Clinical trial NCT03548987
Conditions: Metabolism and Nutrition Disorder Obesity
Sponsor: Novo Nordisk A/S
Start date: 2018-06-04; Completion date: 2020-03-20
Enrollment: 902 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will look at the change in participant's body weight from the start to the end of the study. This is to compare the effect on body weight in people taking semaglutide (a new medicine) and people taking "dummy" medicine. In addition to taking the medicine, the participant will have talks with study staff about healthy food choices, how to be more physically active and what a participant can do to lose weight.

The participant will get semaglutide for the first 20 weeks. Then the participant will get either semaglutide or "dummy" medicine - which treatment the participant gets after the 20 weeks is decided by chance. The participants will need to take 1 injection once a week. The study medicine is injected with a thin needle in a skin fold in the stomach, thigh or upper arm. The study will last for about 1.5 years.

Detailed description:

Arms: arm 1: Run-in Period: Participants will receive semaglutide at an escalating doses (0.25 mg, 0.5 mg, 1 mg, 1.7 mg, 2.4 mg) for 20 weeks (week 0 to week 20). The dose will be escalated to next level every 4 weeks.

Maintenance period: Participants will be randomized to receive semaglutide injection for 48 weeks (from week 20 to week 68).

The trial product will be administered as an adjunct to a reduced-calorie diet and increased physical activity during the trial period. arm 2: Run-in Period: Participants will receive semaglutide at an escalating doses (0.25 mg, 0.5 mg, 1 mg, 1.7 mg, 2.4 mg) for 20 weeks (week 0 to week 20). The dose will be escalated to next level every 4 weeks.

Maintenance period: Participants will be randomized to receive semaglutide placebo injection for 48 weeks (from week 20 to week 68).

The trial product will be administered as an adjunct to a reduced-calorie diet and increased physical activity during the trial period.
Interventions: intervention 1: Semaglutide intervention 2: Placebo
Intervention descriptions: intervention 1: Subcutaneous (under the skin) injection of semaglutide once-weekly. intervention 2: Subcutaneous (under the skin) injection of semaglutide placebo once-weekly.

Protocol documents:
Prot_000.pdf: 
Cover Page for Protocol 
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT03548987 
Sponsor trial ID: 
NN9536-4376 
Official title of study: 
Effect and safety of semaglutide 2.4 mg once-weekly in 
subjects with overweight or obesity who have reached target 
dose during run-in period 
Document date: 
03-June-2020 
 


Link
Link
Link
Link
Link
List of contents
Protocol ...............................................................................................................................................
Attachment I and II............................................................................................................................
Amendment 1 - SE..............................................................................................................................
Amendment 2 - Global.......................................................................................................................
Amendment 3 - Global.......................................................................................................................
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
SemaglutideVFPJRQFHZHHNO\
Trial ID: NN9536-437667(3
Clinical Trial Report
Appendix 16.1.1
03 JunH 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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Date:
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Trial ID: NN9536-4376
Version:
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Status:
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Protocol
Protocol title: Effect and safety of semaglutide 2.4 mg once-weekly in subjects with 
overweight or obesity who have reached target dose during run-in period
Substance name: semaglutide
Universal Trial Number: U1111-1201-0898 
EudraCT Number: 2017-003473-34 
Trial phase: 3a
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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CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


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Table of Contents   
Page
Table of Contents........................................................................................................................................2
1
Synopsis................................................................................................................................................5
2
Flowchart .............................................................................................................................................8
3
Introduction .......................................................................................................................................12
3.1
Trial rationale..........................................................................................................................12
3.2
Background.............................................................................................................................13
3.2.1
Semaglutide...........................................................................................................13
3.2.2
Trial population .....................................................................................................13
3.3
Benefit-risk assessment ...........................................................................................................14
3.3.1
Benefits .................................................................................................................14
3.3.2
Risks and precautions.............................................................................................14
3.3.3
Conclusion on benefit-risk profile ..........................................................................15
4
Objectives and endpoints...................................................................................................................16
4.1
Primary, secondary and exploratory objectives ........................................................................16
4.1.1
Primary objective...................................................................................................16
4.1.2
Secondary objectives .............................................................................................16
4.1.3
Exploratory objectives ...........................................................................................17
4.2
Primary, secondary and exploratory endpoints.........................................................................18
4.2.1
Primary endpoint ...................................................................................................18
4.2.2
Secondary endpoints ..............................................................................................18
4.2.2.1
Confirmatory secondary endpoints ...................................................18
4.2.2.2
Supportive secondary endpoints .......................................................18
4.2.3
Exploratory endpoints............................................................................................19
5
Trial design ........................................................................................................................................20
5.1
Overall design.........................................................................................................................20
5.2
Subject and trial completion....................................................................................................21
5.3
End of trial definition ..............................................................................................................21
5.4
Scientific rationale for trial design...........................................................................................22
5.5
Justification for dose ...............................................................................................................22
6
Trial population .................................................................................................................................22
6.1
Inclusion criteria .....................................................................................................................23
6.2
Exclusion criteria ....................................................................................................................23
6.3
Run-in criteria and randomisation criteria................................................................................24
6.3.1
Run-in criteria........................................................................................................24
6.3.2
Randomisation criteria ...........................................................................................25
6.4
Lifestyle restrictions................................................................................................................25
6.4.1
Meals and dietary restrictions.................................................................................25
6.4.2
Caffeine and tobacco..............................................................................................25
6.5
Screen failures ........................................................................................................................25
7
Treatments .........................................................................................................................................26
7.1
Treatments administered .........................................................................................................26
7.1.1
Medical devices .....................................................................................................28
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7.1.2
Diet and physical activity counselling ....................................................................28
7.2
Dose modification...................................................................................................................29
7.3
Method of treatment assignment..............................................................................................29
7.4
Blinding..................................................................................................................................29
7.5
Preparation/Handling/Storage/Accountability..........................................................................30
7.6
Treatment compliance.............................................................................................................31
7.7
Concomitant medication..........................................................................................................31
7.7.1
Rescue medication.................................................................................................32
7.8
Treatment after the end of the trial...........................................................................................32
8
Discontinuation/Withdrawal criteria ................................................................................................32
8.1
Discontinuation of trial treatment ............................................................................................32
8.1.1
Temporary discontinuation of trial treatment..........................................................33
8.2
Withdrawal from the trial ........................................................................................................33
8.2.1
Replacement of subjects.........................................................................................34
8.3
Lost to follow-up.....................................................................................................................34
9
Trial assessments and procedures .....................................................................................................34
9.1
Efficacy assessments...............................................................................................................36
9.1.1
Body measurements...............................................................................................36
9.1.2
Clinical outcome assessment..................................................................................36
9.1.3
Clinical efficacy laboratory assessments.................................................................37
9.2
Adverse events........................................................................................................................37
9.2.1
Time period and frequency for collecting AE and SAE information........................37
9.2.1.1
Events for adjudication.....................................................................39
9.2.2
Method of detecting AEs and SAEs .......................................................................39
9.2.3
Follow-up on AEs and SAEs..................................................................................40
9.2.4
Regulatory reporting requirements for SAEs ..........................................................40
9.2.5
Hypoglycaemic, cardiovascular and death events ...................................................40
9.2.6
Disease-related events and/or disease-related outcomes not qualifying as an AE 
or SAE...................................................................................................................40
9.2.7
Pregnancies and associated adverse events .............................................................40
9.2.8
Medical device incidents (including malfunctions).................................................41
9.2.9
Technical complaints .............................................................................................41
9.3
Treatment of overdose.............................................................................................................42
9.4
Safety assessments ..................................................................................................................42
9.4.1
Mental health assessment instruments ....................................................................43
9.4.2
Physical examinations............................................................................................44
9.4.3
Vital signs..............................................................................................................44
9.4.4
Electrocardiograms ................................................................................................44
9.4.5
Clinical safety laboratory assessments....................................................................44
9.5
Pharmacokinetics ....................................................................................................................45
9.6
Pharmacodynamics .................................................................................................................45
9.7
Genetics..................................................................................................................................45
9.8
Biomarkers .............................................................................................................................45
9.9
Severe hypersensitivity............................................................................................................45
10
Statistical considerations ...................................................................................................................45
10.1
Sample size determination.......................................................................................................46
10.2
Definition of analysis sets........................................................................................................48
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10.3
Statistical analyses ..................................................................................................................48
10.3.1
Primary endpoint ...................................................................................................49
10.3.2
Secondary endpoints ..............................................................................................53
10.3.2.1
Confirmatory secondary endpoints ...................................................53
10.3.2.2
Supportive secondary endpoints .......................................................54
10.3.3
Exploratory endpoints............................................................................................57
10.3.4
Other analyses .......................................................................................................57
10.4
Pharmacokinetic and/or pharmacodynamic modelling .............................................................57
11
Appendices .........................................................................................................................................58
Abbreviations and Trademarks.......................................................................................59
Appendix 1
Clinical laboratory tests ...................................................................................................62
Appendix 2
Trial governance considerations......................................................................................65
Appendix 3
Adverse events: definitions and procedures for recording, evaluation, follow-up, 
Appendix 4
and reporting .....................................................................................................................................75
Contraceptive guidance and collection of pregnancy information .................................80
Appendix 5
Technical complaints: Definition and procedures for recording, evaluation, follow-
Appendix 6
up and reporting ................................................................................................................................83
Monitoring of calcitonin...................................................................................................85
Appendix 7
Country-specific requirements ........................................................................................88
Appendix 8
12
References ..........................................................................................................................................89
Attachment I Global list of key staff and relevant departments and suppliers
Attachment II Country list of key staff and relevant departments
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1
Synopsis
Rationale:
The present trial is a 68-week trial designed to show reduction in body weight and compare the 
effect and safety of semaglutide subcutaneous (s.c.) 2.4 mg once-weekly versus semaglutide 
placebo as an adjunct to reduced-calorie diet and increased physical activity in subjects with 
overweight or obesity who have reached target dose of semaglutide during a 20 weeks run-in 
period. 
The purpose of the trial is:
!
to investigate the effect of semaglutide on body weight in subjects who have reached the 
target dose during run-in
!
to access the weight development after switching to semaglutide placebo (withdrawal trial 
design) as recommended in the regulatory guidelines
!
to generate data to support maintained weight loss in subjects continuing semaglutide 
treatment compared to subjects switching to semaglutide placebo
Objectives and endpoints:
Primary objective
Effect-related: randomisation (week 20) to week 68
To compare the effect of semaglutide s.c. 2.4 mg once-weekly versus semaglutide placebo as an 
adjunct to reduced-calorie diet and increased physical activity in subjects with overweight or 
obesity who have reached target dose of semaglutide during the run-in period, on body weight. 
Key secondary objectives
Effect-related: randomisation (week 20) to week 68
To compare the effect of semaglutide s.c. 2.4 mg once-weekly versus semaglutide placebo as an 
adjunct to reduced-calorie diet and increased physical activity in subjects with overweight or 
obesity who have reached target dose of semaglutide during the run-in period, on 
!
cardiovascular risk factors 
!
clinical outcome assessments
Safety and tolerability: randomisation (week 20) to week 75
To compare the safety and tolerability of semaglutide s.c. 2.4 mg once-weekly versus semaglutide  
placebo as an adjunct to reduced-calorie diet and increased physical activity in subjects with 
overweight or obesity who have reached target dose of semaglutide during the run-in period. 
Primary estimand 
The estimand will quantify the average treatment effect of semaglutide relative to semaglutide 
placebo after 48 weeks’ treatment with semaglutide at the target dose, as an adjunct to reduced-
calorie diet and increased physical activity, in all randomised subjects regardless of adherence to
treatment provided that the subjects are able to reach the target dose of semaglutide during 20 
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Trial ID: NN9536-4376
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weeks run-in with escalating semaglutide doses and regardless of starting rescue interventions 
(weight management drugs or bariatric surgery) (“effectiveness”/”treatment policy” estimand).
The primary estimand will cover all objectives except the secondary objective addressing ‘Effect-
related: week 0 to week 68’.
Primary endpoint
Change from randomisation (week 20) to week 68 in body weight (%)
Confirmatory secondary endpoints
Effect endpoints from randomisation (week 20) to week 68 
Change in:
!
Waist circumference (cm)
!
Systolic blood pressure (mmHg)
!
Physical functioning score (SF-36)
!
Total score (Weight Related Sign and Symptom Measure (WRSSM))
Overall design:
This is a 68-week, randomised, double-blind, placebo-controlled, two-armed multi-centre, 
multinational withdrawal clinical trial comparing once-weekly semaglutide s.c. 2.4 mg with 
semaglutide placebo in subjects with overweight or obesity. 
Key inclusion criteria
!
Male or female, age ≥ 18 years at the time of signing informed consent
!
BMI ≥ 30 kg/m2 or ≥ 27 kg/m2 with the presence of at least one of the following weight-
related comorbidities (treated or untreated): hypertension, dyslipidaemia, obstructive sleep 
apnoea or cardiovascular disease 
!
History of at least one self-reported unsuccessful dietary effort to lose body weight
Key exclusion criteria
!
HbA1c ≥ 48 mmol/mol (6.5%) as measured by central laboratory at screening 
!
A self-reported change in body weight > 5 kg (11 lbs) within 90 days before screening 
irrespective of medical records
Randomisation criteria
!
attend the randomisation visit (week 20), and
!
have escalated to target dose after 16 weeks ± 3 days since week 0, and
!
are at target dose at the randomisation visit (week 20)
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Date:
21 December 2017
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Trial ID: NN9536-4376
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Number of subjects:
Approximately 1059 subjects will be screened to achieve 900 subjects to be included in the run-in 
period to reach the anticipated 750 subjects randomly assigned to trial product in the maintenance 
period.
Treatment groups and duration:
The total trial duration for the individual subject will be approximately 76 weeks. The trial includes 
a screening period of approximately 1 week. Eligible subjects will at V2 (week 0) start dose 
escalation with semaglutide as an adjunct to a reduced-calorie diet and increased physical activity 
for 20 weeks (run-in period). Subjects fulfilling all randomisation criteria at V12 (week 20) will be 
randomised in a 2:1 manner to either continue receiving semaglutide s.c. 2.4 mg once-weekly for 
additional 48 weeks or being switched to once-weekly semaglutide placebo for 48 weeks, still as an 
adjunct to a reduced-calorie diet and increased physical activity. The treatment continues until the 
‘end of treatment’ visit followed by a 7 weeks follow-up period.
The following trial products will be supplied by Novo Nordisk A/S:
!
Semaglutide B 1.0 mg/mL PDS290, solution for injection, 3 mL PDS290 pre-filled pen-
injector
!
Semaglutide B 3.0 mg/mL PDS290, solution for injection, 3 mL PDS290 pre-filled pen-
injector
!
Semaglutide placebo, solution for injection, 3 mL PDS290 pre-filled pen-injector
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Date:
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2
Flowchart
Screening
Run-in
Rando-
misation
Maintenance period
End of 
treatment
End
of trial
Visit(V), Phone (P)
V1
V2 P3 V4 P5 V6 P7 V8 P9 V10 P11
V12
V13 V14 P15 V16 P17 V18 P19 V20P21V22P23
V24
V25
Timing of Visit (Weeks)
-1
0
2
4
6
8
10 12 14
16
18
20
24
28
32
36
40
44
48
52 56 60 64
68
75
Visit Window (Days)
-7 to 0
0
±3 ±3 ±3 ±3 ±3 ±3 ±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3 ±3 ±3 ±3
±3
0 to +5
SUBJECT RELATED 
INFORMATION AND 
ASSESSMENTS
Informed consent and Demographya 
(Appendix 3)
X
Childbearing potentialb (Appendix 5)
X
Inclusion criteria (6.1)
X
X
Exclusion criteria (6.2)
X
X
Run-in criteria  (6.3.1)
X
Randomisation criteria and 
randomisationc (6.3.2)
X
Medical history/Concomitant illness 
(9.4)
X
Weight History (9)
X
History of Gallbladder Disease (9.4)
X
History of Breast Neoplasmb (9.4)
X
History of Colon Neoplasm (9.4)
X
History of Skin Cancer (9.4)
X
History of Psychiatric Disorder (9.4)
X
Tobacco Used
X
Concomitant medication (7.7)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Trial product compliance (7.1, 7.6)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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Date:
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Screening
Run-in
Rando-
misation
Maintenance period
End of 
treatment
End
of trial
Visit(V), Phone (P)
V1
V2 P3 V4 P5 V6 P7 V8 P9 V10 P11
V12
V13 V14 P15 V16 P17 V18 P19 V20P21V22P23
V24
V25
Timing of Visit (Weeks)
-1
0
2
4
6
8
10 12 14
16
18
20
24
28
32
36
40
44
48
52 56 60 64
68
75
Visit Window (Days)
-7 to 0
0
±3 ±3 ±3 ±3 ±3 ±3 ±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3 ±3 ±3 ±3
±3
0 to +5
Evaluation of lipid-lowering treatment 
(9)
X
X
Evaluation of antihypertensive 
treatment (9)
X
X
Evaluation of glycaemic status (9)
X
X
X
EFFICACY
Body measurements (9.1.1)
     Height 
X
     Body Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
     Waist Circumference
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HbA1c 
X
X
X
X
X
Fasting plasma glucose 
X
X
X
X
Fasting serum insulin 
X
X
X
Lipids (Appendix 2)
X
X
X
Vital Signs (6.4.2, 9.4.3)
     Systolic Blood Pressure
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
     Diastolic Blood Pressure
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Clinical Outcome Assessments (9.1.2)
     Short Form-36 (SF-36)
X
X
X
X
X
X
X
     Weight Related Sign and Symptom   
Measure (WRSSM)
X
X
X
X
X
X
X
     Patient Global Impression of      
Severity (PGI-S)
X
X
X
X
X
X
X
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Protocol
     
