategy for the risk of lower limb amputations potentially associated with 
canagliflozin, currently under review by the FDA and the EMA. This strategy includes 
additional exclusion and premature discontinuation criteria, physical examination of legs 
and feet at every site visits and description of this potential risk...................................................3
1.2
Updates of identified risks for semaglutide ...................................................................................4
1.3
Other minor corrections and clarifications.....................................................................................4
2
Changes......................................................................................................................................................5
2.1
Section 1  Summary.......................................................................................................................5
2.2
Section 2 Flowchart .......................................................................................................................6
2.3
Section 5.3 Treatment of subjects (Canagliflozin treatment arm) .................................................6
2.4
Section 6.1 Number of subjects .....................................................................................................7
2.5
Section 6.3 Exclusion criteria ........................................................................................................7
2.6
Section 6.6 Criteria for premature discontinuation of trial product...............................................9
2.7
Section 7 Milestones......................................................................................................................9
2.8
Section 8.4.1 Physical examination .............................................................................................10
2.9
Section 12.2 Reporting of adverse events (Novo Nordisk assessment of AE expectedness)......10
2.10
Section 18.1.2 Identified risks .....................................................................................................10
2.11
Section 18.1.4 Other safety considerations..................................................................................11
2.12
References....................................................................................................................................12
Table of Figures  (N/A)  
Page
No table of figures entries found.
Table of Tables (N/A)  
Page
No table of figures entries found.
CONFIDENTIAL


Protocol Amendment No 1
CONFIDENTIAL
Date:
16 December 2016
1RYR1RUGLVN
Trial ID: NN9535-4270
Version:
1.0
UTN:U1111-1180-3651
Status:
Final
EudraCT No.:2016-000989
Page:
3 of 12
1
Introduction including rationale for the protocol amendment
This protocol amendment introduces:
1. Risk-mitigation strategy for the risk of lower limb amputations potentially associated with 
canagliflozin, currently under review by the FDA and the EMA. This strategy includes 
additional exclusion and premature discontinuation criteria, physical examination of legs
and feet at every site visits and description of this potential risk.
2. Update of identified risks for semaglutide
3. Other minor corrections and clarifications
1.1
Risk-mitigation strategy for the risk of lower limb amputations potentially associated 
with canagliflozin, currently under review by the FDA and the EMA. This strategy 
includes additional exclusion and premature discontinuation criteria, physical 
examination of legs and feet at every site visits and description of this potential risk.
Protocol sections updated: 1, 2, 6.3, 6.6, 8.4.1, and 18.1.4.
The European Medicines Agency (EMA)1 and The U.S. Food and Drug Administration (FDA)2
have started a review of the diabetes medicine canagliflozin after an increase in amputations, mostly 
affecting toes, based on data emerged from the ongoing clinical trial called Canagliflozin 
Cardiovascular Assessment Study (CANVAS) sponsored by Janssen Research & Development, 
LLC.
In the CANVAS trial an increased risk of leg and foot amputations have been identified. The 
amputations occurred about twice as often in patients treated with canagliflozin compared to 
patients treated with placebo. An interim analysis showed that over a year’s time, the risks of 
amputation for patients in the trial were equivalent to:
!
7 out of every 1,000 patients treated with 100 mg daily of canagliflozin
!
5 out of every 1,000 patients treated with 300 mg daily of canagliflozin
!
3 out of every 1,000 patients treated with placebo
Based on feedback from several National Health Authorities (HAs) for trial NN9535-4270, a full 
risk-mitigation strategy has been implemented in this trial, which includes:
!
an additional exclusion criterion
!
a premature discontinuation criterion 
!
legs and feet examinations at every clinic visit
!
additional information on this potential new risk associated with canagliflozin 
!
Information to this potential new risk is added to the Subject Information/Informed Consent 
(SI/IC).
CONFIDENTIAL


Protocol Amendment No 1
CONFIDENTIAL
Date:
16 December 2016
1RYR1RUGLVN
Trial ID: NN9535-4270
Version:
1.0
UTN:U1111-1180-3651
Status:
Final
EudraCT No.:2016-000989
Page:
4 of 12
1.2
Updates of identified risks for semaglutide
Identified risks
Protocol section updated: 18.1.2
This protocol section is updated in order to reflect the recent IB amendment (amendment 1, to IB V 
11, dated 18-Oct-2016) describing diabetic retinopathy complications as an identified risk. In 
addition, a new paragraph describing the new identified risk of cholelithiasis has been added, based 
on recent analyses of the SUSTAIN phase 3a development program.
1.3
Other minor corrections and clarifications
Canagliflozin treatment arm
Protocol section updated: 5.3
This protocol section is updated to align with section below. 
Number of subjects
Protocol section updated: 6.1
This protocol section is updated due to a subject re-allocation between countries participating in this 
trial. The number of subjects to be randomised for Mexico has increased by 5 subjects, hence a total 
number of 50 subjects are planned to be randomised in Mexico.
Milestones
Protocol section updated: 7.0
This protocol section is updated to accommodate for the potential delay in approving this 
amendment and thereby the trial start in some countries.
Reporting of adverse event (Novo Nordisk assessment of AE expectedness)
Protocol section updated: 12.2
This protocol section is updated to align with the current process in place in Novo Nordisk.
References
Protocol section updated: 27
This protocol section is updated with 2 references added for the EMA and FDA safety 
announcements on the increased risk of small limb amputation.
CONFIDENTIAL


Protocol Amendment No 1
CONFIDENTIAL
Date:
16 December 2016
Novo Nordisk
Trial ID: NN9535-4270
Version:
1.0
UTN:U1111-1180-3651
Status:
Final
EudraCT No.:2016-000989
Page:
5 of 12
2
Changes
In this protocol amendment:
x
Any new text is written in Italics.
x
Any text deleted from the protocol is written using strike through
2.1
Section 1 
Summary
For an eligible subject, all exclusion criteria must be answered “no”. 
1. Known or suspected hypersensitivity to trial product(s) or related products. 
2. Previous participation in this trial. Participation is defined as signed informed consent.
3. Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing 
potential and not using an adequate contraceptive method (adequate contraceptive measure 
as required by local regulation or practice). 
4. Participation in any clinical trial of an approved or non-approved investigational medicinal 
product within 90 days prior to the day of screening. 
5. Any disorder which in the investigator’s opinion might jeopardise subject’s safety or 
compliance with the protocol.
6. Subjects with ALT >2.5 x upper normal limit (UNL).
7. Family or personal history of multiple endocrine neoplasia type 2 or medullary thyroid 
carcinoma. Family is defined as a first degree relative.
8. History or presence of pancreatitis (acute or chronic).
9. History of diabetic ketoacidosis (DKA).
10. Any of the following: myocardial infarction (MI), stroke, hospitalization for unstable angina 
or transient ischaemic attack within the past 180 days prior to the day of screening.
11. Subjects presently classified as being in New York Heart Association (NYHA) Class IV.
12. Planned coronary, carotid or peripheral artery revascularisation known on the day of 
screening.
13. Renal impairment measured as eGFR <60 ml/min/1.73 m2 as defined by Kidney Disease 
Improving global outcomes (KDIGO 2012) classification using isotope dilution mass 
spectrometry (IDMS) for serum creatinine measured at screening. .
14. Treatment with any medication for the indication of diabetes or obesity other than stated in 
the inclusion criteria within the past 90 days prior to the day of screening. However, short 
term insulin treatment for a maximum of 14 days prior to the day of screening is allowed.
15. Proliferative retinopathy or maculopathy requiring acute treatment. Verified by fundus 
photography or dilated fundoscopy performed within the past 90 days prior to 
randomisation.
