Efficacy and Safety of Semaglutide 2.0 mg s.c. Once-weekly Compared to Semaglutide 1.0 mg s.c. Once-weekly in Subjects With Type 2 Diabetes
Phase: PHASE3
Conditions: Diabetes Mellitus, Type 2
Sponsor: Novo Nordisk A/S

Cover Page for Protocol 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT03989232 
Sponsor trial ID: 
NN9535-4506 
Official title of study: 
Efficacy and Safety of Semaglutide 2.0 mg s.c. Once-weekly 
Compared to Semaglutide 1.0 mg s.c. Once-weekly in Subjects 
With Type 2 Diabetes 
Document date*: 
'HFHPEHU 2020 
*Document date refers to the date on which the document was most recently updated.
Note: The date in the header from Page 2 is the date of compilation of the documents and not of an update to content.

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Attachment I and II............................................................................................................................
Protocol amendment 1 - CZ ..............................................................................................................
Protocol Amendment  2 - Global.......................................................................................................
CONFIDENTIAL
Date:
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Version:
Status:
Once-weekly Semaglutide
Trial ID: NN9535-4506
Clinical Trial Report
Appendix 16.1.1
08 December 2020
1.0
Final
16.1.1 Protocol and protocol amendments
CONFIDENTIAL
 
 
 
 
 
Redacted protocol 
Includes redaction of personal identifiable information only. 
 
 
 
. 
 
 

Protocol
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Protocol
Protocol title: Efficacy and safety of semaglutide 2.0 mg s.c. once-weekly compared to 
semaglutide 1.0 mg s.c. once-weekly in subjects with type 2 diabetes
Substance : Semaglutide
Universal Trial Number: U1111-1224-5162
EUdraCT Number: 2018-004529-96
Trial phase: 3b
In the following, Novo Nordisk A/S and its affiliates will be stated as “Novo Nordisk”.
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
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This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.