Date:
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Status:
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Trial ID: NN9536-4376
     
Version:
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Screening
Run-in
Rando-
misation
Maintenance period
End of 
treatment
End
of trial
Visit(V), Phone (P)
V1
V2 P3 V4 P5 V6 P7 V8 P9 V10 P11
V12
V13 V14 P15 V16 P17 V18 P19 V20P21V22P23
V24
V25
Timing of Visit (Weeks)
-1
0
2
4
6
8
10 12 14
16
18
20
24
28
32
36
40
44
48
52 56 60 64
68
75
Visit Window (Days)
-7 to 0
0
±3 ±3 ±3 ±3 ±3 ±3 ±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3 ±3 ±3 ±3
±3
0 to +5
     Patient Global Impression of 
Change (PGI-C)
X
X
X
X
X
X
X
     Stanford Presenteeism Scale (SPS-
6)
X
X
X
SAFETY
Physical examination (9.4.2)
X
X
X
Pregnancy test (9.4.5, Appendix 5)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECG (9.4.4)
X
X
X
Adverse event (9.2, Appendix 4)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Technical complaint (9.2.9, Appendix
6)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Breast neoplasms follow-upb (9.4)
X
X
Colon neoplasms follow-up (9.4)
X
X
Haematology (Appendix 2)
X
X
X
X
Biochemistry (Appendix 2)
X
X
X
X
Vital Signs (6.4.2, 9.4.3)
     Pulse
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Clinical Outcome Assessments (9.4.1)
     Patient Health Questionnaire – 9 
(PHQ-9)
X
X
X
X
X
X
X
     Columbia Suicide Severity Rating 
Scale (C-SSRS)
X
X
X
X
X
X
X
TRIAL MATERIAL
First date on trial product
X
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Protocol
     