16. Presence or history of malignant neoplasms within the past 5 years prior to the day of 
screening. Basal and squamous cell skin cancer and any carcinoma in-situ are allowed.
CONFIDENTIAL


Protocol Amendment No 1
CONFIDENTIAL
Date:
16 December 2016
Novo Nordisk
Trial ID: NN9535-4270
Version:
1.0
UTN:U1111-1180-3651
Status:
Final
EudraCT No.:2016-000989
Page:
6 of 12
17. Medical history of diabetes-related lower limb amputations or signs of critical lower limb 
ischemia, (e.g. skin ulcer, osteomyelitis, or gangrene) within the last 26 weeks prior to 
screening.
2.2
Section 2
Flowchart
Trial Periods
Screeni
ng
Randomis
ation
Treatment
End of 
Treat
ment
Follow
-up
End of 
treatment, 
Premature 
discontinu
ation
Follo
w-up
Visit (V)/ phone contact (P)
V1
V2
V3
V4
P5
V6
V7
V8
V9
V10
P11
V10A
P11A
Timing of visit (weeks)
-2
0
4
8
10
12
16
28
40
52
57
Visit window (days)
±7
±3
±3
±3
±7
±7
±7
±7
±7
+7
SUBJECT RELATED
INFO/ASSESSMENTS
TRIAL MATERIAL 
cont.
Secti
on
SAFETY
Physical examination
8.4.1
x
x
x
        - Legs and Feet 
examination
8.4.1
x
x
x
x
x
x
x
x
x
x
2.3
Section 5.3
Treatment of subjects (Canagliflozin treatment arm)
Canagliflozin treatment arm
Treatment with canagliflozin, once-daily must follow a fixed dose escalation. The maintenance dose 
of canagaliflozin 300 mg is reached after 56 doses (8 weeks) of 100 mg. After the maintenance dose 
of 300 mg is reached the dose must not be changed during the course of the trial unless the eGFR 
falls <45 60 mL/min/1.73 m2, see below. In addition, all subjects randomised to canagliflozin will 
receive semaglutide placebo once-weekly.
Treatment with canagliflozin must be in compliance with current local prescribing information. 
Canagliflozin should be taken orally once a day, preferably before the first meal of the day. Tablets 
should be swallowed whole. Treatment with canagliflozin or canagliflozin placebo should be 
temporarily stopped in subjects who are hospitalized for major surgical procedures or acute serious 
medical illnesses. In subjects whose eGFR falls persistently <60 mL/min/1.73 m2, the dose of 
canagliflozin or canagliflozin placebo should be reduced to 100 mg once-daily. The dose can be re-
escalated to 300 mg once-daily in case the renal function improves (eGFR ≥60 mL/min/1.73 m2)
during the trial. If the eGFR falls <45 mL/min/1.73 m2, treatment with all trial products should be 
discontinued (see section 2.6)1.
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2.4
Section 6.1
Number of subjects
Number of subjects planned to be screened (meaning the number of subjects providing 
informed consent): 
1307
Number of subjects planned to be randomised in a 1:1 manner:
784
Number of subjects planned to be randomised in sub-study on body composition: 
174
Number of subjects planned to complete the trial on randomised trial product without 
rescue medication.
549
For Mexico only: Approximately 7583 subjects are planned to be screened and 4550
subject are planned to be randomised in Mexico.
2.5
Section 6.3
Exclusion criteria
For an eligible subject, all exclusion criteria must be answered “no”. 
1. Known or suspected hypersensitivity to trial product(s) or related products. 
2. Previous participation in this trial. Participation is defined as signed informed consent.
For Brazil Only: Participation in other trials within one year prior to screening visit (Visit 
1) unless there is a direct benefit to the research subject at the investigator's discretion.
3. Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing 
potential and not using an adequate contraceptive method (adequate contraceptive measure as 
required by local regulation or practice). 
For Brazil only: For women who expressly declare free of the risk of pregnancy, either by 
not engaging in sexual activity or by having sexual activity with no birth potential risk, use 
of contraceptive method will not be mandatory.
For EU countries only:
The following contraceptive measures are considered adequate:
x
Combined estrogen and progestogen containing hormonal contraception associated 
with inhibition of ovulation (oral, intravaginal, transdermal)
x
Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, 
injectable, implantable)
x
Placement of an intrauterine device (IUD) or intrauterine hormone-releasing system 
(IUS)
x
Bilateral tubal occlusion
x
Barrier methods of contraception (condom or occlusive cap with spermicidal 
foam/gel/film/cream/suppository). (Not applicable for Sweden and the UK). 
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x
Vasectomised partner (where partner is sole partner of subject) and that the 
vasectomised partner has received medical assessment of the surgical success.
x
True sexual abstinence. Sexual abstinence is defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the trial treatments. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the subject. 
4. Participation in any clinical trial of an approved or non-approved investigational medicinal 
product within 90 days prior to the day of screening. 
5. Any disorder which in the investigator’s opinion might jeopardise subject’s safety or 
compliance with the protocol.
6. Subjects with ALT >2.5 x upper normal limit (UNL).
7. Family or personal history of multiple endocrine neoplasia type 2 or medullary thyroid 
carcinoma. Family is defined as a first degree relative.
8. History or presence of pancreatitis (acute or chronic).
9. History of diabetic ketoacidosis (DKA).
10. Any of the following: myocardial infarction (MI), stroke, hospitalization for unstable angina 
or transient ischaemic attack within the past 180 days prior to the day of screening.
11. Subjects presently classified as being in New York Heart Association (NYHA) Class IV.
12. Planned coronary, carotid or peripheral artery revascularisation known on the day of 
screening.
13. Renal impairment measured as eGFR <60 ml/min/1.73 m2 as defined by Kidney Disease 
Improving global outcomes (KDIGO 2012) classification using isotope dilution mass 
spectrometry (IDMS) for serum creatinine measured at screening.
14. Treatment with any medication for the indication of diabetes or obesity other than stated in 
the inclusion criteria within the past 90 days prior to the day of screening. However, short 
term insulin treatment for a maximum of 14 days prior to the day of screening is allowed.
15. Proliferative retinopathy or maculopathy requiring acute treatment. Verified by fundus 
photography or dilated fundoscopy performed within the past 90 days prior to 
randomisation.
16. Presence or history of malignant neoplasms within the past 5 years prior to the day of 
screening. Basal and squamous cell skin cancer and any carcinoma in-situ are allowed.
17. Medical history of diabetes-related lower limb amputations or signs of critical lower limb 
ischemia, (e.g. skin ulcer, osteomyelitis, or gangrene) within the last 26 weeks prior to 
screening.
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2.6
Section 6.6
Criteria for premature discontinuation of trial product 
All efforts should be made to keep the subject on trial product. However, the subject might be 
prematurely discontinued from trial product at the discretion of the investigator due to a safety 
concern. 
If so, all efforts must be made to ensure the subjects attend and complete all scheduled visit 
procedures. Subjects should stay in the trial irrespective of lack of adherence to randomised 
treatment, lack of adherence to visit schedule or missing assessments. Only subjects who decline 
any further contact with the site in relation to the trial will be considered as withdrawn from the trial 
(see Section 6.7).
The subject must be prematurely discontinued from trial product, if the following applies:
1. Included in the trial in violation of the inclusion and/or exclusion criteria 
2. Safety concern related to trial product or unacceptable intolerability at the discretion of the 
investigator
3. Pregnancy*
4. Intention of becoming pregnant*
5. Simultaneous participation in another clinical trial of an approved or non-approved 
investigational medicinal product.