Protocol
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Trial ID: NN9535-4506
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Protocol amendment summary of changes table
DOCUMENT HISTORY
Document version
Date
Applicable in country (-ies) and/or 
sites
Protocol version 4.0
15 June 2020
All
Protocol version 3.0
05 March 2020
All
Protocol version 2.0
05 July 2019
All
Original protocol version 1.0
21 March 2019
All
Protocol version 4 (15 June 2020)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union1.
Overall rationale for preparing protocol, version 4:
Primary statistical analysis for the treatment policy estimand has been revised.
Section # and name
Description of change
Brief Rationale
10.3.1 Analyses 
addressing the treatment 
policy estimand
Primary analysis
Revision of the primary analysis for the 
treatment policy estimand.
To revise the imputation method for 
missing data.
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Table of Contents
Page
Protocol amendment summary of changes table...........................................................................................2 
Table of Contents..............................................................................................................................................3 
1 
Synopsis......................................................................................................................................................6 
2 
Flowchart .................................................................................................................................................10 
3 
Introduction.............................................................................................................................................17 
3.1 
Trial rationale...............................................................................................................................17 
3.2 
Background..................................................................................................................................17 
3.3 
Benefit-risk assessment................................................................................................................18 
3.3.1 
Risks related to semaglutide ......................................................................................18 
3.3.2 
Benefits......................................................................................................................21 
3.3.3 
Risk-benefit conclusion .............................................................................................22 
4 
Objectives and endpoints........................................................................................................................23 
4.1 
Objectives ....................................................................................................................................23 
4.1.1 
Primary objective.......................................................................................................23 
4.1.2 
Secondary objective...................................................................................................23 
4.2 
Estimands.....................................................................................................................................23 
4.3 
Endpoints .....................................................................................................................................24 
4.3.1 
Primary endpoint........................................................................................................24 
4.3.2 
Secondary endpoints..................................................................................................24 
4.3.2.1 
Confirmatory secondary endpoint.......................................................24 
4.3.2.2 
Supportive secondary endpoints..........................................................24 
5 
Trial design ..............................................................................................................................................25 
5.1 
Overall design..............................................................................................................................25 
5.2 
Subject and trial completion ........................................................................................................26 
5.3 
End of trial definition...................................................................................................................27 
5.4 
Scientific rationale for trial design...............................................................................................27 
5.5 
Justification for dose....................................................................................................................27 
6 
Trial population.......................................................................................................................................29 
6.1 
Inclusion criteria ..........................................................................................................................29 
6.2 
Exclusion criteria.........................................................................................................................29 
6.3 
Lifestyle restrictions ....................................................................................................................30 
6.3.1 
Meals and dietary restrictions....................................................................................30 
6.4 
Screen failures..............................................................................................................................30 
7 
Treatments...............................................................................................................................................32 
7.1 
Treatments administered..............................................................................................................32 
7.1.1 
Medical devices .........................................................................................................34 
7.2 
Dose modification........................................................................................................................35 
7.3 
Method of treatment assignment..................................................................................................35 
7.4 
Blinding .......................................................................................................................................35 
7.5 
Preparation/Handling/Storage/Accountability.............................................................................36 
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7.6 
Treatment compliance..................................................................................................................36 
7.7 
Concomitant medication..............................................................................................................37 
7.7.1 
Rescue medication.....................................................................................................38 
7.8 
Treatment after the end of the trial ..............................................................................................38 
8 
Discontinuation/Withdrawal criteria ....................................................................................................39 
8.1 
Discontinuation of trial treatment ................................................................................................39 
8.1.1 
Temporary discontinuation of trial treatment ............................................................40 
8.1.2 
Rescue criteria............................................................................................................40 
8.2 
Withdrawal from the trial.............................................................................................................41 
8.2.1 
Replacement of subjects ............................................................................................41 
8.3 
Lost to follow-up .........................................................................................................................41 
9 
Trial assessments and procedures .........................................................................................................42 
9.1 
Efficacy assessments....................................................................................................................42 
9.1.1 
Clinical efficacy laboratory assessments ...................................................................43 
9.1.2 
Body measurements...................................................................................................43 
9.2 
Adverse events.............................................................................................................................43 
9.2.1 
Time period and frequency for collecting AE and SAE information ........................43 
9.2.2 
Method of detecting AEs and SAEs ..........................................................................45 
9.2.3 
Follow-up on AEs and SAEs.....................................................................................45 
9.2.4 
Regulatory reporting requirements for SAEs.............................................................45 
9.2.5 
Cardiovascular and death events................................................................................46 
9.2.6 
Disease-related events and/or disease-related outcomes not qualifying as an AE 
or SAE........................................................................................................................46 
9.2.7 
Pregnancies and associated adverse events................................................................47 
9.2.8 
Medical device incidents (including malfunctions)...................................................47 
9.2.9 
Technical complaints.................................................................................................47 
9.3 
Treatment of overdose .................................................................................................................48 
9.4 
Safety assessments.......................................................................................................................48 
9.4.1 
Physical examinations................................................................................................49 
9.4.2 
Vital signs ..................................................................................................................49 
9.4.3 
Eye examination ........................................................................................................49 
9.4.4 
Clinical safety laboratory assessments.......................................................................50 
9.5 
Pharmacokinetics.........................................................................................................................50 
9.6 
Pharmacodynamics ......................................................................................................................51 
9.7 
Genetics .......................................................................................................................................51 
9.8 
Biomarkers...................................................................................................................................51 
9.9 
Severe hypersensitivity................................................................................................................51 
10 Statistical considerations ........................................................................................................................52 
10.1 
Sample size determination...........................................................................................................52 
10.2 
Definition of analysis sets............................................................................................................53 
10.3 
Statistical analyses.......................................................................................................................54 
10.3.1 
Primary endpoint........................................................................................................55 
10.3.2 
Secondary endpoints..................................................................................................57 
10.3.2.1 
Confirmatory secondary endpoint.......................................................57 
10.3.2.2 
Supportive secondary endpoints..........................................................59 
10.3.3 
Other analyses............................................................................................................60 
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10.4 
Pharmacokinetic and/or pharmacodynamic modelling................................................................61 
10.5 
Partial database lock ....................................................................................................................61 
11 References................................................................................................................................................62 
12 Appendices...............................................................................................................................................65 
Appendix 1 
Abbreviations and Trademarks ..........................................................................................65 
Appendix 2 
Clinical laboratory tests .......................................................................................................68 
Appendix 3 
Trial governance considerations .........................................................................................70 
Appendix 4 
Adverse events: definitions and procedures for recording, evaluation, follow-up, 
and reporting...........................................................................................................................................79 
Appendix 5 
Contraceptive guidance and collection of pregnancy information...................................85 
Appendix 6 
Technical complaints: Definition and procedures for recording, evaluation, follow-
up and reporting......................................................................................................................................88 
Appendix 7 
Hypoglycaemic episodes.......................................................................................................90 
Appendix 8 
NN9535-4191 Clinical Trial Report Synopsis ....................................................................95 
Appendix 9 
Country-specific requirements..........................................................................................113 
Appendix 10 Protocol amendment history..............................................................................................114 
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1
Synopsis
Rationale:
Glucagon–like peptide-1 receptor agonists (GLP-1 RAs) are recommended for the treatment of 
patients with type 2 diabetes (T2D) who cannot reach their target HbA1c and need to lose weight or 
minimise weight gain. It has been consistently demonstrated that weight loss in patients with T2D 
has a beneficial impact on glycaemic control.
Currently, there are two doses of semaglutide available for treatment of subjects with T2D (0.5 mg 
and 1.0 mg). Although these are effective, results across the phase 3a trials in the clinical 
development program showed that ~20−30% of patients treated with semaglutide 1.0 mg did not 
achieve the treatment target of HbA1c of <7%.
Dose-dependent effects of semaglutide at doses exceeding the currently maximum approved dose 
for the treatment of T2D (1.0 mg once-weekly), have been demonstrated in relation to glycaemic 
control and body weight.
The present trial has been designed to investigate the effects of semaglutide 2.0 mg on glycaemic 
control, weight loss and safety in subjects with T2D.
Objectives and endpoints
Primary Objective
To establish the superior effect of semaglutide s.c. 2.0 mg once-weekly versus semaglutide s.c.
1.0 mg once-weekly on glycaemic control in subjects with T2D, on a background of metformin 
with or without sulphonylurea (SU) treatment. 
Secondary Objective
To compare the effect of semaglutide s.c. 2.0 mg once-weekly versus semaglutide s.c. 1.0 mg once-
weekly in subjects with T2D on a background of metformin with or without SU treatment, on:
x
Body weight
x
Vital signs
x
Hypoglycaemia
x
General safety and tolerability
Hypothetical estimand for the primary objective
The hypothetical estimand for the primary objective will be estimated as the absolute treatment 
difference in mean change from baseline to week 40 in HbA1c (%-point) of semaglutide 2.0 mg 
versus semaglutide 1.0 mg, both as an add-on to metformin with or without SU, in all randomised 
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subjects with T2D, regardless of change in treatment dose and had they not discontinued treatment 
due to adverse events (AEs) or initiated any rescue medication (anti-diabetic medications).
Hypothetical estimand for the secondary objective regarding body weight
This estimand will be similar to the hypothetical estimand for the primary objective, however, with 
“HbA1c (%-point)” replaced by “body weight (kg)”.
Treatment policy estimand for the primary objective
The treatment policy estimand for the primary objective will be estimated as the absolute treatment 
difference in mean change from baseline to week 40 in HbA1c (%-point) of semaglutide 2.0 mg 
versus semaglutide 1.0 mg, both as an add-on to metformin with or without SU, in all randomised 
subjects with T2D, regardless of change in treatment dose, discontinuation of treatment due to AEs 
and initiation of rescue medication (anti-diabetic medications).
Treatment policy estimand for the secondary objective regarding body weight
This estimand will be similar to the treatment policy estimand for the primary objective, however, 
with “HbA1c (%-point)” replaced by “body weight (kg)”.
The hypothetical estimand will be considered the primary estimand except in the US, where FDA 
specifically has requested the treatment policy estimand to be the primary.
Primary Endpoint
x
Change from baseline (week 0) to week 40 in HbA1c (%-point)
Confirmatory Secondary Endpoint
x
Change from baseline (week 0) to week 40 in body weight (kg)
Supportive Secondary Endpoints
Change from baseline (week 0) to week 40 in:
x
Fasting plasma glucose (FPG) (mmol/l)
x
Body mass index (BMI) (kg/m2)
x
Waist circumference (cm)
x
HbA1c < 7% at week 40 (yes/no)
x
HbA1c ≤ 6.5% at week 40 (yes/no)
x
Weight loss ≥ 5% at week 40 (yes/no)
x
Weight loss ≥ 10% at week 40 (yes/no)
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Supportive Secondary Safety Endpoints
x
Number of treatment emergent severe or blood glucose confirmed symptomatic hypoglycaemic 
episodes from first dose to week 40
x
Change from baseline (week 0) to week 40 in pulse rate (bpm)
Overall design:
This is a 40-week, randomised, double blind, active comparator, two-armed, multi-centre, 
multinational clinical trial comparing semaglutide s.c. 2.0 mg once-weekly with semaglutide 
s.c.1.0 mg once-weekly in subjects with T2D, on a background of metformin with or without SU 
treatment.
Key Inclusion Criteria
x
Male or female, age ≥18 years at the time of signing informed consent
x
Diagnosed with T2D ≥180 days prior to the day of screening
x
HbA1c of 8-10% (64−86 mmol/mol) (both inclusive)
x
Stable daily dose(s) for 90 days prior to the day of screening of:
x
Any metformin formulations (≥1500 mg or maximum tolerated or effective dose) alone or 
in combination with sulfonylureas (SU) (≥half of the maximum approved dose according to 
local label or maximum tolerated or effective dose)
Key Exclusion Criteria
x
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, as is prior 
insulin treatment for gestational diabetes
x
Renal impairment measured as estimated glomerular filtration rate (eGFR) value of 
<30 mL/min/1.73 m2 according to Chronic Kidney Disease Epidemiology Collaboration (CKD-
EPI) creatinine equation as defined by KDIGO 2012 classification
x
Uncontrolled and potentially unstable diabetic retinopathy or maculopathy. Verified by a fundus 
examination performed within the past 90 days prior to screening or in the period between 
screening and randomisation. Pharmacological pupil-dilation is a requirement unless using a 
digital fundus photography camera specified for non-dilated examination
Number of subjects:
Approximately 1377 subjects will be screened to achieve 964 randomised subjects. Number of 
subjects expected to complete the trial will be 867. Subjects will be followed for the planned 
duration of the trial.
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Treatment groups and duration:
The total trial duration for the individual subject will be approximately 49 weeks. The trial includes 
a screening period of approximately 2 weeks followed by randomisation. Eligible subjects fulfilling 
all eligibility criteria at visit 2 (V2) will be randomised in a 1:1 manner to receive either:
x
Semaglutide s.c. 2.0 mg once-weekly
x
Semaglutide s.c. 1.0 mg once-weekly
Randomisation will be stratified based on country (Japan/other).
Dose escalation to the target maintenance doses of semaglutide 1.0 mg or 2.0 mg once-weekly 
should take place during the first 12 weeks after randomisation.
The following trial products will be supplied by Novo Nordisk A/S for the duration of the trial:
Trial products
x
Semaglutide 1.34 mg/mL, solution for 1.5 mL pre-filled PDS290 pen injector. One pre-filled
pen contains 2.0 mg of semaglutide
x
Semaglutide placebo, solution for injection, 1.5 mL pre-filled PDS290 pen injector
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2
Flowchart
Trial Periods
Protocol section
Screening
Randomisation
Treatment
End of treatmentb
Follow upb
Treatment 
discontinuation
End of 
treatmentb
Follow upb
Site visit (V)/
phone contact (P)
V1
V2
V3
V4
V5
V6
V7
V8
P9
V10
P11
V10A
P11A
Timing of visit (weeks)
-2
0
4
8
12
16
20
28
34
40
End of 
treatment 
+ 7 weeks
End of 
treatment 
+ 7 weeks
Visit window (days)
±7
±7
±7
±7
±7
±7
±14
±14
±7
+7
SUBJECT RELATED 
INFO/ASSESSMENTS
Informed consent
Appendix 
3
X
In/exclusion criteria
6.1
6.2
X
X
Randomisation
X
Discontinuation criteria
8.1
X
X
X
X
X
X
X
Concomitant illness
9.4
X
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Trial Periods
Protocol section
Screening
Randomisation
Treatment
End of treatmentb
Follow upb
Treatment 
discontinuation
End of 
treatmentb
Follow upb
Site visit (V)/
phone contact (P)
V1
V2
V3
V4
V5
V6
V7
V8
P9
V10
P11
V10A
P11A
Timing of visit (weeks)
-2
0
4
8
12
16
20
28
34
40
End of 
treatment 
+ 7 weeks
End of 
treatment 
+ 7 weeks
Visit window (days)
±7
±7
±7
±7
±7
±7
±14
±14
±7
+7
Concomitant medication
7.7
X
X
X
X
X
X
X
X
X
X
X
X
X
Demographya
X
Diagnosis of diabetes
X
Diabetes history and 
diabetes complications
X
Medical history
9.4
X
Tobacco usec
X
Childbearing potential
Appendix 
5
X
EFFICACY
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Trial Periods
Protocol section
Screening
Randomisation
Treatment
End of treatmentb
Follow upb
Treatment 
discontinuation
End of 
treatmentb
Follow upb
Site visit (V)/
phone contact (P)
V1
V2
V3
V4
V5
V6
V7
V8
P9
V10
P11
V10A
P11A
Timing of visit (weeks)
-2
0
4
8
12
16
20
28
34
40
End of 
treatment 
+ 7 weeks
End of 
treatment 
+ 7 weeks
Visit window (days)
±7
±7
±7
±7
±7
±7
±14
±14
±7
+7
Body weight
9.1.2
X
X
X
X
X
X
X
X
X
X
Height 
9.1.2
X
Waist circumference
9.1.2
X
X
X
X
Systolic blood pressure
9.4.2
X
X
X
X
X
X
X
X
Diastolic blood pressure
9.4.2
X
X
X
X
X
X
X
X
FPG
Appendix 
2
X
X
X
X
X
HbA1c
Appendix 
2
X
X
X
X
X
X
X
X
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Trial Periods
Protocol section
Screening
Randomisation
Treatment
End of treatmentb
Follow upb
Treatment 
discontinuation
End of 
treatmentb
Follow upb
Site visit (V)/
phone contact (P)
V1
V2
V3
V4
V5
V6
V7
V8
P9
V10
P11
V10A
P11A
Timing of visit (weeks)
-2
0
4
8
12
16
20
28
34
40
End of 
treatment 
+ 7 weeks
End of 
treatment 
+ 7 weeks
Visit window (days)
±7
±7
±7
±7
±7
±7
±14
±14
±7
+7
Semaglutide plasma 
concentration
9.5
X
X
X
X
X
SAFETY
Hypoglycaemic episodes
9.2.6
Appendix7
X
X
X
X
X
X
X
X
X
X
X
X
Eye examination
9.4.3
X
X
X
Physical examination
9.4.1
X
X
X
Pulse
9.4.2
X
X
X
X
X
X
X
X
Biochemistry
Appendix 
2
X
X
X
X
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Trial Periods
Protocol section
Screening
Randomisation
Treatment
End of treatmentb
Follow upb
Treatment 
discontinuation
End of 
treatmentb
Follow upb
Site visit (V)/
phone contact (P)
V1
V2
V3
V4
V5
V6
V7
V8
P9
V10
P11
V10A
P11A
Timing of visit (weeks)
-2
0
4
8
12
16
20
28
34
40
End of 
treatment 
+ 7 weeks
End of 
treatment 
+ 7 weeks
Visit window (days)
±7
±7
±7
±7
±7
±7
±14
±14
±7
+7
Creatinine (including 
eGFR) 
Appendix 
2
X
X
X
X
Haematology
Appendix 
2
X
X
X
X
Pregnancy test
Appendix 
2
Appendix 
5
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events
9.2
Appendix 
4
X
X
X
X
X
X
X
X
X
X
X
X
Calcitonin
Appendix 
2
X
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Trial Periods
Protocol section
Screening
Randomisation
Treatment
End of treatmentb
Follow upb
Treatment 
discontinuation
End of 
treatmentb
Follow upb
Site visit (V)/
phone contact (P)
V1
V2
V3
V4
V5
V6
V7
V8
P9
V10
P11
V10A
P11A
Timing of visit (weeks)
-2
0
4
8
12
16
20
28
34
40
End of 
treatment 
+ 7 weeks
End of 
treatment 
+ 7 weeks
Visit window (days)
±7
±7
±7
±7
±7
±7
±14
±14
±7
+7
TRIAL MATERIAL
Dispensing visit
X
X
X
X
X
X
Drug accountability
7.5
X
X
X
X
X
X
X
X
IWRS session
7.3 7.4
X
X
X
X
X
X
X
X
X
REMINDERS
End of treatment
X
X
End of trial
X
Attend visit fasting
6.3.1
X
X
X
X
X
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Trial Periods
Protocol section
Screening
Randomisation
Treatment
End of treatmentb
Follow upb
Treatment 
discontinuation
End of 
treatmentb
Follow upb
Site visit (V)/
phone contact (P)
V1
V2
V3
V4
V5
V6
V7
V8
P9
V10
P11
V10A
P11A
Timing of visit (weeks)
-2
0
4
8
12
16
20
28
34
40
End of 
treatment 
+ 7 weeks
End of 
treatment 
+ 7 weeks
Visit window (days)
±7
±7
±7
±7
±7
±7
±14
±14
±7
+7
Directions for use (DFU)
X
Training in trial product 
and pen handling
7.1.1
X
X
X
Handout ID card
X
Handout and instruct in 
diary
9.2.6
X
Handout and instruct in 
BG meter
7.1 9.2.6
X
a Demography consists of date of birth, sex, ethnicity and race (according to local regulation).
b Please refer to Section 8 for details on discontinuation and withdrawal.
c Smoking is defined as smoking at least one cigarette or equivalent daily
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3
Introduction
3.1
Trial rationale
Glucagon–like peptide-1 receptor agonists (GLP-1 RAs) are recommended for the treatment of 
patients with T2D who cannot reach their target HbA1c and need to lose weight or minimise weight 
gain2. It has been consistently demonstrated that weight loss in patients with T2D has a beneficial 
impact on glycaemic control3, 4.
Currently, there are two doses of semaglutide available for treatment of subjects with T2D (0.5 mg 
and 1 mg). Although these are effective, results across the phase 3a trials5-9 (excluding the 
cardiovascular outcomes trial10) in the clinical development program showed that ~20−30% of 
patients treated with semaglutide 1 mg did not achieve the treatment target of HbA1c of <7%.
Dose-dependent effects of semaglutide at doses exceeding the currently maximum approved dose 
for the treatment of T2D (1 mg once-weekly), have been demonstrated in relation to glycaemic 
control and body weight11, 12.
The present trial has been designed to investigate the effects of semaglutide 2.0 mg on glycaemic 
control, weight loss and safety in subjects with T2D.
3.2
Background
Semaglutide s.c. 0.5 mg and 1 mg once-weekly (Ozempic®) is indicated as an adjunct to diet and
exercise to improve glycaemic control in adults with T2D13, 14. The currently approved indication 
was based on a comprehensive global phase 3a clinical development programme for semaglutide 
s.c. once-weekly (the SUSTAIN programme). The present trial will investigate a 3rd maintenance 
dose of semaglutide s.c. 2.0 mg once-weekly, for additional glycaemic control in subjects with 
T2D.
In the SUSTAIN programme, semaglutide provided superior long-term glycaemic control in 
addition to clinically relevant reductions in body weight as compared to commonly used marketed 
products across the spectrum of patients with T2D, ranging from treatment-naïve to insulin-treated. 
The safety profile of semaglutide is well-documented based on data from the non-clinical and 
clinical development programmes, and is consistent with the safety profile of other drugs within the 
GLP-1 RA drug class13, 14.
Two recent dose-finding trials have investigated the efficacy and tolerability of semaglutide s.c. at
doses higher than previously studied; both for the use in T2D11 and in weight management12.
For the dose-finding trial for once-daily semaglutide in T2D, semaglutide at doses up to 0.3 mg 
once-daily (equivalent to 2.1 mg once-weekly and thereby exceeding the maximum approved dose 
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of 1 mg once-weekly) were investigated. In this trial, 65 and 63 patients were exposed to doses 
equivalent to 1.4 mg and 2.1mg, respectively. In subjects with T2D and overweight or obesity, 
once-daily semaglutide (in doses of 0.05, 0.1, 0.2, or 0.3 mg/day, corresponding to doses of 0.35 to 
2.1 mg/week), demonstrated dose-dependent changes in HbA1c from baseline to week 26 ranging 
from -1.05%-points with semaglutide 0.05 mg to -1.88%-points with semaglutide 0.30 mg. In 
addition, semaglutide showed dose-dependent changes from baseline to week 26 in body weight, 
ranging from -2.76 kg with semaglutide 0.05 mg to -8.23 kg with semaglutide 0.30 mg11. The rate 
of AEs increased with increasing semaglutide dose, however, no marked differences across the 
semaglutide groups were observed in the proportion of subjects with AEs leading to premature 
treatment discontinuation. The majority of AEs were gastrointestinal (GI) AEs, and for these, a 
dose-dependency was seen, with an increasing proportion of subjects reporting GI AEs at increasing 
dose of semaglutide. GI adverse events were typically mild to moderate and no dose-dependency 
was observed in relation to GI AEs leading to premature treatment discontinuation with few of 
these events across the semaglutide groups. In conclusion, the safety profile of the doses equivalent 
to above 1 mg of semaglutide was generally well tolerated in subjects with T2D during 26 weeks of 
treatment and no unanticipated safety concerns were identified. For further details on efficacy and 
safety of semaglutide s.c. once-daily please refer to Appendix 8.
In a 52-week dose-finding trial for semaglutide s.c. in overweight or obese subjects without 
diabetes, treatment with once-daily semaglutide in doses up to 0.4 mg (equivalent to a weekly sum 
of 2.8 mg/week) resulted in a clear and dose-dependent weight loss, with the semaglutide s.c. 
0.4 mg once-daily dose providing a 13.8% reduction in body weight from baseline to week 52, 
while displaying an acceptable tolerability profile12. All semaglutide doses were generally well 
tolerated, with no new safety concerns. The most common adverse events were dose-related 
gastrointestinal symptoms, primarily nausea, as seen previously with GLP-1 receptor agonists. A
semaglutide s.c. dose of 2.4 mg once-weekly is currently being investigated as the target 
maintenance dose for semaglutide s.c. in weight management in a large phase 3a development 
programme.
A comprehensive review of results from the non-clinical and clinical studies of semaglutide can be 
found in the current edition of the investigator’s brochure (IB) and any updates hereof15.
3.3
Benefit-risk assessment
3.3.1
Risks related to semaglutide
The sections below describe identified and potential risks associated with semaglutide treatment. 
For further details of the risks, please refer to the current version of the IB or any updates hereof15.
The identified/potential risks are based on findings in non-clinical studies and clinical trials with 
semaglutide as well as other GLP-1 RAs. For each of these risks, mitigating actions have been 
implemented to minimise the risks for subjects enrolled in this trial.
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Identified risks
Gastrointestinal disorders
Consistent with findings with other GLP-1 RAs, the most frequently reported 
adverse events (AE) in clinical trials with semaglutide were gastrointestinal 
AEs. A dose dependency has been observed for most of the gastrointestinal 
disorders. A low starting dose and dose escalation steps will be implemented 
in the trial to mitigate the risk of gastrointestinal AEs.
In patients treated with GLP-1 RAs, nausea, vomiting and diarrhoea may lead 
to significant dehydration. This should be considered when treating patients 
with impaired renal function as it may cause a deterioration of renal function. 
Patients with GI AEs are recommended to drink plenty of fluids to avoid 
volume depletion.
Hypoglycaemia
There is a low risk of hypoglycaemic episodes when semaglutide is used as 
monotherapy. Subjects treated with semaglutide in combination with  SU or 
insulin have an increased risk of hypoglycaemia. The risk of hypoglycaemia 
can be lowered by reducing the dose of SU when initiating treatment with 
semaglutide (or insulin if subjects have been allowed to use insulin as rescue 
therapy).
Cholelithiasis 
In the semaglutide s.c. T2D clinical development programme (NN9535), 
events of cholelithiasis were reported more frequently with semaglutide s.c. 
than with comparators. Few events were serious and there was no clear 
correlation between events of cholelithiasis and weight loss. Events of 
cholelithiasis did not lead to an increased risk of complications such as 
cholecystitis or pancreatitis. 
Diabetic retinopathy 
complications
The cardiovascular outcome trial in the semaglutide T2D development 
programme showed an increased risk of events related to diabetic retinopathy 
complications in subjects treated with semaglutide compared to placebo, 
albeit the proportion of subjects with an event of diabetic retinopathy 
complications was low. The imbalance was driven by subjects with a history 
of diabetic retinopathy at baseline and subjects who were treated with insulin. 
Rapid improvement in glucose control has been associated with a temporary 
worsening of diabetic retinopathy. Long-term glycaemic control decreases the 
risk of diabetic retinopathy. Patients with a history of diabetic retinopathy 
should be monitored for worsening and treated according to clinical 
guidelines. 
As a precaution, subjects with a history of uncontrolled and potentially 
unstable diabetic retinopathy or maculopathy will be excluded from the trial, 
and fundus photography or slit-lamp biomicroscopy examination with 
pharmacologically dilated pupils will be performed according to flowchart.
Other risks
Patients treated with semaglutide may also experience decreased appetite, 
dizziness, dysgeusia, fatigue, increased heart rate, increased lipase and 
amylase, injection site reactions and weight decrease.
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In a phase 2 trial in doses of up 0.4mg/day in non-diabetic patients with 
obesity, early satiety, insomnia, dry mouth, and alopecia were also reported 
more with semaglutide.
Potential risks
Allergic reactions
As is the case with all protein-based pharmaceuticals, subjects treated with 
semaglutide are at risk of developing immunogenic and allergic reactions. As a
precaution, subjects with known or suspected hypersensitivity to semaglutide or 
related products will not be enrolled in this trial.
Acute pancreatitis
Acute pancreatitis has been observed with the use of GLP-1 RAs. Patients should 
be informed of the characteristic symptoms of acute pancreatitis and if 
pancreatitis is suspected, semaglutide should be discontinued. If confirmed, 
semaglutide should not be restarted.
Malignant neoplasms
There is no indication of a causal relationship between semaglutide and 
malignant neoplasm based on the available data. However, it is not possible to 
draw any firm conclusions due to very low numbers. As a precaution, subjects 
with a history of malignant neoplasms within the past 5 years prior to screening 
will be excluded from 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 non-clinical studies, 
clinical trials or post-marketing data that GLP-1 RA-based therapies increase the 
risk of pancreatic cancer, but pancreatic cancer has been classified as a potential 
class risk of GLP-1 RAs by European Medicines Agency. As a precaution, 
subjects with a history of malignant neoplasms within the past 5 years prior to
screening will be excluded from the trial.
Medullary thyroid 
cancer
Expected proliferative thyroid C-cell changes were seen in the mouse and rat 
carcinogenicity studies after daily exposure to semaglutide for 2 years. No 
hyperplasia was observed in monkeys after 52 weeks exposure up to 13-fold 
above the clinical plasma exposure at 2.4 mg/week. In clinical trials with 
semaglutide, there have been no clinically relevant changes in calcitonin levels. 
The C-cell changes in rodents are mediated by the GLP-1 receptor, which is not 
expressed in the normal human thyroid. Accordingly, the risk of GLP-1 receptor-
mediated C-cell changes in humans is considered to be low. However, as a 
precaution an exclusion criterion related to medical history of multiple endocrine
neoplasia type2 (MEN 2) or medullary thyroid cancer (MTC) and elevated 
plasma levels of calcitonin (biomarker for MTC) have been implemented in the 
trial.
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Other safety considerations
Drug interactions
Semaglutide delays gastric emptying and has the potential to impact the rate of 
absorption of concomitantly administered oral medicinal products. The potential 
effect of semaglutide on the absorption of co-administered oral medications was 
studied in trials at semaglutide 1 mg/week steady state exposure. No clinically 
relevant drug-drug interactions with semaglutide were observed based on the 
evaluated medications.
Semaglutide did not change the overall pharmacodynamics of warfarin as 
measured by the international normalised ratio (INR). However, upon initiation of 
semaglutide treatment in patients on warfarin and/or coumarin derivatives, 
frequent monitoring of INR is recommended.
Pregnancy, lactation 
and fertility
Studies in animals have shown reproductive toxicity. There are limited data from 
the use of semaglutide in pregnant women. Therefore, semaglutide should not be 
used during pregnancy. If a patient wishes to become pregnant, or pregnancy 
occurs, semaglutide should be discontinued. Semaglutide should be discontinued at 
least 7 weeks before a planned pregnancy due to the long half-life. 
In lactating rats, semaglutide was excreted in milk. As a risk to a breast-fed child 
cannot be excluded, semaglutide should not be used during breast-feeding.
The effect of semaglutide on fertility in humans is unknown. Semaglutide did not 
affect male fertility in rats. In female rats, an increase in oestrous length and a 
small reduction in number of ovulations were observed at doses associated with 
maternal body weight loss.
3.3.2
Benefits
Semaglutide s.c. once-weekly in doses of 0.5 mg and 1 mg has demonstrated clinically relevant and 
dose-dependent improvements in glycaemic control and body weight in subjects with T2D. Also, 
the reduction in HbA1c was consistently greater with higher baseline HbA1c16. Further dose-
dependent reductions in HbA1c and body weight have been observed in phase 2 trials with 
semaglutide doses exceeding 1 mg/week, both for the use in T2D11 and in weight management12.
Consequently, it is expected that semaglutide 2.0 mg will provide equal or better glycaemic and 
body weight control as compared to semaglutide 1.0 mg in subjects with T2D. All subjects will 
therefore be treated with a more efficacious regimen compared to the treatment they receive at trial 
entry.
In addition, it is expected that all subjects will benefit from participation through close contact with 
the trial site with close monitoring and treatment of T2D and a careful medical examination, all of 
which will most likely result in an intensified management of their diabetes.
Investigators will ensure that subjects are treated according to recommended standard-of-care for 
T2D management. Safety and efficacy will be monitored regularly, and acceptable glycaemic 
control will be reinforced at all times during the trial.
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All subjects in this trial will receive trial product and auxiliary supplies free of charge.
3.3.3
Risk-benefit conclusion
Necessary precautions have been implemented in the design and planned conduct of the trial in 
order to minimise the risks and inconveniences of participation in the trial. The safety profile for 
semaglutide generated from the clinical and non-clinical development programme has not revealed 
any safety issues that would prohibit administration of semaglutide 2.0 mg once-weekly. The results 
of the two phase 2 trials indicate that semaglutide provides dose-dependent reductions in HbA1c and 
weight11, 12.
It is therefore concluded that the potential benefits from the trial will outweigh the potential risks 
for the subjects. More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events (AEs) of semaglutide s.c. may be found in the Investigator’s 
Brochure (IB) and any updates hereof15, and in Appendix 8.
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4
Objectives and endpoints
4.1
Objectives
4.1.1
Primary objective
To establish the superior effect of semaglutide s.c. 2.0 mg once-weekly versus semaglutide s.c.
1.0 mg once-weekly on glycaemic control in subjects with T2D, on a background of metformin 
with or without SU treatment.
4.1.2
Secondary objective
To compare the effect of semaglutide s.c. 2.0 mg once-weekly versus semaglutide s.c. 1.0 mg once-
weekly in subjects with T2D, on a background of metformin with or without SU treatment, on:
x
Body weight
x
Vital signs
x
Hypoglycaemia
x
General safety and tolerability
4.2
Estimands
Hypothetical estimand for the primary objective
The hypothetical estimand for the primary objective will be estimated as the absolute treatment 
difference in mean change from baseline to week 40 in HbA1c (%-point) of semaglutide 2.0 mg 
versus semaglutide 1.0 mg, both as an add-on to metformin with or without SU, in all randomised 
subjects with T2D, regardless of change in treatment dose and had they not discontinued treatment 
due to AEs or initiated any rescue medication (anti-diabetic medications).
Hypothetical estimand for the secondary objective regarding body weight
This estimand will be similar to the hypothetical estimand for the primary objective, however, with 
“HbA1c (%-point)” replaced by “body weight (kg)”.
Treatment policy estimand for the primary objective
The treatment policy estimand for the primary objective will be estimated as the absolute treatment 
difference in mean change from baseline to week 40 in HbA1c (%-point) of semaglutide 2.0 mg 
versus semaglutide 1.0 mg, both as an add-on to metformin with or without SU, in all randomised 
subjects with T2D, regardless of change in treatment dose, discontinuation of treatment due to AEs 
and initiation of rescue medication (anti-diabetic medications).
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Treatment policy estimand for the secondary objective regarding body weight
This estimand will be similar to the treatment policy estimand for the primary objective, however, 
with “HbA1c (%-point)” replaced by “body weight (kg)”.
The hypothetical estimand will be considered the primary estimand except in the US, where FDA 
specifically has requested the treatment policy estimand to be the primary.
4.3
Endpoints
4.3.1
Primary endpoint
x
Change from baseline (week 0) to week 40 in HbA1c (%-point)
4.3.2
Secondary endpoints
4.3.2.1
Confirmatory secondary endpoint
x
Change from baseline (week 0) to week 40 in body weight (kg)
4.3.2.2
Supportive secondary endpoints
Supportive secondary effect endpoints
Change from baseline (week 0) to week 40 in:
x
Fasting plasma glucose (FPG) (mmol/l)
x
Body mass index (BMI) (kg/m2)
x
Waist circumference (cm)
x
HbA1c < 7% at week 40 (yes/no)
x
HbA1c ≤ 6.5% at week 40 (yes/no)
x
Weight loss ≥ 5% at week 40 (yes/no)
x
Weight loss ≥ 10% at week 40 (yes/no)
Supportive secondary safety endpoints
x
Number of treatment emergent severe or blood glucose confirmed symptomatic hypoglycaemic 
episodes from first dose to week 40
x
Change from baseline (week 0) to week 40 in pulse rate (bpm)
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5
Trial design
5.1
Overall design
x
This is a 40-week, randomised, double-blind, active comparator, two-armed, multi-centre,
multinational clinical trial.
x
Subjects will be randomised in a 1:1 manner to receive either:
x
Semaglutide s.c. 2.0 mg once-weekly
x
Semaglutide s.c. 1.0 mg once-weekly
x
Randomisation will be stratified based on country (Japan/other).
x
There is a 2-week screening period followed by a randomisation visit and a 40-week treatment
period. The treatment period is divided into a dose escalation period of 12 weeks and a
maintenance period of 28 weeks. After the end of treatment visit (V10), all subjects will enter a
follow-up period of 7 weeks, ended by a follow up phone contact, which corresponds to the end
of trial (P11). Total trial duration for the individual subject will be approximately 49 weeks.
x
The trial population will consist of subjects with T2D using metformin with or without SU, with
an HbA1c of 8-10% (both inclusive)
A schematic illustration of the trial design is provided in Figure 5-1.
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Figure 5-1
A schematic diagram of the trial design, with the duration of the trial periods.
As outlined in the figure, all subjects in the trial will receive one injection per 
week during a 12-week dose escalation period, until the target dose for 
semaglutide 2.0 mg is reached. Starting week 13 to end of treatment, all subjects 
in the trial will receive two injections using two pens per week to ensure 
blinding of the target maintenance dose of semaglutide 2.0 mg (Table 7-2)
5.2
Subject and trial completion
Approximately 1377 subjects will be screened in order to achieve 964 subjects to be randomly 
assigned to trial product. The number of subjects expected to complete the trial will be 867 subjects 
(see Section 10.1 for further details on the sample size considerations). Subjects will be followed 
for the planned duration of the trial.
Trial period completion for a subject:
Trial period completion is defined as when the randomised subject has completed the final 
scheduled visit ‘end of trial’ according to the flowchart in Section 2).
'Date of trial completion' is the date the subject completed the final scheduled visit, as mentioned 
above.
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Treatment period completion for a subject: 
Treatment period completion is defined as when the randomised subject has received the required 
treatment and attended the 'end of treatment' visit according to the flowchart in Section 2.
5.3
End of trial definition
The end of the trial is defined as the date of the last visit of the last subject in the trial.
5.4
Scientific rationale for trial design
The treatment duration of the trial is 40 weeks, with an additional 7 weeks of follow-up. A follow 
up phone contact, that will take place 7 weeks after the end of treatment, is included to account for 
the exposure and long half-life of semaglutide. A 40-week treatment duration (including 28 weeks 
on target doses) will provide robust data for the evaluation of efficacy and safety parameters.
A randomised, double blind, active comparator, two armed, multicentre, multinational trial design is 
chosen to minimise bias in the assessment of the effect and safety of semaglutide 2.0 mg and 
semaglutide 1.0 mg.
The trial includes a screening visit to assess the subject’s eligibility. After randomisation visit, visits 
are scheduled every 4 weeks to support the subject during dose escalation. To mimic usual clinic 
practice, from week 20, a visit is planned at week 28, a phone contact at week 34 and the end of 
treatment visit at week 40. A follow-up visit (‘end of trial’) for safety assessments is scheduled 7 
weeks after end of treatment to account for the exposure and the long half-life of semaglutide.
The trial population will consist of subjects with T2D treated with stable doses of metformin only or 
metformin in combination with sulphonylurea, in need of the treatment intensification. Subjects 
with an HbA1c of 8-10% are included as they are anticipated to particularly benefit from advancing 
to a higher dose of semaglutide. Further, this population represents a clinically relevant population,
as it is likely to benefit both from the better glycaemic control, as well as from the anticipated body 
weight loss.
5.5
Justification for dose
Results from the phase 2 dose-finding trial (NN9536-4191) showed that the semaglutide 0.3 mg 
once-daily dose was the most effective in terms of both glycaemic control and weight management, 
while displaying an acceptable tolerability profile (refer to Appendix 8). The daily dose of 0.3mg 
corresponds to a weekly dose of 2.1mg.
A target dose of 2.0 mg has been selected for this trial and as an intended 3rd maintenance dose of 
semaglutide s.c. once-weekly for glycaemic control in T2D, in addition to 0.5 mg and 1.0 mg. A 