Date:
21 December 2017
Status:
Final
Novo Nordisk
Trial ID: NN9536-4376
     
Version:
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Screening
Run-in
Rando-
misation
Maintenance period
End of 
treatment
End
of trial
Visit(V), Phone (P)
V1
V2 P3 V4 P5 V6 P7 V8 P9 V10 P11
V12
V13 V14 P15 V16 P17 V18 P19 V20P21V22P23
V24
V25
Timing of Visit (Weeks)
-1
0
2
4
6
8
10 12 14
16
18
20
24
28
32
36
40
44
48
52 56 60 64
68
75
Visit Window (Days)
-7 to 0
0
±3 ±3 ±3 ±3 ±3 ±3 ±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3 ±3 ±3 ±3
±3
0 to +5
IWRS session
X
X
X
X
X
X
X
X
X
X
X
Administration of trial product (7.1, 
7.5)
     Dispensing visit
X
X
X
X
X
X
X
X
X
     Drug accountability
X
X
X
X
X
X
X
X
X
X
REMINDERS
Criteria for discontinuation (8.1)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Barriers and motivation interview (9)
X
Diet and physical activity counselling 
(7.1.2)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Training in trial product, pen-handling 
(7.1.1)
X
X
X
X
X
X
X
X
X
X
X
Hand out direction for use (7.1.1)
X
Hand out dose reminder card (7.1)
X
X
X
X
X
Hand out and instruct in food diary (9)
X
Hand out ID card 
X
Attend visit fasting (6.4.1)
X
X
X
X
a Demography consists of date of birth, sex, ethnicity, and race (according to local regulation)
b For all female subjects
c If subjects not fulfil randomisation criteria see Section 6.3.2
d Smoking is defined as smoking at least one cigarette or equivalent daily
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3
Introduction
3.1
Trial rationale
The prevalence of obesity has reached epidemic proportions in most countries around the world and 
the prevalence is still increasing at an alarming rate1-7. The medical and societal impacts are 
considerable and obesity is one of the most significant public health challenges worldwide1-7.
Obesity is associated with increased risk of a variety of comorbidities including hyperglycaemia, 
type 2 diabetes (T2D), hypertension, dyslipidaemia, obstructive sleep apnoea, atherosclerosis, 
osteoarthritis, urinary incontinence, non-alcoholic steatohepatitis, cardiovascular disease, certain 
types of cancer, and risk of early death8-22. Moreover, obesity adversely affects physical and mental 
health and reduces health related quality of life23, 24. Obesity is also associated with decreased 
cardiorespiratory fitness, which also increases the risk of cardiovascular disease and all-cause 
mortality25.
The risk of obesity-related complications and comorbidities increases with increasing body mass 
index (BMI), and a weight loss of 5−10% has significant health benefits in terms of slowing 
progression to T2D26-29. Furthermore, a weight loss of 5−10% improves many other obesity related 
comorbidities as well as physical symptoms and quality of life 30-37. Finally, studies suggest a 
beneficial impact of weight loss on cardiovascular risk and mortality in both people with diabetes 
and obesity38-40.
Lifestyle intervention in the form of diet and exercise is first line treatment for obesity, but most 
people with obesity struggle to achieve and maintain their weight loss41-50. Surgical treatments offer 
an effective alternative for some people with severe obesity, but surgery carries a risk in connection 
with the procedure and is not without complications. Furthermore, surgery requires close follow-up 
of the individual which can be cumbersome and costly41-46, 51, 52. Pharmacotherapy may therefore 
serve as a valuable adjunct to lifestyle intervention for individuals with obesity in order to achieve 
and sustain a clinically relevant weight loss, to improve comorbid conditions and to facilitate a 
healthier lifestyle. Few anti-obesity medications are currently available and there is a need for more 
safe and effective therapeutic options for treatment of obesity, especially treatments that also target 
weight maintenance, prevention and treatment of comorbidities41-45, 53, 54.
The present trial is a 68-week trial designed to show reduction in body weight and compare the 
effect and safety of once-weekly semaglutide 2.4 mg versus semaglutide placebo as an adjunct to 
reduced-calorie diet and increased physical activity in subjects with overweight or obesity who have 
reached target dose of semaglutide during a 20 weeks run-in period. 
The purpose of the trial is:
!
to investigate the effect of semaglutide on body weight in subjects who have reached the 
target dose during run-in
!
to access the weight development after switching to semaglutide placebo (withdrawal trial 
design) as recommended in the regulatory guidelines
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!
to generate data to support maintained weight loss in subjects continuing semaglutide 
treatment compared to subjects switching to semaglutide placebo
3.2
Background
3.2.1
Semaglutide
Semaglutide is the next generation glucagon-like peptide-1 (GLP-1) receptor agonist (RA) currently 
under development by Novo Nordisk for the treatment of weight management (NN9536). 
Semaglutide has been optimised resulting in a longer half-life of approximately 160 hours, making 
it suitable for once-weekly dosing55. GLP-1 RA is a physiological regulator of appetite and GLP-1 
receptors are present in several areas of the brain involved in appetite regulation56.
A 52-week phase 2 dose-finding trial within weight management (NN9536-4153) has recently been 
completed. A total of 957 randomised subjects with obesity (without diabetes) were exposed to 
semaglutide (n=718), liraglutide 3.0 mg (n=103) or placebo (n=136). In this trial, an overall 
monotone dose-dependent weight loss was observed across the 5 semaglutide doses tested (0.05 to 
0.4 mg once-daily). The estimated weight loss at week 52 was 13.8% at the highest dose tested (0.4 
mg once-daily) compared to the weight loss of 2.3% achieved by diet, exercise and placebo alone57.
Clinical58-62 and non-clinical data63 indicate that the body weight-reducing effect of semaglutide is 
mainly mediated by a reduced energy intake. No unexpected safety findings were identified and the 
tolerability and safety profile was overall consistent with previous findings in the T2D development 
programme and the GLP-1 RA class in general. 
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)57 and any updates hereof.
3.2.2
Trial population 
The trial population will consist of subjects with obesity (BMI ≥ 30 kg/m2) or with overweight 
(BMI ≥ 27 kg/m2) and weight-related comorbidities. These subjects represent a clinically relevant 
population for pharmacotherapeutic weight management as they are at significant risk for weight-
related morbidities and mortality, and are likely to benefit from weight reduction. Information about 
weight-related comorbidities, including hypertension, dyslipidaemia, obstructive sleep apnoea or 
cardiovascular disease, will be collected systematically at screening by the investigators as part of 
the medical history.
Subjects with T2D are excluded from the trial. Subjects with overweight or obesity and T2D will be 
addressed in a dedicated trial.
First line treatment in weight management should always be lifestyle modification through a 
reduced-calorie diet and increased physical activity. Thus only subjects who have tried but failed a 
dietary weight loss intervention will be included in accordance with regulatory guidelines.64, 65
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3.3
Benefit-risk assessment
3.3.1
Benefits
Subjects will be treated with a regimen anticipated to be better than or equal to the weight 
management they receive at the time of entry into the trial. Results from the phase 2 trial (NN9536-
4153) demonstrated that semaglutide once-daily as an adjunct to a reduced-calorie diet and 
increased physical activity was effective for weight loss in subjects with obesity, while displaying a 
satisfactory tolerability profile. Overall, a monotone dose-dependent weight loss was observed 
across all tested doses of semaglutide (0.05 to 0.4 mg once-daily). The weight loss was 11.55 
percentages point larger for the 0.4 mg group compared with placebo. Weight loss was 
accompanied by a consistent improvement in the weight-related comorbidities, indicated by 
cardiovascular risk factors, lipid profile and glycaemic factors, as well as improvements in clinical 
outcome assessments.
In addition, it is expected that all subjects will benefit from participation through close contact with 
the trial site and counselling by a dietician or a similar qualified healthcare professional, all of 
which will most likely result in intensified weight management.
3.3.2
Risks and precautions
The sections below describe identified and potential risks associated with semaglutide treatment. 
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.
Identified risks
!
Gastrointestinal adverse events
Consistent with findings with other GLP-1 RAs, the most frequently reported adverse events 
(AE) in clinical trials with semaglutide were gastrointestinal AEs. A low starting dose and 
dose escalation steps will be implemented in the trial to mitigate the risk of gastrointestinal 
AEs.
!
Cholelithiasis
Events of cholelithiasis were the most frequently reported gallbladder events in the phase 2 
weight management trial (NN9536-4153) and were in a few instances co-reported with the 
event adjudication committee (EAC) confirmed acute pancreatitis. As a precaution, if 
cholelithiasis is suspected, appropriate clinical follow-up is to be initiated at the 
investigator’s discretion. 
!
Acute pancreatitis
Acute pancreatitis has been observed with the use of GLP-1 RA drug class. As a precaution, 
subjects with a history of chronic pancreatitis or recent acute pancreatitis will not be 
enrolled in the trial. In addition, trial product should be discontinued in case of suspicion of 
acute pancreatitis in accordance to Section 8.1. 
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Potential risks
!
Medullary thyroid cancer (MTC) (based on non-clinical data)
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 reports of 
MTC or 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, exclusion and discontinuation criteria related to medical 
history of multiple endocrine neoplasia type 2 (MEN2) or MTC and elevated plasma levels 
of calcitonin (biomarker for MTC) have been implemented in the trial. 
!
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. 
!
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. 
Other risks
!
Pregnancy and fertility (based on non-clinical data)
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. Exclusion and discontinuation criteria related to pregnancy have been 
implemented in the trial.
3.3.3
Conclusion on benefit-risk profile
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 s.c. 2.4 mg once-weekly. The 
results of the phase 2 trial (NN9536-4153) indicate that semaglutide will provide a clinically 
meaningful weight loss.
In conclusion, the potential risk to the subjects in this trial is considered low and outweighed by the 
anticipated benefits that semaglutide would provide subjects included in the trial.
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More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of semaglutide s.c. may be found in the IB57 and any updates hereof.
4
Objectives and endpoints
4.1
Primary, secondary and exploratory objectives 
4.1.1
Primary objective
Effect-related: randomisation (week 20) to week 68
To compare the effect of semaglutide s.c. 2.4 mg once-weekly versus semaglutide placebo as an 
adjunct to reduced-calorie diet and increased physical activity in subjects with overweight or 
obesity who have reached target dose of semaglutide during the run-in period, on body weight. 
4.1.2
Secondary objectives
Effect-related: randomisation (week 20) to week 68
To compare the effect of semaglutide s.c. 2.4 mg once-weekly versus semaglutide placebo as an 
adjunct to reduced-calorie diet and increased physical activity in subjects with overweight or 
obesity who have reached target dose of semaglutide during the run-in period, on 
!
cardiovascular risk factors 
!
clinical outcome assessments
!
glucose metabolism
Effect-related: week 0 to week 68
To investigate the effect of semaglutide s.c. 2.4 mg once-weekly as an adjunct to reduced-calorie 
diet and increased physical activity in subjects with overweight or obesity who have reached target 
dose during the run-in period, on body weight. 
Safety and tolerability: week 0 to randomisation (week 20)
To investigate the safety and tolerability of semaglutide s.c. 2.4 mg once-weekly as an adjunct to 
reduced-calorie diet and increased physical activity in subjects with overweight or obesity during 
the run-in period.
Safety and tolerability: randomisation (week 20) to week 75
To compare the safety and tolerability of semaglutide s.c. 2.4 mg once-weekly versus semaglutide  
placebo as an adjunct to reduced-calorie diet and increased physical activity in subjects with 
overweight or obesity who have reached target dose of semaglutide during the run-in period. 
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4.1.3
Exploratory objectives
Effect-related: randomisation (week 20) to week 68
To compare the effect of semaglutide s.c. 2.4 mg once-weekly versus semaglutide  placebo as an 
adjunct to reduced-calorie diet and increased physical activity in subjects with overweight or 
obesity who have reached target dose of semaglutide during the run-in period, on 
!
glycaemic status
!
use of medication for hypertension and dyslipidaemia
!
work productivity
!
treatment discontinuation
Effect-related: week 0 to randomisation (week 20)
To investigate the effect of semaglutide s.c. 2.4 mg once-weekly as an adjunct to reduced-calorie 
diet and increased physical activity in subjects with overweight or obesity during the run-in period, 
on treatment discontinuation. 
Primary estimand 
The estimand will quantify the average treatment effect of semaglutide relative to semaglutide 
placebo after 48 weeks’ treatment with semaglutide at the target dose, as an adjunct to reduced-
calorie diet and increased physical activity, in all randomised subjects regardless of adherence to
treatment provided that the subjects are able to reach the target dose of semaglutide during 20 
weeks run-in with escalating semaglutide doses and regardless of starting rescue interventions 
(weight management drugs or bariatric surgery) (“effectiveness”/”treatment policy” estimand).
The primary estimand will cover all objectives except the secondary objective addressing ‘Effect-
related: week 0 to week 68’.
Secondary estimand  
The estimand will quantify the average treatment effect of semaglutide relative to semaglutide 
placebo after 48 weeks’ treatment with semaglutide at the target dose, as an adjunct to reduced-
calorie diet and increased physical activity, in all randomised subjects had they remained on their 
randomised treatment for the entire 48 weeks after reaching the target dose of semaglutide during 
the 20 weeks run-in with escalating semaglutide doses and not started any rescue intervention 
(weight management drugs or bariatric surgery) (“efficacy”/”hypothetical” estimand). 
The secondary estimand will cover the primary objective.
Tertiary estimand 
The estimand will quantify the average treatment effect of semaglutide after 68 weeks, as an adjunct 
to reduced-calorie diet and increased physical activity, in all randomised subjects regardless of 
adherence to treatment and regardless of starting rescue interventions (weight management drugs or 
bariatric surgery) (“effectiveness”/”treatment policy” estimand).
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The tertiary estimand will cover the secondary objective addressing ‘Effect-related: week 0 to
week 68’.
4.2
Primary, secondary and exploratory endpoints
4.2.1
Primary endpoint
Change from randomisation (week 20) to week 68 in body weight (%)
4.2.2
Secondary endpoints
4.2.2.1
Confirmatory secondary endpoints
Effect endpoints from randomisation (week 20) to week 68 
Change in:
!
Waist circumference (cm)
!
Systolic blood pressure (mmHg)
!
Physical functioning score (SF-36)
!
Total score (WRSSM)
4.2.2.2
Supportive secondary endpoints
Effect endpoints from randomisation (week 20) to week 68 
Change in:
!
Body weight (kg)
!
BMI (kg/m2)
!
Haemoglobin A1c (HbA1c) (%, mmol/mol)
!
Fasting plasma glucose (FPG) (mg/dL)
!
Fasting serum insulin (mIU/L)
!
Diastolic blood pressure (mmHg)
!
Lipids (mg/dL)
o
Total cholesterol
o
High-density lipoproteins (HDL)
o
Low-density lipoproteins (LDL)
o
Very low-density lipoproteins (VLDL)
o
Free fatty acids 
o
Triglycerides
!
SF-36: 
o
Role-Physical score
o
Bodily Pain score 
o
General Health score
o
Vitality score
o
Social Functioning score 
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o
Role-Emotional score 
o
Mental Health score 
o
Physical component summary
o
Mental component summary
Subjects who achieve (yes/no):
!
Responder definition value for SF-36 physical functioning score
!
Responder definition value for WRSSM total score
Subjects who gain weight (yes/no)
Effect endpoints from week 0 to week 68 
Change in body weight (%)
Subjects who achieve (yes/no): 
!
Body weight reduction < 0% 
!
Body weight reduction ≥ 5% 
!
Body weight reduction ≥ 10%
!
Body weight reduction ≥ 15%
Safety endpoints from week 0 to randomisation (week 20)
Number of treatment-emergent AEs 
Number of serious adverse events (SAEs)
Change in:
!
Pulse (bpm)
!
Amylase (U/L)
!
Lipase (U/L) 
!
Calcitonin (ng/L)
Safety endpoints from randomisation (week 20) to week 75
Number of treatment-emergent AEs 
Number of SAEs 
Change in:
!
Pulse (bpm)
!
Amylase (U/L)
!
Lipase (U/L) 
!
Calcitonin (ng/L)
4.2.3
Exploratory endpoints
Change from randomisation (week 20) to week 68 in:
!
Glycaemic category (normo-glycaemia, pre-diabetes, T2D)
!
Antihypertensive medication (decrease, no change, increase)
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!
Lipid-lowering medication (decrease, no change, increase)
!
The Stanford Presenteeism Scale (SPS-6), total score
Subjects who from week 0 to randomisation (week 20) have permanently discontinued trial product 
(yes/no)
Time to permanent discontinuation of trial product (weeks) from week 0 to randomisation
(week 20)
Subjects who from randomisation (week 20) to week 68 have permanently discontinued randomised 
trial product (yes/no)
Time to permanent discontinuation of randomised trial product (weeks) from randomisation 
(week 20) to week 68
5
Trial design
5.1
Overall design
This is a 68-week, randomised, double-blind, placebo-controlled, two-armed multi-centre, 
multinational withdrawal clinical trial66comparing once-weekly semaglutide s.c. 2.4 mg with 
semaglutide placebo in subjects with overweight or obesity.
The trial includes a screening visit to assess the subject’s eligibility followed by visits/phone 
contacts every 2ndweek during dose escalation (run-in period). From randomisation (week 20), 
visits/phone contacts will take place every 4thweek for the remaining maintenance period until ‘end 
of treatment’(week 68). A follow-up visit (‘end of trial’) for safety assessments is scheduled 7 
weeks after ‘end of treatment’to account for the exposure to the long half-life of semaglutide.
The trial design is outlined 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 
including follow-up period
Eligible subjects fulfilling all run-in criteria (see Section 6.3.1) at week 0 will all start on 
semaglutide as an adjunct to a reduced-calorie diet and increased physical activity. 
At week 20, subjects who have reached target dose of semaglutide (2.4 mg) during the run-in period 
and fulfil the randomisation criteria (Section 6.3.2) will be randomised in a 2:1 manner to either 
continue receiving semaglutide 2.4 mg once-weekly for additional 48 weeks or being switched to 
semaglutide placebo once-weekly for 48 weeks, still as an adjunct to a reduced-calorie diet and 
increased physical activity. 
5.2
Subject and trial completion
Approximately 1059 subjects will be screened to achieve 900 subjects to be included in the run-in 
period to reach the anticipated 750 subjects randomly assigned to trial product in the maintenance 
period.
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).
'Date of trial completion' is the date the subject completed the final scheduled visit.
Treatment period completion for a subject: 
Treatment period completion is defined as when the randomised subject has attended the 'end of 
treatment' visit according to the flowchart.
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. 
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5.4
Scientific rationale for trial design
The treatment duration of the trial is 68 weeks with an additional 7 weeks follow-up (without 
treatment). The 7 weeks follow-up period is included to account for the exposure and long half-life 
of semaglutide. A 68-week treatment duration is considered sufficient to assess weight loss, safety 
and tolerability in the phase 3 weight management development programme in accordance with 
regulatory guidelines64, 65.
A randomised, double-blinded, placebo-controlled, multi-centre withdrawal trial design is chosen to 
minimise bias in the assessment of the effect and safety of semaglutide 2.4 mg once-weekly versus 
semaglutide placebo, as an adjunct to a reduced-calorie diet and increased physical activity. 
A withdrawal clinical trial design is chosen in order for the trial to support the purpose and 
objectives set for the trial.
5.5
Justification for dose
Results from the phase 2 dose-finding trial (NN9536-4153) showed that the semaglutide 0.4 mg 
once-daily dose was most effective in terms of weight loss while displaying an acceptable 
tolerability profile. Using population pharmacokinetic modelling, it was estimated that a once-
weekly maintenance dose of 2.4 mg semaglutide will result in similar Cmax at steady-state as that 
obtained by the once-daily 0.4 mg semaglutide dose in trial NN9536-4153.
A maintenance dose of 2.4 mg semaglutide once-weekly has been chosen for the phase 3 weight 
management development programme. The once-weekly dosing is anticipated to ease the burden of 
drug administration in clinical practice. Subjects will 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, 
1.7 and 2.4 mg/week), until the target dose is reached after 16 weeks.
It is well known that to mitigate gastrointestinal side effects with GLP-1 RA treatment, dose 
escalation to the target dose is required. Based on experience from the semaglutide T2D 
development programme, a similar fixed-dose escalation regimen was selected, with dose escalation 
every 4 weeks until the target dose of 2.4 mg is reached after 16 weeks.
Please refer to Section 7.1 for more details on treatment doses.
6
Trial population
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
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6.1
Inclusion criteria
Subjects are eligible to be included in the trial only if all of 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. BMI ≥ 30 kg/m2 or ≥ 27 kg/m2 with the presence of at least one of the following weight-
related comorbidities (treated or untreated): hypertension, dyslipidaemia, obstructive 
sleep apnoea or cardiovascular disease 
4. History of at least one self-reported unsuccessful dietary effort to lose body weight
The criteria will be assessed at the investigator’s discretion unless otherwise stated.
6.2
Exclusion criteria 
Subjects are excluded from the trial if any of the following criteria apply: 
Glycaemia related:
1. HbA1c ≥ 48 mmol/mol (6.5%) as measured by central laboratory at screening 
2. History of type 1 or type 2 diabetes mellitus 
3. Treatment with glucose lowering agent(s) within 90 days before screening 
Obesity related:
4. A self-reported change in body weight > 5 kg (11 lbs) within 90 days before screening 
irrespective of medical records
5. Treatment with any medication for the indication of obesity within the past 90 days 
before screening
6. Previous or planned (during the trial period) obesity treatment with surgery or a weight 
loss device. However, the following are allowed: (1) liposuction and/or abdominoplasty, 
if performed > 1 year before screening, (2) lap banding, if the band has been removed > 
1 year before screening, (3) intragastric balloon, if the balloon has been removed > 1 
year before screening or (4) duodenal-jejunal bypass sleeve, if the sleeve has been 
removed > 1 year before screening
7. Uncontrolled thyroid disease, defined as thyroid stimulating hormone (TSH) > 6.0 
mIU/L or < 0.4 mIU/L as measured by the central laboratory at screening
Mental health:
8. History of major depressive disorder within 2 years before screening 
9. Diagnosis of other severe psychiatric disorder (e.g. schizophrenia, bipolar disorder)
10. A Patient Health Questionnaire-9 (PHQ-9) score of ≥ 15 at screening 
11. A lifetime history of a suicidal attempt
12. Suicidal behaviour within 30 days before screening 
13. Suicidal ideation corresponding to type 4 or 5 on the Columbia-Suicide Severity Rating 
Scale (C-SSRS) within the past 30 days before screening  
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General safety:
14. Presence of acute pancreatitis within the past 180 days prior to the day of screening
15. History or presence of chronic pancreatitis
16. Calcitonin ≥ 100 ng/L as measured by the central laboratory at screening
17. Personal or first degree relative(s) history of multiple endocrine neoplasia type 2 or 
medullary thyroid carcinoma
18. Renal impairment measured as estimated Glomerular Filtration Rate (eGFR) value of 
eGFR < 15 ml/min/1.73 m2 as defined by KDIGO 201267 by the central laboratory at 
screening
19. History of malignant neoplasms within the past 5 years prior to screening. Basal and 
squamous cell skin cancer and any carcinoma in-situ is allowed
20. Any of the following: myocardial infarction, stroke, hospitalization for unstable angina 
or transient ischaemic attack within the past 60 days prior to screening
21. Subject presently classified as being in New York Heart Association (NYHA) Class IV
22. Surgery scheduled for the duration of the trial, except for minor surgical procedures, in 
the opinion of the investigator 
23. Known or suspected abuse of alcohol or recreational drugs
24. Known or suspected hypersensitivity to trial product(s) or related products
25. Previous participation in this trial. Participation is defined as signed informed consent 
26. Participation in another clinical trial within 90 days before screening 
27. Other subject(s) from the same household participating in any semaglutide trial
28. 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
29. Any disorder, unwillingness or inability, not covered by any of the other exclusion 
criteria, which in the investigator’s opinion, might jeopardise subject’s safety or 
compliance with the protocol
The criteria will be assessed at the investigator’s discretion unless otherwise stated.
For country specific requirements, see Appendix 8.
6.3
Run-in criteria and randomisation criteria
6.3.1
Run-in criteria
1. Have kept a food diary with at least one entry per day between screening and week 0. 
However, missed entries for a maximum of two days are allowed
2. A PHQ-9 score of < 15 at week 0
3. No suicidal behaviour in the period between screening and week 0
4. No suicidal ideation corresponding to type 4 or 5 on the C-SSRS in the period between 
screening and week 0
To be eligible to enter run-in, all run-in criteria must be answered “yes”.
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Subject not fulfilling the run-in criteria will be considered screen failure, see Section 6.5.
6.3.2
Randomisation criteria
1. attend the randomisation visit (week 20), and
2. have escalated to target dose after 16 weeks ± 3 days since week 0, and
3. are at target dose at the randomisation visit (week 20)
To be randomised, all randomisation criteria must be answered “yes”.
Subject not fulfilling the randomisation criteria will be considered run-in failure. All run-in failures 
should attend the ‘end of trial’ visit 7 weeks ± 5 days after their week 20 visit.
6.4
Lifestyle restrictions
To ensure alignment in regards to performance of assessments across subjects and trial sites, the 
below restrictions apply.
6.4.1
Meals and dietary restrictions
!
Subjects must attend the visits fasting according to the flowchart.
!
Fasting is defined as at least 8 hours overnight before 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. 
!
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. Procedures requiring subject to fast 
include blood sampling of FPG, fasting serum insulin, and free fatty acid.
6.4.2
Caffeine and tobacco
!
Subject should avoid caffeine and smoking at least 30 minutes prior to measuring the blood 
pressure.
6.5
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 or run-in 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 informed consent, 
date of visit, demography, screen failure details, eligibility criteria, and any SAE. A screen failure 
session must be made in the interactive web response system (IWRS). 
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 
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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. 
7
Treatments
7.1
Treatments administered
!
All trial products listed in Table 7-1 are considered investigational medicinal products 
(IMP).
!
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 B
1.0 mg/mL PDS290*
Semaglutide B
3.0 mg/mL PDS290
Semaglutide 
placebo
Dosage form:
Solution for injection
Solution for injection
Solution for injection
Route of administration: 
Subcutaneous
Subcutaneous
Subcutaneous
Dosing instructions:
Once-weekly
Once-weekly
Once-weekly
Delivery device
3 mL PDS290 pre-filled 
pen-injector
3 mL PDS290 pre-filled 
pen-injector
3 mL PDS290 pre-filled 
pen-injector
*Semaglutide B 1.0 mg/mL PDS290 will only be dispensed at the first dispensing visit.
!
Dose escalation of semaglutide should take place during the 20 weeks run-in period as 
described in Table 7-2. All subjects should aim at reaching the recommended target dose of 
semaglutide 2.4 mg once-weekly or the corresponding volume of semaglutide placebo. 
!
If a subject does not tolerate the recommended target dose of 2.4 mg once-weekly, the 
subject may stay at the lower dose level of 1.7 mg once-weekly. This should only be 
allowed if the subject would otherwise discontinue trial product completely and if 
considered safe to continue on trial product, as per the investigator’s discretion. It is 
recommended that the subject makes at least one attempt to re-escalate to the recommended 
target dose of 2.4 mg once-weekly, as per the investigator’s discretion. 
!
It is recommended that the investigator consult Novo Nordisk in case of persistent deviation 
from the planned escalation regimen.
!
A dose reminder card will be handed out to the subjects at each site visit during the 