6. If the eGFR falls persistently <45 mL/min/1.73m2, treatment with any trial product should 
be discontinued (see section 5.3)
7. Calcitonin ≥100 ng/L (see appendix A)
8. Lower limb amputations or signs of critical lower limb ischemia, (e.g. skin ulcer, 
osteomyelitis, or gangrene)
*No DXA scans can be performed on these subjects.
See Section 8.1.8 for procedures to be performed for subjects discontinuing trial product 
prematurely.
The primary reason for discontinuation of trial product must be specified in the eCRF.
If a criterion for premature discontinuation of trial product is met, trial product should not be re-
initiated but subjects should continue with protocol-specified visit schedule.
2.7
Section 7
Milestones
Planned duration of recruitment period 2428 weeks.
Planned date for FPFV: 15-Mar-2017
Planned date for LPLV: 24-Oct-2018 21-Nov-2018
End of trial (P11) is defined as LPLV.
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2.8
Section 8.4.1
Physical examination 
A physical examination must be performed at V1, V8 and V10/V10A (or as specified below) and
include the following:
x
General appearance 
x
Skin
x
Thyroid gland
x
Respiratory system 
x
Cardiovascular system 
x
Gastrointestinal system including mouth
x
Central and peripheral nervous system
x
Lymph node palpation
x
Legs and feet*
*Physical examination of legs and feet must be performed at every site visit.
2.9
Section 12.2
Reporting of adverse events (Novo Nordisk assessment of AE 
expectedness)
Novo Nordisk assessment of AE expectedness is performed according to the following reference 
documents:
x
Semaglutide: NN9535 IB current version and any updates thereto
x
Canagliflozin: Current version of the Invokana SmPC and any updates thereto.EU PI and U.S.
Food and Drug Administration (FDA) prescribing information and any updates thereto.
2.10
Section 18.1.2
Identified risks
The section below on Diabetic retinopathy complications has been moved from section 18.1.4 Other 
safety considerations to section 18.1.2 Identified risks
Diabetic retinopathy complications
A transient worsening of diabetic retinopathy is a recognised complication in selected patients with 
diabetes after initiation of intensive anti-diabetic treatment61-63. Risk factors for these events include 
long-standing poor glycaemic control and presence of proliferative retinopathy, and initial large 
improvements in blood glucose may be an additional aggravating factor. Several studies have, 
however, documented long-term beneficial effects of intensive glycaemic treatment in reducing 
retinopathy progression5, 64 even in intensively treated patients who experienced early worsening62.
In a cardiovascular outcomes trial with s.c. semaglutide, results indicate an increased risk of events 
related to diabetic retinopathy in subjects treated with semaglutide compared to placebo. As a 
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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 trial65.
Cholelithiasis 
Events of gallstones (cholelithiasis) have been reported from clinical trials with semaglutide. These 
events may lead to hospitalisation and removal of the gallbladder. If cholelithiasis is suspected 
potential discontinuation of trial product and appropriate clinical follow-up should be considered 
at the investigator’s discretion.
2.11
Section 18.1.4
Other safety considerations
The section below on Diabetic retinopathy complications has been moved from section 18.1.4 Other 
safety considerations to section 18.1.2 Identified risks
Diabetic retinopathy
A transient worsening of diabetic retinopathy is a recognised complication in selected patients with 
diabetes after initiation of intensive anti-diabetic treatment61-63. Risk factors for these events include 
long-standing poor glycaemic control and presence of proliferative retinopathy, and initial large 
improvements in blood glucose may be an additional aggravating factor. Several studies have, 
however, documented long-term beneficial effects of intensive glycaemic treatment in reducing 
retinopathy progression5, 64 even in intensively treated patients who experienced early worsening62.
In a cardiovascular outcomes trial with s.c. semaglutide, results indicate an increased risk of events 
related to diabetic retinopathy in subjects treated with semaglutide compared to placebo. As a 
precaution in this trial, all subjects are required to have a fundus photography or dilated fundoscopy 
performed before enrolment into the trial; moreover, subjects with proliferative retinopathy or 
maculopathy requiring acute treatment will be excluded. As part of good diabetes management the 
investigator is encouraged to ensure adequate monitoring and treatment of diabetic retinopathy in 
subjects enrolled into the trial65.
Canagliflozin
Subjects should be considered suitable for treatment with canagliflozin and the use of canagliflozin 
should be in accordance with the current, approved label. It is important to monitor renal function 
and for signs and symptoms of volume depletion during therapy. Serum creatinine will be measured 
regularly for monitoring of renal function.
The most common adverse reactions reported with canagliflozin are female genital mycotic 
infections, urinary tract infections and increased urination. Other events include hypoglycaemia 
(with concomitant use of insulin or insulin secretagogues), hypotension, hyperkalemia, increased 
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LDL-C levels and bone fracture. Canagliflozin and other SGLT-2 inhibitors have also been 
associated with a risk of urinary tract infections and ketoacidosis. Symptoms of ketoacidosis include 
nausea, vomiting, abdominal pain, tiredness, general malaise and shortness of breath. Ketoacidosis 
associated with the use of SGLT-2 inhibitors can occur even if blood sugar levels are only relatively 
elevated or non-elevated. If ketoacidosis is suspected, canagliflozin or canagliflozin placebo should 
be discontinued and appropriate treatment should be instituted promptly.
A signal of increased risk of lower limp amputations has been associated with the use of 
canagliflozin and is currently under investigation by the EMA1 and the FDA2. While the review of 
this risk by the Health Authorities is ongoing, subjects at risk are excluded from participation in 
this clinical trial and assessment of leg and foot is required at every site visit. The investigators 
should instruct the subjects enrolled about the importance of regular leg and foot care and to 
further notify the investigator in case they notice any new pain or tenderness, sores or ulcers, or 
infections in legs or feet.
2.12
References
1.
Agency EMA. EMA reviews diabetes medicine canagliflozinReview follows data on toe
amputations in ongoing study 2016 [cited 2016 15 Apr].
2.
U.S. Food and Drug Administration. Interim clinical trial results find increased risk of leg 
and foot amputations, mostly affecting the toes, with the diabetes medicine canagliflozin 
(Invokana, Invokamet); FDA to investigate 2016 [cited 2016 18 May].
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Global and country key Novo Nordisk staff
Attachments I and II (if applicable) to the protocol are located in the Trial Master File.
Content: Global key staff and Country key staff
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Clinical Trial Report
Appendix 16.1.1
-XQH
.
)LQDO
CONFIDENTIAL

SAP_001.pdf: 
Cover Page for Statistical Analysis Plan 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT03136484 
Sponsor trial ID: 
NN9535-4270 
Official title of study: 
Efficacy and Safety of Semaglutide Versus Canagliflozin as 
add-on to Metformin in Subjects With Type 2 Diabetes 
Document date: 
03 June 2019 


Link
List of contents
Statistical analysis plan......................................................................................................................
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Appendix 16.1.9
03 June 2019
1.0
Final
16.1.9 Documentation of statistical methods
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Redacted VWDWLVWLFDODQDO\VLVSODQ 
Includes redaction of personal identifiable information only. 
. 