single, intuitive dose escalation step is implemented to ensure simplicity when progressing the dose 
from 1.0 mg to 2.0 mg in clinical practice.
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Subjects will therefore be initiated at a once-weekly dose of 0.25 mg and follow a fixed-dose 
escalation regimen, with dose increases every 4 weeks (to doses of 0.5, 1.0 and 2.0 mg/week), until 
the target maintenance dose of 2.0 mg is reached after 12 weeks.
Semaglutide s.c. 2.0 mg once-weekly will provide a simpler treatment intensification regimen as 
compared to advancing treatment with additional anti-hyperglycaemic agents or combination 
injectable therapy in order to reach glycaemic targets. The added benefit of significant weight loss 
observed with higher dose would also allow clinicians to further individualise the treatment to meet 
the needs of the subject with T2D.
A treatment arm with semaglutide 1.0 mg once-weekly is included to be able to compare the effect 
on glycaemic control, body weight and safety between the two semaglutide doses (1.0 and 2.0 mg).
Please refer to Section 7.1 for more details on treatment doses.
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6
Trial population
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known as 
protocol waivers or exemptions, is not permitted.
6.1
Inclusion criteria
Subjects are eligible to be included in the trial only if all the following criteria apply:
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 ≥ 180 days prior to the day of screening.
4. HbA1c of 8-10% (64−86 mmol/mol) (both inclusive)
5. Stable daily dose(s) for 90 days prior to the day of screening of: any metformin formulations 
(≥1500 mg or maximum tolerated or effective dose) alone or in combination with sulfonylureas 
(SU) (≥half of the maximum approved dose according to local label or maximum tolerated or 
effective dose).
Japan: For country specific requirements, refer to Appendix 9.
6.2
Exclusion criteria 
Subjects are excluded from the trial if any of the following criteria apply:
Diabetes related
1. 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, as is prior 
insulin treatment for gestational diabetes
2. Anticipated initiation or change in concomitant medications (for more than 14 consecutive days) 
known to affect weight or glucose metabolism (e.g. treatment with orlistat, thyroid hormones, or 
corticosteroids)
3. Renal impairment measured as estimated glomerular filtration rate (eGFR) value of
<30 mL/min/1.73 m2 according to CKD-EPI creatinine equation as defined by KDIGO 2012 
classification17
4. Uncontrolled and potentially unstable diabetic retinopathy or maculopathy. Verified by a fundus 
examination performed within the past 90 days prior to screening or in the period between 
screening and randomisation. Pharmacological pupil-dilation is a requirement unless using a 
digital fundus photography camera specified for non-dilated examination
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General safety
5. Personal or first degree relative(s) history of multiple endocrine neoplasia type 2 or medullary 
thyroid carcinoma
6. Calcitonin ≥ 100 ng/L as measured by the central laboratory at screening
7. Presence or history of pancreatitis (acute or chronic)
8. Myocardial infarction, stroke, hospitalization for unstable angina pectoris or transient ischaemic 
attack within 180 days prior to the day of screening
9. Presently classified as being in New York Heart Association (NYHA) Class IV
10. Planned coronary, carotid or peripheral artery revascularisation
11. Presence or history of malignant neoplasm within 5 years prior to the day of screening. Basal 
and squamous cell skin cancer and any carcinoma in-situ is allowed
12. Known or suspected hypersensitivity to trial product(s) or related products 
13. Previous participation in this trial. Participation is defined as signed informed consent 
14. Receipt of any investigational medicinal product within 30 days before screening
15. Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing 
potential and not using a highly effective contraceptive method
16.Any disorder, unwillingness or inability, which in the investigator’s opinion, might jeopardise 
the subject’s safety or compliance with the protocol 
6.3
Lifestyle restrictions
To ensure alignment in regard to performance of assessments across subjects and trial sites, the 
below restrictions apply.
6.3.1
Meals and dietary restrictions
x
Subjects must attend the visits fasting according to the flowchart.
x
Fasting is defined as at least 6 hours prior to the visit without food or liquids, except for water. 
Trial product and any medication which should be taken with or after a meal should be withheld 
on the day of the visit until blood samples have been obtained.
x
If the subject is not fasting as required, the subject should be called in for a new visit within the 
visit window to have the fasting procedures done.
6.4
Screen failures
Screen failures are defined as subjects who consent to participate in the clinical trial but are not 
eligible for participation according to in/exclusion criteria. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure subjects to meet 
requirements from regulatory authorities. Minimal information includes date of inform consent, 
demography, date of visit, screen failure details, eligibility criteria, and any SAE. A screen failure 
session must be made in the Interactive Web Response System (IWRS).
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Individuals who do not meet the criteria for participation in this trial may not be rescreened. Re-
sampling is not allowed if the subject has failed one of the inclusion criteria or fulfilled one of the 
exclusion criteria related to laboratory parameters. However, in case of technical issues (e.g. 
haemolysed or lost), re-sampling is allowed for the affected parameters.
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7
Treatments
7.1
Treatments administered
The investigational medicinal products (trial products) provided by Novo Nordisk are listed in 
Table 7-1. Trial product must only be used, if it appears clear and colourless.
Table 7-1
Trial products provided by Novo Nordisk A/S
Trial product name:
semaglutide 1.34 mg/mL
semaglutide placebo
Dosage form:
Solution for injection
Solution for injection
Route of administration:
Subcutaneous
Subcutaneous
Dosing instructions:
Once-weekly
Once-weekly
Packaging
1.5 mL pre-filled PDS290 
pen-injector
1.5 mL pre-filled PDS290 
pen-injector
Dose escalation
All subjects are to reach the target maintenance dose of semaglutide 1.0 mg or 2.0 mg once-weekly.
Dose escalation to the target maintenance doses of semaglutide 1.0 mg or 2.0 mg once-weekly 
should take place during the first 12 weeks after randomisation. From V5 (week 12) the treatment 
will include 2 injections using 2 pens as described in Figure 5-1 and Table 7-2.
If a subject does not tolerate the designated target dose, the subject may stay at a lower dose level. 
This should only be allowed if the subject would otherwise discontinue trial product completely and 
if considered safe to continue trial product at a lower dose, as per the investigator’s discretion. The 
subject should make at least one attempt to re-escalate to the designated target dose, as per the 
investigator’s discretion.
It is recommended that the investigator consults Novo Nordisk in case of persistent deviations from 
the planned escalation regimen.
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Table 7-2
Dose escalation and maintenance
Trial periods
Screening 
Treatment 
period 1
Treatment 
period 2
Treatment 
period 3
Treatment 
period 4
Follow-up
Alias for trial period
Screening
Dose 
escalation
Dose 
escalation
Dose 
escalation
Maintenance
Follow-up
Visits in each period
V1
V2
V3
V4
V5-V10
P11
Duration of each period
2 weeks
4 weeks
4 weeks
4 weeks
28 weeks
Treatment arm
semaglutide s.c. 1.0 mg
Screening
semaglutide 
0.25 mg
semaglutide 
0.5 mg
semaglutide 
1.0 mg
semaglutide 
1.0 mg and 
semaglutide 
placebo 1.0 mg
Follow-up
semaglutide s.c. 2.0 mg
Screening
semaglutide 
0.25 mg
semaglutide 
0.5 mg
semaglutide 
1.0 mg
semaglutide 
1.0 mg and 
semaglutide 
1.0 mg
Follow-up
All subjects on background medication of metformin with or without sulphonylurea treatment.
Please refer to Figure 5-1 for more information.
Instructions for the subject
Subjects will be instructed to inject the trial product(s) subcutaneously once weekly in the abdomen, 
thigh, or upper arm. The injection site can be changed without dose adjustment.Subjects must be 
trained in handling the pen-injectors when dispensed the first time and training must be repeated 
during the trial as indicated per flowchart Section 2.The investigator may choose to observe the 
subject when administering the first dose.
The investigator must document that directions for use (DFU) are given to the subject orally and in 
writing at the first dispensing visit and again during the trial, if the investigator finds it relevant. The 
injection can be administered at any time of the day irrespective of meals, but on the same day of 
the week. The day of weekly administration can be changed if necessary if the time between two 
doses is at least 2 days (>48 hours) or in accordance with the local label. After selecting a new 
dosing day, once weekly dosing should be continued.
The investigator should give the dose reminder card at each dispensing visit. At V5 the investigator 
should also give the pen differentiation guide to the subject.
Missed doses
If a semaglutide dose is missed, it should be administered as soon as noticed, provided the time to 
the next scheduled dose is at least 2 days (48 hours). If a dose is missed and the next scheduled dose 
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is less than 2 days (48 hours) away, the subject should not administer the missed dose. A missed 
dose should not affect the scheduled dosing day of the week.
If ≥ 2 consecutive doses of trial product are missed, the subject should be encouraged to re-
commence the treatment if considered safe as per the investigator’s discretion and if the subject 
does not meet any of the discontinuation criteria (Section 8.1). The trial product should be 
continued as early as the situation allows. The missed doses should not affect the scheduled dosing 
day of the week. The start dose for re-initiation of trial product is at the investigator’s discretion. In 
case of questions related to re-initiation of trial product, the investigator should consult Novo 
Nordisk global medical experts. If doses are missed blood glucose should be more closely 
monitored if judged necessary by the investigator.
Auxiliary supplies
The following auxiliary supplies will be provided by Novo Nordisk:
x
Needles for the pre-filled PDS290 pen-injectors
x
Directions for use (DFU) for the pre-filled PDS290 pen-injector
x
Blood glucose (BG) meter and related auxiliaries
Subjects will be instructed in how to use the BG-meter and the instructions will be repeated during 
the trial as needed.
Only needles provided by Novo Nordisk must be used for administration of trial product. The 
subject should be advised to discard the injection needle after each injection and store the pen 
without an injection needle attached. Needles to be used with the trial product should be provided 
throughout the trial as needed.
7.1.1
Medical devices
Information about the PDS290 pre-filled pen-injector for semaglutide 1.34 mg/mL may be found in 
the IB and any updates hereof.
Information about the use of the PDS290 pre-filled pen-injector for semaglutide 1.34 mg/mL and 
semaglutide placebo can be found in the DFU.
Training for the pre-filled PDS290 pen-injector
When training the subjects, the following should be emphasised:
x
Always use a new needle for each injection as this will prevent contamination and ensure 
correct dose.
x
Remember to prime the pen-injector the first time it is used to ensure product flow.
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x
Check the dose counter to see that the correct dose has been dialled.
x
The needle should be kept in the skin while counting slowly to 6 after the dose counter has 
returned to zero after injection. If the needle is removed too early then the full dose may not 
have been delivered.
x
In-use conditions of the pen-injector including in-use time and storage (see Section 7.5).
7.2
Dose modification
Not applicable for this trial. Please refer to Section 7.1 for description of missed dose(s).
7.3
Method of treatment assignment
All subjects will be centrally randomised using an IWRS and assigned to the next available 
treatment according to randomisation schedule. Trial product will be dispensed/allocated at the trial 
visits summarised in the flowchart.
At screening, each subject will be assigned a unique 6-digit subject number which will remain the 
same throughout the trial. Each site is assigned a 3-digit number and all subject numbers will start 
with the site number.
7.4
Blinding
The first 12 weeks during escalation all the trial products are packed open-label. From week 13 the 
subject will receive trial product which is packed open-label as well as trial product which is packed 
blinded containing either semaglutide 1.34 mg/mL or semaglutide placebo. The active drug and 
placebo drug are visually identical.
The IWRS is used for blind-breaking instructions. The blind may be broken in a medical emergency 
if knowing the actual treatment would influence the treatment of the subject. Novo Nordisk will be 
notified immediately after breaking the blind. The date when and reason why the blind was broken 
must be recorded in the source documentation.
Whenever the blind is broken, the person breaking the blind must print the “code break 
confirmation” notification generated by the IWRS, record the reason and sign and date the 
document.
When the blind 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 blind break, the 
IWRS helpdesk should be contacted. Contact details are listed in Attachment I.
If the blind has been broken by investigator, the subject must discontinue treatment with trial 
product and a treatment discontinuation session must be completed in IWRS.
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7.5
Preparation/Handling/Storage/Accountability
Only subjects enrolled in the trial may receive trial product and only authorised site staff may 
supply or administer trial product. 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 screening and randomisation.
The investigator must confirm that appropriate temperature conditions have been maintained during 
transit for all trial products received and any discrepancies are reported and resolved before use of 
the trial products.
All trial products must be stored in a secure, controlled, and monitored (manual or automated) area 
in accordance with the labelled storage conditions with access limited to the investigator and 
authorised site staff. For the storage and in-use conditions see the trial materials manual (TMM) and 
the labels of trial product. The investigator must inform Novo Nordisk immediately if any trial 
product has been stored outside specified conditions. 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.
Subjects must return all used, partly used and unused trial products as instructed by the investigator. 
The investigator is responsible for drug accountability and record maintenance (i.e. receipt, 
accountability and final disposition records). Drug accountability must be performed in the IWRS 
by registering pen-injectors as returned either as used/partly used, unused or as lost.
Destruction of trial products can be performed on an ongoing basis and will be done according to 
local procedures after accountability is finalised by the site and reconciled by the monitor. 
Destruction of trial products must be documented in the IWRS.
All returned, expired or damaged trial products (for technical complaint samples see Appendix 6) 
must be stored separately from non-allocated trial products. No temperature monitoring is required. 
Non-allocated trial products including expired or damaged products must be accounted as unused, 
at the latest at closure of the trial site.
Japan: For country specific requirements, refer to Appendix 9
7.6
Treatment compliance
Throughout the trial, the investigator will remind the subjects to follow the trial procedures and 
requirements to ensure subject compliance. If a subject is found to be non-compliant the 
investigator will remind the subject of the importance of following the instructions given including 
taking the trial products as prescribed.
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Treatment compliance of trial product will be assessed by asking subject about changes in the dose 
taken or missed doses, and by monitoring of drug accountability. Information about compliance 
should be described in the subject’s source documents.
7.7
Concomitant medication
Any medication (including over-the-counter or prescription medicines) other than the trial product 
that the subject is receiving at the time of the first visit or receives during the trial must be recorded 
along with:
x
Trade name or generic name
x
Indication
x
Dates of administration including start and stop dates
x
Dose (only to be recorded for anti-hyperglycaemic medication)
After signing the informed consent, subjects must continue their anti-diabetic background 
medication (metformin with or without SU) throughout the entire trial. 
To mitigate SU-induced hypoglycaemia, subjects treated with SU should, at the discretion of the 
investigator, reduce the SU dose at randomisation by approximately 50%.
Apart from the initial dose reduction of SU, background medication dose should remain at the same 
dose level and with the same frequency during the entire treatment period unless glycaemic rescue 
treatment is needed (as described in Section 8.1.2) or safety concern related to the use of 
background medications arises.
In addition, all background medication(s):
x
is considered to be non-investigational medicinal product.
x
will not be provided by Novo Nordisk A/S, except if required by local regulations and not in 
contradiction to local regulations.
x
should be used in accordance with standard of care and current approved label in the individual 
country.
x
should not exceed the maximum approved dose in the individual country.
Investigators can switch OAD treatment within the same drug class, e.g. in case specific drugs 
become unavailable. 
Any change in concomitant medication, including switch of OAD treatment within the same drug 
class, must be recorded at each visit. If a change is due to an AE, then this must be reported 
according to Section 9.2.
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7.7.1
Rescue medication 
Glycaemic rescue medication, i.e. intensification of background OAD treatment and/or initiation of 
new anti-hyperglycaemic treatment, should be implemented at the discretion of the investigator in 
case of persistent hyperglycaemia. Please see Section 8.1.2.
Rescue medication should be selected according to ADA/EASD guideline2 (excluding GLP-1 RAs, 
dipeptidyl peptidase-4 (DPP-4) inhibitors and amylin analogues). 
Subjects that are started on rescue medication should continue to follow the protocol-specified visit 
schedule and stay on randomised treatment unless the investigator judge that it jeopardises subject’s 
safety.
Rescue medication should be documented in medical records and reported on the concomitant 
medication form in the case report form (CRF).
Rescue medication will not be supplied by Novo Nordisk but reimbursed as long as subject is 
participating in the trial, if required according to local regulations (Appendix 9).
7.8
Treatment after the end of the trial
When discontinuing trial product at the ‘end-of-treatment visit’, the subject should be transferred to 
a suitable marketed product at the discretion of the investigator. Considering the long half-life of 
semaglutide and to avoid over-exposure to GLP-1 RAs and interference with safety data collection, 
initiating GLP-1RA or DPP-4i should be avoided between the ‘end-of-treatment’ visit and the 
follow up visit.
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8
Discontinuation/Withdrawal criteria
The subject may be discontinued at any time during the trial at the discretion of the investigator for 
safety, behavioural, compliance or administrative reasons.
Efforts must be made to have the subjects, who discontinue trial product, to continue in the trial.
Subjects must be educated about the continued scientific importance of their data, even if they 
discontinue trial product. Only subjects who withdraw informed consent will be considered as 
withdrawn from the trial.
8.1
Discontinuation of trial treatment
Discontinuation of trial treatment can be decided by either the investigator or the subject.
Subjects who discontinue trial product should continue with the scheduled visits and assessments to 
ensure continued counselling and data collection.
The subject must be discontinued from trial product, if the following applies:
17. Safety concern as judged by the investigator
18. Confirmation of acute pancreatitis
19. Pregnancy
20. Intention of becoming pregnant
21. Simultaneous participation in another clinical trial of an approved or non-approved 
investigational medicinal product
As soon as possible after the decision to discontinue trial product, the subject should attend the 
treatment discontinuation visit (V10A), followed by the treatment discontinuation follow-up visit 
(P11A) 7 weeks after treatment discontinuation. See the flowchart (Section 2) for data to be 
collected at the time of treatment discontinuation and follow-up and for any further evaluations that 
need to be completed.
The subjects should continue with the remaining scheduled visits and assessments until the time of 
the originally scheduled ‘end of treatment’ visit (V10) and “end of trial” visit (phone contact P11).
All efforts should be made to have the subject attend at least the ‘end of treatment’ clinic visit 
containing the final data collection of primary and confirmatory secondary efficacy endpoints, and 
the “end of trial” visit. If the subject does not wish to attend the scheduled clinic visits efforts 
should be made to have the remaining visits converted to phone contacts. 
The investigator should discuss with the subject about the continued scientific importance of their 
data even if they discontinue trial product. If a subject is unwilling to attend any of the visits, 
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information about the attempts to follow up with the subject must be documented in the subject’s 
medical record.
The primary reason for discontinuation of trial product must be specified in the end-of-treatment 
form in the case report form (CRF), and final drug accountability must be performed. A treatment 
discontinuation session must be made in the IWRS.
8.1.1
Temporary discontinuation of trial treatment
In case of suspicion of acute pancreatitis, the trial product should promptly be interrupted (treatment 
discontinuation session should not be made in IWRS before diagnosis of acute pancreatitis is 
confirmed). Appropriate actions should be initiated, including local measurement of amylase and 
lipase (see Appendix 4 for reporting).
If acute pancreatitis is confirmed, trial product should not be restarted, and a treatment 
discontinuation session should be made in IWRS. If the Atlanta criteria18 are not fulfilled and thus, 
the suspicion of acute pancreatitis is not confirmed, trial product may be resumed.
If a subject has discontinued trial product due to temporary safety concern not related to trial 
product and is allowed to resume, the subject should follow the guide for missed doses 
(Section 7.1). Similarly, a subject who discontinues trial product on their own initiative should be 
encouraged to resume the trial product (Section 7.1).
8.1.2
Rescue criteria
Subjects with persistent and unacceptable hyperglycaemia should be offered treatment 
intensification. To allow time for dose escalation to maximum dose and to observe the expected 
effect of treatment on glycaemic parameters, rescue criteria will be applied at week 16 and onwards.
If any of the HbA1c values exceeds the limit outlined below and no intercurrent cause of the 
hyperglycaemia can be identified, a confirmatory HbA1c in the central laboratory should be 
obtained within 30 days.
If the confirmatory HbA1c exceeds the value described below then the subject should be offered 
treatment intensification (rescue medication) at the discretion of the investigator and in accordance 
with the ADA/EASD guidelines2 (excluding GLP-1RAs, DPP-4 inhibitors and amylin analogues).
Rescue medication should be offered from week 16 to week 40 to:
x
subjects with persistent poor glycaemic control, as expressed by a stable HbA1c value above 
8.5% (69 mmol/mol) that is confirmed within 30 days by the central laboratory and 
considered unacceptably high according to investigator’s assessment.
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Refer to Section 7.7.1 for description of rescue medication.
8.2
Withdrawal from the trial
A subject may withdraw consent at any time at his/her own request.
If a subject withdraws consent, the investigator must ask the subject if he/she is willing, as soon as 
possible, to have assessment performed according to visit 10A. See the flowchart (Section 2) for 
data to be collected.
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.
If a subject withdraws from the trial, he/she may request destruction of any samples taken and not 
tested, and the investigator must document this in the medical record.
If the subject withdraws consent, Novo Nordisk may retain and continue to use any data collected 
before such a withdrawal of consent.
Although a subject is not obliged to give his/her reason(s) for withdrawing, the investigator must 
make a reasonable effort to ascertain the reason(s), while fully respecting the subject's rights. Where 
the reasons are obtained, the primary reason for withdrawal must be specified in the end of trial 
form in the CRF.
8.2.1
Replacement of subjects
Subjects who discontinue trial product or withdraw from trial will not be replaced.
8.3
Lost to follow-up
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the trial site.
The following actions must be taken if a subject fails to return to the trial site for a required visit:
x
The site must attempt to contact the subject and reschedule the missed visit as soon as possible 
and counsel the subject on the importance of maintaining the assigned visit schedule and 
ascertain whether the subject wishes to and/or should continue in the trial.
x
Before a subject is deemed lost to follow-up, the investigator must make every effort to regain 
contact with the subject (where possible, at least three telephone calls and, if necessary, a 
certified letter to the subject's last known mailing address or local equivalent methods). These 
contact attempts should be documented in the subject's source document.
x
Should the subject continue to be unreachable, he/she will be considered to have withdrawn 
from the trial with a primary reason of lost to 'follow-up'.
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9
Trial assessments and procedures
x
Trial procedures and their timing are summarised in the flowchart.
x
Informed consent must be obtained before any trial related activity, see Appendix 3.
x
All screening evaluations must be completed and reviewed to confirm that potential subjects 
meet all eligibility criteria.
x
The investigator will maintain a screening log to record details of all subjects screened and to 
confirm eligibility or record reason for screen failure, as applicable.
x
At screening, subjects will be provided with a card stating that they are participating in a trial 
and giving contact details of relevant trial site staff.
x
Adherence to the trial design requirements, including those specified in the flowchart, is 
essential and required for trial conduct.
x
A subject who does not fulfil the eligibility criteria must not be randomised. If a subject is 
randomised in violation of inclusion and exclusion criteria, this will be handled as an important 
protocol deviation, and the IEC/IRB and regulatory authorities must be notified according to 
local requirements.
x
The investigator must ensure they keep regular contact with each subject throughout the entire 
trial, and always have updated contact information. Even if a visit is missed and it is not 
possible to reschedule, every effort to have all subjects followed for the primary endpoint and
AEs must be made.
x
It is the responsibility of the investigator to schedule the visits and contacts as per the protocol 
flowchart (Section 2) and to ensure they take place.
x
Assessments should be carried out according to the clinic’s standard of practice unless 
otherwise specified in the current section. Efforts should be made to limit the bias between 
assessments.
x
Review of completed hypoglycaemic episode diaries must be documented either on the 
documents or in the subject's source documents. If clarification of entries or discrepancies in the 
diary is needed, the subject must be questioned and a conclusion made in the subject's source 
documents. Care must be taken not to bias the subject.
x
Review of laboratory reports must be documented either on the documents or in the subject's 
source documents.
x
Repeat samples may be taken for technical issues and unscheduled samples or assessments may 
be taken for safety reasons. Refer to Appendix 2 for further details on laboratory samples.
US and Canada: For country specific requirements, refer to Appendix 9
9.1
Efficacy assessments 
Planned time points for all efficacy assessments are provided in the flowchart.
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9.1.1
Clinical efficacy laboratory assessments
All protocol-required laboratory assessments, as defined in Appendix 2, must be conducted in 
accordance with the flowchart and the laboratory manual.
9.1.2
Body measurements
Body measurements (height, weight, waist circumference) will be measured and recorded as 
specified in the flowchart.
Height is measured without shoes in centimetres or inches and recorded to nearest ½cm or ¼inch.
Body weight should be measured without shoes and only wearing light clothing and recorded in the 
eCRF in kilogram or pound [kg/lb], with a precision of 1/10 unit, (e.g. 45.2 kg / 137.2 lb). BMI will 
be calculated in the eCRF.
The waist circumference is defined as the minimal abdominal circumference located midway 
between the lower rib margin and the iliac crest and will be measured using a non-stretchable 
measuring tape. The measurement of waist circumference should be performed and recorded in the 
eCRF to the nearest ½ cm or ¼inch. 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.
9.2
Adverse events
The definitions of AEs and SAEs can be found in Appendix 4.
The investigator is responsible for detecting, documenting, recording and following up on events 
that meet the definition of an AE or SAE.
9.2.1
Time period and frequency for collecting AE and SAE information
All AEs will be collected from the first trial-related activity after obtaining informed consent and 
until the follow up phone contact, at the time points specified in the flowchart.
All SAEs will be recorded and reported to Novo Nordisk or designee within 24 hours, as indicated 
in Appendix 4. The investigator must submit any updated SAE data to Novo Nordisk within 24 
hours of it being available.
Investigators are not obligated to actively seek for AE or SAE in former trial subjects. However, if 
the investigator learns of any SAE, including a death, at any time after a subject has been 
discontinued from/completed the trial, and the investigator considers the event to be 
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possibly/probably related to the investigational trial product or trial participation, the investigator 
must promptly notify Novo Nordisk.
The method of recording, evaluating and assessing causality of AE and SAE and the procedures for 
completing and transmitting SAE reports are provided in Appendix 4.
Timelines for reporting of AEs are listed in Figure 9-1.
Some AEs require additional data collection via a specific event form. This includes medication 
errors observed during the trial. The relevant specific events are listed in Table 9-1 and the 
reporting timelines in Figure 9-1.
AE identified
AE form ≤  24 hours
SIF ≤ 5 calendar days
Sign off ≤ 7 calendar days
Is the AE serious or 
non-serious?
AE form
Is the AE listed as 
requiring a Specific Event 
Form to be completed?
Non-serious
Serious
No additional action
No
Specific event form
For SAE:
 ≤ 14 calendar days
Yes
Timelines are from the awareness of an AE.
Queries and follow-up requests to be resolved ≤ 14 calendar days.
AE: Adverse Events, SAE: Serious Adverse Events, SIF: Safety Information Form
Figure 9-1
Decision tree for determining the event type and the respective forms to 
complete with associated timelines
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Table 9-1
AEs requiring additional data collection (via specific event form)
Event type
Acute gallbladder disease
Acute pancreatitis
Acute renal failure
Diabetic retinopathy
Hepatic event
Malignant neoplasms
Medication error
9.2.2
Method of detecting AEs and SAEs
Care should be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non-
leading verbal questioning of the subject is the preferred method to inquire about events.
9.2.3
Follow-up on AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each subject at 
subsequent visits/contacts. All SAEs, will be followed until resolution, stabilisation, or if the event 
is otherwise explained (e.g. chronic condition) or the subject is lost to follow-up (as defined in
Section 8.3). Further information on follow-up procedures is given in Appendix 4.
9.2.4
Regulatory reporting requirements for SAEs
Prompt notification by the investigator to Novo Nordisk of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects and the safety of a trial 
product under clinical investigation are met.
Novo Nordisk has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a trial product under clinical investigation. Novo Nordisk 
will comply with country-specific regulatory requirements relating to safety reporting to the 
regulatory authority, IRB/IEC, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory requirements 
and Novo Nordisk policy and forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE or other specific safety 
information (e.g. summary or listing of SAEs), from Novo Nordisk will review and then file it 
along with the investigator's brochure and will notify the IRB/IEC, if appropriate according to local 
requirements.
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9.2.5
Cardiovascular and death events
Cardiovascular and death events will be handled and reported according to AE/SAEs description in 
Section 9.2.1.
9.2.6
Disease-related events and/or disease-related outcomes not qualifying as an AE or 
SAE
The following Disease-Related Events (DREs) are common in subjects with T2D and can be 
serious/life threatening:
x
Hypoglycaemic episodes
Definitions, classification and reporting requirements are described in Appendix 7.
Hypoglycaemia
Non-serious hypoglycaemia must be reported on a hypoglycaemic episode form.
If the hypoglycaemic episode fulfils the criteria for an SAE then in addition to the above, an AE 
form and a safety information form must also be filled in. One AE form and safety information 
form can cover several hypoglycaemic episode forms, if the subject has not recovered between the 
episodes.
BG meter and hypoglycaemic episode diary
Subjects will be provided with a blood glucose (BG) meter including auxiliaries as well as 
instructions for use. The subjects will be instructed in how to use the device and the instruction will
be repeated at regular intervals as indicated in the flowchart.
The BG meters use test strips calibrated to plasma values. Therefore, all measurements performed 
with capillary blood are automatically calibrated to plasma equivalent glucose values, which will be 
shown on the display.
The BG meter provided by Novo Nordisk should be used for the measurements required in the 
protocol as described in Appendix 7.
Subjects will also be provided with a hypoglycaemic episode diary. When subject experiences a 
hypoglycaemic episode, subject should use the BG meter and record the general information in 
relation to the hypoglycaemia in a diary as described in Appendix 7.
Relevant data from the diary must be transcribed into the CRF, as specified in Appendix 7, during 
or following the contact. If obtained via phone and a discrepancy is later detected, the values in the 
CRF must be corrected.
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Occasional review by the investigator of the BG meter values stored in the memory of the BG meter 
and correct reporting of these in the diary is advised in order to ensure adequacy of the data reported 
in the trial database.
9.2.7
Pregnancies and associated adverse events
Details of pregnancies in female subjects will be collected after the first-trial-related activity after 
obtaining informed consent and until the follow up phone contact (7 weeks after the end of 
treatment).
If a pregnancy is reported in female subjects, the investigator should inform Novo Nordisk within 
14 calendar days of learning of the pregnancy and should follow the procedures outlined in 
Figure 9-2 and Appendix 5.
Pregnancy outcome should be documented in the subject's medical record. Abnormal pregnancy 
outcome (e.g. spontaneous abortion, foetal death, stillbirth, congenital anomalies and ectopic 
pregnancy) is considered an SAE.
Maternal form 1b 
≤ 14 calendar days after birth
Maternal form 1a
≤ 14 calendar days
After birth/
termination 
of pregnancy
No additional 
action
Normal outcome 
Maternal form 2 ≤ 14 calendar days
Paternal form*1 ≤ 14 calendar days
Abnormal outcome 
Pregnancy 
verified
*1 Further information collected on Paternal form for male partners of 
female subjects requires signing of specific informed consent.
AE/SAEs in connection with the pregnancy and in the foetus/newborn 
should follow the timelines in Figure 9.1.
Prior to 
birth or 
pregnancy 
termination 
For female subjects
Figure 9-2
Decision tree for determining the forms to complete with associated timelines 
for pregnancy.
9.2.8
Medical device incidents (including malfunctions)
Section not applicable for this trial. Refer to technical complaints in Section 9.2.9.
9.2.9
Technical complaints
The investigator must assess whether a technical complaint is related to an AE.
The definitions and reporting process for technical complaints can be found in Appendix 6.
Timelines for reporting technical complaints are listed in Figure 9-3.
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Technical complaint form: ≤ 24 hours 
AE form: ≤ 24 hours 
SIF: ≤ 5 calendar days
Is it related 
to an SAE?
Technical complaint 
identified
Is it related 
to an AE?
Yes
No
Technical complaint form
≤ 5 calendar days
Technical complaint form: 
≤ 5 calendar days
AE form: ≤ 5 calendar days
No
Yes
AE: Adverse Event, SAE: Serious Adverse Event,  SIF: Safety Information Form
Figure 9-3
Decision tree for determining the forms to complete with associated timelines 
for technical complaints.
9.3
Treatment of overdose
Overdoses of up to 4.0 mg in a single dose and up to 4.0 mg in a week have been reported in 
clinical trials. The most commonly reported AE was nausea. All subjects recovered without 
complications.
There is no specific antidote for overdose with semaglutide. In the event of an overdose, appropriate 
supportive treatment should be initiated according to subject’s clinical signs and symptoms.
Accidental overdose must be reported as a medication error. Refer to Section 9.2.1 for further 
details.
In the event of an overdose, the investigator should closely monitor the subject for overdose-related 
AE/SAE and laboratory abnormalities. A prolonged period of observation and treatment may be 
necessary, taking into account the long half-life of semaglutide of approximately one week.
Decisions regarding dose interruptions or modifications will be made by the investigator based on 
the clinical evaluation of the subject.
For more information on overdose, also consult the current version of the investigator's brochure 
and any updates hereof15.
9.4
Safety assessments 
Planned time points for all safety assessments are provided in the flowchart.
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A concomitant illness is any illness that is present at the start of the trial (i.e. at the first visit) or 
found as a result of a screening procedure or other trial procedures performed before exposure to 
trial product.
Medical history is a medical event that the subject has experienced in the past. Only relevant and
significant medical history as judged by the investigator should be recorded in the eCRF at the 
screening visit. Findings of specific medical history should de described in designated forms.
In case of an abnormal and clinically significant finding, the investigator must record the finding on 
the Medical History/Concomitant Illness form if it is present at screening. Any new finding 
fulfilling the AE definition (see Appendix4) during the trial and any clinically significant worsening 
from baseline must be reported as an AE (see Section 9.2).
9.4.1
Physical examinations
x
A physical examination must be performed and include the following:
General appearance, skin, thyroid gland, respiratory system, cardiovascular system, 
gastrointestinal system including mouth, central and peripheral nervous system, and lymph node 
palpation
x
Investigators should pay special attention to clinical signs related to previous serious illnesses.
9.4.2
Vital signs
x
Pulse rate as well as diastolic and systolic blood pressure will be assessed.
x
Blood pressure at randomisation will consist of 3 diastolic and systolic blood pressure 
measurements with intervals of at least 1 minute.
x
Pulse rate at randomisation will also consist of 3 measurements.
x
At randomisation, all blood pressure and pulse readings must be entered in the eCRF and the 
average of the 3 blood pressure and the average of the 3 pulse readings will be calculated in the 
eCRF. At the subsequent visits, the blood pressure and pulse should only be measured once.
x
Blood pressure (diastolic and systolic) and pulse measurements should be preceded by at least 5 
minutes of rest for the subject in a quiet setting without distractions (e.g. television, cell 
phones).
x
Blood pressure and pulse measurements will be assessed in a sitting position with a completely 
automated device. Manual techniques will be used only if an automated device is not available.
9.4.3
Eye examination
Subjects with uncontrolled and potentially unstable diabetic retinopathy or maculopathy are not
eligible, as this indicates retinopathy that has recently progressed to a level that requires 
intervention or is approaching intervention but has yet to be brought under control.
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Results of an eye examination performed by an ophthalmologist or another suitably qualified 
healthcare provider must be available and evaluated by the investigator before randomisation to
assess eligibility. The eye examination should be performed as a fundus photography (e.g. 2-field
60 degree or better, colour or red-free) or by slit-lamp biomicroscopy examination (e.g. using a pre-
corneal or corneal contact lens examination). Pharmacological pupil-dilation is a requirement unless 
using a fundus photography camera specified for non-dilated examination.
If the subject had such an eye examination performed within 90 days prior to screening, the 
investigator may base his/her evaluation upon the results of that examination. The examination must
be repeated before randomisation if the subject has experienced worsening of visual function since
the last examination. If the applicable eye examination was performed before the subject signed the
informed consent form, it must be documented that the reason for performing the examination was
not related to this trial.
After randomisation an eye examination performed according to the above must be performed as 
per the flowchart in Section 2. Results must be available at V10 (end of treatment visit). An eye 
examination performed within 3 weeks prior to V10 is acceptable, provided no clinical symptoms 
suggestive of eye disease have occurred in the meantime.
The investigator should indicate the outcome of each eye examination. Relevant findings prior to 
randomisation must be recorded as concomitant illness/medical history, while relevant findings 
occurring after randomisation should be reported as an AE, if applicable according to Section 9.2.
9.4.4
Clinical safety laboratory assessments
All protocol-required laboratory assessments, as defined in Appendix 2, must be conducted in 
accordance with the laboratory manual and the flowchart in 2.
9.5
Pharmacokinetics
x
Single blood samples for measuring plasma concentration of semaglutide will be drawn on 
visits specified in the flowchart.
x
Subject must be instructed to withhold their trial product dose in the morning of the clinic visit 
until blood sampling has been performed.
x
The exact timing of obtaining the pharmacokinetic (PK) sample must be recorded on the 
laboratory form.
x
The purpose of measuring plasma semaglutide levels is to conduct exposure-response, to 
evaluate the dose response and the adherence to the treatment.
x
Blood samples for PK assessments must be collected, handled and shipped according to the 
description in the laboratory manual supplied by the central laboratory. The bioanalysis of 
semaglutide PK will be performed by a special laboratory. Semaglutide PK samples will be 
stored at the special laboratory responsible for PK until final Clinical Trial Report (CTR) in case 
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Novo Nordisk requests further analysis of the PK samples. Details of the bioanalysis will be 
outlined in a bioanalytical study plan issued by the special laboratory.
9.6
Pharmacodynamics
Not applicable for this trial.
9.7
Genetics
Not applicable for this trial.
9.8
Biomarkers
Not applicable for this trial.
9.9
Severe hypersensitivity
In the event of a severe immediate hypersensitivity reaction to trial product, blood sampling for 
assessment of anti-semaglutide IgE and binding antibodies should be conducted after 1–2 weeks 
and 7 weeks of trial product wash-out (i.e. after the subject had the last dose of the trial product). In 
these cases, it is also recommended to test for tryptase (total and/or mature tryptase) within 3 hours 
of the hypersensitivity reaction. In case a tryptase sample was collected within 3 hours of the event 
of hypersensitivity reaction, a baseline tryptase sample should be taken at the same time points as 
the IgE sample is obtained (after 1-2 weeks of drug wash-out). Tryptase concentrations (if 
measured) as well as results of anti-semaglutide antibody and IgE isotype anti-semaglutide 
antibodies will be collected by Novo Nordisk and the results will be reported in the CTR.
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10 Statistical considerations 
10.1
Sample size determination 
The primary endpoint is change from baseline (week 0) to week 40 in HbA1c (%-point) and the 
confirmatory secondary endpoint is change from baseline (week 0) to week 40 in body weight (kg). 
Both endpoints will be tested for superiority. The type-I error rate will be controlled in the strong 
sense across the primary and the confirmatory secondary hypotheses, separately for each estimand, 
at an overall alpha level (two-sided) of 0.05. Multiplicity control and criteria for confirming the 
hypotheses is described in Section 10.3 below.
The sample size calculation is performed to ensure sufficient power for confirming superiority of 
semaglutide 2.0 mg vs. semaglutide 1.0 mg on change from baseline to week 40 in HbA1c (%-point) 
based on each estimand separately.
Primary endpoint
An on-treatment HbA1c treatment effect of −0.26%-point was predicted based on exposure-response 
modelling.
To accommodate the treatment policy estimand, the on-treatment effect is adjusted by 15% based 
on results from the SUSTAIN phase 3a programme, where a lower effect was observed for the
treatment policy estimand as compared to the on-treatment effect. With the adjusted HbA1c
treatment effect of −0.22%-point and a standard deviation of 1.1%-point, 964 subjects will be 
randomised in order to obtain 87% power for confirming superiority for the primary endpoint based 
on the treatment policy estimand and at least 87% power for confirming superiority for the primary 
endpoint based on the hypothetical estimand. This is based on a 1:1 randomisation, a two-sided
significance level of 0.05, and a t-test. The assumed standard deviation is based on the SUSTAIN 
programme.
Confirmatory secondary endpoint
With 964 subjects randomised to ensure sufficient power (87%) for confirming superiority for the 
primary endpoint based on the treatment policy estimand, a marginal power of 90% for confirming 
that semaglutide 2.0 mg is superior to semaglutide 1.0 mg on change from baseline to week 40 in 
body weight (based on each estimand) is obtained if the true treatment difference is as low as 
- 0.84 kg. This is based on a 1:1 randomisation, a two-sided significance level of 0.05, a t-test, and a 
standard deviation of 4.0 kg. The assumed standard deviation is based on the SUSTAIN 
programme.