escalation period. This is to remind the subjects of the dose to be taken until next site visit 
and provide a conversion of the dose to value shown in the dose counter. Once the target 
dose has been reached, the dose reminder card is only handed out as needed. 
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Table 7-2
Dose escalation and maintenance of semaglutide/semaglutide placebo
Trial product name
Dose
Volume
Value shown in 
dose counter*
Duration
Run-in period
Semaglutide B 1.0 mg/mL PDS290 0.25 mg
0.25 mL
25*
4 weeks
Semaglutide B 1.0 mg/mL PDS290 0.5 mg
0.50 mL
50*
4 weeks
Semaglutide B 3.0 mg/mL PDS290 1.0 mg
0.34 mL
34*
4 weeks
Semaglutide B 3.0 mg/mL PDS290 1.7 mg
0.57 mL
57*
4 weeks
Semaglutide B 3.0 mg/mL PDS290 2.4 mg
0.80 mL
80*
4 weeks
Maintenance period
Semaglutide B 3.0 mg/mL PDS290
or Semaglutide placebo
2.4 mg
0.80 mL
80*
48 weeks
* Conversion to dose is calculated based on 0.01 mL/value for both strengths.
!
Subjects will be instructed to inject semaglutide/semaglutide placebo once-weekly at the 
same day of the week (to the extent possible) throughout the trial.
!
Injections may be administered in the thigh, abdomen or upper arm, at any time of day 
irrespective of meals. Subjects should be encouraged to inject in the same area throughout 
the trial, but changing between left and right side is allowed.
!
If a single dose of trial product is missed, it should be administered as soon as noticed, 
provided the time to the next scheduled dose is at least 2 days (48 hours). If a dose is missed 
and the next scheduled dose is less than 2 days (48 hours) away, the subject should not 
administer a dose until the next scheduled dose. A missed dose should not affect the 
scheduled dosing day of the week.
!
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. 
!
Auxiliary supplies will be provided in accordance with the trial materials manual (TMM)
please see Table 7-3.
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Table 7-3
Auxiliary supplies provided by Novo Nordisk A/S
Auxiliary supply
Details
Needles
Needles for pre-filled pen system. Details provided in the TMM.
Only needles provided and approved by Novo Nordisk must be used for administration 
of trial product. 
Direction for use (DFU)
DFU for 3 mL PDS290 pre-filled pen-injector
Not included in the dispensing unit and to be handed out separately 
7.1.1
Medical devices
Information about the PDS290 pre-filled pen-injector may be found in the IB57 and any updates 
hereof.
Information about the use of the PDS290 pre-filled pen-injector for semaglutide 1.0 mg/mL, 
semaglutide 3.0 mg/mL, and semaglutide placebo can be found in the DFU. 
Training in the PDS290 pre-filled pen-injector
The investigator must document that training in the DFU has been given to the subjects orally and
in writing at the first dispensing visit. Training must be repeated during the trial at regular intervals 
in order to ensure correct use of the medical device. Training is the responsibility of the investigator 
or a delegate.
7.1.2
Diet and physical activity counselling
All subjects will receive counselling with regards to diet (500 kcal deficit per day relative to the 
estimated total energy expenditure (TEE) calculated once at randomisation) and physical activity 
(150 min of physical activity per week is encouraged, e.g. walking or use the stairs). Counselling 
should be done by a dietician or a similar qualified healthcare professional every 4th week via 
visits/phone contacts. 
Subjects will be asked to record their food intake and physical activity at least 3 days prior to the 
phone contacts and clinic visits according to the flowchart to assist their lifestyle intervention. 
However, the subject should be encouraged to keep diary of their food intake and physical activity
on a daily basis. After week 0 the subjects can use a tool of their own choice (paper/app/other tool) 
for recording, ensuring it can be reviewed during diet and physical activity counselling. Subjects 
must receive instructions in how to capture the physical activity and food intake. 
Calculation of estimated TEE
The TEE is calculated by multiplying the estimated Basal Metabolic Rate (BMR) (see Table 7-4)
with a Physical Activity Level value of 1.368. 
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TEE = BMR × 1.3
Table 7-4
Equation for estimated BMR
Sex
Age
BMR (kcal/day)
Men
18-30 years
31-60 years
> 60 years
15.057 × weight at week 0 in kg + 692.2
11.472 × weight at week 0 in kg + 873.1
11.711 × weight at week 0 in kg + 587.7
Women
18-30 years
31-60 years
> 60 years
14.818 × weight at week 0 in kg + 486.6
8.126 × weight at week 0 in kg + 845.6
9.082 × weight at week 0 in kg + 658.5
If a BMI ≤ 22.5 kg/m2 is reached the recommended energy intake should be recalculated with no 
kcal deficit (maintenance diet) for the remainder of the trial. If deemed necessary the investigator 
could consult Novo Nordisk to discuss when maintenance diet can be initiated. 
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 IWRS and assigned to the next available 
treatment according to randomisation schedule. Trial product will be dispensed at the trial 
visits summarised in the flowchart. 
7.4
Blinding
The following trial products will be packed open labelled during the run-in period:
!
Semaglutide B 1.0 mg/mL PDS290
!
Semaglutide B 3.0 mg/mL PDS290
After randomisation the active drug and placebo are double-blinded and visually identical for the 
following trial product:
!
Semaglutide B 3.0 mg/mL PDS290 or semaglutide placebo
The specific trial product for a subject will be assigned using an IWRS. The site will access the 
IWRS before the start of trial product administration for each subject.
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 subject’s medical records.
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Whenever the blind is broken, the person breaking the blind must print the "code break 
confirmation" notification generated by the IWRS 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. 
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. 
Table 7-5
Trial product storage conditions
Trial product name
Storage conditions 
(not-in-use)
In-use conditions
In-use timea
Semaglutide B 1.0 mg/mL
PDS290
Store in refrigerator 
(2°C-8°C/36°F-46°F)
Do not freeze
Protect from light
In-use conditions will be 
available on the trial product 
label
In-use time will be available 
on the trial product label
Semaglutide B 3.0 mg/mL
PDS290
Store in refrigerator 
(2°C-8°C/36°F-46°F)
Do not freeze
Protect from light
In-use conditions will be 
available on the trial product 
label
In-use time will be available 
on the trial product label
Semaglutide placebo
Store in refrigerator 
(2°C-8°C/36°F-46°F)
Do not freeze
Protect from light
In-use conditions will be 
available on the trial product 
label
In-use time will be available 
on the trial product label
aIn-use time starts when the product is taken out of the refrigerator in the subject’s home. 
!
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 
number of subjects screened, entered run-in and randomised.
!
The investigator must confirm that appropriate temperature conditions have been maintained 
during transit for all trial products received (see Table 7-5) 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.
!
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.
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!
The investigator is responsible for drug accountability and record maintenance (i.e. receipt, 
accountability and final disposition records).
!
Drug accountability should be performed on a pen level and must be documented in the 
IWRS.
!
The subject must return all used, partly used and unused trial product including empty 
packaging materials during the trial as instructed by the investigator. 
!
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. 
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.
Treatment compliance of trial product will be assessed by asking subject about missed doses.
Information about compliance and missed doses should be described in the subject’s medical 
records. 
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-hypertensive and lipid-lowering medication)
During the trial subjects should not initiate any anti-obesity treatment (e.g. medication) which is not 
part of the trial procedures. If such anti-obesity treatment is initiated, the subject should be 
instructed to stop the anti-obesity treatment.
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Changes in concomitant medication must be recorded at each visit. If a change is due to an AE, then 
this must be reported according to Section 9.2.
7.7.1
Rescue medication
This section is not applicable for this trial.
7.8
Treatment after the end of the trial
After the end of the trial the subject should be treated at the discretion of the investigator. 
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 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.
o
If the subject does not wish to attend the scheduled clinic visits, efforts should be 
made to have the visits converted to phone contacts. However, 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.
o
If the subject refuses to attend the ‘end of treatment’ and/or ‘end of trial’ visit,
information about the attempts to follow up with the subject must be documented in 
the subject’s medical record.
The subject must be discontinued from trial product, if any of the following applies:
1. Included in the trial in violation of the inclusion and/or exclusion criteria and/or run-in 
criteria and/or randomisation criteria
2. Safety concern as judged by the investigator
3. Calcitonin ≥ 100 ng/L (see Appendix 7)
4. Suspicion of pancreatitis
5. Pregnancy
6. Intention of becoming pregnant
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7. Simultaneous participation in another clinical trial of an approved or non-approved 
investigational medicinal product.
If acute pancreatitis is suspected appropriate actions should be initiated, including local 
measurement of amylase and lipase (see Appendix 4 for reporting).
Subjects meeting discontinuation of trial product criterion no. 4 are allowed to resume trial product 
if the Atlanta criteria69 are not fulfilled and thus, the suspicion of acute pancreatitis is not 
confirmed. Trial product may be resumed for subjects with a gallstone-induced pancreatitis in case 
of cholecystectomy.
Subjects meeting discontinuation of trial product criteria no. 2, 5 and 6 are allowed to resume trial 
product, if the criteria are no longer met (see Section 8.1.1).
A subject who does not fulfil the eligibility criteria must not be randomised. If a subject is 
randomised in violation of inclusion, exclusion, run-in or randomisation criteria, this will be 
handled as an important protocol deviation, and the IEC/IRB and regulatory authorities must be 
notified according to local requirements.
The primary reason for discontinuation of trial product must be specified in the source data at the 
time of discontinuation, and subject should continue to follow the visit and assessment schedule. A 
change in ‘treatment status’ must be made in IWRS to discontinue trial product. If subject is not 
allowed to resume trial product, then the reason for discontinuation will be recorded in the ‘end of
treatment’ form in the case report form (CRF), and final drug accountability must be performed. 
8.1.1
Temporary discontinuation of trial treatment
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). 
Each missed dose should be recorded in the CRF, as per subject’s recollection. If a ‘treatment 
status’ session previously has been made in IWRS to indicate discontinuation of trial product, a new 
‘treatment status’ session must be made to resume trial product.
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 the ‘end of treatment’ visit. See the flowchart 
for data to be collected. 
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Final drug accountability must be performed even if the subject is not able to come to the trial site. 
The investigator must make a ‘treatment status’ session in IWRS to discontinue trial product. 
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:
!
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 or not the subject wishes to and/or should continue in the 
trial.
!
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). If attempts have failed, family members or other contacts consented by the 
subject can be contacted for alternative contact details. These contact attempts should be 
documented in the subject's source document.
!
Should the subject continue to be unreachable at ‘end of treatment’ visit, he/she will be 
considered to have withdrawn from the trial with a primary reason of ‘lost to follow-up'. 
9
Trial assessments and procedures
!
Trial procedures and their timing are summarised in the flowchart. 
!
Informed consent must be obtained before any trial related activity, see Appendix 3.
!
All screening evaluations must be completed and reviewed to confirm that potential subjects 
meet all eligibility criteria. 
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!
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.
!
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. 
!
Adherence to the trial design requirements, including those specified in the flowchart, is 
essential and required for trial conduct. 
!
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. The suggested order of the assessments:
1. Electrocardiogram (ECGs) and vital signs
2. Blood samples
3. Patient reported outcomes (see Section 9.1.2) and mental health assessment instruments 
(see Section 9.4.1)
4. Other assessments
!
Source data of clinical assessments performed and recorded in the CRF must be available 
and will usually be the subject’s medical records. Additional recording to be considered 
source data includes, but is not limited to laboratory reports, ECG, diary recordings, clinical 
outcome assessments.
!
Subjects must receive instructions in how to capture their daily food intake in the handed out 
food diary from screening to week 0. Entries must be evaluated in accordance with the run-
in criteria.
!
Only the subject can make entries and corrections in the diaries, unless the section is 
specified for site staff.
!
The barriers and motivation interview identifies barriers to and motivation for lifestyle 
change and compliance with the protocol. The interview must be conducted at screening to 
assist in identifying subjects who are unable or unwilling to comply with protocol 
procedures as per the exclusion criteria. In addition, the interview will ensure that any minor 
barriers are addressed during lifestyle counselling.
o
The results of the interview will not be entered into the CRF. It will be at the 
investigator’s discretion to evaluate the motivation of the subject and related 
eligibility.
!
Subject’s weight history must be recorded in the subject’s medical record.
!
Review of mental health assessment instruments, ECG, and laboratory reports must be 
documented either on the documents or in the subject's medical record. If clarification of 
entries or discrepancies 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.
!
Repeat laboratory samples may be taken for technical issues and unscheduled samples or 
assessments may be taken for safety reasons. Please refer to Appendix 2 for further details 
on laboratory samples.
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!
For subjects receiving antihypertensive or lipid-lowering treatment, the investigator should 
evaluate changes in the subject’s treatment intensity within each therapeutic area. The 
evaluation should be based on whether an overall change from randomisation until the time 
of the evaluation has occurred (i.e., either increase, decrease or no change) after reviewing 
all available relevant information e.g., changes in drug dose, drug class, number of drugs or 
a combination of these.
!
The investigator will evaluate the subject’s glycaemic status periodically during the trial as 
detailed in the flowchart based on all available relevant information e.g. medical records, 
concomitant medication, blood glucose parameters (HbA1c, FPG) and AEs. The subject’s 
glycaemic status will be categorised as normo-glycaemia, prediabetes or diagnosed with 
type 2 diabetes according to the American Diabetes Association’s definitions70.
9.1
Efficacy assessments 
Planned time points for all efficacy assessments are provided in the flowchart.
9.1.1
Body measurements
!
Body weight should be measured at all site visits without shoes, on an empty bladder and 
only wearing light clothing. It should be measured on a digital scale and recorded in 
kilograms or pounds (one decimal) using the same scale throughout the trial. The scale must 
be calibrated yearly as a minimum.
!
Height is measured without shoes in centimetres or inches (one decimal). BMI will be 
calculated by the CRF from screening data and must be in agreement with inclusion 
criterion no. 3.
!
Waist circumference is defined as the abdominal circumference located midway between the 
lower rib margin and the iliac crest. Measures must be obtained in standing position with a 
non-stretchable measuring tape and to the nearest cm or inch. The tape should touch the skin 
but not compress soft tissue and twists in the tape should be avoided. The subject should be 
asked to breathe normally. The same measuring tape should be used throughout the trial.
The measuring tape will be provided by Novo Nordisk to ensure standardisation.
9.1.2
Clinical outcome assessment
Subjects should be given the opportunity to complete the questionnaires by themselves without 
interruption. Each of the questionnaires takes approximately 10 minutes to complete.
The following patient reported outcome questionnaires will be used: 
!
The Stanford Presenteeism Scale (SPS-6), 2001 version
The SPS-6 evaluates workforce productivity. Absenteeism affects productivity; however, 
even when employees are physically present at their jobs, they may experience decreased 
productivity and below-normal work quality - a concept known as decreased presenteeism.71
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!
Weight Related Sign and Symptom Measure (WRSSM), version 2.0
The WRSSM measures the presence and bothersomeness of 10 weight-related symptoms. 
The tool assesses the multifaceted aspects of obesity on symptom experience.
!
Patient Global Impression of Severity (PGI-S) (WRSSM) for signs and symptoms, version 4
!
Patient Global Impression of Change (PGI-C) (WRSSM) for signs and symptoms, version 
4b
!
Short Form 36 v2.0 acute (SF-36)
SF-36 measures the subject’s overall health related quality of life. It is a 36-item generic 
measure of health status that yields 2 summary scores for physical health and mental health, 
and 8 domain scores72
9.1.3
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.
9.2
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 ‘end of trial’ visit, 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 
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 including events for adjudication, Section 9.2.1.1, are listed in 
Figure 9-2.
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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 9-2.
AE identified
Is the event to be 
adjudicated?
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 ?
Adjudication form
≤14 calendar days
Source data ≤  4 weeks
Non-serious
Serious
Yes
No additional action
No
Specific event form
For SAE:
≤14 calendar days
Yes
Timelines are from the awareness of an AE.
Queries to be resolved ≤14 calendar days.
AE: Adverse Events, SAE: Serious Adverse Events, SIF: Safety Information Form
No additional action
No
Figure 9-1
Decision tree for determining the event type and the respective forms to 
complete with associated timelines
Table 9-1
AEs requiring additional data collection (via specific event form) and events for 
adjudication
Event type 
AE via specific event form
Event for adjudication (Section 
9.2.1.1)
Medication error
X
Death
X
Cardiovascular events
      Acute Coronary Syndrome
X
      Cerebrovascular event 
X
      Heart failure
X
      Coronary artery revascularisation
X
Acute pancreatitis
X
X
Acute gallbladder disease
X
Malignant neoplasms
X
Hepatic event 
X
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9.2.1.1
Events for adjudication
Event adjudication will be performed for adverse events in subjects who have entered the run-in 
period. These events are reviewed by an independent external EAC in a blinded manner, refer to 
Appendix 3 for further details.
There are four ways to identify events relevant for adjudication as described below:
!
Investigator-reported events for adjudication: When reporting AEs, the investigator must 
select the appropriate AE category based on pre-defined criteria (see Table 9-1 and 
Appendix 4)
!
Death
!
AE Search (standardised screening): All AEs not directly reported by the investigator as 
requiring adjudication, will undergo screening to identify potential events for adjudication. 
The investigator can be queried to provide additional information related to the reported AE, 
e.g. alternative aetiology, underlying cause(s) and/or clinical details.
!
EAC-identified events: When reviewing source documents provided for another event for 
adjudication, the EAC can identify additional events in scope for adjudication that were not 
initially reported by the investigator. In these instances, the investigator will be notified of 
the newly identified event and has the option to report the EAC-identified event. Regardless 
of whether the investigator decides to report the event, it will undergo adjudication. 
Occasionally, EAC-identified events may require the investigator to collect additional 
source documents, which should be provided by uploading to the event adjudication system
(EAS).
With the exception of EAC-identified events, an event-specific adjudication form for the event in 
question should be completed in the CRF within 14 calendar days of the investigator's first 
knowledge of the event. 
Copies of collected source documents should be labelled with trial ID, subject and AE number, 
redacted (anonymised of personal identifiers) and uploaded to the EAS within 4 weeks according to 
instructions outlined in the event adjudication site manual. If no, or insufficient source documents 
are provided to the adjudication supplier, the investigator can be asked to complete a clinical 
narrative and to be uploaded to the EAS. 
If new information becomes available for an event sent for adjudication, it is the responsibility of 
the investigator to ensure the new information is uploaded to the EAS. 
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.
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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, stabilization, 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 suspected unexpected serious adverse reactions 
(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 IB and will notify the IRB/IEC, if appropriate according to local requirements.
9.2.5
Hypoglycaemic, cardiovascular and death events
Hypoglycaemic, 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
Not applicable for this trial.
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 ‘end of trial’ visit.
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 9-3 and Appendix 5. 
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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 9.2.
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 is 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 mg in a single dose, and up to 4 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.
The overdose must be reported as a medication error (see Appendix 4) and for reporting timeline 
see Section 9.2.1.
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 IB57 and any updates 
hereof.
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. Findings of specific 
medical history should be described in designated forms.
As part of the medical history information related to history of gallbladder disease, breast neoplasm, 
colon neoplasm, skin cancer, and psychiatric disorder will be recorded. Follow-up questions will be 
asked at the end of trial related to the breast neoplasm and colon neoplasm.
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 Appendix 4) during the trial and any clinically significant 
worsening from baseline must be reported as an AE (see Section 9.2).
9.4.1
Mental health assessment instruments
!
PHQ-973 is a 9-item depression module of the patient health questionnaire, which is a self -
administered diagnostic tool used for assessment of mental disorders. The questionnaire will 
be available in a linguistically validated translated version. 
!
C-SSRS74 is a detailed questionnaire assessing both suicidal behaviour and suicidal ideation. 
The questionnaire will be administered as an interview by the investigator or a qualified 
delegate. The questionnaire (C-SSRS Baseline and C-SSRS Since Last Visit) will be 
available in a linguistically validated translated version.
o
Prior to administering the C-SSRS questionnaire, the investigator or qualified 
delegate must complete sufficient training.
If a subject has a PHQ-9 score of 10-14 both inclusive the subject should be referred to a mental 
health professional (MHP) if judged relevant by the investigator. If referral is not deemed relevant 
this, along with the reason why, must be documented in the subject’s medical records.
A subject must be referred to a MHP if:
!
the subject has a PHQ-9 score ≥15 or
!
the subject has any suicidal behaviour or
!
the subject has any suicidal ideation of type 4 or type 5 on any C-SSRS assessment or
!
in the opinion of the investigator, it is necessary for the safety of the subject
If one or more of the referral criteria are met, the investigator should explain to the subject why the 
referral and psychiatric evaluation by a MHP is needed. If the subject refuses to be referred to a 
MHP, the subject’s decision should be documented in subject’s medical record and the investigator 
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must assess if it is safe for the subject to continue in the trial or if the subject should be discontinued 
from trial product.
If a subject’s psychiatric disorder can be adequately treated with psychotherapy and/or 
pharmacotherapeutic treatment, then the subject, at the discretion of the investigator (and in 
agreement with the MHP), may continue in the trial. Otherwise, the subject must be discontinued 
from trial product due to safety concern as judged by the investigator.
9.4.2
Physical examinations
!
A physical examination will include assessments of the general appearance, thyroid gland, 
breast (females) and abdomen, as well as the cardiovascular and respiratory systems. 
!
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
9.4.3
Vital signs
!
The method for measuring systolic and diastolic blood pressure needs to follow the standard 
clinical practice at site.
!
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).
!
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.
9.4.4
Electrocardiograms
!
12-lead ECG will be obtained as outlined in the flowchart using a local ECG machine that 
automatically calculates the heart rate and measures PR, QRS, QT intervals.
9.4.5
Clinical safety laboratory assessments
All protocol-required laboratory assessments, as defined in Appendix 2, must be conducted in 
accordance with the flowchart and the laboratory manual.
!
If the laboratory finding based on the results from central laboratory meets the criteria for 
laboratory outliers, a laboratory outlier form in the CRF should be completed. Please refer to 
Appendix 2 for the criteria for the laboratory outliers.
!
Urine pregnancy tests provided by central laboratory must be performed for women of 
childbearing potential at screening and as specified in the flowchart. Urine pregnancy test 
must be repeated at any time during the trial if pregnancy is suspected. Further instructions 
can be found in the laboratory manual.
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9.5
Pharmacokinetics
Not applicable for this trial. 
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 as 
the IgE sample is obtained (after 1-2 weeks of trial product 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 clinical trial 
report.
10 Statistical considerations 
Taxonomy of week 68 assessments
For each subject a given assessment at week 68 may be available or missing and Table 10-1
describes the taxonomy for this. Note, this is done per assessment and per subject; subjects may be 
a different type for different assessments (a subject may have “available on randomised treatment 
(AT)” for body weight but “missing on randomised treatment (MT)” for waist circumference).
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Table 10-1
Taxonomy for subjects based on week 68 assessments
Assessment
at week 68
Subjects on 
randomised 
treatment at 
week 68
Type description
Type
Abbreviation
Available
Yes
Available on randomised treatment:
Subjects who complete the trial on randomised treatment with an assessment at week 68: 
Includes those that stop and restart trial product
AT
No
Available but discontinued
Subjects who discontinued randomised treatment prematurely but returned to have an 
assessment at week 68. These are also called retrieved subjects
AD
Missing
Yes
Missing on randomised treatment:
Subjects who complete the trial on randomised treatment without an assessment at week 
68: Includes those that stop and restart trial product
MT
No
Missing and discontinued:
Subjects who discontinued randomised treatment prematurely and did not return to have 
an assessment at week 68. These are also called non-retrieved subjects
MD
10.1
Sample size determination 
The sample size and thereby the power for this trial is primarily defined to support safety. However,
no formal statistical inference is planned based on number of adverse events. Given the trial sample 
size, the power of statistical tests for effect endpoints is described below.
The tests of superiority of semaglutide 2.4 mg to semaglutide placebo for the primary and 
confirmatory secondary endpoints are performed using the fixed-sequence statistical strategy. This 
strategy tests the endpoints using a predefined hierarchical order, all at the significance level of 5%, 
moving to test the next endpoint only after a statistically significant superiority result (p-value < 
5%) on the previous endpoint. The test hierarchy is given in Table 10-2 with underlying 
assumptions, marginal power and effective power. The effective power is calculated under the 
assumption of independence of endpoints by multiplying the respective marginal powers 
successively.
In the analysis approach addressing the primary estimand, week 68 assessments from retrieved 