Statistical Analysis Plan
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Statistical Analysis Plan
Trial ID: NN9535-4270
SUSTAIN 8 – semaglutide versus canagliflozin
Efficacy and safety of semaglutide versus canagliflozin as add-
on to metformin in subjects with type 2 diabetes
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
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This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Statistical Analysis Plan
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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 .....................................................................................................................4
2.1
General considerations ..............................................................................................................4
2.1.1
Data transformations................................................................................................5
2.1.2
Definition of baseline...............................................................................................5
2.1.3
Primary estimand.....................................................................................................5
2.1.4
Trial completion ......................................................................................................5
2.1.5
Missing data considerations at week 52....................................................................6
2.2
Sample size calculation .............................................................................................................6
2.2.1
Sample size for the sub-study (dual X-ray absorptiometry).......................................8
2.3
Definition of analysis sets..........................................................................................................8
2.3.1
Data selections and observation periods ...................................................................9
2.4
Primary endpoint.....................................................................................................................11
2.4.1
Primary analysis for the primary estimand..............................................................11
2.4.2
Primary hypotheses................................................................................................12
2.4.3
Multiplicity and criteria for confirming hypotheses ................................................12
2.4.4
Statistical subgroup analyses of HbA1c ...................................................................12
2.4.5
Sensitivity analyses................................................................................................13
2.4.5.1
Sensitivity analyses for the primary estimand ...................................13
2.4.5.2
Other sensitivity analyses .................................................................13
2.5
Secondary endpoints ...............................................................................................................14
2.5.1
Confirmatory secondary endpoints.........................................................................14
2.5.2
Supportive secondary endpoints .............................................................................16
2.5.2.1
Efficacy endpoints............................................................................16
2.5.2.2
Safety endpoints...............................................................................17
2.6
Health economics and/or patient reported outcomes.................................................................22
3
Changes to the statistical analyses planned in the protocol..............................................................22
4
References ..........................................................................................................................................24
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Statistical Analysis Plan
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List of abbreviations
AACE
American Association of Clinical Endocrinologists
ADA
American Diabetes Association
AE
adverse event
ANCOVA 
analysis of covariance
BG
blood glucose
BMI 
body mass index
CoEQ
Control of Eating Questionnaire
DTSQ
Diabetes Treatment Satisfaction Questionnaire
DXA
DXA analysis set / dual X-ray absorptiometry 
ECG
electrocardiogram
FAS 
full analysis set
FPG
fasting plasma glucose
HbA1c
glycosylated haemoglobin
HDL
high-density lipoprotein
LDL
low-density lipoprotein
LLOQ
lower limit of quantification
MAR
missing at random
MCMC
Markov Chain Monte Carlo
MedDRA 
Medical Dictionary for Regulatory Activities
OW
once weekly
PP 
per protocol
PRO
patient reported outcome
PT
preferred term
SAS 
safety analysis set
SAP 
statistical analysis plan
SD
standard deviation
SE
standard errors
SF-36v2TM
Short form healthy survey
SMPG
self-measured plasma glucose
SUSTAIN
Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes
T2D
type 2 diabetes
TEAE
treatment emergent adverse events
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Statistical Analysis Plan
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1
Introduction
1.1
Trial information
This is a 52-week, confirmatory, randomised, double-blind, double dummy, active-controlled,
multicentre, multinational, two-arm, parallel-group trial.
Primary objective
To compare the effect of once-weekly (OW) dosing of subcutaneous semaglutide (1.0 mg) versus
once-daily dosing of oral canagliflozin (300 mg) on glycaemic control in subjects with type 2
diabetes (T2D) on a background treatment of metformin.
Secondary objectives
To compare the effects of semaglutide s.c. 1.0 mg once-weekly versus canagliflozin 300 mg once
daily after 52 weeks of treatment in subjects with T2D with regards to:
!
Weight management
!
Other parameters of effect, safety and Patient Reported Outcomes
See the protocol for trial NN9535-4270 for further details.
1.2
Scope of the statistical analysis plan
This SAP is based on the protocol “SUSTAIN 8 – semaglutide versus canagliflozin, Efficacy and 
safety of semaglutide versus canagliflozin as add-on to metformin in subjects with type 2 diabetes”, 
version 3.0.
2
Statistical considerations
2.1
General considerations
No interim analyses or other analyses of un-blinded or between group data will be performed before 
the database is locked.
Laboratory values below the lower limit of quantification (LLOQ) will be set to ½LLOQ. 
Results from a statistical analysis will be presented by the estimated treatment contrasts at week 52 
with associated two-sided 95% confidence intervals and p-values corresponding to two-sided tests 
of no difference if not otherwise specified.
The comparison presented from a statistical analysis will be semaglutide 1.0 mg versus 
canagliflozin 300 mg
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If no statistical analysis is specified, data will be presented using relevant summary statistics.
Data from all trial sites will be analysed and reported together. 
The regions used in the statistical analyses are defined as:
!
North America (United States and Canada)
!
Region Europe (United Kingdom, Ireland and Sweden)
!
International Operations (Lebanon, Malaysia, Argentina, Mexico, Brazil, India)
2.1.1
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).
2.1.2
Definition of baseline
For each assessment, the baseline assessment is defined as the latest available measurement at or 
prior to the randomisation visit. This specifically implies that if a visit 2 assessment is missing 
(whether it was planned or not planned) then the screening assessment (from visit 1), if available, 
will be used as the baseline assessment.
2.1.3
Primary estimand
To further detail the trial objective an estimand is defined which is a de-jure (efficacy) estimand: 
Primary estimand
!
The treatment difference between semaglutide and canagliflozin at week 52 for all 
randomised subjects if all subjects completed treatment and did not initiate rescue 
medication
This primary de-jure estimand is considered clinically relevant as it assesses the glycaemic benefit a 
person with T2D is expected to achieve if initiating and continuing treatment with semaglutide 
compared to canagliflozin. Accordingly, only data collected prior to discontinuation of trial product 
or initiation of rescue medication will be used to draw inference. This will avoid confounding from 
rescue medication.
2.1.4
Trial completion
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Unless subjects withdraw their informed consent, data collection will continue for the full duration 
of the trial. The full duration of the trial is defined as up to and including the follow-up visit (P11). 
Subjects completing the follow-up visit (P11) will be considered trial completers.
2.1.5
Missing data considerations at week 52
The actual rate of missing data at week 52 is expected to be maximum 10% based on the rate of trial 
completers from the subcutaneous semaglutide phase 3a clinical development programme. The 
frequency of missing data is expected to be similar in the semaglutide and the canagliflozin groups.
When estimating the primary estimand, the combined rate of missing data, subjects discontinuing 
treatment prematurely or initiating rescue medication on top of trial product, is expected to be 
maximum 30%. This is based on the results from the subcutaneous semaglutide phase 3a clinical 
development program. Based on these data, premature treatment discontinuation due to 
gastrointestinal adverse events (AEs) is expected to be low but more frequent in semaglutide 
compared to canagliflozin. Other reasons for discontinuing treatment are assumed to be unrelated to 
treatment and therefore occur with similar rates, so overall the frequency of missing data or data not 
used at week 52 in the primary analysis is expected to be slightly larger in semaglutide as compared 
to canagliflozin.
To document the extent and reason(s) for missing data, descriptive summaries and graphical 
representation of extent, reason(s) for and pattern of missing data will be presented by treatment 
group.
2.2
Sample size calculation
The primary endpoint, change from baseline to week 52 in HbA1c (%-point) will be tested for non-
inferiority and superiority of semaglutide vs. canagliflozin. The confirmatory secondary endpoints, 
change from baseline to week 52 in body weight (kg) and change from baseline to week 52 in total 
fat mass (kg) are planned to be tested for superiority of semaglutide vs. canagliflozin.
The sample size calculation is made to ensure a power of at least 90% for meeting HbA1c
superiority of semaglutide vs. canagliflozin out of the four pre-specified confirmatory hypotheses 
shown in Table 2-2. The closed testing procedure described in Bretz et.al. 20111 combined with a 
hierarchical approach is used to control the overall type-1 error at a two-sided 5% level. The 
statistical testing strategy is built on the following principle:
!
Glycaemic efficacy must be established by HbA1c non-inferiority before testing for added 
benefits in terms of superiority in terms of HbA1c or body weight.
!
HbA1c and body weight superiority must be established before testing for added benefits in 
terms of superiority in terms of total fat mass.