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Sensitivity analyses for the sample size calculation
The sensitivity of power for confirming superiority for the primary endpoint based on the treatment 
policy estimand for a fixed sample size of 964 subjects is presented in Table 10-1.
Table 10-1
Power for different scenarios
Scenario
On-treatment 
effect 
Adjusted for the 
treatment policy 
estimand 
Adjusted 
treatment effect
Randomised 
subjects
Power
Scenario 1
-0.25 %-point
15 %
-0.21
964
84 %
Scenario 2
-0.25 %-point
20 %
-0.20
964
81 %
Scenario 3
-0.27 %-point
15 %
-0.23
964
90 %
Scenario 4
-0.27 %-point
20 %
-0.22
964
87%
Scenario 5
-0.29 %-point
15 %
-0.25
964
94 %
Scenario 6
-0.29 %-point
20 %
-0.23
964
90 %
10.2
Definition of analysis sets
Data selection for statistical analyses will be a two-step process, first selecting subjects based on the 
analysis population and subsequently events/data for those subjects based on the observation period. 
Full analysis set (FAS): All randomised subjects. Subjects will be analysed according to the 
treatment to which they were assigned at randomisation.
Safety analysis set (SAS): All subjects exposed to at least one dose of trial product. Subjects will be 
analysed according to the trial product received for the majority of the period they were 
on treatment.
‘In-trial’ observation period: This observation period is defined as the period from the date of 
randomisation to the first of the following dates, both inclusive:
x
Date of the end-of-treatment visit (V10)
x
Date of death
x
Date when subject withdrew informed consent
x
Date of last contact for subjects lost to follow-up
‘On-treatment’ observation period: This observation period is a sub-set of the ‘in-trial’ observation 
period and represents the time period where subjects are considered exposed to trial product. The 
observation period starts at the date of first dose of trial product and ends at an endpoint-specific 
end-date. For adverse events including hypoglycaemic events, the observation period ends at the
first date of any of the following:
x
The follow-up visit (P11)
x
The treatment discontinuation follow-up visit (P11A)
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x
The date of last dose of trial product +49 days
x
The end-date for the ‘in-trial’ observation period
The follow-up visit is scheduled to take place 7 weeks after the last date on trial product, i.e., 49 
days.
For efficacy and other safety assessments (laboratory assessments, body measurements, and vital 
signs) the ‘on-treatment’ observation period ends at the last date on trial product with a visit 
window of +14 days. Hence, for these assessments, the ‘on-treatment’ observation period reflects 
the period in which subjects are treated.
‘On-treatment without rescue medication’ observation period: This observation period is a sub-set 
of the ‘on-treatment’ observation period and represents the time period where subjects are 
considered treated with trial product but have not initiated any rescue medications. The observation 
period starts at the date of first dose of trial product and ends at the first date of any of the 
following:
x
Initiation of rescue medication
x
The date of last dose of trial product +14 days
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.
Before data are locked for statistical analysis, a review of all data will take place. In general 
subjects should not be excluded from an analysis set and observations should not be excluded from
an observation period, if they fulfil the criteria. If subjects or observations are excluded, the reasons 
for their exclusion must be documented before database lock and described in the clinical trial 
report. Any decision to exclude either a subject or single observation from the statistical analysis is 
the joint responsibility of the members of the Novo Nordisk study group.
10.3
Statistical analyses
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 
the partial database lock.
General considerations
The comparison presented from a statistical analysis will be semaglutide 2.0 mg versus 
semaglutide 1.0 mg and results will be presented by the estimated treatment contrast with associated 
two-sided 95% confidence intervals and p-values corresponding to two-sided tests of no difference 
if not otherwise specified.
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Data from all sites will be analysed and reported together. 
If no statistical analysis is specified, data will be presented using relevant summary statistics. 
Accordingly, adverse events will be summarised descriptively. Data collected before randomisation 
(V2) will only be summarised descriptively.
Multiplicity control and criteria for confirming hypotheses
The statistical testing strategy will be performed for the primary analysis of each of the two 
estimands separately. In order to preserve the overall type-I error in the strong sense at a 5% 
significance level (two-sided), the conclusion of superiority of semaglutide 2.0 mg versus 
semaglutide 1.0 mg will be evaluated hierarchically according to the sequence below. The treatment 
difference is defined as μ = (semaglutide 2.0 mg minus semaglutide 1.0 mg).
1. Superiority of semaglutide 2.0 mg versus semaglutide 1.0 mg on change from baseline to 
week 40 in HbA1c
x
H0: μ ≥ 0.0 %-point against Ha: μ < 0.0 %-point
2. Superiority of semaglutide 2.0 mg vs. semaglutide 1.0 mg on change from baseline to week 
40 in body weight
x
H0: μ ≥ 0.0 kg against Ha: μ < 0.0 kg
10.3.1
Primary endpoint
The primary endpoint is change from baseline (week 0) to week 40 in HbA1c (%-point).
Analyses addressing the hypothetical estimand
Primary analysis
The hypothetical estimand will be estimated based on FAS using post-baseline data collected up to 
and including week 40 from the ‘on-treatment without rescue medication’ observation period. 
Imputation of missing data will be handled by multiple imputation (MI) assuming that missing data 
are missing at random (MAR). The imputation will be performed separately within each treatment 
group defined by randomised treatment. First, intermittent missing values are imputed using a 
Markov Chain Monte Carlo (MCMC) method, to obtain a monotone missing data pattern, 
generating 500 complete data sets. Secondly, a sequential conditional linear regression approach for 
imputing monotone missing values will be implemented starting with the first visit after baseline 
and sequentially continuing to the last planned visit at week 40. The model used for imputation will 
include the baseline and post-baseline HbA1c values observed prior to the visit in question as 
covariates. 
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The 500 complete datasets will be analysed using an analysis of covariance (ANCOVA) with 
treatment and stratification as fixed factors and the baseline HbA1c as covariate. Rubin’s rule19 will 
be applied to obtain inference.
Tipping point sensitivity analysis
For the tipping point sensitivity analysis, the primary analysis will be repeated, however, prior to 
analysis subjects from the semaglutide 2.0 mg group with missing observations at week 40 will be 
given a penalty, i.e., it is assumed that subjects with missing observations who are randomised to 
semaglutide 2.0 mg will receive a treatment that is less beneficial than subjects with observed 
values who are randomised to semaglutide 2.0 mg. The addition of the penalty values and 
subsequent analysis steps should be repeated with increasing penalty values until a significant result 
in the corresponding superiority analysis is no longer significant. This analysis will only be 
performed if superiority is confirmed based on the primary analysis.
Analyses addressing the treatment policy estimand
Primary analysis
The treatment policy estimand will be estimated based on the FAS using week 40 data from the ‘in-
trial’ observation period.
Imputation of missing data will be handled by MI assuming that missing data are missing at 
random. The imputation will be performed by imputing missing week 40 data separately within 
groups defined by randomised treatment and treatment status at week 40 (retrieved drop-out), in 
total, four groups as follows; (i) semaglutide 1.0 mg and on-treatment at week 40, (ii) semaglutide 
1.0 mg and off-treatment at week 40, (iii) semaglutide 2.0 mg and on-treatment at week 40, (iv) 
semaglutide 2.0 mg and off-treatment at week 40.
For each of the four groups an ANCOVA with baseline HbA1c as covariate will be fitted to 
observed values of the change from baseline in HbA1c at week 40. The estimated parameters for 
location and dispersion will then be used to impute 500 values for each subject with missing week 
40 data based on only baseline HbA1c. 
The 500 complete datasets will be analysed using an analysis of covariance (ANCOVA) with 
treatment and stratification as fixed factors and the baseline HbA1c as covariate. Rubin’s rule[ref 
19] will be applied to obtain inference.
Tipping point sensitivity analysis
The tipping point analysis will be performed in the same manner as for the tipping point sensitivity 
analysis addressing the hypothetical estimand, however, with the primary analysis addressing the 
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treatment policy estimand as foundation. This analysis will only be performed if superiority is 
confirmed based on the primary analysis.
10.3.2
Secondary endpoints
10.3.2.1
Confirmatory secondary endpoint
The confirmatory secondary endpoint is change from baseline (week 0) to week 40 in body weight 
(kg).
Analyses addressing the hypothetical estimand
Similar analyses as for the primary endpoint including body weight values instead of HbA1c values 
will be performed.
Analyses addressing the treatment policy estimand
Similar analyses as for the primary endpoint including body weight values instead of HbA1c values 
will be performed.
Overview of statistical analyses and intercurrent events
An overview of all analyses addressing the two estimands for the confirmatory endpoints is 
provided in Table 10-2.
Table 10-2
Statistical analyses of the confirmatory endpoints
Endpoint
Estimand
Analysis 
set
Observation 
period
Statistical 
model
Imputation approach
Sensitivity 
analysis
Primary endpoint
Change in 
HbA1c (%-point)
Hypothetical
FAS
On-
treatment 
w/o rescue
ANCOVA
MAR within randomised 
treatment group
Tipping 
point 
analysis
Treatment 
policy
FAS
In-trial
ANCOVA
MAR within group 
defined by randomised 
treatment and treatment 
status at week 40
Tipping 
point 
analysis
Confirmatory secondary endpoint
Change in body 
weight (kg)
Hypothetical
FAS
On-
treatment 
w/o rescue
ANCOVA
MAR within randomised 
treatment group
Tipping 
point 
analysis
Treatment 
policy
FAS
In-trial
ANCOVA
MAR within group 
defined by randomised 
treatment and treatment 
status at week 40
Tipping 
point 
analysis
Abbreviations: ANCOVA; Analysis of Covariance; FAS: Full Analysis Set; MAR: Missing At Random.
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The following Table 10-3 describes how anticipated intercurrent events during the trial are handled 
for confirmatory endpoints. The different intercurrent events will be handled in the same manner for 
both confirmatory endpoints.
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Table 10-3
Statistical handling of intercurrent events for the primary analyses of the 
confirmatory endpoints
Intercurrent event
Handling
Hypothetical estimand
Treatment policy estimand
Strategy
Data
Strategy
Data
x Change in dose 
during and after the 
dose escalation 
period
Treatment 
policy
Assessments will be 
performed and collected 
at scheduled visits after 
the intercurrent event and 
used in the analysis
Treatment 
policy
Assessments will be 
performed and collected 
at scheduled visits after 
the intercurrent event and 
used in the analysis
x Treatment 
discontinuation due 
to AEs
x Initiation of rescue 
(anti-diabetic) 
medication
Hypothetical
Assessments for 
scheduled visits after the 
time of the intercurrent 
event are considered 
missing and will be 
imputed assuming MAR 
as described in the 
analysis
Treatment 
policy
Assessments will be 
performed and collected 
at scheduled visits after 
the intercurrent event and 
used in the analysis
10.3.2.2
Supportive secondary endpoints
The supportive secondary endpoints are listed in Section 4.3.2.2. All analyses of these endpoints 
will be addressing a hypothetical estimand similar to the hypothetical estimand for the primary 
objective and based on the FAS using data from the ‘on-treatment without rescue medication’ 
observation period unless otherwise stated.
Continuous endpoints 
The continuous endpoints will be analysed using a similar model approach as for the primary 
analysis of the primary endpoint with the associated baseline value as covariate instead of HbA1c for 
their respective analyses. The analysis of change from baseline to week 40 in pulse rate will be 
based on SAS using data from the ‘on-treatment’ observation period.
Responder endpoints
To account for missing data, the binary endpoints will be derived from the 500 imputed datasets 
from the associated primary analysis addressing the hypothetical estimand. Each of the complete 
data sets will be analysed using a logistic regression (LR) model with treatment and stratification as 
fixed effects and associated baseline response as covariate. Estimated odds ratios will be 
log-transformed and inference will be drawn using Rubin’s rule19. The results will be back-
transformed and described by the odds ratio between treatments and the associated 95% CI and p-
value for no treatment difference.
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Other endpoints
Number of treatment emergent severe or blood glucose confirmed symptomatic hypoglycaemic 
episodes at week 40 will be analysed using a negative binomial regression (NBR) model with a 
log-link function and the logarithm of the time period covered by the subject’s ‘on-treatment’ 
observation period as offset. The model will include treatment and stratification as fixed factors and 
baseline HbA1c as a covariate. This analysis will be based on the SAS using the ‘on-treatment’ 
observation period. The results will be described by the rate ratio between treatments and the 
associated 95% CI and p-value for no treatment difference.
Overview of statistical analyses
An overview of all analyses of the supportive secondary endpoints is provided in Table 10-4.
Table 10-4
Statistical analyses of the supportive secondary endpoints
Endpoint
Estimand
Analysis 
set
Observation 
period
Statistical 
model
Imputation approach
Supportive secondary endpoints (effect related)
Change in FPG 
(mmol/)
Hypothetical
FAS
On-treatment 
w/o rescue
ANCOVA
MAR within randomised 
treatment group
Change in BMI 
(kg/m2)
Hypothetical
FAS
On-treatment 
w/o rescue
ANCOVA
MAR within randomised 
treatment group
Change in waist 
circumference (cm)
Hypothetical
FAS
On-treatment 
w/o rescue
ANCOVA
MAR within randomised 
treatment group
HbA1c < 7% (yes/no)
Hypothetical
FAS
On-treatment 
w/o rescue
LR
MAR within randomised 
treatment group
HbA1c ≤ 6.5% 
(yes/no)
Hypothetical
FAS
On-treatment 
w/o rescue
LR
MAR within randomised 
treatment group
Weight loss ≥ 5% 
(yes/no)
Hypothetical
FAS
On-treatment 
w/o rescue
LR
MAR within randomised 
treatment group
Weight loss ≥ 10% 
(yes/no)
Hypothetical
FAS
On-treatment 
w/o rescue
LR
MAR within randomised 
treatment group
Supportive secondary endpoints (safety related)
Change in pulse 
(bpm)
-
SAS
On-treatment 
ANCOVA
MAR within randomised 
treatment group
Number of 
hypoglycaemic 
episodes
-
SAS
On-treatment 
NBR
-
Abbreviations: ANCOVA; Analysis of Covariance; FAS: Full Analysis Set; LR: Logistic Regression; MAR: Missing 
At Random; NBR: Negative Binomial Regression; SAS: Safety Analysis Set
10.3.3
Other analyses
The binary assessment indicating whether a subject has had no treatment emergent severe or blood 
glucose confirmed symptomatic hypoglycaemic episodes at week 40 or at least one will be analysed 
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using a logistic regression model. The model will include treatment and stratification as fixed 
effects and baseline HbA1c as covariate, and the analysis will be based on SAS using data from the 
‘on-treatment’ observation period. The results will be described by the odds ratio between 
treatments and the associated 95% confidence interval and p-value for no treatment difference.
10.4
Pharmacokinetic and/or pharmacodynamic modelling
Population PK modelling and exposure-response analyses may be included to support dose 
selection and to explore the benefits of high versus lower doses of semaglutide in subjects with 
T2D. 
The modelling will include data from all randomised subjects that were exposed to semaglutide in 
this trial and might be performed as a meta-analysis including data from historical trials. Actual 
dose and date of administration of last dose before PK sampling will be registered in the CRF and 
used in the analysis, together with actual time point for PK sampling. The analysis will be further 
specified in a modelling analysis plan that is to be prepared before database lock. 
The modelling analyses will be performed by Quantitative Clinical Pharmacology at Novo Nordisk 
A/S and will be reported separately from the CTR. 
10.5
Partial database lock
A partial database lock will be performed at the end of the treatment period for all subjects, i.e. after 
the date of the last patient last treatment (LPLT) visit. The database will be updated after the partial 
database lock to include remaining PK data and any additional safety information. The full database 
lock will be performed after the date of the last patient last visit (LPLV).
Novo Nordisk will become unblinded at the time of the partial database lock, whereas subjects and 
investigators will remain blinded until after last patient last visit (LPLV). The analysis of the 
primary endpoint and all other efficacy endpoints will be performed based on the data from the 
partial database lock. Analysis of safety and PK data will be performed after the full database lock. 
This approach is implemented to allow earlier availability of semaglutide 2 mg to the patient 
population expected to benefit from a higher dose and to support further development activities with 
semaglutide s.c. A detailed plan for data handling and operational aspects of the partial database 
lock and the database update will be finalised before the partial database lock.
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11 References
1.
The European Parliament and the Council of the European Council. Directive 2001/20/EC 
of the European Parliament and of the Council of 4 April 2001 on the approximation of the 
laws, regulations and administrative provisions of the Member States relating to the 
implementation of good clinical practice in the conduct of clinical trials on medicinal 
products for human use, article 11. Official Journal of the European Communities. 01 May
2001.
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Davies M, D’Alessio D, Fradkin J, Kernan W, Mathieu C, Mingrone G, et al. Management 
of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes 
Association (ADA) and the European Association for the Study of Diabetes (EASD). 
Diabetes Care. 2018;41(12):2669-701.
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Pi-Sunyer FX. Weight loss in type 2 diabetic patients. Diabetes Care. 2005;28(6):1526-7.
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Look AHEAD Research Group, Wing RR. Long-term effects of a lifestyle intervention on 
weight and cardiovascular risk factors in individuals with type 2 diabetes mellitus: four-year 
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Sorli C, Harashima SI, Tsoukas GM, Unger J, Karsbøl JD, Hansen T, et al. Efficacy and 
safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 
diabetes (SUSTAIN 1): a double-blind, randomised, placebo-controlled, parallel-group, 
multinational, multicentre phase 3a trial. Lancet Diabetes Endocrinol. 2017;5(4):251-60.
6.
Ahrén B, Masmiquel L, Kumar H, Sargin M, Karsbøl JD, Jacobsen SH, et al. Efficacy and 
safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, 
thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): a 56-week, 
double-blind, phase 3a, randomised trial. Lancet Diabetes Endocrinol. 2017;5(5):341-54.
7.
Ahmann AJ, Capehorn M, Charpentier G, Dotta F, Henkel E, Lingvay I, et al. Efficacy and 
Safety of Once-Weekly Semaglutide Versus Exenatide ER in Subjects With Type 2 
Diabetes (SUSTAIN 3): A 56-Week, Open-Label, Randomized Clinical Trial. Diabetes 
Care. 2018;41(2):258-66.
8.
Rodbard HW, Lingvay I, Reed J, de la Rosa R, Rose L, Sugimoto D, et al. Semaglutide 
Added to Basal Insulin in Type 2 Diabetes (SUSTAIN 5): A Randomized, Controlled Trial. 
J Clin Endocrinol Metab. 2018;103(6):2291-301.
9.
Aroda VR, Bain SC, Cariou B, Piletič M, Rose L, Axelsen M, et al. Efficacy and safety of 
once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or 
without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): a 
randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial. Lancet 
Diabetes Endocrinol. 2017;5(5):355-66.
10.
Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, et al. Semaglutide and 
Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 
2016;375(19):1834-44.
11.
Lingvay I, Desouza CV, Lalic KS, Rose L, Hansen T, Zacho J, et al. A 26-Week 
Randomized Controlled Trial of Semaglutide Once Daily Versus Liraglutide and Placebo in 
Patients With Type 2 Diabetes Suboptimally Controlled on Diet and Exercise With or 
Without Metformin. Diabetes Care. 2018;41(9):1926-37.
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12.
O'Neil PM, Birkenfeld AL, McGowan B, Mosenzon O, Pedersen SD, Wharton S, et al. 
Efficacy and safety of semaglutide compared with liraglutide and placebo for weight loss in 
patients with obesity: a randomised, double-blind, placebo and active controlled, dose-
ranging, phase 2 trial. Lancet. 2018;392(10148):637-49.
13.
Novo Nordisk A/S. Ozempic® (semaglutide), EU Summary of Product Characteristics 
(SmPC). 2018.
14.
Novo Nordisk A/S. Ozempic ® (semaglutide), US Prescribing Information (PI). Dec 2017.
15.
Novo Nordisk A/S. Investigator's Brochure, semaglutide s.c. (Ozempic®), project NN9535 
(edition 14), or any updates hereof. 31 Jul 2018.
16.
Aroda V, Ahmann A, Cariou B, Chow F, Davies M, J´odar E, et al. Comparative efficacy, 
safety, and cardiovascular outcomes with once-weekly subcutaneous semaglutide in the 
treatment of type 2 diabetes: Insights from the SUSTAIN 1–7 trials. Diabetes & 
Metabolism. 2018.
17.
Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 
Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. 
Kidney Int Suppl. 2013;3(1):1-150.
18.
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.
19.
Little RJA, Rubin DB. Statistical analysis with missing data. New York: Wiley. 1987. xiv, 
278 p. p.
20.
World Medical Association. WMA Declaration of Helsinki - Ethical Principles for Medical 
Research Involving Human Subjects. Last amended by the 64th WMA General Assembly, 
Fortaleza, Brazil. October 2013.
21.
ICH Harmonised Tripartite Guideline. Guideline for Good Clinical Practice E6(R2), Step 4 
version. 09 Nov 2016.
22.
International Committee of Medical Journal Editors. Recommendations for the Conduct,
Reporting, Editing, and Publication of Scholarly Work in Medical Journals. December 
update 2017.
23.
De Angelis C, Drazen JM, Frizelle FA, Haug C, Hoey J, Horton R, et al. Clinical trial 
registration: a statement from the International Committee of Medical Journal Editors. N 
Engl J Med. 2004;351(12):1250-1.
24.
U.S. Department of Health and Human Services, Food and Drug Administration. Food and 
Drug Administration Amendments Act of 2007 as amended by the Final Rule "Clinical 
Trials Registration and Results Information Submission". 21 September 2016.
25.
The European Parliament and the Council of the European Council. Regulation (EC) No 
726/2004 of the European Parliament and of the Council of 31 March 2004 laying down 
Community procedures for the authorisation and supervision of medicinal products for 
human and veterinary use and establishing a European Medicines Agency, article 57. 30 
April 2004.
26.
Schwartz NS, Clutter WE, Shah SD, Cryer PE. Glycemic thresholds for activation of 
glucose counterregulatory systems are higher than the threshold for symptoms. J Clin Invest. 
1987;79(3):777-81.
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27.
Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, et al. Hypoglycemia 
and diabetes: a report of a workgroup of the American Diabetes Association and the 
Endocrine Society. Diabetes Care. 2013;36(5):1384-95.
28.
U.S. Department of Health and Human Services, Food and Drug Administration. Guidance 
for Industry. Patient-Reported Outcome Measures: Use in Medical Product Development to 
Support Labeling Claims. Avaliable from: 
http://www.fda.gov/downloads/Drugs/Guidances/UCM193282.pdf. 2009.
29.
Stull DE, Leidy NK, Parasuraman B, Chassany O. Optimal recall periods for patient-
reported outcomes: challenges and potential solutions. Curr Med Res Opin. 2009;25(4):929-
42.
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12 Appendices
Appendix 1
Abbreviations and Trademarks
AACE
American Association of Clinical Endocrinologists
ADA
American Diabetes Association
AE
adverse event
ALT
alanine aminotransferase
ANCOVA 
analysis of covariance
AST
aspartate aminotransferase
BG
blood glucose
BMI 
body mass index 
BUN
blood urea nitrogen 
CFR
Code of Federal Regulations 
CI 
confidence interval
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CRF
case report form
CTR
clinical trial report
CV
cardiovascular
DBP
diastolic blood pressure 
DMC
data monitoring committee
DFU
directions for use 
DPP-4i 
dipeptidyl peptidase-4 inhibitor
DRE
disease related event
DUN
dispensing unit number
EAC
event adjudication committee
EASD
European Association for the Study of Diabetes
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ECG
electrocardiogram
eGFR
estimated glomerular filtration rate
ETD
estimated treatment differences 
FAS
full analysis set
FDA
U.S. Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FPG
fasting plasma glucose
FSH
follicle-stimulating hormone 
GCP
Good Clinical Practice
GI 
gastrointestinal
GIAE
gastrointestinal adverse event
GLP-1 RA 
glucagon-like peptide-1 receptor agonist
HbA1c
glycated haemoglobin
hCG
human chorionic gonadotropin 
HRT
hormone replacement therapy
IB
investigator’s brochure
ICH
International Council for Harmonisation
IEC
independent ethics committee
INR
international normalised ratio 
IRB
institutional review board
IUD
intrauterine device
IUS
intrauterine hormone-releasing system 
IWRS
interactive web response system
KDIGO
Kidney disease improving global outcomes
LOCF
last available observation carried forward 
LR
logistic regression 
LSFT
last subject first treatment 
MAR
missing at random
MCMC
Markov Chain Monte Carlo 
MEdDRA
medical dictionary for regulatory activities
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MEN2
multiple endocrine neoplasia type 2 
MI
multiple imputation
MMRM
mixed model for repeated measurement
MTC
medullary thyroid cancer 
NBR
negative binomial regression 
NYHA
New York Heart Association
OD
once daily
PCD
primary completion date
PG
plasma glucose
PK 
pharmacokinetic
PMM
pattern mixture model 
PP
per protocol
PT
preferred terms 
PYE
patient-years of exposure 
SBP 
systolic blood pressure 
SAE
serious adverse event
SAP
statistical analysis plan
SMQ
standardised MedDRA queries 
SMPG
self-measured plasma glucose
SOC
system organ class 
SUSAR
suspected unexpected serious adverse reaction
T2D
type 2 diabetes
TEAE
treatment-emergent adverse event
TMM
trial materials manual
ULN
upper limit of normal
WOCBP
woman of child bearing potential
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Appendix 2
Clinical laboratory tests
x
The tests detailed in Table 12-1 and Table 12-2 will be performed by the central laboratory.
x
Additional tests may be performed at any time during the trial as determined necessary by the
investigator or required by local regulations. Only laboratory samples specified in the protocol 
should 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.
x
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. 
x
The investigator must review all laboratory results for concomitant illnesses and AEs.
x
Laboratory samples will be destroyed no later than at finalisation of the clinical trial report.
Table 12-1
Protocol-required efficacy laboratory assessments
Laboratory assessments
Parameters
Glucose metabolism 
x Fasting plasma glucose1
x HbA1c
NOTES:
1A FPG result ≤3.9 mmol/L (70 mg/dL) in relation to planned fasting visits should not be reported as a 
hypoglycaemic episode.
Table 12-2
Protocol-required safety laboratory assessments
Laboratory assessments
Parameters
Haematology
x Basophils
x Eosinophils
x Erythrocytes
x Haematocrit
x Haemoglobin
x Leucocytes
x Lymphocytes
x Monocytes
x Neutrophils
x Thrombocytes
Biochemistry1
x Alanine Aminotransferase (ALT)
x Alkaline phosphatase
x Amylase
x Aspartate Aminotransferase (AST)
x Creatinine
x Lipase
x Potassium
x Sodium
x Total Bilirubin
x Urea
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Hormones
x Calcitonin (only for screening purposes)
Pregnancy Testing
x Urine human chorionic gonadotropin (hCG) pregnancy test (as needed for women of 
childbearing potential)2
Other tests
x eGFR calculated by the central laboratory based on the creatinine value using the 
CKD-EPI equation
Notes:
1Details of required actions and follow-up assessments for increased liver parameters including any discontinuation 
criteria are given in Appendix 4 (Hy’s Law) and Section 8.1.
2Local urine testing will be standard unless serum testing is required by local regulation or IRB/IEC.
All trial-required laboratory assessments will be performed by a central laboratory, with the 
exception of:
x
urine pregnancy testing, which will be performed locally
x
semaglutide plasma concentrations, which will be performed at a specialised laboratory and
x
anti-semaglutide IgE and binding antibodies (in the event of a severe immediate hypersensitivity 
reaction to trial product), which will be performed at a specialised laboratory 
Laboratory/analyte results that could unblind the trial will not be reported to the trial sites until the 
trial has been unblinded.
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Appendix 3
Trial governance considerations
1) Regulatory and ethical considerations
x
This trial will be conducted in accordance with the protocol and with the following:
x
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki20 and applicable ICH Good Clinical Practice (GCP) Guideline21
x
Applicable laws and regulations
x
The protocol, informed consent form, investigator’s brochure (as applicable) and other relevant 
documents (e.g. advertisements), must be submitted to an IRB/IEC and reviewed and approved 
by the IRB/IEC before the trial is initiated.
x
Regulatory authorities will receive the clinical trial application, protocol amendments, reports 
on SAEs, and the clinical trial report according to national requirements.
x
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the trial design, except for changes necessary to eliminate an immediate safety 
hazard to trial subjects.
x
Before a trial site is allowed to start screening subjects, written notification from Novo Nordisk 
must be received.
x
The investigator will be responsible for:
x
providing written summaries of the status of the trial annually or more frequently in 
accordance with the requirements, policies, and procedures established by the IRB/IEC 
and/or regulatory authorities
x
notifying the IRB/IEC of SAEs or other significant safety findings as required by IRB/IEC 
procedures
x
providing oversight of the conduct of the trial at the site and adherence to requirements of 
ICH guidelines, the IRB/IEC, and all other applicable local regulations ensuring submission 
of the clinical trial report (CTR) synopsis to the IRB/IEC.
Japan: For country specific requirements, refer to Apppendix 9
2) Financial disclosure
Investigators and sub-investigators will provide Novo Nordisk with sufficient, accurate financial 
information as requested to allow Novo Nordisk to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the trial and one 
year after completion of the trial.
For US trial sites: verification under disclosures per Code of Federal Regulations (CFR) of 
Financial Conflict of Interest.
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3) Informed consent process
x
The investigator or his/her representative will explain the nature of the trial to the subject and 
answer all questions regarding the trial.
x
The investigator must ensure the subject ample time to come to a decision whether or not to 
participate in the trial. 
x
Subjects must be informed that their participation is voluntary.
x
Subjects will be required to sign and date a statement of informed consent that meets the 
requirements of local regulations, ICH guidelines21, Declaration of Helsinki20 and the IRB/IEC 
or trial site.
x
The medical record must include a statement that written informed consent was obtained before 
any trial related activity and the date when the written consent was obtained. The authorised 
person obtaining the informed consent must also sign and date the informed consent form before 
any trial related activity.
x
The responsibility of seeking informed consent must remain with the investigator, but the 
investigator may delegate the task of informing to a medically qualified person, in accordance 
with local requirements.
x
Subjects must be re-consented to the most current version of the informed consent form(s) 
during their participation in the trial.
x
A copy of the informed consent form(s) must be provided to the subject.
4) Information to subjects during trial
The site will be offered a communication package for the subject during the conduct of the trial. 
The package content is issued by Novo Nordisk. The communication package will contain written 
information intended for distribution to the subjects. The written information will be translated and 
adjusted to local requirements and distributed to the subject at the discretion of the investigator. The 
subject may receive a “welcome to the trial letter” and a “thank you for your participation letter” 
after completion of the trial. Further the subject may receive other written information during the 
trial.
All written information to subjects must be sent to IRB/IEC for approval/favourable opinion and to 
regulatory authorities for approval or notification according to local regulations.
5) Data protection
x
Subjects will be assigned a 6-digit unique identifier, a subject number. Any subject records or
datasets that are transferred to Novo Nordisk will contain the identifier only; subject names or 
any information which would make the subject identifiable will not be transferred.
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x
The subject and any biological material obtained from the subject will be identified by subject 
number, visit number and trial ID. Appropriate measures such as encryption or leaving out 
certain identifiers will be enforced to protect the identity of subjects as required by local, 
regional and national requirements. 
x
The subject must be informed that his/her personal trial related data will be used by Novo 
Nordisk in accordance with local data protection law. The disclosure of the data must also be 
explained to the subject. 
x
The subject must be informed that his/her medical records may be examined by auditors or 
other authorised personnel appointed by Novo Nordisk, by appropriate IRB/IEC members, and 
by inspectors from regulatory authorities.
6) Committee structure
Novo Nordisk safety committee
Novo Nordisk will constitute an internal semaglutide s.c. safety committee to perform ongoing 
safety surveillance. The semaglutide s.c. 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.
7) Publication policy
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 investigators 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) investigator (s) will be appointed by Novo Nordisk to review and sign the clinical trial 
report (signatory investigator) on behalf of all participating investigators. The signatory 
investigator(s) will be appointed based upon the criteria defined by the International Committee of 
Medical Journal Editors for research publications.22
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Communication of results
Novo Nordisk commits to communicate and disclose results of trials regardless of outcome. 
Disclosure includes publication of a manuscript in a peer-reviewed 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. Novo Nordisk reserves the right to defer the release of data 
until specified milestones are reached, for example when the clinical trial report is available. This 
includes the right not to release the results of interim analyses, because the release of such 
information may influence the results of the entire trial.
At the end of the trial, one or more scientific publications may be prepared collaboratively by the 
investigator(s) and Novo Nordisk. Novo Nordisk reserves the right to postpone publication and/or 
communication for up to 60 days to protect intellectual property.
In all cases the trial results will be reported in an objective, accurate, balanced and complete 
manner, with a discussion of the strengths and limitations. 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.
Authorship
Novo Nordisk will work with one or more investigator(s) and other experts who have contributed to 
the trial concept or design, acquisition, analysis or interpretation of data to report the results in one 
or more publications.
Authorship of publications should be in accordance with the Recommendations for the Conduct, 
Reporting, Editing and Publication of Scholarly Work in Medical Journals by the International 
Committee of Medical Journal Editors22.
All authors will be provided with the relevant statistical tables, figures, and reports needed to 
evaluate the planned 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. 
Site-specific publication(s) by investigator(s)
For a multicentre 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. Thus, Novo Nordisk may deny a 
request or ask for deferment of the publication of individual site results until the primary manuscript 
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is accepted for publication. In line with Good Publication Practice, such individual reports should
not precede the primary manuscript and should always reference the primary manuscript of the trial.
Investigator access to data and review of results
As owner of the trial database, Novo Nordisk has the discretion to determine who will have access 
to the database.
Individual investigators will have their own research subjects' data and will be provided with the 
randomisation code after results are available.
8) Dissemination of clinical trial data
Information of the trial will be disclosed at clinicaltrials.gov and novonordisk-trials.com. It will also 
be disclosed according to other applicable requirements such as those of the International 
Committee of Medical Journal Editors (ICMJE)23, the Food and Drug Administration Amendments
Act (FDAAA)24, European Commission Requirements1, 25 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.
The Primary Completion Date (PCD) is the last assessment of the primary endpoint and is for this 
trial Last Subject First Treatment (LSFT) + 40 weeks corresponding to V10 (end of treatment visit). 
If the last subject is withdrawn early, the PCD is considered the date when the last subject would 
have completed V10. The PCD determines the deadline for results disclosure at clinicaltrials.gov 
according to FDAAA.
9) Data quality assurance
Case Report Forms (CRFs)
x
Novo Nordisk or designee is responsible for the data management of this trial including quality 
checking of the data.
x
All subject data relating to the trial will be recorded on electronic CRFs unless transmitted 
electronically to Novo Nordisk or designee (e.g. laboratory data). The investigator is responsible 
for verifying that data entries are accurate and correct by physically or electronically signing the 
CRF.
The following will be provided as paper CRFs:
x
Pregnancy forms
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The following will be provided as paper CRFs to be used when access to the CRF is revoked or the 
CRF is temporarily unavailable:
x
AE forms 
x
Safety information forms 
x
Technical complaint forms (also to be used to report complaints that are not subject related, 
e.g. discovered at trial site before allocation)
x
Corrections to the CRF data may be made by the investigator or the investigator’s delegated 
staff. An audit trail will be maintained in the CRF application containing as a minimum: the old 
and the new data, identification of the person entering the data, date and time of the entry and 
reason for the correction. If corrections are made by the investigator’s delegated staff after the 
date when the investigator signed the CRF, the CRF must be signed and dated again by the 
investigator.
x
The investigator must ensure that data is recorded in the CRF as soon as possible, preferably 
within 5 working days after the visit. Once data has been entered, it will be available to Novo 
Nordisk for data verification and validation purposes.
Monitoring
x
The investigator must permit trial-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data 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).
x
Trial monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorised site personnel are accurate, complete and verifiable from source 
documents; that the safety and rights of subjects are being protected, to monitor drug 
accountability and collect completed paper CRF pages, if applicable, and that the trial is being 
conducted in accordance with the currently approved protocol and any other trial agreements, 
ICH GCP, and all applicable regulatory requirements.
x
Monitoring will be conducted using a risk-based approach including risk assessment, 
monitoring plans, centralised monitoring (remote assessment of data by Novo Nordisk) and 
visits to trial sites.
x
Monitors will review the subject’s medical records and other source data to ensure consistency 
and/or identify omissions compared to the CRF.
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Protocol compliance
Deviations from the protocol should be avoided. If deviations do occur, the investigator must 
inform the monitor and the implications of the deviation must be reviewed and discussed.
Deviations must be documented and explained in a protocol deviation by stating the reason, date, 
and the action(s) taken. Some deviations, for which corrections are not possible, can be 
acknowledged and confirmed via edit checks in the CRF or via listings from the trial database.
10) Source documents
x
All data entered in the CRF must be verifiable in source documentation other than the CRF.
x
If source data is entered directly in a paper CRF, each data entry or clear series of data entries 
must be signed and dated separately by the trial staff making the entry.
x
The original of the completed diaries must not be removed from the trial site, unless they form 
part of the CRF and a copy is kept at the site.
x
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the trial site.
x
Data reported on the paper CRF or entered in the electronic CRF that are transcribed from 
source documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer records. 
Also, current medical records must be available.
x
It must be possible to verify subject’s medical history in source documents such as subject’s 
medical record.
x
The investigator must document any attempt to obtain external medical information by noting 
the date(s) when information was requested and who was contacted.
x
Definition of what constitutes source data can be found in a source document agreement at each 
trial site. There will only be one source document defined at any time for any data element.
11) Retention of clinical trial documentation
x
Records and documents, including signed informed consent forms, pertaining to the conduct of 
this trial must be retained by the investigator for 15 years after end of trial unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of Novo Nordisk. No records
may be transferred to another location or party without written notification to Novo Nordisk.
x
The investigator must be able to access his/her trial documents without involving Novo Nordisk 
in any way. If applicable, electronic CRF and other subject data will be provided in an 
electronic readable format to the investigator before access is revoked to the systems and/or 
electronic devices supplied by Novo Nordisk. Site-specific CRFs and other subject data (in an 
electronic readable format or as paper copies or prints) must be retained by the trial site. If the 
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provided electronic 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.
x
Subject’s medical records must be kept for the maximum period permitted by the hospital, 
institution or private practice
12) Trial and site closure
Novo Nordisk reserves the right to close the trial site or terminate the trial at any time for any 
reason at the sole discretion of Novo Nordisk. If the trial is suspended or 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.
Trial sites will be closed upon trial completion. A trial site is considered closed when all required 
documents and trial supplies have been collected and a trial site closure visit has been performed.
The investigator may initiate trial site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a trial site by Novo Nordisk or investigator may include but are not 
limited to:
x
failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or local 
health authorities, Novo Nordisk procedures or GCP guidelines
x
inadequate recruitment of subjects by the investigator
x
discontinuation of further trial product development.
13) 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 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 
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code list must be kept in a secure locked facility so that no unauthorised 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).
14) 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.
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Appendix 4 Adverse events: definitions and procedures for 
recording, evaluation, follow-up, and reporting
AE definition
x An AE is any untoward medical occurrence in a clinical trial subject that is temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product.
x An AE can be any unfavourable and unintended sign, including an abnormal laboratory finding, symptom or 
disease (new or exacerbated) temporally associated with the use of a medicinal product.
Events meeting the AE definition
x Any abnormal laboratory test results or safety assessments, including those that worsen from baseline, considered 
clinically significant in the medical and scientific judgment of the investigator.
x A clinical abnormal laboratory finding 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.
x Abuse: Persistent or sporadic, intentional excessive use of a medicinal product, which is accompanied by harmful 
physical or psychological effects (e.g. overdose with the intention to cause harm)
x Misuse: Situations where the medicinal product is intentionally and inappropriately used not in accordance with 
the protocol or the terms of the marketing authorisation.
x Exacerbation of a chronic or intermittent pre-existing condition including either an increase in frequency and/or 
intensity of the condition.
x Signs, symptoms or the clinical sequelae of a suspected drug-drug interaction.
x Signs, symptoms or the clinical sequelae of a suspected overdose of trial product regardless of intent.
x • A “lack of efficacy” or “failure of expected pharmacological action” per se will not be reported as an AE or 
SAE. Such instances will be captured in the efficacy assessments. However, the signs, symptoms and/or clinical 
sequelae resulting from lack of efficacy will be reported as AE or SAE if they fulfil the definition. 
Events NOT meeting the AE definition 
x Pre-existing conditions, anticipated day-to-day fluctuations of pre-existing conditions, including those identified 
during screening or other trial procedures performed before exposure to trial product. 
Note: pre-existing conditions should be recorded as medical history/concomitant illness.
x 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.
Definition of an SAE
An SAE is an AE that fulfils at least one of the following criteria:
x Results in death
x Is life-threatening
The term 'life-threatening' in the definition of 'serious' 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 were more 
severe.
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x Requires inpatient hospitalisation or prolongation of existing hospitalisation
x Hospitalisation signifies that the subject has been detained at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or outpatient setting. 
Complications that occur during hospitalisation are AEs. If a complication prolongs hospitalisation or fulfils 
any other serious criteria, the event is serious. When in doubt as to whether “hospitalisation” occurred or was 
necessary, the AE should be considered serious.
x Hospitalisation for elective treatment of a pre-existing condition that did not worsen from baseline is not 
considered an AE.
Note:

Hospitalisations for administrative, trial related and social purposes do not constitute AEs and should 
therefore not be reported as AEs or SAEs.

Hospital admissions for surgical procedures, planned before trial inclusion, are not considered AEs or SAEs.
x Results in persistent or significant disability/incapacity
x The term disability means a substantial disruption of a person’s ability to conduct normal life functions.
x This definition is not intended to include experience of relatively minor medical significance such as 
uncomplicated headache, nausea, vomiting, diarrhoea, influenza, and accidental trauma (e.g. sprained ankle), 
which may interfere with or prevent everyday life functions but do not constitute a substantial disruption.
x Is a congenital anomaly/birth defect
x Important medical event:
x Medical or scientific judgment should be exercised in deciding whether SAE reporting is appropriate in other 
situations. This includes important medical events that may not be immediately life-threatening or result in 
death or hospitalisation but may jeopardise the subject or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These events should usually be considered 
serious and reported as SAEs using the important medical event criterion.
x The following adverse events must always be reported as SAEs 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 alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 x 
UNL and total bilirubin >2 x UNL, where no alternative aetiology exists (Hy's law).
Description of AEs requiring additional data collection (via specific event form)
AEs 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 (Table 9-1). The selection of these events is based on the non-clinical and clinical data with 
semaglutide, knowledge from the GLP-1 RA drug class as well as regulatory requirements.
Event type
Description
Medication error: 
A medication error is an unintended failure in the trial drug treatment 
process that leads to, or has the potential to lead to, harm to the subject 
such as:
x
Administration of wrong drug or use of wrong device.
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Note: Use of wrong dispensing unit number (DUN) is not 
considered a medication error unless it results in an 
administration of wrong drug. 
x
Wrong route of administration, such as intramuscular instead of 
subcutaneous. 
x
Accidental administration of higher dose than intended during 
dose escalation or maintenance. However, the administered dose 
must deviate from the intended dose to an extent where clinical 
consequences for the trial subject were likely to happen as judged 
by the investigator, although they did not necessarily occur.
Acute pancreatitis
The diagnosis of acute pancreatitis requires two of the following three 
features:
(1) abdominal pain consistent with acute pancreatitis (acute onset of a 
persistent, severe, epigastric pain often radiating to the back)
(2) serum lipase activity (and/or amylase activity) at least three times 
greater than the upper limit of normal
(3) characteristic findings of acute pancreatitis on imaging
Acute gallbladder disease
Events of symptomatic acute gallbladder disease (including gallstones and 
cholecystitis)
Malignant neoplasm
Confirmed malignant neoplasm by histopathology or other substantial 
clinical evidence
Hepatic event
Hepatic event defined as:
– Disorders of the liver including cholestatic conditions and liver related 
signs and symptoms
– ALT or AST > 3x UNL and total bilirubin > 2x UNL*
– ALT or AST > 3x UNL with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, and/or 
eosinophilia (>5%)
*Please note that in case of a hepatic event defined as ALT or AST > 3x 
UNL and total bilirubin > 2x UNL, where no alternative aetiology exists 
(Hy's law), this must be reported as an SAE using the important medical 
event criterion if no other seriousness criteria are applicable.
Acute renal failure
Events of an abrupt or rapid decline in renal filtration function. This 
condition is usually marked by a rise in serum creatinine concentration or 
by azotemia (a rise in blood urea nitrogen [BUN] concentration)
Diabetic retinopathy
New onset or worsening of diabetic retinopathy
AE and SAE recording
x The investigator will record all relevant AE/SAE information in the CRF.
x The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or other clinical 
information. In such cases, the diagnosis (not the individual signs/symptoms) will be documented as the AE/SAE.
x When an AE/SAE occurs, it is the responsibility of the investigator to review all documentation (e.g. hospital 
progress notes, laboratory and diagnostics reports) related to the event.
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x There may be instances when copies of source documents (e.g. medical records) for certain cases are requested by 
Novo Nordisk. In such cases, all subject identifiers, with the exception of the subject number, will be redacted on 
the copies of the source documents before submission to Novo Nordisk.
x 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. For sign-off of SAE related forms refer to “SAE reporting via paper CRF” later in this section.
x 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.
Assessment of severity
The investigator will assess intensity for each event reported during the trial and assign it to one of the following 
categories: 
x Mild: An event that is easily tolerated by the subject, causing minimal discomfort and not interfering with 
everyday activities.
x Moderate: An event that causes sufficient discomfort and interferes with normal everyday activities.
x Severe: An event that prevents normal everyday activities. 
Note: Severe is a category used for rating the intensity of an event; and both an AE and SAE can be assessed as 
severe. An event is defined as ‘serious’ when it meets at least one of the outcomes described in the definition of an 
SAE and not when it is rated as severe.
Assessment of causality
The investigator is obligated to assess the relationship between trial product and the occurrence of each AE/SAE.
Relationship between an AE/SAE and the relevant trial product(s) should be assessed as: 
x Probable - Good reason and sufficient documentation to assume a causal relationship.
x Possible - A causal relationship is conceivable and cannot be dismissed.
x Unlikely - The event is most likely related to aetiology other than the trial product.
Alternative aetiology, such as underlying disease(s), concomitant medication, and other risk factors, as well as the 
temporal relationship of the event to trial product administration will be considered and investigated.
The investigator should use the investigator’s brochure for the assessment. For each AE/SAE, the investigator must 
document in the medical records that he/she has reviewed the AE/SAE and has provided an assessment of causality.
There may be situations in which an SAE has occurred, and the investigator has minimal information to include in 
the initial report. However, it is important that the investigator always makes an assessment of causality for 
every event before the initial transmission of the SAE data.
The investigator may change his/her opinion of causality in light of follow-up information and send a follow-up 
report with the updated causality assessment.
The causality assessment is one of the criteria used when determining regulatory reporting requirements.
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Final outcome
The investigator will select the most appropriate outcome:
x 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.
x 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.
x 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.
x Not recovered/not resolved: The condition of the subject has not improved, and the symptoms are unchanged, or 
the outcome is not known.
x 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 a fatal 
outcome must be reported as an SAE.
x Unknown: This term is only applicable if the subject is lost to follow-up.
Follow-up of AE and SAE
The investigator is obligated to perform or arrange for the conduct of supplemental measurements and/or evaluations 
as medically indicated or as requested by Novo Nordisk to elucidate the nature and/or causality of the AE or SAE as 
fully as possible (e.g. severe hypersensitivity reactions). This may include additional laboratory tests (e.g. skin prick 
test) or investigations, histopathological examinations, or consultation with other health care professionals.
If a subject dies during participation in the trial or during a recognised follow-up period, the investigator should 
provide Novo Nordisk with a copy of autopsy report including histopathology.
New or updated information will be recorded in the CRF.
SAE reporting via electronic CRF
x Relevant forms (AE and safety information form) must be completed in the CRF. 
x For reporting and sign-off timelines, see box below. 
x If the CRF is unavailable for more than 24 hours, then the site will use the paper AE form and if the CRF is 
unavailable for more than 5 calendar days then the site will use the paper safety information form (see box below).
x The site will enter the SAE data into the CRF as soon as it becomes available, see 9.2.1.
x After the trial is completed at a given site, the CRF will be decommissioned to prevent
the entry of new data or changes to existing data. If a site receives a report of a new
SAE from a subject or receives updated data on a previously reported SAE after CRF
decommission, then the site can report this information on a paper AE and safety
information form (see box below) or to Novo Nordisk by telephone.
SAE reporting via paper CRF
x Relevant CRF forms (AE and safety information form) must be forwarded to Novo Nordisk either by fax, e-mail 
(in an encrypted manner) or courier.
x Initial notification via telephone is acceptable, although it does not replace the need for the investigator to 
complete the AE and safety information forms within the designated reporting time frames (as illustrated in 
Figure 9-1):
x AE form within 24 hours.
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x Safety information form within 5 calendar days. 
x Both forms must be signed within 7 calendar days.
Contact details for SAE reporting can be found in the investigator trial master file.
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Appendix 5
Contraceptive guidance and collection of pregnancy 
information
It must be recorded in the CRF whether female subjects are of childbearing potential. 
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile. 
Women in the following categories are not considered WOCBP
22. Premenarcheal 
23. Premenopausal female with one of the following:
x
Documented hysterectomy
x
Documented bilateral salpingectomy
x
Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s review of subject’s medical records, 
medical examination or medical history interview.
24. Postmenopausal female
x
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high Follicle Stimulating Hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or Hormonal Replacement Therapy (HRT). However, in the absence of 12 
months of amenorrhea, a single Follicle-Stimulating Hormone (FSH measurement is 
insufficient. 
x
Females on HRT and whose menopausal status is in doubt will be required to use one of the 
non-hormonal highly effective contraception methods if they wish to continue their HRT 
during the trial. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before trial enrolment.
Contraception guidance
Male subjects 
No contraception measures are required for male subjects as the risk of teratogenicity/fetotoxicity 
caused by transfer of semaglutide in seminal fluid is unlikely. 
Female subjects
Female subjects of childbearing potential are eligible to participate if they agree to use methods of 
contraception consistently and correctly as described in table(s) below:
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Table 12-3
Highly effective contraceptive methods
Highly effective contraceptive methods that are user dependent a and b
Failure rate of <1% per year when used consistently and correctly.
Combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation 
x oral 
x intravaginal 
x transdermal 
Progestogen only hormonal contraception associated with inhibition of ovulation
x oral 
x injectable 
Highly effective methods that are user independent b
Implantable progestogen only hormonal contraception associated with inhibition of ovulation 
x Intrauterine Device (IUD)
x Intrauterine hormone-releasing System (IUS)
x Bilateral tubal occlusion
Vasectomised partner 
A vasectomised partner is a highly effective contraception method provided that the partner is the sole male sexual 
partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used.
Sexual abstinenceb
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse 
during the entire period of risk associated with the trial product. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the trial and the preferred and usual lifestyle of the subject.
Notes: 
aTypical use failure rates may differ from those when used consistently and correctly. Use should be consistent with 
local regulations regarding the use of contraceptive methods for subjects participating in clinical trials. 
bContraception should be utilised during the treatment period and for at least 7 weeks after the last dose of trial product.
In certain cases, it is accepted to use double barrier methods (a condom combined with an occlusive 
cap (e.g. diaphragm) with/without the use of spermicide). This should only be allowed in females 
with:
1) known intolerance to the highly effective methods mentioned in Table 12-3 or where the use 
of any of the listed highly effective contraceptive measures are contraindicated in the 
individual subject, and/or
2) if the risk of initiating treatment with a specific highly effective method outweighs the 
benefit for the female.
Justification for accepting double barrier method should be at the discretion of the investigator 
taking into consideration his/her knowledge about the female’s medical history, concomitant illness, 
concomitant medication and observed AEs. The justification must be stated in the medical records.
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Pregnancy testing
x
WOCBP should only be included after a negative highly sensitive urine pregnancy test.
x
Additional urine pregnancy testing should be performed at every site visit (every 4-8 weeks)
during the treatment period, at the end of treatment and after the 7 weeks follow-up period after 
the end of treatment, according to the flow chart.
x
Pregnancy testing should be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected.
x
All subjects will be provided with a pregnancy test prior to the phone visits to perform them 
prior to the phone call, not only if pregnancy is suspected. 
Collection of pregnancy information 
Female subjects who become pregnant 
x
Investigator will collect pregnancy information on any female subject, who becomes pregnant 
while participating in this trial.
x
Information will be recorded on the appropriate form and submitted to Novo Nordisk within 14 
calendar days of learning of a subject's pregnancy.
x
Subject will be followed to determine the outcome of the pregnancy. The investigator will 
collect follow-up information on subject and neonate, which will be forwarded to Novo 
Nordisk. Generally, follow-up will not be required for longer than 1 month beyond the delivery 
date.
x
Any termination of pregnancy will be reported, regardless of foetal status (presence or absence 
of anomalies) or indication for procedure.
x
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy will be reported as an AE or SAE. 
x
A spontaneous abortion is always considered to be an SAE and will be reported as such.
x
Any SAE occurring as a result of a post-trial pregnancy which is considered possibly/probably 
related to the trial product by the investigator will be reported to Novo Nordisk as described in 
Appendix 4. While the investigator is not obligated to actively seek this information in former 
subjects, he or she may learn of an SAE through spontaneous reporting.
Any female subject who becomes pregnant while participating in the trial will discontinue trial 
product.
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Appendix 6 Technical complaints: Definition and procedures for 
recording, evaluation, follow-up and reporting
Technical complaint definition
x 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:
x
Problems with the physical or chemical appearance of trial products (e.g. discoloration, particles
or contamination).
x
Problems with packaging material including labelling.
x
Problems related to medical devices (e.g. to the injection mechanism, dose setting mechanism,
push button or interface between the pen-injector and the needle).
Time period for detecting technical complaints 
All technical complaints, which occur from the time of receipt of the product at trial site until the time of the last 
usage of the product, must be collected for products predefined on the technical complaint form. 
Reporting of technical complaints to Novo Nordisk
Contact details (fax, e-mail and address) for Customer Complaint Center – refer to Attachment I
Technical complaints must be reported on a separate technical complaint form:
1.
One technical complaint form must be completed for each affected DUN
2.
If DUN is not available, a technical complaint form for each batch, code or lot number must be completed
Timelines for reporting of technical complaints to Novo Nordisk
The investigator must complete the technical complaint form in the CRF within the timelines specified in 9.2.9
If the CRF 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 CRF becomes available again, the investigator must enter the information on the 
technical complaint form in the CRF.
Follow-up of technical complaints 
The investigator is responsible for ensuring that new or updated information will be recorded on the originally 
completed form.
Collection, storage and shipment of technical complaint samples
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The investigator must collect the technical complaint sample and all associated parts that were packed in the same 
DUN and notify the monitor within 5 calendar days of obtaining the sample at trial site. The sample and all 
associated parts must be sent as soon as possible to Customer Complaint Center, Novo Nordisk, together with a copy 
of the completed technical complaint form. The technical complaint sample should contain the batch, code or lot 
number and, if available, the DUN. If the technical complaint sample is unobtainable, the reason must be stated on 
the technical complaint form. If several samples are shipped in one shipment, the sample and the corresponding 
technical complaint form should be kept together.
Storage of the technical complaint sample must be done in accordance with the conditions prescribed for the product.
Reporting of technical complaints for Novo Nordisk products not included in technical complaint form
Technical complaints on Novo Nordisk products not included in the technical complaint form should be reported to 
local Novo Nordisk affiliate with a reference to trial ID.
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Appendix 7
Hypoglycaemic episodes
Novo Nordisk classification of hypoglycaemia
In normal physiology, symptoms of hypoglycaemia occur below a PG level of 3.1 mmol/L (56 
mg/dL)26. Therefore, Novo Nordisk has included hypoglycaemia with PG levels below this cut-off 
point in the definition of BG confirmed hypoglycaemia.
Novo Nordisk uses the following classification (Figure 12-1) in addition to the ADA 
classification27:
25. Severe hypoglycaemia according to the ADA classification27.
26. Symptomatic BG confirmed hypoglycaemia: An episode that is BG confirmed by PG value 
<3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia.
27. Asymptomatic BG confirmed hypoglycaemia: An episode that is BG confirmed by PG value 
<3.1 mmol/L (56 mg/dL) without symptoms consistent with hypoglycaemia.
28. BG confirmed hypoglycaemia: The union of 2. and 3.
29. Severe or BG confirmed symptomatic hypoglycaemia: The union of 1. and 2.
30. Severe or BG confirmed hypoglycaemia: The union of 1., 2. and 3.
For hypoglycaemic episodes reported with missing information related to the classification, the 
following applies when classifying the episode according to the Novo Nordisk classification:
x
A hypoglycaemic episode with missing information on symptoms will be classified as without 
symptoms. 
x
A hypoglycaemic episode with missing information on being able to self-treat will be regarded 
as an episode where the subject was able to self-treat and classified in accordance with the able 
to self-treat classifications.
Episodes that cannot be classified according to the above, are included in one of the following 
categories:
x
‘Novo Nordisk unclassifiable’ includes episodes where subjects were able to self-treat and with 
PG≥3.1 mmol/L (56 mg/dL) and hypoglycaemic episodes for a subject able to self-treat with 
missing PG as it is to be treated as an episode with PG>3.9 mmol/L (70 mg/dL).
x
‘Not able to self-treat – unclassifiable’ includes episodes where the subjects were not able to 
self-treat but neither of the following conditions were reported: PG≤3.9 mmol/L (70 mg/dL), 
alleviation of symptoms, seizure, unconscious/comatose or fatal.
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Hypoglycaemic
episode
PG ≤ 3.9 mmol/L 
(70 mg/dL) 
or 
Alleviation of 
symptoms 
or
Seizure, 
unconscious/
comatose or fatal 
SMPG
measurement
PG < 3.1 mmol/L
(56 mg/dL)
with symptoms
PG < 3.1 mmol/L
(56 mg/dL)
without 
symptoms
2. Symptomatic 
BG confirmed 
hypoglycaemia
3. Asymptomatic 
BG confirmed 
hypoglycaemia
Yes
No
5. Severe or 
BG confirmed 
symptomatic 
hypoglycaemia
4. BG confirmed 
hypoglycaemia
6. Severe or 
BG confirmed 
hypoglycaemia
Note: Glucose measurements are performed with capillary blood calibrated to plasma equivalent glucose values
BG: blood glucose  PG: plasma glucose  SMPG: Self-measured plasma glucose  
Subject 
able to 
treat him/
herself
1.Severe 
hypoglycaemia 
(ADA 2013)
Figure 12-1
Novo Nordisk classification of hypoglycaemia
ADA classification27 of hypoglycaemia
x
Severe hypoglycaemia: An episode requiring assistance of another person to actively administer 
carbohydrate, glucagon or take other corrective actions. PG concentrations may not be available 
during an event, but neurological recovery following the return of PG to normal is considered 
sufficient evidence that the event was induced by a low PG concentration.
x
Asymptomatic hypoglycaemia: An episode not accompanied by typical symptoms of 
hypoglycaemia, but with a measured PG concentration ≤3.9 mmol/L (70 mg/dL).
x
Documented symptomatic hypoglycaemia: An episode during which typical symptoms of 
hypoglycaemia are accompanied by a measured PG concentration ≤ 3.9 mmol/L (70 mg/dL).
x
Pseudo-hypoglycaemia: An episode during which the person with diabetes reports any of the
typical symptoms of hypoglycaemia with a measured PG concentration > 3.9 mmol/L 
(70 mg/dL) but approaching that level.
x
Probable symptomatic hypoglycaemia: An episode during which symptoms of hypoglycaemia 
are not accompanied by a PG determination but that was presumably caused by a PG 
concentration ≤ 3.9 mmol/L (70 mg/dL).
For hypoglycaemic episodes reported with missing information related to the classification, the 
following applies when classifying the episode according to the ADA classification:
x
A hypoglycaemic episode with missing information on symptoms will be classified as without 
symptoms.
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x
A hypoglycaemic episode with missing information on being able to self-treat will be regarded 
as an episode where the subject was able to self-treat and classified in accordance with the able 
to self-treat classifications
Episodes that cannot be classified according to the above, are included in one of the following 
categories
x
‘ADA unclassifiable’ includes episodes where subjects were able to self-treat and with PG>3.9 
mmol/L (70 mg/dL) or missing PG, and with no information on symptoms.
x
‘Not able to self-treat – unclassifiable’ includes episodes where the subjects were not able to 
self-treat but neither of the following conditions were reported: PG≤3.9 mmol/L (70 mg/dL), 
alleviation of symptoms, seizure, unconscious/comatose or fatal.
Hypoglycaemic 
episode 
PG ≤ 3.9 mmol/L 
(70 mg/dL) 
or 
Alleviation of 
symptoms 
or
Seizure, 
unconscious/
comatose or fatal 
SMPG
measurement
Asymptomatic 
hypoglycaemia
Documented 
symptomatic 
hypoglycaemia
Pseudo- 
hypoglycaemia
Probable 
symptomatic 
hypoglycaemia
No
Yes
No measurement 
with symptoms
PG > 3.9 mmol/L 
(70 mg/dL)
with symptoms
PG ≤ 3.9 mmol/L 
(70 mg/dL)
with symptoms
PG ≤ 3.9 mmol/L 
(70 mg/dL)
without symptoms
No
Yes
Note: Glucose measurements are performed with capillary blood calibrated to plasma equivalent glucose values
PG: plasma glucose  SMPG: Self-measured plasma glucose  
Subject 
able to 
treat him/
herself
Severe 
hypoglycaemia 
(ADA 2013)
Figure 12-2
ADA classification of hypoglycaemia
Treatment-emergent: hypoglycaemic episodes will be defined as treatment-emergent, if the onset of 
the episode occurs in the on-treatment period (see definition in Section 10.2).
Nocturnal hypoglycaemic episodes: episodes occurring between 00:01 and 05:59 both inclusive.
Hypoglycaemic episodes are classified according to the Novo Nordisk classification of 
hypoglycaemia and the ADA classification of hypoglycaemia.27
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Reporting of hypoglycaemic episodes:
PG should always be measured and recorded when a hypoglycaemic episode is suspected. 
All PG values:
≤3.9 mmol/L (70 mg/dL) or 
>3.9 mmol/L (70 mg/dL) occurring in conjunction with hypoglycaemic symptoms should be 
reported as a hypoglycaemic episode according to the flowchart and instructions below. When 
subject experiences a hypoglycaemic episode, subject should record the general information in 
relation to the hypoglycaemia (timing, PG measurements, symptoms etc. as described in the diary).
In case a subject is not able to fill in the diary (e.g. in case of hospitalisation or at the ‘follow-up
phone contact’), then investigator should report the hypoglycaemic episode in the CRF.
Upon onset of a hypoglycaemic episode the subject is recommended to measure PG every 15 
minutes until the self-measured plasma glucose (SMPG) value is >3.9 mmol/L (70 mg/dL) and/or 
symptoms have been resolved in accordance with current guidelines27.
Repeated SMPG measurements and/or symptoms will by default be considered as one 
hypoglycaemic episode until a succeeding SMPG value is >3.9 mmol/L (70 mg/dL) and/or 
symptoms have been resolved. One hypoglycaemic episode form is to cover these measurements 
and/or symptoms. 
In case of several low SMPG values within the hypoglycaemic episode, the lowest value is the one 
that will be reported as the SMPG value for the hypoglycaemic episode, but the start time of the 
episode will remain as the time for the first low SMPG value and/or symptom.
The lowest value measured during the hypoglycaemic episode will be reported as the PG value for 
the episode. The remaining values will be kept as source data in the diary.
A hypoglycaemic episode starting without symptoms should be updated to symptomatic if the 
subject experiences symptoms later during the episode.
If the severity of a hypoglycaemic episode worsens, only one hypoglycaemic episode should be 
reported, reflecting the most severe degree of hypoglycaemia.
Investigator must instruct subjects that the answer to the question: "Was the subject able to treat 
him/herself?" must be answered "No" for an episode requiring assistance of another person to 
actively administer carbohydrate, glucagon, or take other corrective actions. PG concentrations may 
not be available during an event, but neurological recovery following the return of PG to normal is 
considered sufficient evidence that the event was induced by a low PG concentration27.
Additional information (e.g. description of symptoms, alleviation of symptoms, seizure, coma, 
fatal) in relation to these severe hypoglycaemic episodes must be recorded.
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Oral carbohydrates must not be given if the subject is unconscious. 
For low SMPG values for hypoglycaemic episodes where the subject was able to self-treat: If a 
hypoglycaemic episode form is not completed within 7 calendar days of the SMPG measurement, 
the episode 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 data28, 29
The subject must be re-trained in how to report hypoglycaemic episodes if the investigator identifies 
low SMPG values not reported as hypoglycaemic episodes.
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Appendix 8
NN9535-4191 Clinical Trial Report Synopsis
CTR synopsis
NAME OF SPONSOR
Novo Nordisk A/S, Novo Allé, DK-2880 Bagsvaerd, Denmark
NAME OF ACTIVE SUBSTANCE
Semaglutide 
Trial registration ID-number
NCT02461589
UTN – U1111-1159-4923
IND number – 79,754
EudraCT number – 2014-003196-39
TITLE OF TRIAL
Dose-finding of semaglutide administered subcutaneously once daily versus placebo and liraglutide in subjects with 
type 2 diabetes
INVESTIGATORS
One principal investigator was appointed at each of the 139 trial sites in the trial. The following were designated 
signatory investigators for the trial, and were responsible for reviewing and approving the clinical trial report:
x
x
TRIAL SITES
The trial was conducted at 139 sites in 10 countries as follows:
Austria: 3 sites; Canada: 8 sites; Czech Republic 9 sites; Germany: 7 sites; Malaysia: 5 sites; Russian Federation: 7 
sites; Serbia: 9 sites; South Africa: 7 sites; United Kingdom: 13 sites; United States: 71 sites.
PUBLICATIONS
No publications were available at the time of this clinical trial report synopsis.
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TRIAL PERIOD
Initiation date: 21 September 2015
Completion date: 13 October 2016
DEVELOPMENT PHASE
Phase 2
DATA CUT-OFF DATE
The results presented reflect the data available in the clinical database as of 07 December 2016 
DATE OF THE REPORT
16 May 2017
OBJECTIVES
Primary objective:
x To compare the efficacy of 4 dose-levels of semaglutide administered subcutaneously (s.c.) once daily (OD) 
versus placebo on glycaemic control after 26 weeks of treatment.
Secondary objectives:
x To compare the efficacy of semaglutide administered s.c. OD versus liraglutide on glycaemic control after 26 
weeks of treatment.
x To compare semaglutide administered s.c. OD versus placebo and liraglutide on other parameters of efficacy, 
patient reported outcomes, safety and tolerability after 26 weeks of treatment.
METHODOLOGY
This was a 26-week multicentre, randomised, 13-arm, dose-finding trial investigating the efficacy and safety of 
semaglutide administered s.c. OD versus placebo and liraglutide in subjects diagnosed with type 2 diabetes (T2D) 
treated with diet and exercise with or without metformin. Subjects randomised to the 12-arm groups (double-blinded 
within dose level) followed a fixed-dosing regimen and a flexible dose-escalation regimen based on tolerability was 
explored for semaglutide in an open-label setting for subjects in the 13th treatment arm. For all treatment arms, 
semaglutide, liraglutide, or placebo was added on to their previous, stable therapy consisting of diet and exercise with 
or without metformin. 
The trial consisted of a 2-week screening period, up to 16 weeks of a dose-escalation period in the fixed-dose arms 
followed by a minimum of 10 weeks of maintenance therapy, and a 7-week follow-up period. The total trial duration 
for individual subjects participating in the trial was 35 weeks. For the fixed-dose groups, the dose was not to be 
changed in the remaining treatment period after the maintenance dose was reached. For the open-label semaglutide 
treatment arm, a flexible dose-escalation regimen based on gastrointestinal (GI) tolerability was followed.
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After the screening visit, eligible subjects were randomised in a 2:2:1 manner to either the semaglutide, liraglutide, or 
placebo arm in one out of four volume-matched dose levels (50 μL, 100 μL, 200 μL, and 300 μL). Subjects were to 
initiate treatment with either 0.05 mg of semaglutide (50 μL), 0.30 mg of liraglutide (50 μL), or 50 μL of placebo. 
Subjects in the lowest dose-volume (50 μL) did not follow a dose-esclation regimen.The doses in the fixed-dose 
groups were escalated from an initial dose of 0.05 mg and maintained for 4 weeks prior to escalating to the next dose, 
and continued up to 12 weeks. The highest dose for any trial subject would be 0.30 mg semaglutide administered OD 
(300 μL), or 1.80 mg liraglutide administered OD (300 μL). All subjects used NovoPen® 4 durable device for trial 
product administration. Metformin was considered a non-investigational medicinal product and was not supplied by 
Novo Nordisk.
Similar to the fixed dose-escalation arms, subjects in the open-label arm would start treatment at 0.05 mg 
semaglutide OD (50 μL) and 4-week dose-escalation steps would be used by default. However, based on the 
investigator’s assessment, the dose level would be temporarily reduced in subjects with poor GI tolerability. Subjects 
experiencing moderate/severe nausea or vomiting for at least 3 days in the week preceding the planned visit/phone 
contact would be required to reduce the dose to the previous dose level. Dose reductions were to be only decided at 
planned visits/phone contacts. Subjects who experienced moderate/severe nausea or vomiting already at the lowest 
dose level were required to stay at least 4 additional weeks at the lowest dose from the decision point before 
reconsidering dose-escalation. An additional, mandatory safety visit was only applicable for subjects in the flexible 
dose-escalation arm who had been dose-escalated at week 20. No dose-escalations were allowed after week 22.
If necessary, for safety reasons suspected to be due to trial product, unacceptable intolerability or at request of 
subject, the trial product could be discontinued (without withdrawing the subject from the trial) at the investigator’s 
discretion. For premature treatment discontinuations, treatment was not to be re-initiated, except in cases where 
suspicion of acute pancreatitis was ruled out. Subjects discontinuing trial product prematurely were to be called in for 
an ‘end of treatment - premature discontinuation visit’ as soon as possible and for a ‘follow-up - premature 
discontinuation visit’ 7 weeks after last dose of trial product. Furthermore, subjects with unacceptable 
hyperglycaemia were to be offered rescue medication and trial product was to be prematurely discontinued.
An external data monitoring committee (DMC) was not constituted for this trial. An independent external event 
adjudication committee (EAC) was constituted to perform ongoing adjudication, standardisation, and assessment of 
selected events. The purpose of the adjudication was to consistently confirm events by independent external medical 
experts according to standardised criteria.
NUMBER OF SUBJECTS PLANNED AND ANALYSED
A total of 1280 subjects were planned for screening and 704 planned for randomisation. In total, 1096 and 706 
subjects were actually screened and randomised, respectively.
Sema
0.05 
mg
N (%)
Sema
0.10 
mg
N (%)
Sema
0.20 
mg
N (%)
Sema
0.30 
mg
N (%)
Lira
0.30 
mg
N (%)
Lira
0.60 
mg
N (%)
Lira
1.20 
mg
N (%)
Lira
1.80 
mg
N (%)
Placebo
N (%)
Sema
flex
N (%)
Total
N (%)
Screened
1096
Randomised
64
63
65
63
64
64
64
65
129
65
706
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Version:
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Exposed
FAS/SAS 
64 
(100.0)
63 
(100.0)
65
(100.0)
63 
(100.0)
64 
(100.0)
64 
(100.0)
64 
(100.0)
65 
(100.0)
129 
(100.0)
64 
(98.5)
705 
(99.9)
Treatment 
completers
53 
(82.8)
56 
( 88.9)
52 
(80.0)
53 
(84.1)
52 
(81.3)
56 
(87.5)
51 
(79.7)
56 
(86.2)
95 
(73.6)
58 
(90.6)
582 
(82.6)
Premature 
treatment 
discontinuation
11 
(17.2)
7
(11.1)
13 
(20.0)
10 
(15.9)
12 
(18.8)
8
(12.5)
13 
(20.3)
9
(13.8)
34 
(26.4)
6
(9.4)
123 
(17.4)
Trial completers 
58 
(90.6)
61 
(96.8)
60 
(92.3)
58 
(92.1)
62 
(96.9)
61 
(95.3)
58 
(90.6)
60 
(92.3)
123 
(95.3)
60 
(93.8)
661 
(93.8)
Premature 
withdrawal at or 
after premature 
treatment 
discontinuation 
6
(9.4)
2
(3.2)
4
(6.2)
5
(7.9)
2
(3.1)
2
(3.1)
6
(9.4)
5
(7.7)
5
(3.9)
2
(3.1)
39 
(5.5)
Premature 
withdrawal after 
treatment 
completion 
1
(1.5)
1
(1.6)
1
(0.8)
2
(3.1)
5
(0.7)
Abbreviations: N: Number of subjects, %: Percentages of subjects, FAS: Full Analysis Set, SAS: Safety Analysis Set; Sema: semaglutide, Lira: liraglutide; flex: 
flexible dose 
DIAGNOSIS AND MAIN CRITERIA FOR INCLUSION
Main inclusion criteria: Male or female, age ≥18 years at the time of signing informed consent; subjects diagnosed 
with T2D at least ≥90 days prior to screening; subjects should be on stable diabetes treatment consisting of diet and 
exercise with or without metformin (≥1500 mg daily or maximum tolerated dose documented in the patient medical 
record) for at least 90 days prior to screening. Glycated haemoglobin (HbA1c): 53-86 mmol/mol (7.0-10.0%) (both 
inclusive). Body mass index (BMI): 25.0 – 40.0 kg/m2 (both inclusive).
Main exclusion criteria: Female who is pregnant, breast-feeding or intends to become pregnant or is of child-
bearing potential and not using adequate contraceptive methods throughout the trial including the 7-week follow-up 
period (adequate contraceptive measures as required by local regulation or practice). Any condition which, in the 
opinion of the investigator, might jeopardise subject safety or compliance with the protocol; treatment with any 
medication for the indication of diabetes or obesity other than stated in the inclusion criteria in a period of 90 days 
before screening (an exception is short-term insulin treatment for acute illnesses for a total of ≤14 days). Anticipated 
initiation or change in concomitant medications (for more than 14 consecutive days or on an frequent basis) known to 
affect weight or glucose metabolism (e.g. orlistat, thyroid hormones, corticosteroids). History of pancreatitis (acute 
or chronic). Screening calcitonin ≥50 ng/L. Family or personal history of Multiple Endocrine Neoplasia Type 2 
(MEN2) or Medullary Thyroid Carcinoma (MTC). Uncontrolled hypertension (defined as systolic blood pressure 
≥160 mmHg and/or diastolic blood pressure ≥100 mmHg) at screening. If white-coat hypertension is suspected at the 
screening visit, repeated measurement at the screening visit is allowed. Severe to moderate renal impairment defined 
as GFR, estimated <60 ml/min/1.73 m2 per Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI). Within 
the past 180 days before screening any of the following: myocardial infarction, stroke or hospitalisation for unstable 
angina or transient ischemic attack. Currently planned coronary, carotid or peripheral artery revascularisation. 
Patients presently classified as being in New York Heart Association (NYHA) Class III or IV.
Main treatment discontinuation criteria: Safety concerns suspected to be related to the trial products or 
unacceptable intolerance to the treatment.
Withdrawal criterion: Subjects could electively withdraw from the trial at any time by withdrawal of informed 
consent.
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TRIAL PRODUCTS, DOSE AND MODE OF ADMINISTRATION, BATCH NUMBER
Trial Product
Dose
Administration Route
Batch Number
Expiry Date
Semaglutide 1.0 mg/mL, 3 mL
0.05, 0.10, 0.20, or 0.30 mg daily
Subcutaneous injection
EW5G922
27 April 2017
Liraglutide, 6.0 mg/mL, 3 mL
0.30, 0.60, 1.20 or 1.80 mg daily
Subcutaneous injection
EW5F506
14 July 2017
Placebo, 0 mg/mL, 3 mL
0 mg daily
Subcutaneous injection
DW5D550
29 March 2017
DURATION OF TREATMENT
26 weeks
CRITERIA FOR EVALUATION – EFFICACY
HbA1c, body weight, fasting plasma glucose, and systolic and diastolic blood pressure.
CRITERIA FOR EVALUATION – SAFETY
Treatment-emergent adverse events (TEAEs, including pre-defined medical events of special interest adjudicated by 
an independent external adjudication committee), hypoglycaemic episodes, pulse rate, and laboratory safety 
variables.
STATISTICAL METHODS
Power calculation
The sample size calculation was based on a comparison of change from baseline to end-of-treatment at week 26 in 
HbA1c between the highest dose of semaglutide OD and the four pooled placebo arms. The assumed treatment effect 
of the highest dose of semaglutide relative to placebo at week 26 was an average of 0.65% improvement in HbA1c.
Due to premature treatment discontinuations, however, this effect could not be expected to manifest itself as the 
statistical model’s estimated treatment effect. A 50% smaller effect was assumed in the 30% of subjects assumed to 
discontinue treatment prematurely leading to a placebo-adjusted treatment effect of 0.55%, which was the value used 
in the sample size calculation. With the above assumptions, 64 subjects would be allocated to each of the semaglutide 
and liraglutide arms and twice that number of subjects to the pooled placebo (32 subjects in each arm) to yield a 90% 
power in order to detect a difference between the highest semaglutide dose and the pooled placebo arms at a Type I 
error rate of 5% 
(2-sided). Thus, the total sample size would be (9×64) + (4×32) = 704 subjects.
Definition of analysis sets
The full analysis set (FAS) included all randomised subjects exposed to at least one dose of trial product. Subjects in 
the FAS would contribute to the evaluation ‘as randomised’. The safety analysis set (SAS) included all randomised 
subjects exposed to at least one dose of trial product. Subjects in the SAS would contribute to the evaluation ‘as 
treated’.
Observation periods
In-trial: The time period in which a subject was considered a trial participant and where data were collected 
systematically. The ‘in-trial’ observation period included observations recorded at or after randomisation and not 
after the last subject-investigator contact, which was scheduled to take place 7 weeks after planned last dose of trial 
product at a follow-up visit. This period was used for supportive analyses of both efficacy and safety.
On-treatment: The observation period where the subject was expected to be treated and exposed to randomised 
treatment. This was the primary observation period for examination of safety endpoints including adjudicated events, 
electrocardiograms (ECGs), and adverse events (AEs) including hypoglycaemic episodes.
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On-treatment until rescue medication: This observation period was a subset of the ‘on-treatment’ observation period. 
To avoid potential confounding of initiation of anti-diabetic rescue therapies on efficacy endpoints, observations that 
were collected until initiation of permanent anti-diabetic rescue therapies were excluded from this observation 
period. ‘On-treatment until rescue’ observation period would be used when examining efficacy endpoints and was 
the observation period used for the primary analysis. Specifically, it included observations recorded at or after date of 
first dose of trial product and not after the first occurrence of the last dose of trial product plus the 7-days visit 
window or date of initiation of rescue therapy. This period was the primary observation period for examination of 
efficacy endpoints.
Statistical analysis
Primary endpoint: change from baseline in HbA1c after 26 weeks of treatment
This analysis was based on FAS and observations within the ‘on-treatment until rescue medication’ period. All post-
baseline measurements obtained at scheduled visits were analysed by a standard mixed model for repeated 
measurement (MMRM). In the primary analysis, all continuous data were evaluated using a standard MMRM 
analysis model with treatment, stratification factor (metformin use at baseline) and region as fixed factors, and the 
corresponding baseline value as covariate. The four placebo groups were pooled into one placebo arm. Missing data 
were assumed to be missing-at-random (MAR).
Supportive secondary efficacy endpoints
Change from baseline to week 26 in:
x
Body weight
x
Fasting plasma glucose (FPG)
x
Systolic and diastolic blood pressure (SBP and DBP, respectively)
for the following pre-specified treatment comparisons:
x
Semaglutide 0.05 mg/day vs. Placebo 
x
Semaglutide 0.10 mg/day vs. Placebo
x
Semaglutide 0.20 mg/day vs. Placebo
x
Semaglutide 0.30 mg/day vs. Placebo
x
Liraglutide 0.30 mg/day vs. Placebo
x
Liraglutide 0.60 mg/day vs. Placebo
x
Liraglutide 1.20 mg/day vs. Placebo
x
Liraglutide 1.80 mg/day vs. Placebo
x
Semaglutide 0.05 mg/day vs. Liraglutide 0.30 mg/day 
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x
Semaglutide 0.10 mg/day vs. Liraglutide 0.60 mg/day 
x
Semaglutide 0.20 mg/day vs. Liraglutide 1.20 mg/day 
x
Semaglutide 0.30 mg/day vs. Liraglutide 1.80 mg/day
Continuous endpoints were analysed separately using the standard MMRM model as for the primary endpoint but 
with the associated baseline value as a covariate. The same estimated treatment differences (ratios) as presented for 
the primary endpoint were presented with two sided p-values and 95% confidence intervals
Sensitivity analyses
To evaluate the robustness of the conclusions of the primary analysis, pre-specified sensitivity analyses were 
performed for change in HbA1c and change in body weight at 26 weeks. These pre-specified sensitivity analyses 
investigated the sensitivity of the results due to the impact of missing values. For the primary analysis, the ‘on-
treatment until rescue medication’ observation period was used for three of the sensitivity analyses (analysis of 
covariance [ANCOVA] based on last available observation carried forward [LOCF] analysis, complete case 
[MMRM-based] analysis, and the placebo and comparator-based imputation models based on the pattern mixture 
model [PMM]).
Subjects who after 26 weeks treatment achieved (yes/no):
x
HbA1c <7.0% (<53 mmol/mol) American Diabetes Association (ADA) target
x
HbA1c ≤6.5% (48 mmol/mol) American Association of Clinical Endocrinologists (AACE) target
These endpoints were analysed separately using a logistic regression model presenting odds ratio and 95% CI for the 
odds ratio and associated p-value. The model included treatment, region, and stratification variable (diet and exercise 
with or without metformin) as fixed effects and baseline value as covariate. Missing response data at 26 weeks were 
imputed from the MMRM used to analyse the two original continuous endpoints.
Supportive secondary safety endpoints
x
Treatment-emergent AEs (TEAEs) were summarised descriptively. TEAEs, along with all other safety 
endpoints, were analysed using SAS. A TEAE was defined as an event that had an onset date (or increase in 
severity) during the on-treatment observation period. TEAEs were 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 (R) per 100 patient-years of exposure (PYE).
x
Episodes of hypoglycaemia were classified according to the Novo Nordisk A/S and the ADA classification of 
hypoglycaemia. Treatment-emergent episodes of hypoglycaemia were summarised descriptively and presented 
as the episode rate per 100 PYE. 
x
Pre-defined groups of AEs of special interest were evaluated based on Medical Dictionary for Regulatory 
Activities (MedDRA) searches (version 19.0). These groups were defined by Novo Nordisk A/S Global Safety 
and consisted of pre-specified preferred terms.
x
Pulse rate was analysed with the standard MMRM.
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x
Laboratory assessments were summarised and evaluated by descriptive statistics using the SAS.
Importantly, for data presentation of all endpoints, the word ‘significant’ is only used if supported by a statistical
analysis and a p-value < 0.05.
DEMOGRAPHY OF TRIAL POPULATION
Sema
0.05mg
Sema
0.10 
mg
Sema
0.20 
mg
Sema
0.30 mg
Lira
0.30 mg
Lira
0.60 mg
Lira
1.20 mg
Lira
1.80 mg
Placebo
Sema
flex
Total
N
64
63
65
63
64
64
64
65
129
65
706
Female, N 
(%)
31 
(48.44)
28 
(44.44)
22 
(33.85)
31 
(49.21)
35 
(54.69)
32 
(50.00)
30 
(46.88)
32 
(49.23)
57 
(44.19)
28 
(43.75)
326 
(46.24)
Age (years)
[min-max]
57.5
57.5
58.4
54.8
57.2
59.5
53.7
55.8
57.1
54.8
56.7
[28-74]
[36-76]
[34-
74]
[31-76]
[35-77]
[32-76]
[25-77]
[32-74]
[29-79]
[33-79]
[25-79]
HbA1c (%), mean 
[min-max]
7.87
7.91
7.96
8.23
8.06
8.12
8.14
8.07
8.12
8.10
8.06
[6.7-
9.8]
[6.3-
10.0]
[6.7-
9.9]
[6.9-
10.3]
[6.8-
10.4]
[6.80-
9.9]
[6.5-
10.3]
[6.6-
10.0]
[6.6-
10.8]
[6.7-
10.1]
[6.3-
10.8]
FPG (mmol/L), 
mean
[min-max]
9.26
8.97
9.20
9.67
9.32
9.34
9.91
9.18
9.67
9.82
9.45
[5.9-
16.3]
[3.3-
17.4]
[5.6-
16.4]
[4.3-
15.6]
[5.2-
17.5]
[5.5-
16.9]
[5.2-
16.6]
[5.5-
16.4]
[4.5-
23.1]
[6.3-
20.6]
[3.25-
23.12]
Diabetes 
duration (years)
[min-max]
6.55
8.12
7.16
6.49
8.10
6.77
6.93
6.63
7.12
8.00
7.18
[0.3-
17.5]
[0.4-
36.1]
[0.3-
25.9]
[0.38-
21.0]
[0.3-
44.9]
[0.6-
24.1]
[0.5-
23.1]
[0.3-
22.8]
[0.4-
20.8]
[0.4-
35.9]
[0.3-
44.9]
Body weight 
(kg)
[min-max]
93.44
92.40
98.07
94.82
92.25
92.68
96.67
93.40
93.98
95.29
94.28
[55.3-
132.9]
[63.9-
133.0]
[63.9-
140.6]
[54.8-
136.1]
[66.4-
137.5]
[63.0-
127.6]
[53.6-
155.6]
[59.6-
151.5]
[58.8-
148.5]
[52.6-
129.5]
[52.6-
155.6]
BMI (kg/m2)
[min-max]
32.32
32.40
32.83
33.10
32.94
33.02
33.29
32.06
32.76
33.22
32.79
[25.2-
39.9]
[24.6-
39.7]
[24.8-
40.0]
[24.4-
40.8]
[24.9-
40.1]
[25.4-
39.9]
[25.1-
39.7]
[24.7-
40.3]
[24.8-
40.2]
[25.1-
39.8]
[24.4-
40.8]
Sema
0.05mg
Sema
0.10 
mg
Sema
0.20 
mg
Sema
0.30 
mg
Lira
0.30 
mg
Lira
0.60 
mg
Lira
1.20 
mg
Lira
1.80 
mg
Placebo
Sema
flex
Total
Ethnicity; N (%)
Not Hispanic or 
Latino
55 
(85.94)
56 
(
88.89)
59 
(
90.77)
59 
( 93.65)
57 
( 89.06)
58 
( 90.63)
58 
( 90.63)
57 
( 87.69)
113 
( 87.60)
57 
( 89.06)
629 
(89.22)
Race; N (%)
American 
Indian or Alaska 
native
1
(1.54)
1 (1.56)
2 (0.28)
Asian
6
( 9.38)
9
(14.29)
5
( 7.69)
7
( 11.11)
4
(  6.25)
2
(  3.13)
4
(  6.25)
11 
( 16.92)
14 
( 10.85)
4
(  6.25)
66 
(9.36)
Black or African 
American
9
(14.06)
4
( 6.35)
6
(9.23)
11 
(17.46)
4
(6.25)
4
(6.25)
6
(9.38)
4
(6.15)
11 
(8.53)
4
(6.25)
63 
(8.94)
White
49 
(76.56)
50 
(79.37)
51 
(78.46)
44 
(69.84)
53 
(82.81)
56 
(87.50)
54 
(84.38)
48 
(73.85)
103 
(79.84)
52 
(81.25)
560 
(79.43)
Other
2
(3.08)
1 (1.59)
2 (3.13)
2 (3.13)
2 ( 
3.08)
1 ( 
0.78)
4 ( 
6.25)
14 
(1.99)
Renal function; N (%)
Normal
36 
(56.25)
34 
(53.97)
34 
(52.31)
43 
(68.25)
39 
(60.94)
33 
(51.56)
44 
(68.75)
45 
(69.23)
78 
(60.47)
46 
(71.88)
432 
(61.28)
Mild
28 
(43.75)
28 
(44.44)
31 
(47.69)
20 
(31.75)
24 
(37.50)
31 
(48.44)
19 
(29.69)
20 
(30.77)
51 
(39.53)
18 
(28.13)
270 
(38.30)
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Moderate
1
(1.59)
1 (1.56)
1 (1.56)
3 (0.43)
Abbreviations: N: Number of subjects, %: Percentage of subjects, BMI: Body mass index, HbA1c: glycosylated haemoglobin,
FPG: fasting plasma glucose; Sema: semaglutide; Lira: liraglutide; Flex: flexible dose
EFFICACY RESULTS
Primary endpoint: change from baseline in HbA1c after 26 weeks of treatment
Treatment with semaglutide significantly improved glycaemic control after a 26-week treatment period as compared 
with placebo or liraglutide. 
x
A dose-dependent significant reduction in HbA1c was obtained with semaglutide as compared with placebo, with 
estimated treatment differences (ETDs) ranging from 
-1.04%-points [-1.30; -0.77]95%CI for semaglutide 0.05 mg vs. placebo to 
-1.86%-points [-2.12; -1.60]95%CI for semaglutide 0.30 mg vs. placebo.
x
A significant reduction in HbA1c was obtained with semaglutide as compared with each volume-matched 
liraglutide dose with ETDs of -0.55%-points [-0.85; -0.25]95%CI for semaglutide 0.05 mg vs. liraglutide 0.30 mg; 
to -0.57%-points [-0.87; -0.27]95%CI for semaglutide 0.30 mg vs. liraglutide 1.80 mg. Overall, semaglutide led to 
reductions in HbA1c between -1.05%-points and -1.88%-points from a mean baseline of 8.06% compared to (-
0.50 to -1.31)%-points for liraglutide and -0.02%-points for placebo. 
x
At week 26, a -1.67%-points reduction in HbA1c was obtained with the open-label semaglutide flexible dose 
group, with an ETD of -1.64%-points [-1.89; -1.39]95%CI as compared to placebo.
x
The robustness of the primary analysis was supported by three sensitivity analyses that showed significantly 
better glycaemic control with similar, dose-dependent, and significant ETDs, ranging -0.86%-points [-1.12; -
0.60]95%CI to -1.02%-points [-1.31; -0.73]95%CI for semaglutide 0.05 mg vs. placebo and -1.54%-points [-1.80; -
1.28]95%CI to 
-1.80%-points [-2.09; -1.50]95%CI for semaglutide 0.30 mg vs. placebo.
x
The dose response modelling potency of semaglutide was 28-fold higher than liraglutide with an estimated 
treatment ratio (ETR) of 27.59 [18.52; 41.11]95%CI for HbA1c, as liraglutide 1.80 mg was equipotent to 
semaglutide 0.062 mg.
Supportive secondary efficacy endpoint: change from baseline in body weight after 26 weeks of treatment
Treatment with semaglutide led to significantly greater weight loss after a 26-week treatment period as compared 
with placebo or liraglutide.
x
A dose-dependent significant reduction in body weight was obtained with semaglutide as compared with 
placebo, with ETDs ranging from 
-1.53 kg [-2.76; -0.31]95%CI for semaglutide 0.05 mg vs. placebo to 
-7.00 kg[-8.23; -5.77]95%CI for semaglutide 0.30 mg vs. placebo.
x
A significant reduction in body weight was obtained with semaglutide as compared with each volume-matched 
liraglutide dose with ETDs of -1.26 kg [-2.67; -0.14]95%CI for semaglutide 0.05 mg vs. liraglutide 0.30 mg to 
-4.48 kg [-5.89; -3.08]95%CI for semaglutide 0.30 mg vs. liraglutide 1.80 mg. Overall, semaglutide led to weight 
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loss between -2.76 kg and -8.23 kg from a mean baseline weight of 94.18 kg compared to -1.50 to -3.75 kg for 
liraglutide and -1.23 kg for placebo.
x
At week 26, a -6.42 kg reduction in body weight was observed with the open-label semaglutide flexible dose 
group, with an ETD of -5.15 kg [-6.47; -3.84]95%CI as compared to placebo.
x
The robustness of the primary analysis was supported by three sensitivity analyses that showed significantly 
better weight loss with similar, dose-dependent, and significant ETDs, ranging from 
-1.33 kg [-2.52; -0.14]95%CI to -1.48 kg [-2.72; -0.24]95%CI for semaglutide 0.05 mg vs. placebo and 
-6.45 kg [-7.65; -5.24]95%CI to -6.66 kg [ -7.93; -5.39]95%CI for semaglutide 0.30 mg vs. placebo.
x
The dose response modelling showed that the potency of semaglutide was 30-fold higher than liraglutide with an 
ETR of 29.81 [17.65; 50.35]95%CI for body weight, as liraglutide 1.80 mg was equipotent to semaglutide 0.06 mg.
Other supportive secondary efficacy endpoints
x
HbA1c treatment targets were achieved by larger proportions of subjects in the semaglutide groups compared 
with placebo or liraglutide groups, and the odds for reaching both targets were significantly higher with 
semaglutide when compared with placebo or liraglutide:
x
HbA1c ≤6.5% (AACE target) was achieved by a greater proportion of subjects with semaglutide (43-73%) 
when compared with liraglutide (14-42%) or placebo (6%). Approximately 67% of subjects in the open-
label semaglutide flexible group achieved this target. The estimated odds ratios ranged from 
10.95 [4.55; 26.36]95%CI for semaglutide 0.05 mg vs. placebo to 
59.58 [23.22; 152.88]95%CI for semaglutide 0.30 mg vs. placebo; and from 
4.31 [1.79; 10.39]95%CI for semaglutide 0.05 mg vs. liraglutide 0.30 mg to 
5.16 [2.33; 11.44]95%CI for semaglutide 0.30 mg vs. liraglutide 1.80 mg.
x
HbA1c <7.0% (ADA target) was achieved by a greater proportion of subjects with semaglutide (58-89%) 
when compared with liraglutide (33-62%) or placebo (13%). Approximately 84% of subjects in the open-
label semaglutide flexible group achieved this target. The estimated odds ratios ranged from 
10.34 [4.77; 22.43]95%CI for semaglutide 0.05 mg vs. placebo to 
101.61 [36.05; 286.39]95%CI for semaglutide 0.20 mg vs. placebo; and from 
2.64 [1.21; 5.76]95%CI for semaglutide 0.05 mg vs. liraglutide 0.30 mg to 
9.01 [3.31; 24.56]95%CI for semaglutide 0.20 mg vs. liraglutide 1.20 mg.
x
A greater reduction in FPG levels from baseline to week 26 was observed with semaglutide compared with 
either placebo or liraglutide with ETDs ranging from 
-1.80 mmol/L [-2.32; -1.27]95%CI for semaglutide 0.05 mg vs. placebo to 
-2.97 mmol/L [-3.50; -2.44]95%CI for semaglutide 0.30 mg vs. placebo; and from 
-0.79 mmol/L [-1.39; -0.19]95%CI for semaglutide 0.05 mg vs. liraglutide 0.30 mg to 
-1.58 mmol/L [-2.19; -0.98]95%CI for semaglutide 0.20 mg vs. liraglutide 1.20 mg.
The ETDs in mg/dL ranged from 
-32.37 mg/dL [-41.85; -22.89]95%CI for semaglutide 0.05 mg vs. placebo to 
-53.50 mg/dL [-63.05; -43.95]95%CI for semaglutide 0.30 mg vs. placebo; and from 
-14.25 mg/dL [-25.07; -3.44]95%CI for semaglutide 0.05 mg vs. liraglutide 0.30 mg to 
-28.56 mg/dL [-39.50; -17.62]95%CI for semaglutide 0.20 mg vs. liraglutide 1.20 mg
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x
At week 26, a -3.40 mmol/L reduction in FPG was obtained with the open-label semaglutide flexible dose 
group, which was greater than fixed-dose semaglutide 0.20 mg (-2.64 mmol/L) but lower than the fixed-
dose semaglutide 0.30 mg group (-3.53 mmol/L).
x
The dose-response modelling showed that the potency of semaglutide was 38-fold higher than liraglutide 
with an ETR of 37.67 [21.49; 66.03]95%CI) for FPG, as liraglutide 1.80 mg was equipotent to 
semaglutide 0.05 mg.
x
Systolic blood pressure levels at week 26 were significantly improved with semaglutide 0.30 mg (-10.02 mmHg) 
as compared with placebo (-2.42 mmHg) and liraglutide 1.80 mg (-3.58 mmHg) with ETDs of 
-7.60 mmHg [-11.35; -3.8]95%CI between semaglutide 0.30 mg and placebo, and 
-6.44 mmHg [-10.66; -2.22]95%CI between semaglutide 0.30 mg and liraglutide 1.80 mg.
x
At week 26, a -6.62 mmHg decrease in SBP was obtained for the open-label semaglutide flexible dose 
group, which was less than the fixed-dose semaglutide 0.30 mg group (-9.85 mmHg).
x
Diastolic blood pressure levels at week 26 were significantly improved with semaglutide 0.30 mg (-3.88 mmHg) 
as compared with placebo (-0.64 mmHg) and liraglutide 1.80 mg (0.36 mmHg) with ETDs of 
-3.24 mmHg [-5.82; -0.66]95%CI between semaglutide 0.30 mg and placebo, and 
-4.23 mmHg [-7.13; -1.33]95%CI between semaglutide 0.30 mg and liraglutide 1.80 mg
x
At week 26, a -1.58 mmHg decrease in DBP was obtained for the open-label semaglutide flexible dose 
group, which was less than the fixed-dose semaglutide 0.30 mg group (-4.02 mmHg).
SAFETY RESULTS
During the 26 weeks of treatment, semaglutide, liraglutide, and placebo were generally safe and well tolerated. 
Overall AE safety profile
x
One (1) fatal event was reported with liraglutide 1.80 mg (due to ‘acute myocardial infarction’) that was assessed 
as unlikely related to treatment.
x
Overall, low proportions of subjects across all treatment groups reported serious adverse events (SAEs) (3.1% to 
9.4% in semaglutide, 1.6% to 10.8% in liraglutide, 3.1% in placebo, and 6.3% in the open-label semaglutide 
flexible group.There was no consistent pattern in reported SAEs across treatment groups or preferred terms 
(PTs). Incidences of SAEs were mainly driven by events within the system organ class (SOC) ‘cardiovascular 
disorders’, infections and infestations’, and ‘neoplasms’ in descending order, with highest frequency reported in 
semaglutide 0.05 mg and liraglutide 1.80 mg. 
x
Adverse events were reported by comparable proportions of subjects among the fixed-dose groups, but at a 
higher rate in all doses of semaglutide than either liraglutide or placebo during the on-treatment period, with the 
highest proportion and rates in the open-label semaglutide flexible dose group:
x
semaglutide 0.05 mg: 62.5%; 538 events per 100 PYE
x
semaglutide 0.10 mg: 69.8%; 590 events per 100 PYE
x
semaglutide 0.20 mg: 73.8%; 590 events per 100 PYE
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x
semaglutide 0.30 mg: 73.0%; 642 events per 100 PYE
x
liraglutide 0.30 mg: 76.6%; 402 events per 100 PYE
x
liraglutide 0.60 mg: 67.2%; 515 events per 100 PYE
x
liraglutide 1.20 mg: 70.3%; 420 events per 100 PYE
x
liraglutide 1.80 mg: 76.9%; 521 events per 100 PYE
x
placebo: 72.9%; 375 events per 100 PYE
x
open-label semaglutide flexible group: 82.8%; 719 events per 100 PYE
x
The differences in AEs were mostly related to gastrointestinal AEs (GIAEs), infections and infestations, nervous 
system disorders, musculoskeletal and connective tissue disorders, and metabolism and nutrition disorders.
x
Overall in all treatment groups, the majority of AEs reported were of mild or moderate severity (in total, 96.4% 
or 2092 events of 2171). Overall, few severe events were reported across all groups (total 31 events of 2171). 
Majority of subjects reporting AEs had recovered or were recovering, with or without sequalae, from the 
majority of the reported AEs at the end of the trial, with only 315 of 2171 events not having been resolved by the 
end of the trial, with highest incidence in liraglutide 0.60 mg within the ‘musculoskeletal and connective tissue 
disorders’ SOC and lowest in the semaglutide 0.30 mg group ‘gastrointestinal disorders’ SOC. 
x
The most frequently reported AEs with semaglutide and liraglutide were within the SOC ‘gastrointestinal 
disorders’, whereas the most frequently reported AEs in subjects treated with placebo were within the SOC 
‘infections and infestations’.
x
The proportion of subjects with AEs leading to premature treatment discontinuation was generally higher with 
placebo (10.9%) than semaglutide (6.3% to 9.2%), liraglutide (3.1% to 7.8%), or the open-label semaglutide 
flexible group (4.7%). The number of AEs leading to premature treatment discontinuation in the semaglutide and 
liraglutide groups was predominantly due to a higher frequency of subjects experiencing gastrointestinal AEs. 
For the placebo group, premature discontinuations were mainly due to hyperglycaemia. In some cases, subjects 
had hyperglycaemic episodes requiring rescue medication, thus these events were included in the ‘lack of 
efficacy’ category as the primary reason of premature treatment withdrawal and not under ‘adverse event’ in the 
end-of-trial form. This discrepancy was more apparent in the subject disposition reporting for the liraglutide and 
placebo groups, since a greater proportion of subjects in those groups reported ‘lack of efficacy’ as compared to 
semaglutide groups. It should be noted that subject disposition was based on end-of-trial form while AEs leading 
to withdrawal information was based on AE summary form. 
x
The proportion of subjects discontinuing treatment due to AEs in the open-label semaglutide flexible group was 
similar to the fixed-dose semaglutide groups.
x
The dose response modelling showed that the potency of semaglutide was 7.5 (ETR: 7.43 [2.36; 23.33]95%CI) for 
treatment discontinuation due to AEs as liraglutide 1.80 mg was equipotent to semaglutide 0.24 mg.
Hypoglycaemia
x
No ‘severe’ hypoglycaemic episodes (as defined by the ADA classification) were reported.
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x
‘Severe or blood glucose (BG)-confirmed symptomatic’ hypoglycemic episodes (as defined by Novo Nordisk 
classification) were reported by 2 subjects (3.1%) with semaglutide 0.05 mg, 2 subjects (3.2%) with 
semaglutide 0.10 mg, 3 subjects (4.6%) with semaglutide 0.20 mg, 2 subjects (3.2%) with semaglutide 0.30 mg; 
2 subjects (3.1%) with liraglutide 0.60 mg, 1 subject (1.6%) with liraglutide 1.20 mg, 3 subjects (4.6%) with 
liraglutide 1.8 mg; 4 subjects (3.1%) with placebo; and 2 subjects (3.1%) with the open-label semaglutide 
flexible group.
x
No significant differences were observed in the proportion of subjects experiencing ‘severe or BG-confirmed 
symptomatic’ hypoglycaemia between semaglutide and liraglutide or placebo groups.
Safety areas of interest
x
Gastrointestinal disorders
x
Gastrointestinal disorders were the most frequently reported AEs with semaglutide and liraglutide, with 
higher reporting in semaglutide with a dose effect observed. Similar proportions of subjects reported GIAEs 
in the fixed-dose semaglutide 0.30 mg (54.0%) and the open-label semaglutide flexible dose groups 
(56.3%).The most frequently (≥5%) reported GIAEs were ‘nausea’, ‘diarrhoea’, ‘vomiting’, ‘constipation’ 
and ‘dyspepsia’ in descending order, with ‘nausea’ and ‘diarrhoea’ reported at a higher rate and by a higher 
proportion of subjects with semaglutide doses than with the liraglutide or placebo.
x
The proportions of subjects reporting the most frequent PTs (respectively for fixed-dose semaglutide; 
liraglutide; placebo; and the open-label semaglutide flexible dose group) were as follows: 
nausea (17.2% to 25.4%; 9.4% to 20.0%; 4.7%; and 39.1%)
diarrhoea (10.9% to 25.4%; 7.8% to 10.8%; 10.9%; and 17.2%)
vomiting (6.3% to 9.5%; 1.6% to 10.9%, 2.3%; and 9.4%)
x
The majority of the events occurred within the initial 12 weeks of treatment and the median duration of the 
GIAEs were slightly higher with semaglutide than liraglutide or placebo, and varied across types of events. 
x
The majority of GIAEs were largely mild or moderate in severity and 2 subjects (1 on semaglutide 0.10 mg 
[‘anal fistula’] and 1 on placebo [‘epiploic appendagitis’]) reported gastrointestinal SAEs.
x
All reported GIAEs in the semaglutide 0.30 mg OD group, a dose level for which Novo Nordisk has had no 
previous experience in humans, were non-serious, mild-to-moderate in severity, and only one AE 
(‘dyspepsia’) led to drug withdrawal. None of the GIAEs reported in the open-label semaglutide flexible 
dose group were serious, majority were mild-to-moderate in severity, and only 2 AEs (‘impaired gastric 
emptying’ and ‘abdominal pain’) led to drug withdrawal. 
x
The dose response modelling showed that the potency of semaglutide was 13 (ETR: 12.81 [6.22; 
26.36]95%CI) for proportion of subjects reporting at least 1 GIAE as liraglutide 1.80 mg was equipotent to 
semaglutide 0.14 mg.
x
Cardiovascular disorders
x
There were 18 EAC-confirmed events in 9 subjects in the trial. Twelve (12) CV events in 7 subjects were 
confirmed during the on-treatment observation period (4 events in 2 subjects in semaglutide 0.05mg, 6 
events in 3 subjects in liraglutide 1.80 mg, 1 event in 1 subject in placebo, and 1 event in the open-label 
semaglutide flexible dose group). Two (2) additional events in semaglutide 0.05 mg and 2 events in 
liraglutide 1.20 mg were EAC-confirmed in the in-trial observation period and 2 events in liraglutide 1.20 
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mg occurred after end of trial. Six (6) EAC-confirmed events in 5 subjects were MACEs (4 acute 
myocardial infarction events in 3 subjects, 1 cardiovascular death, and 1 stroke). 
x
A total of 68 cardiovascular disorder events were captured by the MedDRA search and reported in 48 
subjects, with varied frequencies across all groups (4.8% to 9.4% in semaglutide; 4.7% to 12.3% in 
liraglutide; 7.0% in placebo; and 4.7% in the open-label semaglutide flexible dose group).).
x
There were a total of 17 cardiovascular SAEs in 11 subjects (4 events in 2 subjects in semaglutide 0.05 mg; 
1 event in semaglutide 0.20 mg; 1 event in semaglutide 0.30 mg; 2 events in 1 subject in liraglutide 1.20 
mg; 6 events in 3 subjects in liraglutide 1.80 mg; 2 events in 2 subjects in placebo; and 1 event in the open-
label semaglutide flexible dose group). Majority of these CV SAEs were severe, none were assessed as 
likely related to treatment. With the exception of the fatal event in liraglutide 1.80 mg (due to ‘acute 
myocardial infarction’) and ischaemic stroke event in the open-label semaglutide flexible dose group, all 
subjects recovered from these SAEs, all subjects recovered from these SAEs. No differences were apparent 
in type and frequency of events among the treatment groups.
x
After 26 weeks of treatment, the estimated mean pulse rate increased with all treatment groups, except 
placebo and semaglutide 0.05 mg, albeit to a greater level with liraglutide 1.20 mg (5 bpm) and liraglutide 
1.80 mg (4 bpm). Increases in semaglutide were 1-3 bpm, compared to 1 bpm for placebo. The increase in 
pulse rate from baseline to end of treatment were only significant for higher doses of liraglutide versus 
placebo, with ETDs in bpm of 4.52 [1.68; 7.36]95%CI and 2.85 [0.07; 5.36]95%CI with liraglutide 1.20 mg and 
1.80 mg, respectively. 
x
Overall, the proportion of subjects with ECG abnormalities was similar among the treatment groups for the 
majority of the abnormality categories and the majority of the measurements were ‘normal’ at baseline and 
persisted at week 26 (77.1-90.0%) and week 33 (77.1%-86.7%) with no apparent differences between 
treatment groups. Three (3) ECG-related AEs and 1 ‘blood pressure increased’ event were reported; all of 
which were non-serious, mild, and unlikely related to trial product
x
Pancreatitis
x
One (1) event of ‘pancreatitis chronic’ and 1 ‘pancreatic enzymes increased’ event were sent for 
adjudication, both of which were non-confirmed by the EAC; no other events were identified by the Novo 
Nordisk pre-defined preferred term query (NN PTQ) search, nor considered adjudicable. 
x
One (1) non-serious, mild, ‘pancreatitis chronic’ event was identified by the MedDRA search, from which 
the subject 
x
Mean lipase and amylase activities from baseline to end of treatment (week 26) were significantly increased 
for semaglutide and liraglutide groups as compared to placebo. The vast majority of the subjects had 
enzyme activities <2xULN throughout the trial, and most of the subjects with lipase activity >5xULN 
(upper limit of normal) and amylase activity >2xULN, only had single incidences of outliers. Only 1 
subject, treated with liraglutide 0.60 mg, had elevated amylase (>2xULN) and lipase (>5xULN) activities 
during treatment, and did not report any concurrent gastrointestinal AEs, hepatobiliary or pancreatitis-
related AEs. 
x
Hepatobiliary disorders
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x
Gallbladder disorder adverse events were reported in 3 subjects (single events in liraglutide 0.30 mg, 
liraglutide 1.80 mg, and placebo). All 3 events were identified via MedDRA search and were reported 
within the SOC ‘hepatobiliary disorders’ as ‘cholelithiasis’ or ‘hydrocholecystis’ (PT). All 3 events were 
non-serious, mild in severity, resulted in no change in treatment dosage, were assessed as unlikely related to 
trial product, two of the subjects had 
 from these events by the end of the trial, and none of 
these events led to premature treatment discontinuation. 
x
Sixteen (16) hepatic disorders were identified via MedDRA search and reported mostly as single events, 
distributed across groups, all of which were non-serious, mild-to-moderate in severity, and only 1 event in a 
placebo-treated subject led to premature treatment discontinuation. 
x
In general, there was a fluctuating pattern in the levels of liver tests, but no mean increases were observed. 
There were 11 cases of outliers in liver function tests: 2 subjects with outliers of alanine aminotransferase
>5xULN (both treated with placebo); 4 subjects with outlier of aspartate aminotransferase >5xULN (1 with 
semaglutide 0.30 mg, 1 with liraglutide 0.60 mg, and 2 with placebo); and 1 subject with outlier of total 
bilirubin >3xULN (semaglutide 0.30 mg). No outliers of alkaline phosphatase >5xULN (>675 U/L) were 
detected. The mean changes for all 4 liver function parameters from baseline were comparable among 
treatment groups and were not considered clinically relevant.
x
One (1) subject (semaglutide 0.30 mg) had concurrent elevation of AST >3xULN and total bilirubin 
>2xULN. Alternative aetiology was present 
, thus did not qualify as a Hy’s law 
case.
x
Neoplasms
x
Overall, the proportions of subjects as well as the number of EAC-confirmed neoplasms were low (5 events 
in 5 subjects; 1.19 events per 100 PYE [0.7%]) and primarily occurred as single events in single subjects 
and were generally equally distributed with regards to type (tissue or organ of origin) across the treatment 
groups: (1 subject each with semaglutide 0.05 mg [‘pancreatic carcinoma’]; semaglutide 0.30 mg [‘spinal 
meningioma’]; liraglutide 0.60 mg [‘basal cell skin carcinoma]; liraglutide 1.80 mg [‘prostate 
adenocarcinoma]; and with open-label semaglutide flexible dose [‘clear cell renal cell carcinoma’]). Four 
(4) events were malignant neoplasms and 1 was benign (‘spinal meningioma’); no pre-malignant/carcinoma 
in situ/ borderline or unclassified neoplasm events were confirmed by the EAC.
x
With respect to the MedDRA search of subjects experiencing at least one event, 21 neoplasm-related events 
were identified in 18 subjects distributed across most groups: 2 events in 2 subjects with semaglutide 0.05 
mg (3.1%), 3 events in 2 subjects in semaglutide 0.20 mg (3.1%), 3 events in 3 subjects in semaglutide 0.30 
mg (4.8%), 1 event in liraglutide 0.30 mg (1.6%), 4 events in 4 subjects in liraglutide 0.60 mg (6.3%), 3 
events in 3 subjects with liraglutide 1.80 mg (4.6%), 1 event in placebo (0.8%), and 4 events in 2 subjects in 
the open-label semaglutide flexible dose group (3.1%). Of the 21 events, 7 were serious, 3 were severe, 18 
were mild-to-moderate in severity, 1 was assessed as possibly related to treatment, 20 were unlikely 
treatment-related, dose was not changed for 19 events, and none led to premature discontinuation of trial 
product. 
x
No thyroid neoplasms were EAC-confirmed in this trial.
x
Thyroid disorders
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x
There was 1 EAC-confirmed event of thyroid disease requiring thyroidectomy (‘post-procedural 
hypothyroidism’) in a subject treated with placebo. This event was non-serious, moderate in severity, 
unlikely related to treatment, did not result in dose change, did not lead to premature treatment 
discontinuation, and from which the subject had 
 by the end of the trial.
x
Ten (10) thyroid disease AEs were captured by the pre-defined MedDRA search, 8 of which were in the on-
treatment period, 1 additional event in the in-trial observation period, and 1 event 13 days prior to 
randomisation. These events were distributed across treatment groups. One clinical laboratory AE (CLAE; 
‘blood calcitonin increased’) was reported by one subject treated with liraglutide 1.80 mg, from which the 
subject 
. 
x
A total of 7 subjects (4 with semaglutide and 3 with placebo) had at least 1 calcitonin value >20 ng/L during 
the trial; 6 of which occurred at the screening visit. There were no other clinically relevant changes in mean 
and individual calcitonin levels throughout the treatment period within or between treatment groups.
x
Renal disorders
x
Few AEs captured by the broad standardised MedDRA queries (SMQ) search ‘acute renal failure’ were 
reported during the trial (7 events in 6 subjects: 5 events in 4 subjects treated with semaglutide and 3 events 
in liraglutide). All events were non-serious, all but 1 were mild-or-moderate in severity, 6 were unlikely 
related to treatment, none led to premature treatment discontinuation, 2 subjects reported concurrent 
dehydration, and subjects 
 from 6 of the 7 events.
x
There were no clinically relevant changes in any renal laboratory parameters or urinalyses over time, 
within, and across treatment groups, with comparable changes in eGFR observed in all groups.
x
Immunogenicity-related AEs and injection site reactions
x
In total, 25 allergic reaction events were reported by 25 subjects (6 events per 100 PYE [3.5%]). Nineteen 
(19) events related to skin disorders distributed across all groups except semaglutide 0.05 mg and 
liraglutide 1.20 mg; 3 events related to immune system disorders; 2 respiratory, thoracic, and mediastinal 
disorder; and 1 event related to gastrointestinal disorders. All events were non-serious, majority were mild-
to-moderate in severity, unlikely related to trial product and resulted in no change in drug dosage, and the 
majority of the subjects 
 from these events by the end of the trial.
x
One (1) subject in the open-label semaglutide flexible group tested positive for anti-semaglutide antibodies 
at all visits; all samples were negative for antibodies cross-reacting with endogenous glucagon-like peptide-
1 (GLP-1). This subject with anti-semaglutide-positive antibodies at follow-up did not show neutralising 
effects to semaglutide and there was no indication of a treatment-induced anti-semaglutide antibody 
response. 
x
Four (4) events of immune complex disease were reported by 4 subjects (1 event per 100 PYE [0.6%]): 
‘nephritis’ (semaglutide 0.10 mg), ‘proteinuria’ (liraglutide 1.20 mg), ‘protein urine present’ (semaglutide 
0.10 mg), and ‘seizure’ (liraglutide 0.60 mg). Three (3) of the 4 events were non-serious, mild-to-moderate 
in severity, one event was an SAE, none led to premature treatment discontinuation, and all subjects 
 from these 4 events.
x
Thirty five (35) events of injection site reactions were reported by 20 subjects (8 events per 100 PYE 
[2.8%]) distributed across all groups except semaglutide 0.05 mg, with highest rate reported in liraglutide 
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0.60 mg (29 events per 100 PYE). The most commonly reported PTs were ‘injection site bruising’ (14 
events in 7 subjects), ‘injection site pain’ (7 events in 6 subjects), and ‘injection site haemorrhage’ (4 events 
in 4 subjects); with 11 AEs reported in 2 subjects treated with liraglutide 0.60 mg. All 35 events were non-
serious, mild-to-moderate in severity, majority were possibly or probably related to trial product, did not 
result in dose change, subjects recovered from all but 1 event, and none led to premature treatment 
discontinuation.
x
Medication errors
x
There were a total of 5 medication error AEs reported in 5 subjects (3 events in 3 subjects treated with 
semaglutide 0.05 mg (‘incorrect dose administered’ and ‘overdose’ and ‘injury associated with device’); 1 
event in liraglutide 0.30 mg (‘accidental overdose’); and 1 event in liraglutide 0.60 mg; (‘accidental 
overdose’). All the events were non-serious, mild-or-moderate in severity, 4 of the 5 events were unlikely 
related to treatment, and subjects recovered from all AEs.
x
Overdose
x
There were 3 overdose AEs in 3 subjects in the trial, single events in semaglutide 0.05 mg (‘overdose’), 
liraglutide 0.30 mg (‘accidental overdose’), and liraglutide 0.60 mg; (‘accidental overdose’). All the events 
were non-serious, mild-or-moderate in severity, 2 of the 3 events were unlikely related to treatment, and 
subjects recovered from all AEs.
x
Suspected transmission of infectious agent
x
No events of suspected transmission of infectious agent via trial product were reported for this trial.
x
Rare events
x
There was 1 rare event 
 identified in a subject treated with liraglutide 1.80 mg. 
The AE was non-serious, mild, unlikely related to treatment, and from which the subject 
x
Diabetic retinopathy
x
There were a total of 11 diabetic retinopathy events reported in 6 subjects (single subjects in 
semaglutide 0.10 mg and 0.30 mg; liraglutide 0.30 mg, 0.60 mg, 1.20 mg, and open-label semaglutide 
flexible group) in the trial in the following PTs: ‘diabetic retinopathy’ (6 events in 4 subjects), ‘macular 
oedema’ (2 events in 2 subjects), ‘maculopathy’ (1 event), ‘retinal detachment’ (2 events in 1 subject). Two 
(2) of the AEs reported were serious events (‘retinal detachment’ in a subject in the liraglutide 1.20 mg 
group). None of the diabetic retinopathy events were assessed as related to respective treatment.
Other clinical laboratory evaluations, physical examination and pregnancies
x
For biochemistry or haematology laboratory parameters not presented in the safety areas of interest, no clinically 
relevant changes were observed.
x
No clinically relevant treatment differences were observed in physical examination findings or fundoscopy.
x
Two (2) pregnancy cases were reported in this trial. One subject treated with semaglutide 0.05 mg, with a history 
of an uncomplicated pregnancy, was treated for 
 days and was discontinued from treatment on trial day 
 