subjects (AD) are used. These data are also used to impute missing measurements at week 68 for 
non-retrieved subjects (MD). The imputation is done separately within each treatment arm (see 
description below). However, for the power calculations missing values (MT and MD), regardless 
of treatment arm, are assumed to be similar to semaglutide placebo subjects. These assumptions are 
likely conservative with respect to the power, and correspond to the jump to reference sensitivity 
analysis planned below.
Assumptions
The common assumptions for the power calculations are
!
The significance level is 5%
!
The randomisation ratio is 2:1
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!
For continuous endpoints the t-test on the mean difference assuming equal variances is used
!
Based on data from NN9536-4153
o
5% of subjects discontinue permanently between randomisation (week 20) and week 
68 and
o
60% of these are retrieved (AD) at week 68 
!
All subjects in the semaglutide placebo arm are assumed to have same effect as subjects who 
complete the trial on semaglutide placebo (AT)
!
Retrieved subjects (AD) in the semaglutide 2.4 mg arm are assumed to have an effect 
corresponding to half the treatment difference (compared to semaglutide placebo) of 
subjects who complete the trial on semaglutide 2.4 mg (AT)
!
Non-retrieved subjects (MD) in the semaglutide 2.4 mg arm are assumed to have an effect 
corresponding to semaglutide placebo
Further assumptions made to calculate the power for each of the primary and confirmatory 
secondary endpoints are based on findings from other projects conducted by Novo Nordisk
(NN8022 (SCALE), NN9535 (SUSTAIN), NN9924 (PIONEER)), and trial NN9536-4153 and are 
presented in Table 10-2. 
Given these assumptions, the sample size of 750 subjects (500 in the semaglutide 2.4 mg once 
weekly and 250 in the semaglutide placebo arm), gives an effective power (marginal powers 
multiplied) of 95% for the first four endpoints in the hierarchical testing procedure. Under the 
additional assumption that minimum 80% of subjects will be eligible for randomisation a total of 
900 subjects will be started on trial product. As sample size is primarily driven by safety, additional 
scenarios for assumptions are not included due to the overall high power.
Table 10-2
Assumptions, marginal power and effective power for each endpoint in the 
hierarchical testing procedure given an anticipated number of 750 randomised 
subjects
Order
Endpoint
Assumed mean (±SD) for 
completers
Expected mean 
(±SD)
Expected 
difference
Marginal 
power 
(%)
Effective 
power 
(%)
Semaglutide
2.4 mg
Semaglutide 
placebo
Semaglutide
2.4 mg
1
% weight change
-4 (±10)
+5 (±10)
-3.7 (±11)
8.7 %-points
> 99
> 99
2
WC change (cm)
-3 (±10)
+3 (±10)
-2.8 (±11)
5.8 cm
> 99
> 99
3
sBP change (mmHg)
-3.1 (±13)
+1 (±13) 
-3 (±14)
4 mmHg
95
95
4
SF-36 PF score 
change
+6 (±10)
+2 (±10)
+5.9 (±11)
3.9 score-
points
> 99
95
5
WRSSM total score 
change
To be confirmed. Is currently being validated in trials N8022-4272 and -4274
SD = standard deviation; WC = waist circumference; sBP = systolic blood pressure; SF-36 = Short Form 36 v2.0 acute; PF = 
physical functioning; WRSSM = Weight Related Sign and Symptom Measure
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10.2
Definition of analysis sets
Two analysis sets are defined:
!
The full analysis set (FAS) includes all randomised subjects according to the intention-to-
treat principle.
!
The safety analysis set (SAS) includes all subjects exposed to at least one dose of trial 
product.
Any observation excluded from the analysis will be documented before database lock with the 
reason for exclusion provided.
Two observation periods are defined for each subject:
!
In-trial: The in-trial period is defined as the uninterrupted time interval from date of week 0 
to date of last contact with trial site.
!
On-treatment (with trial product): A time-point is considered as ‘on-treatment’ if any dose 
of trial product has been administered within the prior 2 weeks (14 days). The on-treatment 
period is defined as all times which are considered on-treatment.
o
In general, the on-treatment period will therefore be from the date of first trial 
product administration to date of last trial product administration excluding potential 
off-treatment time intervals triggered by at least two consecutive missed doses.
o
For the evaluation of adverse events the lag time for each on-treatment time interval 
is 7 weeks (49 days) applicable to all subjects treated with trial product including 
those who are not eligible for randomisation.
The in-trial and on-treatment periods define the patient years of observation (PYO) and patient 
years of exposure (PYE), respectively, as the total time duration in the periods.
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 
database lock.
Effect endpoints will be analysed using the FAS; safety endpoints will be analysed using the SAS.
Results from statistical analyses will generally be accompanied by two-sided 95% confidence 
intervals and corresponding p-values. Superiority will be claimed if p-values are less than 5% and 
the estimated treatment contrasts favours semaglutide 2.4 mg. 
Handling of missing baseline data
The last available and eligible observation at or before randomisation is used as the baseline 
(randomisation) value. If no assessments are available during the run-in period, the mean value at 
randomisation across all subjects is used as the baseline (randomisation) value. For endpoints 
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evaluating the change from week 0, the last available and eligible observation at or before the week 
0 visit is used as the baseline (week 0) value. If no assessments are available, the mean value at 
week 0 across all subjects is used as the baseline (week 0) value.
10.3.1
Primary endpoint
Definition of primary endpoint: % weight change
Change from baseline (randomisation/week 20) to week 68 in body weight (%) is defined as
% weight change = (body weight at week 68 – body weight at baseline)
body weight at baseline
×100.
Analyses addressing the primary estimand
The following statistical analysis and imputation methods are designed to address the primary 
estimand, i.e. to assess the effectiveness of semaglutide 2.4 mg. 
The analysis model for % weight change is a linear regression (ANCOVA) of % weight change 
with randomised treatment as a factor and baseline body weight (kg) as covariate. The estimated 
treatment difference between semaglutide 2.4 mg and semaglutide placebo will be reported together 
with the associated two-sided 95% confidence interval (CI) and corresponding p-value.
The superiority tests of semaglutide 2.4 mg vs. semaglutide placebo will be carried out as follows.
Let μsemaglutide and μsemaglutide placebo denote the true mean of % weight change for semaglutide 2.4 mg 
and semaglutide placebo group, respectively. The null and alternative hypotheses tested are
:  ≥   !
":  <  .
The hypothesis will be rejected and superiority claimed, if the upper limit of the estimated two-
sided 95% CI is below 0.
Handling of missing week 68 values for the primary estimand
All available data at week 68 (AT and AD) are used and missing values (MT and MD) at week 68 
will be imputed and the endpoint will be derived from the imputed values. Several approaches for 
imputation will be applied. First, a description of the primary imputation approach to address the 
primary estimand for the primary endpoint is given followed by a description of the sensitivity 
analyses used to assess the robustness of the primary analysis results. The sensitivity analyses 
investigate how assumptions on body weight development after discontinuation of randomised 
treatment impact the estimated treatment contrasts between semaglutide 2.4 mg and semaglutide 
placebo. An illustration of all imputation approaches for the effectiveness estimand is given in 
Figure 10-1.
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Primary imputation approach for the primary estimand
Multiple imputation approach using retrieved subjects (RD-MI): The primary imputation approach 
for the primary estimand is a multiple imputation similar to the one described by McEvoy. 75
Missing body weight measurement at week 68 for non-retrieved subjects (MD) are imputed using
assessments from retrieved subjects (AD) in each randomised treatment arm. This will be done 
according to the timing of last available observation (LAO) of body weight. Missing body weight 
measurements at week 68 for subjects on randomised treatment (MT) are imputed by sampling from 
available measurements at week 68 from subjects on randomised treatment (AT) in the relevant 
randomised treatment arm. The multiple imputation approach is done in three steps:
1. Imputation: Defines an imputation model using retrieved subjects (AD) from FAS and done 
within groups defined by randomised treatment and the timing of the LAO of body weight. The 
model will be a linear regression of body weight (kg) at week 68 with gender (male/female), 
baseline BMI (kg/m2) (in categories 27-<35, 35-<40, ≥40) as factors and baseline
(randomisation) body weight (kg) and LAO of body weight (kg) as covariates. No interactions 
will be included. The grouping of timing will be done by quarters (intervals of 12 weeks for 
endpoints evaluating the change from randomisation, intervals of 17 weeks for endpoints 
evaluating the change from week 0). If timing by quarters is too restrictive, halves (intervals of 
24 weeks for endpoints evaluating the change from randomisation, intervals of 34 weeks for 
endpoints evaluating the change from week 0) or excluding timing will be used. If any subjects 
are MT, an imputation model for missing body weight measurements at week 68 for MT subjects 
will also be defined using AT subjects in a similar way. The estimated posterior distribution for 
the parameters (regression coefficients and variances) in the imputation models are then used to 
impute missing week 68 body weight values for each randomised treatment arm. This will be 
done 1,000 times and results in 1,000 complete data sets.
2. Analysis: Analysis of each of the 1,000 complete data sets, using the analysis model
(ANCOVA) results in 1,000 estimations.
3. Pooling: Integrates the 1,000 estimation results into a final result using Rubin’s formula.
Based on NN9536-4153 phase 2 results 1,000 copies should be sufficient to establish stable results. 
If 1,000 copies are insufficient, 10,000 copies will be used. The multiple imputations will be 
generated using Novo Nordisk trial number 95364376 as seed number. 
Sensitivity analyses
Jump to reference multiple imputation approach (J2R-MI): Missing values of body weight at week 
68 (MT and MD) for both the semaglutide 2.4 mg and semaglutide placebo group are imputed by 
sampling among all available assessments at week 68 in the semaglutide placebo group (AT and 
AD). This approach makes the assumption that subjects instantly after discontinuation lose any 
effect of randomised treatment beyond what can be expected from semaglutide placebo treatment as 
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adjunct to reduced-calorie diet and increased physical activity.76 The multiple imputation approach 
is done as above with the first step replaced by
1. Imputation: Defines an imputation model using semaglutide placebo subjects from FAS with a 
week 68 measurement (AT and AD). The model will be a linear regression of body weight (kg) 
at week 68 with gender (male/female), BMI (kg/m2) (in categories 27-<35, 35-<40, ≥40) as 
factors and baseline (randomisation) body weight (kg) as covariate. No interactions will be 
included. The estimated posterior distribution for the parameters (regression coefficients and 
variances) in the imputation models are then used to impute missing week 68 body weight values 
for each randomised treatment arm. This will be done 1,000 times and results in 1,000 complete 
data sets.
The jump to reference approach is the basis for the sample size calculations. 
A single imputation approach as done by Sacks77 (S1-SI and S2-SI): Missing weight measurements
at week 68 for non-retrieved subjects (MD) are imputed using a weight regain rate of 0.3 kg/month 
after LAO but truncated at no change from baseline whenever the extrapolation would lead to a 
positive weight gain relative to baseline. If a subject's weight at drug discontinuation represented a 
gain in weight relative to baseline, no additional gain will be imputed, and the unfavourable gain is 
carried forward to week 68. The weight regain imputation will be done for both randomised arms
(S1-SI). Additionally, a version where only the semaglutide 2.4 mg arm uses the regain rate while 
the semaglutide placebo arm uses last available observation (corresponding to a weight regain rate 
of 0 kg/month) will be performed (S2-SI). For both versions, missing weight measurements at week 
68 for subjects on randomised treatment (MT) are imputed by using LAO.
Tipping-point multiple imputation analysis (TP-MI): First, missing data are imputed according to 
the primary multiple imputation approach. Second, for the semaglutide 2.4 mg treatment arm a 
penalty will be added to the imputed values at week 68. The approach is to gradually increase this 
penalty until all confirmed conclusions from the primary analysis are reversed. For each hypothesis 
tested the specific value of the penalty that reverses the conclusion will be used to evaluate the 
robustness of the primary analysis results. This sensitivity analysis evaluates the robustness of the 
superiority conclusions.
Mixed model for repeated measurements (MMRM): This ‘MMRM for effectiveness’ will use all 
assessments regardless of adherence to randomised treatment, including assessments at week 68 for 
retrieved drop-outs (AD). The MMRM for effectiveness will be fitted using the same factor and 
covariate as for the primary analysis all nested within visit. An unstructured covariance matrix for 
measurements within the same subject will be employed, assuming that measurements for different 
subjects are independent.
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Figure 10-1
Illustration of imputation approaches for the effectiveness estimand
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Analysis addressing the secondary estimand
The secondary estimand for % weight change addresses the efficacy of semaglutide 2.4 mg and will 
be assessed using a ‘MMRM for efficacy’. Week 68 assessments for retrieved drop-outs (AD) are 
not used in this analysis. The MMRM for efficacy will use assessments only from subjects who are 
taking the randomised treatment until end of treatment or until first discontinuing of randomised 
treatment. The derived date of the second consecutive missed dose will be used as the latest date for 
using assessments in this MMRM. The assessment closest in time and before the derived date of the 
second consecutive missed dose will be used as last assessment on randomised treatment. For 
subjects who initiate rescue interventions before completion or first discontinuing of randomised 
treatment, the date of starting weight management drugs or undergoing bariatric surgery will be 
used as latest date for using assessments in this MMRM. Similarly, the assessment closest in time 
and before the date of starting weight management drugs or undergoing bariatric surgery will be 
used as last assessment on randomised treatment. The MMRM for efficacy will be fitted using % 
weight change and the same factor and covariate as for the primary analysis all nested within visit. 
An unstructured covariance matrix for measurements within the same subject will be employed, 
assuming that measurements for different subjects are independent. 
An overview of all analysis and imputation methods to address the effectiveness and efficacy 
estimands for the primary endpoint is given in Table 10-3.
10.3.2
Secondary endpoints
10.3.2.1
Confirmatory secondary endpoints
Confirmatory secondary endpoints are listed in section 4.2.2.1 and are all included in the fixed-
sequence statistical strategy, see above. All tests are tests of superiority of semaglutide 2.4 mg to 
semaglutide placebo. 
Analyses addressing the primary estimand
All confirmatory secondary endpoints will be analysed using the same imputation approach as used 
for the primary endpoint and to address the primary estimand. The imputation model is the same as 
for the primary endpoint with body weight replaced by assessments of the endpoint to be analysed. 
The statistical model for continuous endpoints will be ANCOVA with factor and covariate as for 
the primary endpoint % weight change with baseline (randomisation) body weight replaced by the
baseline (randomisation) assessment of the endpoint to be analysed. 
Analyses addressing the secondary estimand
The confirmatory secondary endpoints which relate to the primary objective will be analysed to 
address the secondary estimand using the same MMRM for efficacy described for the primary 
endpoint.
Sensitivity analyses for confirmatory secondary endpoints
For all continuous confirmatory secondary endpoints a sensitivity analysis using jump to reference 
as imputation approach will be carried out. 
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An overview of all analysis and imputation methods to address the effectiveness and efficacy 
estimands for confirmatory secondary endpoints is given in Table 10-3.
Table 10-3
Analysis and imputation methods to address the effectiveness and efficacy 
estimands for the primary and confirmatory secondary endpoints in the 
statistical testing hierarchy
Objective
Endpoint
Test 
order
Endpoint 
type
Estimand
Analysis 
set
Statistical 
model
Imputation 
approach
Sensitivity 
analyses
Primary endpoint
From randomisation (week 20) to week 68
Primary
% weight change
1
Continuous
Primary
FAS
ANCOVA
RD-MI
J2R-MI
S1-SI
S2-SI
TP-MI
MMRM
Secondary
FAS
MMRM
-
-
Confirmatory secondary endpoints
From randomisation (week 20) to week 68
Primary
WC change (cm)
2
Continuous
Primary
FAS
ANCOVA
RD-MI
J2R-MI
Secondary
FAS
MMRM
-
-
Secondary
sBP change (mmHg)
3
Continuous
Primary
FAS
ANCOVA
RD-MI
J2R-MI
Secondary
SF-36 PF score change
4
Continuous
Primary
FAS
ANCOVA
RD-MI
J2R-MI
Secondary
WRSSM total score 
change
5
Continuous
Primary
FAS
ANCOVA
RD-MI
J2R-MI
FAS = full analysis set; ANCOVA = analysis of covariance; RD-MI = multiple imputation using retrieved subjects; 
J2R-MI = jump to reference multiple imputation; S1-SI and S2-SI = single imputation as done by Sacks; TP-MI = 
tipping point multiple imputation; MMRM = mixed model for repeated measurements; WC = waist circumference; sBP 
= systolic blood pressure; SF-36 = Short Form 36 v2.0 acute; PF = physical functioning; WRSSM = Weight Related 
Sign and Symptom Measure
10.3.2.2
Supportive secondary endpoints
Supportive secondary endpoints are listed in section 4.2.2.2. All tests are tests of superiority of 
semaglutide 2.4 mg to semaglutide placebo. 
Analyses addressing the primary estimand
The effect-related supportive secondary endpoints will be analysed using the same imputation 
approach as used for the primary endpoint and to address the primary estimand. The imputation 
model is the same as for the primary endpoint with body weight replaced by assessments of the 
endpoint to be analysed. The statistical model for continuous endpoints will be ANCOVA with 
factor and covariate as for the primary endpoint % weight change with baseline (randomisation)
body weight replaced by the baseline (randomisation) assessment of the endpoint to be analysed.
The statistical model for responder endpoints relating to clinical outcome assessments will be 
logistic regression with randomised treatment as a factor and t he baseline (randomisation) 
assessment of the endpoint to be analysed as covariate.
The supportive secondary endpoint subjects who gain weight from randomisation (week 20) to
week 68 (yes/no)’ is used to describe weight maintenance. It will be analysed using logistic 
regression with randomised treatment as a factor and body weight (kg) at baseline (randomisation) 
as covariate.
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For lipids a multiplicative model will be used, i.e. the ratio between post randomisation 
measurements and baseline (randomisation) will be calculated instead of differences, and both the 
dependent variable and covariate will be log-transformed.
Analyses addressing the secondary estimand
The supportive secondary endpoints which relate to the primary objective will be analysed to 
address the secondary estimand using the same MMRM for efficacy described for the primary 
endpoint.
Analyses addressing the tertiary estimand
The effect-related supportive secondary endpoints addressing the tertiary estimand will be analysed 
using the same imputation approach as used for the primary endpoint, where baseline 
(randomisation) body weight (kg) is replaced by baseline (week 0) body weight (kg). The 
continuous endpoint on body weight will be analysed using ANCOVA with factor and covariate as 
for the primary endpoint % weight change with the baseline (randomisation) value replaced with 
baseline (week 0). The binary endpoints on body weight will be analysed using logistic regression 
with randomised treatment as a factor and baseline (week 0) assessment of body weight as 
covariate.
Sensitivity analyses for supportive secondary endpoints
For supportive secondary endpoints no sensitivity analysis will be carried out.
Additional considerations for statistical analyses 
To evaluate the predictive value of short-term weight changes for long-term benefit of the use of 
semaglutide 2.4 mg, subjects will be categorised based on the weight change achieved in the run-in
phase. If the weight change from week 0 to week 20 exceeds a certain pre-specified threshold 
subjects are classified as early “responders” whereas subjects are classified as early “non-
responders” if the weight has changed less than the pre-specified threshold. Different thresholds of 
3%, 4% and 5% will be investigated. These sub-group analyses will be done using the primary 
endpoint and the statistical model described for the primary endpoint.
Analysis of safety endpoints
The safety endpoint pulse will be analysed using an MMRM for efficacy as described in Section 
10.3.1. For amylase, lipase and calcitonin descriptive statistics will be provided. The analysis of 
calcitonin will be stratified by gender.
Adverse events will be defined as “treatment-emergent” (TEAE), if the onset of the event occurs in 
the on-treatment period (see definition in Section 10.2). TEAEs and SAEs will be summarised by 
descriptive statistics, such as frequencies and rates. No formal statistical inference will be carried 
out based on the number of TEAEs and SAEs.
An overview of all analysis and imputation methods to address the effectiveness and efficacy 
estimands for supportive secondary endpoints is given in Table 10-4.
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Table 10-4
Analysis and imputation methods to address the effectiveness and efficacy 
estimands for supportive secondary endpoints
Objective
Endpoint
Endpoint 
type
Estimand
Analysis 
set
Statistical 
model
Imputation 
approach
Sensitivity 
analyses
Supportive secondary endpoints (effect related)
From randomisation (week 20) to week 68
Primary
Weight change (kg)
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
FAS
MMRM
-
-
Primary
BMI change (kg/m2)
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
FAS
MMRM
-
-
Secondary
HbA1c change (%, mmol/mol)
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
FPG change (mg/dL)
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
Fasting serum insulin change 
(mIU/L)
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
dBP change (mmHg)
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
Total cholesterol change (mg/dL)
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
HDL change (mg/dL)
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
LDL change (mg/dL)
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
VLDL change (mg/dL)
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
FFA change (mg/dL)
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
Triglycerides change (mg/dL)
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
SF-36 PF score responders #
Binary
Primary
FAS
LR
RD-MI
-
Secondary
SF-36 RP score change
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
SF-36 BP score change
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
SF-36 GH score change
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
SF-36 VT score change
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
SF-36 SF score change
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
SF-36 RE score change
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
SF-36 MH score change
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
SF-36 PCS score change
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
SF-36 MCS score change
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
WRSSM total score responders ##
Binary
Primary
FAS
LR
RD-MI
-
Secondary
Proportion of subjects who gain 
weight
Continuous
Primary
FAS
ANCOVA
RD-MI
-
From week 0 to week 68
Secondary
% weight change
Continuous
Tertiary
FAS
ANCOVA
RD-MI
-
Secondary
Weight reduction <0%
Binary
Tertiary
FAS
LR
RD-MI
-
Secondary
Weight reduction ≥5%
Binary
Tertiary
FAS
LR
RD-MI
-
Secondary
Weight reduction ≥10%
Binary
Tertiary
FAS
LR
RD-MI
-
Secondary
Weight reduction ≥15%
Binary
Tertiary
FAS
LR
RD-MI
-
Supportive secondary endpoints (safety related)
From week 0 to randomisation (week 20)
Secondary
Number of TEAEs
Continuous
-
SAS
-
-
-
Secondary
Number of SAEs
Continuous
-
SAS
-
-
-
Secondary
Pulse change (bpm)
Continuous
-
SAS
MMRM
-
-
Secondary
Amylase change (U/L)
Continuous
-
SAS
Descriptive 
statistics
-
-
Secondary
Lipase change (U/L)
Continuous
-
SAS
Descriptive 
statistics
-
-
Secondary
Calcitonin change (ng/L)
Continuous
-
SAS
Descriptive 
statistics
-
-
From randomisation (week 20) to week 75
Secondary
Number of TEAEs
Continuous
-
SAS
-
-
-
Secondary
Number of SAEs
Continuous
-
SAS
-
-
-
Secondary
Pulse change (bpm)
Continuous
-
SAS
MMRM
-
-
Secondary
Amylase change (U/L)
Continuous
-
SAS
Descriptive 
statistics
-
-
Secondary
Lipase change (U/L)
Continuous
-
SAS
Descriptive 
statistics
-
-
Secondary
Calcitonin change (ng/L)
Continuous
-
SAS
Descriptive 
statistics
-
-
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FAS = full analysis set; ANCOVA = analysis of covariance; RD-MI = multiple imputation using retrieved subjects; 
MMRM = mixed model for repeated measurements; BMI = body mass index; HbA1c = Hemoglobin A1c; FPG = 
fasting plasma glucose; dBP = diastolic blood pressure; HDL = high density lipoprotein; LDL = low density 
lipoprotein; VLDL = very low density lipoprotein; FFA = free fatty acids; LR = logistic regression; SF-36 = Short Form 
36 v2.0 acute; PF= Physical Functioning; RP = Role-Physical; BP = Bodily Pain; GH = General Health; VT = Vitality; 
SF = Social Functioning; RE = Role-Emotional; MH = Mental Health; PCS = Physical component summary; MCS = 
Mental component summary; WRSSM = Weight Related Sign and Symptom Measure; TEAEs = treatment emergent 
adverse events; SAEs = serious adverse events; # responder value = 4.3; ## responder value to be validated in trials 
NN8022-4272 and -4274
10.3.3
Exploratory endpoints
Exploratory endpoints are listed in Section 4.2.3. Observed data for exploratory endpoints will be 
summarised by descriptive statistics. 
10.3.4
Other analyses
All collected data that were not defined as endpoints will be summarised by descriptive statistics. 
10.4
Pharmacokinetic and/or pharmacodynamic modelling
Not applicable for this trial. 
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11 Appendices
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Abbreviations and Trademarks
Appendix 1
AD
available but discontinued
AE
adverse event
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
AT
available on treatment
BMI
body mass index
BMR
basal metabolic rate 
CI
confidence interval 
CLAE
clinical laboratory adverse event
CRF
case report form
C-SSRS
Columbia-Suicide Severity Rating Scale 
DFU
direction for use 
DUN
dispensing unit number
EAC
event adjudication committee 
EAS
event adjudication system
ECG
electrocardiogram
eGFR
estimated Glomerular Filtration Rate 
FAS
full analysis set
FDA
U.S. Food and Drug Administration
FDAAA
FDA Amendments Act
FPG
fasting plasma glucose
FSH
follicle-stimulating hormone 
GCP
Good Clinical Practice
GLP-1
glucagon-like peptide-1 
HbA1c
glycated haemoglobin
HDL
high-density lipoproteins 
HRT
hormone replacement therapy
IB
investigator’s brochure
ICH
International Council for Harmonisation
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IEC
independent ethics committee
IMP
investigational medicinal product
IRB
institutional review board
IWRS
interactive web response system
KDIGO
kidney disease improving global outcome
LAO
last available observation
LDL
low density lipoprotein 
MD
missing and discontinued
MEN2
multiple endocrine neoplasia type 2
MHP
mental health professional
MMRM
mixed model for repeated measurements
MT
missing on treatment
MTC
medullary thyroid cancer 
PCD
primary completion date
PGI-C
Patient Global Impression of Change
PGI-S
Patient Global Impression of Severity 
PHQ-9
Patient Health Questionaire-9 
RA
receptor agonist
SAE
serious adverse event
SAS
safety analysis set 
sBP
systolic blood pressure
s.c.
subcutaneous 
SD
standard deviation
SF-36
Short Form 36 v2.0 acute 
SIF
safety information form
SPS-6
Stanford Presenteeism Scale 
SUSAR
suspected unexpected serious adverse reaction
T2D
type 2 diabetes 
TEAE
treatment-emergent adverse event
TEE
total energy expenditure 
TMM
trial materials manual
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TSH
thyroid stimulating hormone 
UNL
upper normal limit
VLDL
very-low-density lipoprotein 
WC
waist circumference
WOCBP
woman of child bearing potential
WRSSM
Weight Related Sign and Symptom Measure 
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Clinical laboratory tests
Appendix 2
!
The tests detailed in Table 11-1 and Table 11-2 will be performed by the central laboratory.
!
Laboratory samples specified in the protocol should be sent to the central laboratory for 
analysis.
!
Additional tests may be performed at local laboratory at any time during the trial as 
determined necessary by the investigator or required by local regulations. 
!
The laboratory equipment may provide analyses not requested in the protocol but produced 
automatically in connection with the requested analyses according to specifications in the 
laboratory standard operating procedures. Such data will not be transferred to the trial 
database, but abnormal values will be reported to the investigator. 
!
The investigator must review all laboratory results for concomitant illnesses and AEs.
!