The sample size is calculated using the calcPower function in the R package, gMCP2 using 10,000 
simulations. All of the four pre-specified confirmatory tests are assumed to be independent. Since 
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some of these tests are positively correlated, the assumption of independence is viewed as 
conservative. The four hypotheses are:
!
HbA1c non-inferiority of semaglutide 1.0 mg vs. canagliflozin 300 mg with a non-inferiority 
margin of 0.3
!
HbA1c superiority of semaglutide 1.0 mg vs. canagliflozin 300 mg
!
Body weight superiority of semaglutide 1.0 mg vs. canagliflozin 300 mg
!
Total fat mass superiority of semaglutide 1.0 mg vs. canagliflozin 300 mg
The sample size assumptions for efficacy based on on-treatment data without rescue medication, a 
treatment effect based on in-trial data (see Section 2.3.1) and the standard deviations (SD) are given 
in Table 2-1. The HbA1c and body weight assumptions are based on the efficacy results and an 
observed reduction of approximately 20% and 15% respectively in in-trial treatment effect compare 
to efficacy in the subcutaneous semaglutide phase 3a clinical development programme.4-7
A similar reduction in the in-trial treatment effect compared to efficacy is assumed with 
canagliflozin as comparator. The total fat mass assumption is based on the relevant literature 
focusing on fat mass8-10, which indicates a smaller SD for total fat mass as compared to body 
weight.
Table 2-1
Assumptions used in the sample size calculation
Semaglutide vs. canagliflozin 
HbA1c (%-points)
Body weight (kg)
Total fat mass (kg)
Efficacy 
-0.32
-2.4
-1.8
In-trial treatment effect 
-0.256
-2.04
-1.53
Standard deviation 
1.1
4.0
3.5
With the above assumptions, allocating 392 subjects to the semaglutide arm and the canagliflozin 
arm provides 90% power to confirm HbA1c superiority of semaglutide vs. canagliflozin across 
plausible assumptions.
Table 2-2
Calculated powers for meeting individual hypotheses
Statistical test
HbA1c
non-inferiority
HbA1c superiority
Body weight 
superiority
Total fat mass 
superiority
Efficacy Power (%)
>99%
90%
>99%
91%
In-trial effect power (%)
>99%
90%
>99%
74%
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 December 2018
Novo Nordisk
Trial ID: NN9535-4270
Version:
1.0
UTN: U1111-1180-3651
Status:
Final
EudraCT No.: 2016-000989-35
Page:
8 of 25
The overall significance level of α = 0.05 (two-sided) is initially allocated to the HbA1c non-inferiority test. The local 
significance level (α-local) will be reallocated if a hypothesis is confirmed according to the weight given by the directed 
edges between nodes (hypotheses). The total fat mass superiority test will receive the overall significance of α = 0.05 
(two-sided) if and only if both HbA1c and body weight superiority are confirmed at their respective local significance 
levels. 
Figure 2-1
Graphical illustration of the closed testing procedure
The overall significance level of α = 0.05 (two-sided) is initially allocated to the HbA1c non-
inferiority test. The local significance level (α-local) will be reallocated if a hypothesis is confirmed 
according to the weight given by the directed edges between nodes (hypotheses). The total fat mass 
superiority test will receive the overall significance of α = 0.05 (two-sided) if and only if both 
HbA1c and body weight superiority are confirmed at their respective local significance levels. 
2.2.1
Sample size for the sub-study (dual X-ray absorptiometry)
For the sub-study on body composition assuming an efficacy treatment difference of 1.8 kg and a 
SD of 3.5 kg, 174 subjects (87 subjects in each arm) will provide 92% power to establish a 
statistical significant difference resulting in 91% power for confirming superiority in the testing 
strategy in terms of fat mass loss (kg) at week 52 using a two-sided significance level of 5%. 
2.3
Definition of analysis sets
The following analysis sets will be defined:
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
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Trial ID: NN9535-4270
Version:
1.0
UTN: U1111-1180-3651
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Full analysis set (FAS): includes all randomised subjects. Subjects in the FAS will contribute to 
evaluation “as randomised”.
DXA analysis set: includes all subjects in FAS who are included in the DXA sub-study. Subjects in 
the DXA analysis set will contribute to the evaluation “as randomised”.
Safety analysis set (SAS): includes all subjects exposed to at least one dose of trial product. 
Subjects in the SAS will contribute to the evaluation based on the trial product received for the 
majority of the period they were on treatment. This will be referred to as contributing to the 
evaluation “as treated”.
Per protocol (PP) analysis set: includes all subjects in the 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
!
Is on trial product at visit 8 and have at least one non-missing HbA1c measurement at or after 
visit 8.
Subjects in the PP analysis set will contribute to the analysis “as treated” as defined for the SAS.
2.3.1
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
!
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 period starts at the date of first 
dose of trial product
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 December 2018
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Trial ID: NN9535-4270
Version:
1.0
UTN: U1111-1180-3651
Status:
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EudraCT No.: 2016-000989-35
Page:
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For DXA assessments the last direct subject-site contact is defined as the date of the last collected 
data for the subject.
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, 
electrocardiograms (ECGs) and AEs including hypoglycaemic episodes, the observation period 
ends at the first date of any of the following: 
!
the follow-up visit (P11)
!
the follow-up prematurely discontinuation visit (P11A)
!
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. 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.
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.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 December 2018
Novo Nordisk
Trial ID: NN9535-4270
Version:
1.0
UTN: U1111-1180-3651
Status:
Final
EudraCT No.: 2016-000989-35
Page:
11 of 25
Before data are locked for statistical analysis, a review of all data will take place. Any decision to 
exclude either a subject or single observations from the statistical analysis is the joint responsibility
of the members of the Novo Nordisk study group.
Exclusion of data from analyses will be used restrictively and normally no data should be excluded 
from the FAS. The subjects or observations to be excluded, and the reasons for their exclusion will 
be documented and signed by those responsible before database lock. The subjects and observations 
excluded from analysis sets, and the reason for this, will be described in the clinical trial report.
2.4
Primary endpoint
The primary endpoint is change from baseline to week 52 in HbA1c.
2.4.1
Primary analysis for the primary estimand 
The primary estimand will be estimated based on the FAS using post-baseline measurements up to 
and including week 52 from the ’on-treatment without rescue medication’ observation period. 
Imputation of missing data will be handled using multiple imputation assuming that missing data is 
missing at random (MAR). Missing data will be imputed using observed data within the same group 
defined by the randomised treatment (semaglutide/canagliflozin). It is hereby assumed that the 
likely values of what the missing data would have been if available are best described by 
information from subjects who receive the same treatment. 
Technically missing values will be imputed as follows:
!
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
!
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 52. 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 (sub-study, non-sub-study) and region as categorical effects and 
baseline and post-baseline HbA1c values observed or imputed prior to the visit in question as 
covariates. 
!
An ANCOVA with treatment, stratification factor (sub-study, non-sub-study) and region as 
categorical effects and baseline HbA1c as a covariate will be used to analyse HbA1c values at 
week 52 for each of the 500 complete data sets generated as part of the imputation of 
missing values. Rubin’s rule will be used to combine the analysis results in order to draw 
inference.
From this analysis, the estimated treatment difference between semaglutide and canagliflozin at 
week 52 will be presented together with the associated two-sided 95% confidence interval and 
unadjusted two sided p-values for testing non-inferiority and superiority.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 December 2018
Novo Nordisk
Trial ID: NN9535-4270
Version:
1.0
UTN: U1111-1180-3651
Status:
Final
EudraCT No.: 2016-000989-35
Page:
12 of 25
2.4.2
Primary hypotheses 
For the primary HbA1c endpoint the following confirmatory one-sided hypotheses are planned to be 
tested for semaglutide versus canagliflozin. Let the mean treatment difference be defined as μ = 
(semaglutide minus canagliflozin):
!