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upon positive pregnancy test. This subject had a spontaneous abortion at trial day 
. The subject reported mild 
nausea on trial day 
, possibly related to treatment, 
. The second subject 
treated with liraglutide 1.80 mg had a positive pregnancy test at the end-of-treatment visit, and no AEs were 
reported in connection to the pregnancy. The subject delivered a healthy 
 child on 
 at 
gestational week 
 and days; no health problems, congentinal abnormalities, or receipt of replacement 
medications have been reported for the infant at 1 month of age.
CONCLUSIONS
In this 26-week multicentre, randomised, double-blinded (within dose level), dose-finding trial, the following is 
concluded:
x
Semaglutide administered once-daily effectively lowered HbA1c and body weight significantly more than 
placebo and dose-matched liraglutide at week 26.
x
Significantly greater reduction in HbA1c from baseline to week 26 was seen with semaglutide 0.30 mg 
(-1.88%-points) than liraglutide 1.80 mg (-1.31%-points) and placebo (-0.02%-points).
x
Significantly greater reductions in body weight was seen with semaglutide 0.30 mg (-8.23 kg) than 
liraglutide 1.80 mg (-3.75 kg) and placebo (-1.23 kg).
x
Semaglutide administered once-daily at doses up to 0.30 mg was well tolerated and no unanticipated safety 
concerns were identified.
x
Dose-response modelling indicated greater efficacy with semaglutide versus liraglutide, whereas the overall 
tolerability was similar between the two treatments.
The trial was conducted in accordance with the Declaration of Helsinki, ICH Good Clinical Practice and EN ISO 
14155 Part 1 and 2, and 21 CFR 312.120.
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Appendix 9
Country-specific requirements 
Section 6.1 Inclusion criteria
For Japan:
Age ≥ 20 years at the time of signing informed consent.
Section 7.5 Preparation/Handling/Storage/Accountability
For Japan: According to Japanese GCP, storage and drug accountability of the trial products at the 
study site is not in charge of Investigator, but in charge of the head of study site. 
The head of study site should assign some or all the responsibilities for accountability of the trial 
products at the sites to a trial product storage manager (a pharmacist in principle). The trial product 
storage manager should control and take accountability of the trial products in accordance with 
procedures specified by the sponsor. The head of study site or the trial product storage manager 
must ensure the availability of proper storage conditions, and record and evaluate the temperature. 
Section 9 Trial assessments and procedures
For US and Canada only: This trial will include an option for subjects to complete an anonymised 
questionnaire, ‘Study Participant Feedback Questionnaire’ for subjects to provide feedback on their 
clinical trial experience at the beginning (V1), the middle (V7) and the end (V10) of the trial. 
Individual subject level responses will not be reviewed by investigators. Responses would be used 
by the sponsor to understand where improvements can be made in the clinical trial process. This 
questionnaire does not collect data about the subject's disease, symptoms, treatment effect or 
adverse events and therefore would not be considered trial data or entered into the trial database.
Appendix 3 Trial governance considerations
For Japan: A seal is accepted as a signature.
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Appendix 10 Protocol amendment history
The protocol amendment summary of changes table for the current protocol version is located 
directly before the table of contents.
Protocol version. 2, including version 1: 05 July 2019, global
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union1.
Overall rationale for preparing protocol version 2:
Section # and name
Description of change
Brief rationale
7.7 Concomitant 
medication 
Update on the concomitant 
medication section to reflect 
stable background treatment 
throughout the trial.
To clarify the requirements for 
stable background medication 
during the trial, further to 
established eligibility criterion 
and protocol recommended initial 
dose reduction of sulphonylurea.
9.4.3 Eye 
examination
Text added to specify that at the 
end of treatment visit the eye 
examination result should be 
available and that the examination 
can be performed within 3 weeks 
prior to the end of treatment visit.
To clarify the timing of the 
availability of the eye 
examination result at the end of 
treatment visit. The extended 
window of availability will also 
facilitate data collection.
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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
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
Once-weekly Semaglutide
Trial ID: NN9535-4506
Clinical Trial Report
Appendix 16.1.1
08 December 2020
1.0
Final
CONFIDENTIAL