Laboratory samples will be destroyed no later than at finalisation of the clinical trial report. 
!
For haematology samples (differential count) where the test result is not normal, then a part 
of the sample may be kept for up to two years or according to local regulations.
Table 11-1
Protocol-required efficacy laboratory assessments
Laboratory assessments
Parameters
Glucose metabolism 
Fasting plasma glucose1
HbA1c
Fasting serum insulin
Lipids
Cholesterol
HDL cholesterol
LDL cholesterol
Triglycerides
VLDL cholesterol
Free fatty acids
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 but as a CLAE at the discretion of the investigator (Appendix 4).
Table 11-2
Protocol-required safety laboratory assessments
Laboratory assessments
Parameters
Haematology
Basophils
Eosinophils
Erythrocytes
Haematocrit
Haemoglobin
Leucocytes
Lymphocytes
Monocytes
Neutrophils
Thrombocytes
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Biochemistry1
Alanine Aminotransferase (ALT)2
Albumin
Albumin corrected calcium
Alkaline phosphatase
Amylase3
Aspartate Aminotransferase (AST)2
Calcitonin3
Creatine kinase
Creatinine
Lipase3
Potassium
Sodium
Thyroid stimulating hormone (TSH)4
Total bilirubin
Urea
Pregnancy Testing
Urine human chorionic gonadotropin (hCG) pregnancy test (as needed for women of 
childbearing potential)5
Other tests
eGFR calculated by the central laboratory based on the creatinine value using the CKD-
EPI equation as defined by KDIGO 201267
(Tryptase in case of severe hypersensitivity, see Section 9.9)
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.
2If ALT or AST > 3 upper normal limit (UNL), additional blood sample should be taken from the subject to analyse 
international normalised ratio (INR) by central laboratory (except at screening visit). Repeat testing of the abnormal 
laboratory assessments should be performed via central laboratory for the subject until abnormalities return to normal or 
baseline state.
3Not collected at week 52.
4If TSH level is out of normal range, additional testing will be performed by central lab: total and free T3 and T4 except 
at screening visit. 
5Local urine testing will be standard unless serum testing is required by local regulation or IRB/IEC.
Laboratory outlier: If the following laboratory parameters are above/below the cut-off values in 
Table 11-3 they are considered to be laboratory outliers and should be reported by completing a 
laboratory outlier form in the CRF:
Table 11-3
Criteria for laboratory outliers
Cut-off
Haematology
Leucocytes
< 1 × 109/L
Lymphocytes
< 25 × 109/L
Thrombocytes
< 25 × 109/L
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Cut-off
Biochemistry
Albumin corrected calcium
< 1.50 mmol/L or > 3.4 mmol/L
Alkaline phosphatase
> 20 × UNL
Calcitonin
> 100 ng/L
Creatinine
> 6 × UNL
Creatine kinase
> 10 × UNL
Potassium
< 2.50 mmol/L or > 7.0 mmol/L
Sodium
< 120 mmol/L or > 160 mmol/L
Hepatic laboratory outlier: If the following hepatic laboratory parameters are above the cut -off
value in Table 11-4, it is considered to be a hepatic laboratory outlier and should be reported by 
completing a hepatic event form in the CRF. It is at the investigator’s discretion to determine 
whether it should also be reported as an adverse event (see Appendix 4).
Table 11-4
Criteria for hepatic laboratory outliers
Cut-off
Alkaline phosphatase
> 20 × UNL
ALT
> 5 × UNL
AST
> 5 × UNL
Total bilirubin
> 10 × UNL
Please note that in case of a hepatic event defined as ALT or AST >3 x UNL and total bilirubin > 2 x UNL, where no 
alternative aetiology exists (Hy's law), this must be reported as an SAE using the important medical event criterion if no 
other seriousness criteria are applicable.
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Trial governance considerations
Appendix 3
1) Regulatory and ethical considerations
!
This trial will be conducted in accordance with the protocol and with the following:
o
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki78 and applicable ICH Good Clinical Practice (GCP) 
Guideline79
o
Applicable laws and regulations
!
The protocol, informed consent form, IB (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.
!
Regulatory authorities will receive the clinical trial application, protocol amendments, 
reports on SAEs, and the clinical trial report according to national requirements.
!
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.
!
Before a trial site is allowed to start screening subjects, written notification from Novo 
Nordisk must be received.
!
The investigator will be responsible for:
o
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
o
notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures
o
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
o
ensuring submission of the clinical trial report synopsis to the IRB/IEC.
2) Financial disclosure
Investigators and subinvestigators 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
!
The investigator or his/her representative will explain the nature of the trial to the subject 
and answer all questions regarding the trial. 
!
The investigator must ensure the subject ample time to come to a decision whether or not to 
participate in the trial. 
!
Subjects must be informed that their participation is voluntary.
!
Subjects will be required to sign and date a statement of informed consent that meets the 
requirements of local regulations, ICH guidelines79, Declaration of Helsinki78 and the 
IRB/IEC or trial site.
!
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.
!
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.
!
Subjects must be re-consented to the most current version of the informed consent form(s) 
during their participation in the trial.
!
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. 
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.
Different initiatives for subject retention will be implemented throughout this trial. Site retention 
activities may include cooking classes, group meetings, and others. Materials and items will be 
supplied if locally acceptable. The retention items will be relevant for the subjects’ participation in 
the trial and/or their obesity and will not exceed local fair market value.
The initiatives for subject retention must be sent to IRB/IEC for approval/favourable opinion and to 
regulatory authorities for approval or notification according to local regulations.
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5) Data protection
!
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.
!
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. 
!
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. 
!
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.
Event adjudication committee
An independent external EAC is established to perform ongoing blinded adjudication of selected 
types of events and deaths (see Table 9-1 and Appendix 4). The EAC will evaluate events sent for 
adjudication using pre-defined definitions and guidelines in accordance with the EAC Charter. The 
evaluation is based on review of pre-defined clinical data collected by the trial sites. 
The EAC is composed of permanent members covering all required medical specialities. EAC 
members must disclose any potential conflicts of interest and must be independent of Novo 
Nordisk. The EAC will have no authorisations to impact on trial conduct, trial protocol or 
amendments.
The assessment made by both the EAC and the investigator will be presented in the clinical trial 
report. 
In this trial, cardiovascular events will be adjudicated in order to adequately characterize the 
cardiovascular safety profile, since cardiovascular disease is an important and serious comorbidity 
of obesity80. In addition, events of acute pancreatitis will be adjudicated because Novo Nordisk 
monitor these events closely as treatment with GLP-1 RA has been associated with acute 
pancreatitis. 
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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.81
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.
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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 Editors 81.
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 
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 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)82, the Food and Drug Administration Amendment 
Act (FDAAA)83, European Commission Requirements84, 85 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) + 68 weeks corresponding to ‘end of treatment’ visit. If 
the last subject is withdrawn early, the PCD is considered the date when the last subject would have 
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completed ‘end of treatment’ visit. The PCD determines the deadline for results disclosure at 
clinicaltrials.gov according to FDAAA.
9) Data quality assurance
Case Report Forms (CRFs)
!
Novo Nordisk or designee is responsible for the data management of this trial including 
quality checking of the data.
!
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. 
!
For some data both electronic and paper CRFs are used.
!
The following will be provided as paper CRFs:
o
Pregnancy forms
!
The following will be provided as paper CRFs to be used when access to the electronic CRF 
is revoked or temporarily unavailable: 
o
AE forms 
o
Safety information forms
o
Technical complaint forms (also to be used to report complaints that are not subject 
related, e.g. discovered at trial site before allocation)
!
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.
!
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
!
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 addit ion the relevant trial site staff 
should be available for discussions at monitoring visits and between monitoring visits (e.g. 
by telephone). 
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!
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.
!
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. 
!
Monitors will review the subject’s medical records and other source data e.g. the diaries and 
mental health assessment instruments, to ensure consistency and/or identify omissions 
compared to the CRF. 
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
!
All data entered in the CRF must be verifiable in source documentation other than the CRF.
!
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. For food and physical activity diary, if 
the subject uses an app or a tool other than the paper diaries, the medical record or 
dietician’s notes from the diet and physical activity counselling can be used as source 
document.
!
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.
!
Data reported in the 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. 
!
It must be possible to verify subject’s medical history in the source documents such as 
subject’s medical record. 
!
Subjects completing electronic patient reported outcome instruments are the data 
originators. Data will be transmitted to a technology service provider database, thus the 
service provider database is the source. 
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!
The investigator must document any attempt to obtain external medical information by 
noting the date(s) when information was requested and who was contacted.
!
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
!
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. 
!
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 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.
!
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:
!
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
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!
inadequate recruitment of subjects by the investigator
!
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 
code list must be kept in a secure locked facility so that no unauthorized persons can get access to 
the data. 
The investigator will take all necessary technical and organisational safety measures to prevent 
accidental or wrongful destruction, loss or deterioration of data. The investigator will prevent any 
unauthorised access to data or any other processing of data against applicable law. The investigator 
must be able to provide the necessary information or otherwise demonstrate to Novo Nordisk that 
such technical and organisational safety measures have been taken.
During any period of unavailability, the investigator must delegate responsibility for medical care of 
subjects to a specific qualified physician who will be readily available to subjects during that time.
If the investigator is no longer able to fulfil the role as investigator (e.g. if he/she moves or retires) a 
new investigator will be appointed in consultation with Novo Nordisk. 
The investigator and other site personnel must have sufficient English skills according to their 
assigned task(s).
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 site or investigator are responsible. 
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Novo Nordisk may pay additional costs incurred in relation to assessments relevant for following 
the safety of the subject. Investigator must contact Novo Nordisk on a case by case basis for 
whether the costs will be covered.
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Adverse events: definitions and procedures for 
Appendix 4
recording, evaluation, follow-up, and reporting
AE definition
! 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.
! 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
! 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.
! A CLAE: 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.
! Exacerbation of a chronic or intermittent pre-existing condition including either an increase in frequency and/or 
intensity of the condition.
! Signs, symptoms or the clinical sequelae of a suspected drug-drug interaction.
! Signs, symptoms or the clinical sequelae of a suspected overdose of trial product regardless of intent.
! 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 
! 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.
! 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:
! Results in death
! 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.
! Requires inpatient hospitalisation or prolongation of existing hospitalisation
!
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.
!
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.
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
Hospital admissions for surgical procedures, planned before trial inclusion, are not considered AEs or SAEs.
! Results in persistent disability/incapacity
!
The term disability means a substantial disruption of a person’s ability to conduct normal life functions.
!
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.
! Is a congenital anomaly/birth defect
! Important medical event:
!
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.
!
The following AEs 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 ALT or 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) and events for adjudication. 
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 (see 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
Acute gallbladder 
disease
Events of symptomatic acute gallbladder disease (including gallstones and
cholecystitis)
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.
Malignant neoplasm
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 or INR > 1.5*
– 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.
Medication error: 
A medication error concerning trial products is defined as:
! Administration of wrong drug.
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!
Note: Use of wrong dispensing unit number (DUN) is not 
considered a medication error unless it results in a confirmed 
administration of wrong drug.
! Wrong route of administration, such as intramuscular instead of 
subcutaneous. 
! Accidental administration of more than 2.4 mg/week or a higher dose than 
intended during dose escalation, 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.
! Administration of an overdose with the intention to cause harm, misuse or 
abuse of trial product.
Events for adjudication
Event type
Description
Adjudication outcome
Death
All-cause death
!
Cardiovascular death 
(including undetermined 
cause of death)
!
Non-Cardiovascular death
Acute Coronary
Syndrome
Acute Coronary Syndrome conditions 
include all types of acute myocardial 
infarction and hospitalisation for unstable 
angina pectoris
!
Acute myocardial infarction 
(including subgroup 
classifications)
!
Hospitalisation for unstable 
angina pectoris
Cerebrovascular events
Episode of focal or global neurological 
dysfunction that could be caused by 
brain, spinal cord, or retinal vascular 
injury as a result of haemorrhage or 
infarction
!
Ischaemic stroke
!
Haemorrhagic stroke
!
Undetermined stroke
!
Transient Ischaemic Attack
Coronary artery 
revascularisation
Coronary revascularisation procedure is a 
catheter-based (PCI) or a surgical 
procedure (CABG) designed to improve 
myocardial blood flow
!
Coronary revascularisation
procedure
Heart failure
Presentation of the patient for an urgent, 
unscheduled clinic/office/emergency
department visit or hospital admission, 
with a primary diagnosis of heart failure
(new episode or worsening of existing 
heart failure)
!
Heart failure hospitalisation
!
Urgent heart failure visit
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 pancreatitis
!
Mild
!
Moderately severe
!
Severe
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AE and SAE recording
! The investigator will record all relevant AE/SAE information in the CRF.
! 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.
! 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.
! 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.
! 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.
! 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 AE 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: 
! Mild: An event that is easily tolerated by the subject, causing minimal discomfort and not interfering with everyday 
activities.
! Moderate: An event that causes sufficient discomfort and interferes with normal everyday activities.
! 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: 
! Probable - Good reason and sufficient documentation to assume a causal relationship.
! Possible - A causal relationship is conceivable and cannot be dismissed.
! Unlikely - The event is most likely related to aetiology other than the trial product.
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 IB 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:
! Recovered/resolved: The subject has fully recovered, or by medical or surgical treatment the condition has returned 
to the level observed at the first trial-related activity after the subject signed the informed consent.
! Recovering/resolving: The condition is improving and the subject is expected to recover from the event. This term is 
only applicable if the subject has completed the trial or has died from another AE.
! Recovered/resolved with sequelae: The subject has recovered from the condition, but with lasting effect due to a 
disease, injury, treatment or procedure. If a sequelae meets an SAE criterion, the AE must be reported as an SAE.
! Not recovered/not resolved: The condition of the subject has not improved and the symptoms are unchanged or the 
outcome is not known.
! Fatal: This term is only applicable if the subject died from a condition related to the reported AE. Outcomes of other 
reported AEs in a subject before he/she died should be assessed as “recovered/resolved”, “recovering/resolving”, 
“recovered/resolved with sequelae” or “not recovered/not resolved”. An AE with a fatal outcome must be reported as 
an SAE.
! 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
! Relevant forms (AE and safety information form) must be completed in the CRF. 
! For reporting and sign-off timelines (see box below). 
! 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).
! The site will enter the SAE data into the CRF as soon as it becomes available, see Section 9.2.1.
! 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
! Relevant CRF forms (AE and safety information form) must be forwarded to Novo Nordisk either by fax, e-mail or 
courier.
! Initial notification via telephone is acceptable, although it does not replace the need for the investigator to complete 
the AE and safety information form within the designated reporting time frames (as illustrated in Figure 9-1):
!
AE form within 24 hours.
!
Safety information form within 5 calendar days. 
!
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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Contraceptive guidance and collection of pregnancy 
Appendix 5
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 using hormonal 
contraception or Hormonal Replacement Therapy (HRT). However, in the absence of 12 
months of amenorrhea, a single 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:
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Table 11-5
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
! Intrauterine hormone-releasing System
! 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 
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 49 days 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 11-5 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/hers knowledge about the female’s obesity history, concomitant 
illness, concomitant medication and observed AEs. The justification must be stated in the medical 
records.
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Pregnancy testing
!
WOCBP should only be included after a negative highly sensitive urine pregnancy test.
!
Urine pregnancy testing should be performed at every site visit (every 4-8 weeks) during the 
treatment period, at ‘end of treatment’ and after the 7 weeks off-drug follow-up period 
according to the flow chart.
!
Additional urine pregnancy testing should be performed at monthly intervals during the 
treatment period, if required locally (Appendix 8).
!
Pregnancy testing should be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise 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.
!
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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Technical complaints: Definition and procedures for 
Appendix 6
recording, evaluation, follow-up and reporting
Technical complaint definition
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:
!
Problems with the physical or chemical appearance of trial products (e.g. discoloration, 
particles or contamination).
!
Problems with packaging material including labelling.
!
Problems related to medical devices (e.g. to the injection mechanism, dose setting 
mechanism, dose 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 Figure 9-3. 
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
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.
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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.
All technical complaints are handled by Custumer Complaint Center, Novo Nordisk. Only technical 
complaints related to adverse events will be included in the clinical trial report. 
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Monitoring of calcitonin
Appendix 7
Background
Treatment with GLP-1 RAs has been shown to be associated with thyroid C-cell changes in rodents 
but not in non-human primates. The human relevance of this finding is unknown. However, based 
on the findings in rodents, monitoring of serum calcitonin (a sensitive biomarker for C-cell 
activation) is currently being performed in clinical trials with semaglutide.
While there is general agreement on the clinical interpretation of substantially elevated calcitonin 
levels (> 100 ng/L) as likely indicative of C-cell neoplasia, the interpretation of values between 
upper normal range (5.0 and 8.4 ng/L for women and men, respectively) and 100 ng/L is less clear 
with regards to indication of disease.
There are several known confounding factors affecting calcitonin levels, e.g.:
!
renal dysfunction
!
tobacco use
!
autoimmune thyroiditis
!
several drug classes (e.g. proton pump inhibitors, beta-blockers, H2-blockers and 
glucocorticoids)
Physiology of C-cell activation in various clinical conditions and in different patient populations 
(i.e. with various comorbidities) is poorly understood. There may be various clinical conditions not 
identified so far which mildly or moderately affect calcitonin secretion by C-cells.
Calcitonin monitoring
A blood sample will be drawn at pre-specified trial visits for measurement of calcitonin.
In case a subject has a calcitonin value ≥ 10 ng/L, the algorithm outlined in Figure 11-1 and 
described below should be followed. The algorithm applies for all calcitonin values in the trial.
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Evaluation of 
calcitonin results
Calcitonin < 10 ng/L
Calcitonin ≥ 10 ng/L and < 50 ng/L
Calcitonin ≥ 50 ng/L and < 100 ng/L
Calcitonin ≥ 100 ng/L 
Calcitonin ≥ 10 ng/L and last 
measurement in the trial
No action
!
Investigate potential confounding 
factors
!
Continue sampling of calcitonin 
according to protocol
!
Discontinue trial product
!
Refer to thyroid specialist
!
Refer to thyroid specialist
!
Refer to thyroid specialist
Figure 11-1 Flow of calcitonin monitoring
Calcitonin ≥ 100 ng/L  
Action: The subject (even if a screen failure) must immediately be referred to a thyroid specialist 
for further evaluation and the trial product must be discontinued (see Section 8.1). The subject 
should remain in the trial; however, all medications suspected to relate to this condition must be 
discontinued until diagnosis has been established.
Background: These values were found in 9 (0.15%) of a population of 5817 patients with thyroid 
nodular disease86 . All of these patients were diagnosed with MTC, resulting in a positive predictive 
value of 100%.
Diagnostic evaluation should include:
!
thyroid ultrasound examination
!
fine needle aspiration of any nodules > 1 cm 
!
potentially, surgery with neck dissection
In case a subject is diagnosed with MTC, it is common clinical practice to explore the family 
history of MTC or MEN2 and perform a genetic test for RET proto-oncogene mutation.
Calcitonin ≥ 50 and < 100 ng/L
Action: The subject (even if a screen failure) should be referred to a thyroid specialist for further 
evaluation. The subject should remain in the trial and can continue on trial product. 
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Background: These values were found in 8 (0.14%) of the population of 5817 patients with thyroid 
nodular disease86. Two of these subjects were diagnosed with MTC and two were diagnosed with C 
cell hyperplasia, resulting in a positive predictive value of a C-cell anomaly of 50%.
Diagnostic evaluation should include: 
!
thyroid ultrasound examination 
!
if available, and if there are no contraindications, a pentagastrin stimulation test should be 
done. For subjects with positive pentagastrin stimulation test, surgery should be considered. 
!
if pentagastrin stimulation test is not available, thyroid ultrasound and fine needle aspiration 
biopsy may add important clinical information about the need for surgery.
Calcitonin ≥ 10 and < 50 ng/L
Action: The subject can continue in the trial on trial product. Continue sampling of calcitonin 
according to the protocol.
If the subject is a screen failure, or if the value is from the last sample taken in the trial, the subject 
should be referred to a thyroid specialist for further evaluation.
Background: Calcitonin values from 20–50 ng/L were found in up to 1% of subjects of the 
population of 5817 patients with thyroid nodular disease86. The predictive value of a C-cell anomaly 
for this calcitonin level was 8.3%. However, the likelihood of having a medullary carcinoma > 1 cm 
with calcitonin in this range is extremely low.
For calcitonin values between 10-20 ng/L Costante et al.86 identified 216 (3.7%) patients. One 
patient out of the 216 had a subsequent basal (unstimulated) calcitonin value of 33 ng/L, and had C-
cell hyperplasia at surgery. Two other studies used a cut-off of calcitonin > 10 ng/L to screen for C-
cell disease, but they do not provide sufficient information on patients with basal CT > 10 and < 20 
ng/L to allow conclusions87, 88.
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Country-specific requirements
Appendix 8
For Denmark: Contraceptive measures considered adequate include intrauterine devices or 
hormonal contraception (oral contraceptive pills, implants, transdermal patches, vaginal rings or 
long-acting injections).
For France – Indemnity statement: The French Public Health Code article L 1121-10 (law n° 
2004-806 of 9 August 2004 art. 88 I,IX, Journal Officiel of 11 August 2004. "The sponsor is 
responsible for identification of the harmful consequences of the biomedical the research for the 
person lending himself thereto and for indemnification of his beneficiaries, except in case of proof, 
incumbent on it, that the prejudice is not attributable to his fault of to the fault of any intervening 
party, without the sponsor's being entitled to call on acts by a third party or the voluntary 
withdrawal of the person who had initially consented to cooperating in the research".
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evaluation of medicinal products used in weight management. EMA/CHMP/311805/2014. 
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Verga U, Ferrero S, Vicentini L, Brambilla T, Cirello V, Muzza M, et al. Histopathological 
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C-cell hyperplasia? Endocr Relat Cancer. 2007;14(2):393-403.
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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:
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Version:
Status:
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Trial ID: NN9536-4376
Clinical Trial Report
Appendix 16.1.1
03 Jun 2020
1.0
Final
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Local Protocol Amendment_SE
CONFIDENTIAL
Date:
07 February 2018
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Trial ID: NN9536-4376
Version:
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UTN: U1111-1201-0898
Status:
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EudraCT: 2017-003473-34
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Protocol Amendment
no 1 to
Protocol, final version 2.0 dated 21 December 2017 
Trial ID: NN9536-4376
Effect and safety of semaglutide 2.4 mg once-weekly in subjects with
overweight or obesity who have reached target dose during run-in period
Trial phase: 3a
Applicable to Sweden
Amendment originator:
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
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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.