Non-inferiority, using a non-inferiority margin of 0.3%-point
!
H0: μ ≥0.3%-point against Ha: μ <0.3%-point
!
Superiority
!
H0: μ ≥0.0%-point against Ha: μ <0.0%-point
Operationally the hypotheses will be evaluated by two-sided tests.
The non-inferiority margin of 0.3 is chosen based on the diabetes guideline11, 12 and the effect of 
canagliflozin on glycaemic effect seen in a similar trial (DIA30063) where canagliflozin was used as 
add on to metformin. In this trial canagliflozin showed an HbA1c treatment difference to placebo of 
-0.77%-point Hence, based on this trial, the chosen margin of 0.3 provides assurance that 
semaglutide has an effect compared to placebo greater than 0 with a clinically relevant size. With 
regards to the constancy assumption, controlled clinical trials have consistently established that 
canagliflozin is an effective anti-diabetic drug. Therefore, lack of trial sensitivity with canagliflozin 
as comparator is not anticipated to be an issue in this trial.
2.4.3
Multiplicity and criteria for confirming hypotheses
The Type-I error for testing the four confirmatory hypotheses related to the HbA1c, body weight, 
and fat mass endpoints will be preserved in the strong sense at 5% (two-sided) using the weighted 
Bonferroni-based closed testing procedure described in Bretz et. al.1 and outlined in Figure 2-1. The 
first hypothesis to be tested is non-inferiority of HbA1c. It will be tested at the overall significance 
level (5%) while allocating 0% local significance level to the remaining three hypotheses. For this 
hypothesis, and in general, if a hypothesis is confirmed the significance level will be reallocated 
according to the weight and the direction of the edges going from the confirmed hypothesis to the 
next hypotheses as specified in Figure 2-1. Total fat mass will be tested at the overall significance 
level if each of the other 3 hypotheses is confirmed, otherwise its local significance level will 
remain 0%. Each of the following hypotheses will be tested at their local significance level (α-
local). This process will be repeated until no further hypotheses can be confirmed. 
Non-inferiority and subsequent superiority will be considered confirmed if the mean treatment 
difference is supporting the corresponding alternative hypothesis and the two-sided p-value from 
the primary analysis of the primary estimand is strictly below its local two-sided significance level 
as defined by the closed testing procedure in Figure 2-1. This is equivalent to using a one-sided p-
value (nominal alpha = 0.025) and a one-sided 2.5% overall significance level in the closed testing 
procedure.
2.4.4
Statistical subgroup analyses of HbA1c
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 December 2018
Novo Nordisk
Trial ID: NN9535-4270
Version:
1.0
UTN: U1111-1180-3651
Status:
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EudraCT No.: 2016-000989-35
Page:
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Five subgroups based on baseline HbA1c values are defined as follows:
1. ≤ 7.5%
2. > 7.5% to 8.0% (inclusive)
3. > 8.0% to 8.5% (inclusive)
4. > 8.5% to 9.0% (inclusive)
5. > 9.0%
Change from baseline in HbA1c at week 52 for subgroups based on baseline HbA1c values will be 
analysed for the primary estimand using a similar multiple imputation approach as described in 
section 2.4.1. The complete data sets from the primary analysis will be reused. However the 
ANCOVA model used to analyse the 500 complete data sets will additionally include the 
interaction effect of subgroup and treatment as a categorical effect. Rubin’s rule will then be used to 
combine the results and the p-value for the interaction effect and estimated treatment differences at 
52 weeks with corresponding two-sided 95% confidence intervals for each subgroup will be 
presented.
2.4.5
Sensitivity analyses
In order to investigate the robustness of the conclusions from the primary analysis and to stress test 
the MAR assumption for missing data tipping point sensitivity analyses will be performed for the 
primary estimand both for the sensitivity of the non-inferiority and the superiority HbA1c
hypotheses.  
2.4.5.1
Sensitivity analyses for the primary estimand
The estimation of the primary estimand will be repeated using the following sensitivity analysis:
!
Tipping-point analysis (pattern mixture model based) based on the FAS using the ’on-
treatment without rescue medication’ observation period. In this analysis, subjects from the 
semaglutide group 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 conclusion of the analyses in terms of statistical significance is changed. 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 canagliflozin to being non-statistically significantly 
better for the superiority test and similarly for the non-inferiority test. Technically, this 
analysis will be implemented by replicating the primary analysis including the assumption 
of MAR but subsequently adding increasing penalty values at week 52 to imputed 
observations in the semaglutide group before applying ANCOVA on the 500 complete data 
sets.
2.4.5.2
Other sensitivity analyses
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 December 2018
Novo Nordisk
Trial ID: NN9535-4270
Version:
1.0
UTN: U1111-1180-3651
Status:
Final
EudraCT No.: 2016-000989-35
Page:
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The following additional sensitivity analyses are specified:
!
Retrieved drop-out analysis based on the FAS using post-baseline measurements up to and 
including week 52 from the in-trial observation period. Missing data will be imputed using 
the same approach as described for the primary analysis of the primary estimand. However 
the imputation will be done within the same group defined not only by the randomised 
treatment  (semaglutide/canagliflozin) but also by the status of treatment completion (still 
on randomised treatment at week 52 yes/no) (4 groups in total). It is hereby assumed that the 
likely values of what the missing data would have been if available are best described by 
information from subjects who at week 52 are similar in terms of randomised treatment and 
treatment completion status. In addition in the imputation step stratification factor and 
region is not included in the model in order to avoid potential issues with sparse data. This 
analysis could be considered addressing an effectiveness estimand. The retrieved drop-out is 
carried out for the superiority testing only.
!
PP analysis based on the PP data set using the ‘on-treatment without rescue’ observation 
period. This analysis will be carried out for non-inferiority testing only. The statistical 
analysis will be the same as the primary analysis for the primary estimand.
2.5
Secondary endpoints
2.5.1
Confirmatory secondary endpoints 
Change from baseline to week 52 in body weight (kg) and change from baseline to week 52 in total 
fat mass (kg) will be confirmatory secondary endpoints. 
The primary estimand will be estimated using the same approach as described for the primary 
HbA1c endpoint. Body weight and total fat mass will be tested for superiority. Baseline and post-
baseline body weight  will be used as covariates instead of HbA1c for the analysis of body weight.
The analysis of total fat mass will be based on the DXA analysis set, stratification factor will not be 
included in the model and baseline fat mass will be used as covariate instead of baseline HbA1c. 
Since only baseline and end-of-treatment DXA scans are performed, the missing data pattern will 
be monotone by default. As a consequence MCMC-imputation is not needed and no post-baseline 
data will be included as covariates in the imputation model.Superiority will be considered 
confirmed if the mean treatment difference is supporting the corresponding hypothesis and the two-
sided p-value from the primary analysis of the primary estimand is strictly below its local two-sided 
significance level resulting from the closed testing procedure in Figure 2-1.