Protocol Amendment No.1
CONFIDENTIAL
Date:
31 May 2019
Novo Nordisk
Trial ID: NN9535-4506
Version:
1.0
UTN: U1111-1224-5162
Status:
Final
EUdraCT Number: 2018-004529-96
Page:
1 of 6
Protocol Amendment
No.1
to Protocol, version 1.0
dated 21 March 2019
Trial ID: NN9535-4506
Efficacy and safety of semaglutide 2.0 mg s.c. once-weekly compared to semaglutide 1.0 mg 
s.c. once-weekly in subjects with type 2 diabetes
Trial phase: 3b
Applicable to Czech Republic
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
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This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.

Protocol Amendment No.1
CONFIDENTIAL
Date:
31 May 2019
Novo Nordisk
Trial ID: NN9535-4506
Version:
1.0
UTN: U1111-1224-5162
Status:
Final
EUdraCT Number: 2018-004529-96
Page:
2 of 6
Table of Contents   
1
Introduction including rationale for the protocol amendment...........................................................3
2
Changes ................................................................................................................................................3
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Protocol Amendment No.1
CONFIDENTIAL
Date:
31 May 2019
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Trial ID: NN9535-4506
Version:
1.0
UTN: U1111-1224-5162
Status:
Final
EUdraCT Number: 2018-004529-96
Page:
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1
Introduction including rationale for the protocol amendment
This Protocol Amendment 1 was created based on the requirements of Czech Regulatory Authority 
(SUKL) and is applicable for the Czech Republic only. Since reproductive toxicity has been 
demonstrated during preclinical studies, Czech Regulatory Authority requires women with 
childbearing potential to use only a highly reliable methods of contraception (Pearls index <1), 
which does not include a two-barrier method. This requirement is in line with the recommendation 
of „Recommendations related to contraception and pregnancy testing in clinical trials“, which can 
be located at:
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01About_HMA/Working_Groups/CTFG/
2014_09_HMA_CTFG_Contraception.pdf. 
Therefore, adequate modification of recommended contraceptive methods in the Protocol –
Appendix 5 has been done.
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
2
Changes
Appendix 5 Contraceptive guidance and collection of pregnancy information
It must be recorded in the CRF whether female subjects are of childbearing potential. 
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile. 
Women in the following categories are not considered WOCBP
1. Premenarcheal 
2. Premenopausal female with one of the following:
!
Documented hysterectomy
!
Documented bilateral salpingectomy
!
Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s review of subject’s medical 
records, medical examination or medical history interview.
3. Postmenopausal female
!
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high Follicle Stimulating Hormone (FSH) level in the 
postmenopausal range may be used to confirm a postmenopausal state in women not 
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Protocol Amendment No.1
CONFIDENTIAL
Date:
31 May 2019
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Trial ID: NN9535-4506
Version:
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UTN: U1111-1224-5162
Status:
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EUdraCT Number: 2018-004529-96
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using hormonal contraception or Hormonal Replacement Therapy (HRT). However, 
in the absence of 12 months of amenorrhea, a single Follicle-Stimulating Hormone 
(FSH measurement is insufficient. 
!
Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-hormonal highly effective contraception methods if they wish to 
continue their HRT during the trial. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before trial enrolment.
Contraception guidance
Male subjects 
No contraception measures are required for male subjects as the risk of teratogenicity/fetotoxicity 
caused by transfer of semaglutide in seminal fluid is unlikely. 
Female subjects
Female subjects of childbearing potential are eligible to participate if they agree to use methods of 
contraception consistently and correctly as described in table(s) below:
Table 12-3
Highly effective contraceptive methods
Highly effective contraceptive methods that are user dependent a and b
Failure rate of <1% per year when used consistently and correctly. 
Combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation 
! oral
! intravaginal
! transdermal
Progestogen only hormonal contraception associated with inhibition of ovulation
! oral 
! injectable 
Highly effective methods that are user independent b
Implantable progestogen only hormonal contraception associated with inhibition of ovulation 
! Intrauterine Device (IUD)
! Intrauterine hormone-releasing System (IUS)
! Bilateral tubal occlusion
Vasectomised partner 
A vasectomised partner is a highly effective contraception method provided that the partner is the sole male sexual 
partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. 
Sexual abstinence b
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse 
during the entire period of risk associated with the trial product. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the trial and the preferred and usual lifestyle of the subject. 
Notes: 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with 
local regulations regarding the use of contraceptive methods for subjects participating in clinical trials. 
b Contraception should be utilised during the treatment period and for at least 7 weeks after the last dose of trial 
product.
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Protocol Amendment No.1
CONFIDENTIAL
Date:
31 May 2019
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Trial ID: NN9535-4506
Version:
1.0
UTN: U1111-1224-5162
Status:
Final
EUdraCT Number: 2018-004529-96
Page:
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In certain cases, it is accepted to use double barrier methods (a condom combined with an occlusive 
cap (e.g. diaphragm) with/without the use of spermicide). This should only be allowed in females 
with:
1. known intolerance to the highly effective methods mentioned in Table 12-3 or where the use 
of any of the listed highly effective contraceptive measures are contraindicated in the 
individual subject, and/or
2. if the risk of initiating treatment with a specific highly effective method outweighs the 
benefit for the female.
Justification for accepting double barrier method should be at the discretion of the investigator 
taking into consideration his/her knowledge about the female’s medical history, concomitant illness, 
concomitant medication and observed AEs. The justification must be stated in the medical records.
Pregnancy testing
!
WOCBP should only be included after a negative highly sensitive urine pregnancy test.
!
Additional urine pregnancy testing should be performed at every site visit (every 4-8 weeks) 
during the treatment period, at the end of treatment and after the 7 weeks follow-up period 
after the end of treatment, according to the flow chart.
!
Pregnancy testing should be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected.
!
All subjects will be provided with a pregnancy test prior to the phone visits to perform them 
prior to the phone call, not only if pregnancy is suspected. 
Collection of pregnancy information 
Female subjects who become pregnant 
!
Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this trial.
!
Information will be recorded on the appropriate form and submitted to Novo Nordisk within 
14 calendar days of learning of a subject's pregnancy.
!
Subject will be followed to determine the outcome of the pregnancy. The investigator will 
collect follow-up information on subject and neonate, which will be forwarded to Novo 
Nordisk. Generally, follow-up will not be required for longer than 1 month beyond the 
delivery date.
!
Any termination of pregnancy will be reported, regardless of foetal status (presence or 
absence of anomalies) or indication for procedure.
!
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication 
or elective termination of a pregnancy will be reported as an AE or SAE. 
!
A spontaneous abortion is always considered to be an SAE and will be reported as such.
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Protocol Amendment No.1
CONFIDENTIAL
Date:
31 May 2019
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Trial ID: NN9535-4506
Version:
1.0
UTN: U1111-1224-5162
Status:
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EUdraCT Number: 2018-004529-96
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!
Any SAE occurring as a result of a post-trial pregnancy which is considered 
possibly/probably related to the trial product by the investigator will be reported to Novo 
Nordisk as described in Appendix 4. While the investigator is not obligated to actively seek 
this information in former subjects, he or she may learn of an SAE through spontaneous 
reporting. 
Any female subject who becomes pregnant while participating in the trial will discontinue trial 
product.
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Protocol Amendment no 2
CONFIDENTIAL
Date:
05 July 2019
Novo Nordisk
Trial ID: NN9535-4506
Version:
1.0
Status:
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Page:
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Protocol Amendment
no 2
to Protocol, version 1
dated 21 March 2019
Trial ID: NN9535-4506
Efficacy and safety of semaglutide 2.0 mg s.c. once-weekly compared to semaglutide 1.0 mg 
s.c. once-weekly in subjects with type 2 diabetes
Trial phase: 3b
Applicable to all countries
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
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CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.