Local Protocol Amendment_SE
CONFIDENTIAL
Date:
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Trial ID: NN9536-4376
Version:
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UTN: U1111-1201-0898
Status:
Final
EudraCT: 2017-003473-34
Page:
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Table of Contents   
Page
Table of Contents........................................................................................................................................2
Table of Figures ..........................................................................................................................................2
Table of Tables............................................................................................................................................2
1
Introduction including rationale for the protocol amendment...........................................................3
2
Changes ................................................................................................................................................3
Table of Figures   
Page
No table of figures entries found.
Table of Tables   
Page
No table of figures entries found.
CONFIDENTIAL


Local Protocol Amendment_SE
CONFIDENTIAL
Date:
07 February 2018
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Trial ID: NN9536-4376
Version:
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UTN: U1111-1201-0898
Status:
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EudraCT: 2017-003473-34
Page:
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1
Introduction including rationale for the protocol amendment
This is the local Swedish amendment to the global protocol in order to comply with the 
requirements for highly effective contraceptive methods in CTFG (Clinical Trial Facilitation 
Group): Recommendations related to contraception and pregnancy testing in clinical trials.
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 8
Country-specific requirements
For Sweden: Contraceptive measures considered adequate include highly effective contraceptive 
methods in accordance with the CTFG (Clinical Trial Facilitation Group): Recommendations 
related to contraception and pregnancy testing in clinical trials. This means use of double barrier 
methods is not applicable for Sweden. 
CONFIDENTIAL