The tipping point sensitivity analysis pre-specified to evaluate the robustness of the conclusions 
from the primary analysis of HbA1c will also be performed to evaluate the robustness of the
conclusions from the body weight and total fat mass superiority tests. The analyses will be based on 
FAS and the DXA analysis set respectively. In addition, the retrieved drop-out sensitivity analysis 
will also be performed for body weight. .For total fat mass, the data collection does not support a 
retrieved drop-out analysis as there are no systematic data collection at visit 10 for subjects 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 December 2018
Novo Nordisk
Trial ID: NN9535-4270
Version:
1.0
UTN: U1111-1180-3651
Status:
Final
EudraCT No.: 2016-000989-35
Page:
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discontinuing treatment prematurely. Therefore, a supplementary in-trial analysis will be performed 
in which the imputation is done within the same group defined by randomised treatment only. The 
observation period for this analysis is the in-trial period. Besides this, the imputation procedure 
follows that of the confirmatory analysis for total fat mass, i.e. region is included in the imputation 
model and no MCMC imputation is performed.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 December 2018
Novo Nordisk
Trial ID: NN9535-4270
Version:
1.0
UTN: U1111-1180-3651
Status:
Final
EudraCT No.: 2016-000989-35
Page:
16 of 25
2.5.2
Supportive secondary endpoints
No sensitivity analyses are planned for the supportive secondary endpoints. 
2.5.2.1
Efficacy endpoints
Continuous endpoints
The continuous endpoints are change from baseline to week 52 in: 
!
Fasting plasma glucose (FPG)
!
Self-measured plasma glucose (SMPG), 7-point profile:
!
Mean 7-point profile
!
Mean post prandial increment (over all meals)
!
Fasting blood lipids (total cholesterol, low-density lipoprotein (LDL) cholesterol, high-
density lipoprotein (HDL) cholesterol, triglycerides)
!
Body mass index (BMI) and waist circumference
!
Systolic and diastolic blood pressure
!
Body weight (%)
!
Total fat mass (%-point)
!
Total lean mass (kg)
!
Total lean mass (%-point)
!
Visceral fat mass (kg)
!
Visceral fat mass (%-point)
!
Ratio between total fat mass and total lean mass
The above continuous endpoints will be analysed for the primary estimand separately using a 
similar model approach as for the primary endpoint with the associated baseline and post-baseline 
responses as covariates instead of HbA1c for their respective analyses. The DXA endpoints (total fat 
mass, total lean mass, visceral fat mass and ratio between total fat mass and total lean mass) will be 
analysed using a similar approach as for the confirmatory secondary endpoint, total fat mass (kg), 
with the associated baseline values as covariate instead of total fat mass (kg).
Fasting lipid profile endpoints will be log-transformed prior to analysis with the associated log-
transformed baseline value as a covariate.
Mean 7-point profile self-measured plasma glucose definition
Subjects will be asked to perform SMPG measurements before and 90 minutes after breakfast, 
lunch, dinner, and at bedtime. 
Mean of the 7-point profile is defined as the area under the profile, calculated using the trapezoidal 
method, divided by the measurement time.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 December 2018
Novo Nordisk
Trial ID: NN9535-4270
Version:
1.0
UTN: U1111-1180-3651
Status:
Final
EudraCT No.: 2016-000989-35
Page:
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Binary endpoints
The binary endpoints are subjects who after 52 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 ≥3%
!
Weight loss ≥5%
!
Weight loss ≥10%
!
HbA1c <7.0% (53 mmol/mol) without severe or blood glucose confirmed symptomatic 
hypoglycaemia episodes and no weight gain
!
HbA1c reduction ≥1%-point
!
HbA1c reduction ≥1%-point and weight loss ≥3%
!
HbA1c reduction ≥1%-point and weight loss ≥5%
!
HbA1c reduction ≥1%-point and weight loss ≥10%
The above 10 endpoints will be analysed for the primary estimand. The analyses for the primary 
estimand for all 10 endpoints will be based on the ’on-treatment without rescue medication’ 
observation period. They will be analysed separately using the same type of logistic regression 
model with treatment, stratification factor (sub-study, non- sub-study), region and associated 
baseline and post-baseline response(s) (i.e. HbA1c responses for HbA1c endpoints, body weight 
responses for weight endpoints and both HbA1c and body weight responses for the binary endpoints 
that combine both parameters) as covariates. To account for missing data, the analysis will be made 
using a sequential multiple imputation approach as described below: 
!
The binary endpoint will be derived based on the 500 complete data sets from the primary 
analysis of  HbA1c and the confirmatory analysis of body weight.
!
Each of the created complete data sets will be analysed with the logistic regression model. 
Estimated odds ratios will be log transformed and inference will be drawn using Rubin’s 
rule.13
The results after applying Rubin’s rule will be back-transformed and described by the odds ratio 
between treatments and the associated 95% confidence interval and p-value for no treatment 
difference.
2.5.2.2
Safety endpoints
The safety endpoints will be evaluated based on SAS using the on-treatment observation period and 
the in-trial observation period unless otherwise stated. 
Adverse Events
The following endpoint related to AEs is used to support the safety objective;
!
Number of treatment emergent adverse events (TEAEs)
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 December 2018
Novo Nordisk
Trial ID: NN9535-4270
Version:
1.0
UTN: U1111-1180-3651
Status:
Final
EudraCT No.: 2016-000989-35
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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 AEs 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’ AEs 
(i.e., AEs with onset date [or increase in severity] during the ‘in-trial’ observation period). AEs 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 AEs 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.
Hypoglycaemic episodes
The following two endpoints related to hypoglycaemic episodes are used to support the safety 
objective:
!
Number of treatment-emergent severe or blood glucose (BG)-confirmed symptomatic 
hypoglycaemic episodes 
!
Treatment-emergent severe or BG-confirmed symptomatic hypoglycaemic episodes (yes/no)
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 episode 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. 
Classification of Hypoglycaemia: 
Treatment emergent: hypoglycaemic episodes will be defined as treatment emergent if the onset is 
in the on-treatment period (see definition of observation period in section 2.3.1)
Nocturnal hypoglycaemic episodes: are episodes occurring between 00:01 and 05.59 both inclusive.
Hypoglycaemic episodes are classified according to the Novo Nordisk classification of 
hypoglycaemia (see Figure 2-2) and the ADA classification of hypoglycaemia (see Figure 2-3).
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).14 Therefore, Novo Nordisk has included hypoglycaemia with plasma 
glucose levels below this cut-off point in the definition of BG confirmed hypoglycaemia.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 December 2018
Novo Nordisk
Trial ID: NN9535-4270
Version:
1.0
UTN: U1111-1180-3651
Status:
Final
EudraCT No.: 2016-000989-35
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Novo Nordisk uses the following classification (see Figure 2-2) in addition to the ADA 
classification:
!
Severe or BG confirmed symptomatic hypoglycaemia: An episode that is severe according 
to the ADA classification15 or BG confirmed by a plasma glucose value <3.1 mmol/L 
(56 mg/dL) with symptoms consistent with hypoglycaemia. 
Figure 2-2
Novo Nordisk classification of hypoglycaemia 
American Diabetes Association classification15 of hypoglycaemia 
!
Severe hypoglycaemia: An episode requiring assistance of another person to actively 
administer carbohydrate, glucagon, or take other corrective actions. Plasma glucose 
concentrations may not be available during an event, but neurological recovery following 
the return of plasma glucose to normal is considered sufficient evidence that the event was 
induced by a low plasma glucose concentration.
!
Asymptomatic hypoglycaemia: An episode not accompanied by typical symptoms of 
hypoglycaemia, but with a measured plasma glucose concentration ≤3.9 mmol/L 
(70 mg/dL).
!
Documented symptomatic hypoglycaemia: An episode during which typical symptoms of 
hypoglycaemia are accompanied by a measured plasma glucose concentration ≤3.9 mmol/L 
(70 mg/dL).
!
Pseudo-hypoglycaemia: An episode during which the person with diabetes reports any of the 
typical symptoms of hypoglycaemia with a measured plasma glucose concentration 
>3.9 mmol/L (70 mg/dL) but approaching that level.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 December 2018
Novo Nordisk
Trial ID: NN9535-4270
Version:
1.0
UTN: U1111-1180-3651
Status:
Final
EudraCT No.: 2016-000989-35
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!