Protocol Amendment no 2
CONFIDENTIAL
Date:
05 July 2019
Novo Nordisk
Trial ID: NN9535-4506
Version:
1.0
Status:
Final
Page:
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Table of Contents  
1
Introduction including rationale for the protocol amendment...........................................................3
2
Changes ................................................................................................................................................3
2.1
Section 7.7 Concomitant medication..........................................................................................3
2.2
Section 9.4.3 Eye examination...................................................................................................4
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Protocol Amendment no 2
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Trial ID: NN9535-4506
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1
Introduction including rationale for the protocol amendment
This protocol is amended for the following reasons: 
!
To clarify requirements for stable background medication during the trial, further to established 
eligibility criterion and protocol recommended initial dose reduction of sulphonylurea
!
To clarify the timing of the availability of the eye examination result at the end of treatment 
visit. The extended window of availability will also facilitate data collection.
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
2
Changes
2.1
Section 7.7 Concomitant medication
Any medication (including over-the-counter or prescription medicines) other than the trial product 
that the subject is receiving at the time of the first visit or receives during the trial must be recorded 
along with:
!
Trade name or generic name
!
Indication
!
Dates of administration including start and stop dates
!
Dose (only to be recorded for anti-hyperglycaemic medication)
Treatment with metformin and SU is considered non-investigational medicinal products and should 
be used according to their respective labels and will be used open-label throughout the trial.
To mitigate SU induced hypoglycaemia, subjects treated with SU will be asked to reduce the SU 
dose by approximately 50% at the discretion of the investigator, from randomisation. In case of 
persistent hyperglycaemia, glycaemic rescue treatment could be initiated as described in Section 
After signing the informed consent, subjects must continue their anti-diabetic background 
medication (metformin with or without SU) throughout the entire trial. 
To mitigate SU-induced hypoglycaemia, subjects treated with SU should, at the discretion of the 
investigator, reduce the SU dose at randomisation by approximately 50%.
Apart from the initial dose reduction of SU, background medication dose should remain at the same 
dose level and with the same frequency during the entire treatment period unless glycaemic rescue 
treatment is needed (as described in Section 8.1.2) or safety concern related to the use of 
background medications arises.
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Trial ID: NN9535-4506
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In addition, all background medication:
!
is considered to be non-investigational medicinal product.
!
will not be provided by Novo Nordisk A/S, except if required by local regulations and not in 
contradiction to local regulations.
!
should be used in accordance with standard of care and current approved label in the 
individual country.
!
should not exceed the maximum approved dose in the individual country.
Investigators can switch OAD treatment within the same drug class, e.g. in case specific drugs 
become unavailable. 
Any change in concomitant medication, including switch of OAD treatment within the same drug 
class, must be recorded at each visit. If a change is due to an AE, then this must be reported 
according to Section 9.2
2.2
Section 9.4.3 Eye examination
Subjects with uncontrolled and potentially unstable diabetic retinopathy or maculopathy are not 
eligible, as this indicates retinopathy that has recently progressed to a level that requires 
intervention or is approaching intervention but has yet to be brought under control.
Results of an eye examination performed by an ophthalmologist or another suitably qualified 
healthcare provider must be available and evaluated by the investigator before randomisation to
assess eligibility. The eye examination should be performed as a fundus photography (e.g. 2-field
60 degree or better, colour or red-free) or by slit-lamp biomicroscopy examination (e.g. using a pre-
corneal or corneal contact lens examination). Pharmacological pupil-dilation is a requirement unless 
using a fundus photography camera specified for non-dilated examination.
If the subject had such an eye examination performed within 90 days prior to screening, the 
investigator may base his/her evaluation upon the results of that examination. The examination must
be repeated before randomisation if the subject has experienced worsening of visual function since
the last examination. If the applicable eye examination was performed before the subject signed the
informed consent form, it must be documented that the reason for performing the examination was
not related to this trial.
After randomisation an eye examination performed according to the above must be performed as 
per the flowchart in Section 2. Results must be available at V10 (end of treatment visit). An eye 
examination performed within 3 weeks prior to V10 is acceptable, provided no clinical symptoms 
suggestive of eye disease have occurred in the meantime.
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Protocol Amendment no 2
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Date:
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Trial ID: NN9535-4506
Version:
1.0
Status:
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The investigator should indicate the outcome of each eye examination. Relevant findings prior to 
randomisation must be recorded as concomitant illness/medical history, while relevant findings 
occurring after randomisation should be reported as an AE, if applicable according to Section 9.2
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