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 2-3
American Diabetes Association classification of hypoglycaemia
Number of treatment emergent severe or blood glucose confirmed symptomatic 
hypoglycaemic episodes
Number of treatment emergent severe or BG confirmed symptomatic hypoglycaemic episodes 
during 56 weeks 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 and stratification factor (sub-study, 
non- sub-study) as categorical factors and baseline HbA1c as covariate. The SAS will be used for the 
analysis.
The results will be described by the rate ratio between treatments and the associated 95% 
confidence interval and p-value for no treatment difference.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 December 2018
Novo Nordisk
Trial ID: NN9535-4270
Version:
1.0
UTN: U1111-1180-3651
Status:
Final
EudraCT No.: 2016-000989-35
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Treatment emergent severe or blood glucose confirmed symptomatic hypoglycaemia 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. The model will include factors for treatment and stratification factor (sub-study, 
non- sub-study) as categorical factors and baseline HbA1c as covariate. The SAS will be used for the 
analysis.
The results will be described by the odds ratio between treatments and the associated 95% 
confidence interval and p-value for no treatment difference.
Laboratory assessments
The laboratory assessments supporting the safety objective are change from baseline to week 52 in:
!
Haematology
!
Biochemistry
!
Calcitonin
The above continuous laboratory assessments will be summarised and evaluated by descriptive 
statistics.
In addition amylase and lipase 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 on-
treatment observation period.
Both analyses will use the associated log-transformed baseline and post-baseline responses as 
covariates instead of HbA1c. Lipase and amylase values will be log-transformed prior to the 
analysis.
Pulse
Change from baseline to week 52 in pulse will be analysed separately with the same model 
approach as for amylase and lipase but with the pulse value (not log-transformed) at baseline and 
post-baseline as covariates instead of HbA1c.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 December 2018
Novo Nordisk
Trial ID: NN9535-4270
Version:
1.0
UTN: U1111-1180-3651
Status:
Final
EudraCT No.: 2016-000989-35
Page:
22 of 25
Categorical safety assessments
The categorical assessments supporting the safety objective are change from baseline to week 52 in:
!
ECG category
!
Physical examination
!
Eye examination category
The above assessments will be summarised descriptively
2.6
Health economics and/or patient reported outcomes
Change from baseline to week 52 in scores for selected PROs:
!
SF-36v2TM Short Form health survey: Total scores (physical component and mental 
component) and scores from the 8 domains
!
Diabetes Treatment Satisfaction Questionnaire (DTSQ): Treatment satisfaction score (sum 
of 6 of 8 items) and the 8 items separately
!
Control of Eating Questionnaire (CoEQ): Scores from the 4 domains and scores from 19 
individual items
The PRO questionnaires, SF-36v2™, DTSQ and CoEQ will be used to evaluate the objective 
regarding Quality of Life. Each of the PRO endpoints will be analysed separately as the other 
continuous efficacy endpoints for the primary estimand using a similar model approach as for the 
primary endpoint with the associated baseline and post-baseline responses as covariates.
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
Italy removed from pre-defined region Europe to be used in the 
statistical analysis (Section 2.1).
Italy was not included in the study.
References updated in Section 2.2and 2.4.2. 
Updated for correctness.
The word nominal removed from the sentence “The closed testing 
procedure described in Bretz et.al. 20111 combined with a 
hierarchical approach is used to control the overall type-1 error at a 
nominal two-sided 5% level. “
Updated for clarification and to 
clearly distinguish the level used for 
testing and the level at which the 
overall type I-error is controlled. 
Definition of DXA analysis set added (Section 2.3)
Was not specified in the protocol.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 December 2018
Novo Nordisk
Trial ID: NN9535-4270
Version:
1.0
UTN: U1111-1180-3651
Status:
Final
EudraCT No.: 2016-000989-35
Page:
23 of 25
Specification of the PP-analysis set criterion on including ‘subjects 
on trial product at week 28 and having at least one non-missing 
HbA1c measurement at or after week 28’. This was revised to 
‘subjects on trial product at visit 8 and having at least one non-
missing HbA1c measurement at or after visit 8 (Section 2.3) .
Revision was done to ease 
programming. Visit 8 corresponded 
to week 28 ±7 days.
Wording on the multiple imputation model for the primary analysis 
updated to specify that observed or imputed values will be used as 
covariates (Section 2.4.1)
Updated for clarification.
The ‘in-trial treatment policy’ sensitivity analysis is renamed to 
‘retrieved drop-out’ analysis and it is clarified that the model will 
only be conducted to test the robustness of the superiority 
hypotheses (Section 2.4.5.2).
Per new preferred terminology, this
type of analysis is no longer called an 
‘in-trial’ analysis, but rather a 
retrieved drop-out analysis.
It was specified that the tipping point analyses for the confirmatory 
secondary endpoints are carried out on FAS and the DXA analysis 
set respectively.
Updated for clarification.
The following clarifications for the analyses of the confirmatory 
secondary endpoint, total fat mass (kg), in the DXA sub-study was 
added (Section 2.5.1):
! For all analyses it is clarified that the analyses are based on the 
DXA analysis set and that stratification factor will not be 
included in the models.
! The DXA analysis set is the 
relevant population and stratum 
DXA/non-DXA is redundant in 
the analysis of DXA endpoints. 
! Clarification that no MCMC-imputation will be performed
! With only 1 post-baseline 
measurement, non-monotone 
missingness is not possible and
MCMC-imputation is redundant.
! For the in-trial sensitivity analysis, imputation will be done 
within the same group of randomised treatment irrespective of 
status of treatment completion and region will be included in the 
imputation model. The analysis was re-categorised to a 
supplementary analysis.
! No systematic collection of off-
treatment DXA scans are done 
according to protocol (only 
premature treatment discontinuers 
not completing the premature end 
of treatment DXA scans are 
planned to have an off-treatment 
scan at the last visit). The data 
therefore does not support 
imputation by status of treatment 
completion. The coarser 
imputation approach is not 
expected to lead to sparse data 
issues, so there is no reason not to 
include region in the imputation 
model.
! Clarification of the in-trial period for DXA assessments
! Re-scans for DXA can occur after 
the P11 follow-up visit.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 December 2018
Novo Nordisk
Trial ID: NN9535-4270
Version:
1.0
UTN: U1111-1180-3651
Status:
Final
EudraCT No.: 2016-000989-35
Page:
24 of 25
It was clarified for statistical analyses of the supportive secondary 
body composition endpoints in the DXA sub-study that the 
analyses were to follow the same approach as for the confirmatory 
secondary endpoint, total fat mass (kg), (Section 2.5.2.1):
Data is collected in the same way and 
similar analysis considerations as for 
total fat mass (kg) apply.
Wording updated for the description of multiple imputation for 
binary endpoints (Section 2.5.2.1)
Updated to clarify that no new 
imputations are done.
Wording updated on analyses of amylase and lipase (Section 
2.5.2.2)
Updated to clarify that baseline 
values of amylase and lipase should 
be log-transformed before being used 
as covariates in the analyses.
Wording updated on analysis on pulse rate (Section 2.5.2.2) 
Updated to clarify that pulse rate 
should not be log-transformed.
For HbA1c, total fat mass, total lean mass and visceral fat mass the 
unit is corrected to’%-point’(multiple places).
Updated for correctness.
Number of imputations revised from 200 to 500 (multiple places).
Revised to align with the other
NN9535 phase 3b trials.
4
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
14 December 2018
Novo Nordisk
Trial ID: NN9535-4270
Version:
1.0
UTN: U1111-1180-3651
Status:
Final
EudraCT No.: 2016-000989-35
Page:
25 of 25
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CONFIDENTIAL