Protocol Amendment no 2
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Date:
04 June 2018
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Trial ID: NN9536-4376
Version:
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Status:
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Protocol Amendment
no 2
to Protocol, version 2
dated 21 Dec 2017
Trial ID:NN9536-4376
Effect and safety of semaglutide 2.4 mg once-weekly in subjects with
overweight or obesity who have reached target dose during run-in period
Trial phase: 3a
Applicable to all countries
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.

CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol Amendment no 2
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Date:
04 June 2018
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Trial ID: NN9536-4376
Version:
1.0
     
Status:
Final
     
Page:
2 of 7
Table of Contents   
1
Introduction including rationale for the protocol amendment...........................................................3
2
Changes ................................................................................................................................................3
2.1
Section 1  Synopsis ...................................................................................................................3
2.2
Section 3.1  Trial rationale ........................................................................................................3
2.3
Section 3.2  Background............................................................................................................3
2.4
Section 4.1.3  Exploratory objectives.........................................................................................4
2.5
Section 4.2.2.2 Supportive secondary endpoints ........................................................................4
2.6
Section 7.1  Treatments administered ........................................................................................5
2.7
Section 7.1.2 Diet and physical activity counselling...................................................................5
2.8
Section 8  Discontinuation/Withdrawal criteria..........................................................................5
2.9
Section 9 Trial assessments and procedures...............................................................................6
2.10
Section 10.1 Sample size determination.....................................................................................6
2.11
Section 10.3.1 Primary endpoints ..............................................................................................6
2.12
Table 10-4 Analysis and imputation methods to address the effectiveness and efficacy 
estimands for supportive secondary endpoints ...........................................................................7
2.13
Appendix 2  Clinical laboratory tests.........................................................................................7
2.14
Appendix 3  Trial governance considerations ............................................................................7
2.15
Appendix 5  Contraceptive guidance and collection of pregnancy information...........................7
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Protocol Amendment no 2
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Date:
04 June 2018
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Trial ID: NN9536-4376
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Status:
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1
Introduction including rationale for the protocol amendment
This protocol is amended for the following reasons: 
!
Removal of criteria for discontinuation of trial treatment for subjects included in the trial in 
violation of the inclusion and/or exclusion criteria and/or randomisation criteria. Subjects will 
not be discontinued from trial product if considered safe to continue. However, prospective 
approval of protocol deviations to recruitment and enrolment criteria, also known as protocol 
waivers or exemptions, is not permitted and deviations from the protocol should be avoided.
!
Classifications of risks have been removed from the protocol and instead a reference to the IB or 
any updates hereof has been added for further details of the risks associated with semaglutide 
treatment.
!
Minor clarification of content and correction of minor errors and typos.
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 1 
Synopsis
The primary estimand will cover all effect-related objectives except the secondary objective 
addressing ‘Effect-related: week 0 to week 68’.
2.2
Section 3.1 
Trial rationale
!
to access assess the weight development after switching to semaglutide placebo (withdrawal 
trial design) as recommended in the regulatory guidelines
2.3
Section 3.2 
Background
Section 3.2.1 
Semaglutide
GLP-1 RA is a physiological regulator of appetite and GLP-1 receptors are present in several areas 
of the brain involved in appetite regulation56.
Clinical58-623 and non-clinical data 63new ref indicate that the body weight-reducing effect of 
semaglutide is mainly mediated by a reduced energy intake. No unexpected safety findings were 
identified and the tolerability and safety profile was overall consistent with previous findings in the 
T2D development programme and the GLP-1 RA class in general.
New ref: Lu T, et al. Presented at the 77th scientific sessions of the American diabetes association, 
9-13 June 2017, San Diego, CA, USA.
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Protocol Amendment no 2
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Date:
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Trial ID: NN9536-4376
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Section 3.3.2 
Risks and precautions
The sections below describe identified and potential risks associated with semaglutide treatment.
For classification and further details of the risks, please refer to the current version of the IB or any 
updates hereof. 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.
Identified risks
!
Gastrointestinal adverse events
Consistent with findings with other GLP-1 RAs, the most frequently reported adverse events (AE) 
in clinical trials with semaglutide were gastrointestinal AEs. A low starting dose and dose 
escalation steps will be implemented in the trial to mitigate the risk of gastrointestinal AEs.
Potential risks
!
Medullary thyroid cancer (MTC) (based on non-clinical data)
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 reports of MTC or 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, exclusion and 
discontinuation criteria related to medical history of multiple endocrine neoplasia type 2 (MEN2) or 
MTC and elevated plasma levels of calcitonin (biomarker for MTC) have been implemented in the 
trial.
Other risks
!
Pregnancy and fertility (based on non-clinical data)
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. 
Exclusion and discontinuation criteria related to pregnancy have been implemented in the trial.
2.4
Section 4.1.3 
Exploratory objectives
The primary estimand will cover all effect-related objectives except the secondary objective 
addressing ‘Effect-related: week 0 to week 68’.
2.5
Section 4.2.2.2
Supportive secondary endpoints
Safety endpoints from randomisation (week 20) to week 75
Number of treatment-emergent AEs 
Number of serious adverse events (SAEs)
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Protocol Amendment no 2
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Date:
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Trial ID: NN9536-4376
Version:
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Status:
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Page:
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Safety endpoints from randomisation (week 20) to week 68
Change in:
!
Pulse (bpm)
!
Amylase (U/L)
!
Lipase (U/L) 
!
Calcitonin (ng/L)
2.6
Section 7.1 
Treatments administered
!
Injections may be administered in the thigh, abdomen or upper arm, at any time of day
irrespective of meals. Subjects should be encouraged to inject in the same area throughout the 
trial, but changing between left and right side is allowed
2.7
Section 7.1.2
Diet and physical activity counselling
All subjects will receive counselling with regards to diet (500 kcal deficit per day relative to the 
estimated total energy expenditure (TEE) calculated once at randomisation week 0) and physical 
activity (150 min of physical activity per week is encouraged, e.g. walking or use the stairs).
2.8
Section 8 
Discontinuation/Withdrawal criteria
Section 8.1 Discontinuation of trial treatment
The subject must be discontinued from trial product, if any of the following applies:
1. Included in the trial in violation of the inclusion and/or exclusion criteria and/or run-in criteria 
and/or randomisation criteria
2 1. Safety concern as judged by the investigator
3.2. Calcitonin ≥ 100 ng/L (see Appendix 7)
4 3. Suspicion of pancreatitis
5.4. Pregnancy
6.5. Intention of becoming pregnant
7.6. Simultaneous participation in another clinical trial of an approved or non-approved 
investigational medicinal product.
Subjects meeting discontinuation of trial product criterion no. 4 3 are allowed to resume trial 
product if the Atlanta criteria69 are not fulfilled and thus, the suspicion of acute pancreatitis is not 
confirmed. Trial product may be resumed for subjects with a gallstone-induced pancreatitis in case 
of cholecystectomy.
Subjects meeting discontinuation of trial product criteria no. 2 1, 5 4 and 6 5 are allowed to resume 
trial product, if the criteria are no longer met (see Section 8.1.1).

CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
04 June 2018
Novo Nordisk
Trial ID: NN9536-4376
Version:
1.0
     
Status:
Final
     
Page:
6 of 7
2.9
Section 9
Trial assessments and procedures
!
For subjects receiving antihypertensive or lipid-lowering treatment, the investigator should 
evaluate changes in the subject’s treatment intensity within each therapeutic area. The 
evaluation should be based on whether an overall change from week 0 until week 24 and from
week 24 until ‘end of treatment’ visit (week 68) randomisation until the time of the evaluation 
has occurred (i.e., either increase, decrease or no change) after reviewing all available relevant 
information e.g., changes in drug dose, drug class, number of drugs or a combination of these.
2.10
Section 10.1
Sample size determination
Table 10-2
Assumptions, marginal power and effective power for each endpoint in the 
hierarchical testing procedure given an anticipated number of 750 randomised subjects
Foot note: SD = standard deviation; WC = waist circumference; sBP = systolic blood pressure; SF-
36 = Short Form 36 v2.0 acute; PF = physical functioning; WRSSM = Weight Related Sign and 
Symptom Measure
All tests in the hierarchy are based on the primary estimand
2.11
Section 10.3.1
Primary endpoints
Table 10-3
Analysis and imputation methods to address the effectiveness and efficacy 
estimands for the primary and confirmatory secondary endpoints in the statistical testing 
hierarchy
Foot note: FAS = full analysis set; ANCOVA = analysis of covariance; RD-MI = multiple 
imputation using retrieved subjects; J2R-MI = jump to reference multiple imputation; S1-SI and S2-
SI = single imputation as done by Sacks; TP-MI = tipping point multiple imputation; MMRM = 
mixed model for repeated measurements; WC = waist circumference; sBP = systolic blood 
pressure; SF-36 = Short Form 36 v2.0 acute; PF = physical functioning; WRSSM = Weight Related 
Sign and Symptom Measure
Test order refers to the order of the endpoint in the statistical test hierarchy outlined in Table 10-2

CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
04 June 2018
Novo Nordisk
Trial ID: NN9536-4376
Version:
1.0
     
Status:
Final
     
Page:
7 of 7
2.12
Table 10-4
Analysis and imputation methods to address the effectiveness and 
efficacy estimands for supportive secondary endpoints
Objective
Endpoint
Endpoint 
type
Estimand
Analysis 
set
Statistical 
model
Imputation 
approach
Sensitivity 
analyses
Supportive secondary endpoints (safety related)
From randomisation (week 20) to week 68 / 75
Secondary
Number of TEAEs
Continuous
-
SAS
-
-
-
Secondary
Number of SAEs
Continuous
-
SAS
-
-
-
Secondary
Pulse change (bpm)
Continuous
-
SAS
MMRM
-
-
Secondary
Amylase change (U/L)
Continuous
-
SAS
Descriptive 
statistics
-
-
Secondary
Lipase change (U/L)
Continuous
-
SAS
Descriptive 
statistics
-
-
Secondary
Calcitonin change (ng/L)
Continuous
-
SAS
Descriptive 
statistics
-
-
2.13
Appendix 2 
Clinical laboratory tests
Table 11-3 Criteria for laboratory outliers
Lymphocytes < 25 0.2 x 109/L
2.14
Appendix 3 
Trial governance considerations
9) Data quality assurance
Protocol compliance
Deviations from the protocol should be avoided. If deviations do occur, the investigator must 
inform the monitor without delay and the implications of the deviation must be reviewed and 
discussed.
2.15
Appendix 5 
Contraceptive guidance and collection of pregnancy information
Table 11-5 Highly effective contraceptive methods
Sexual abstinenceb

CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
04 September 2019
Novo Nordisk
Trial ID: NN9536-4376
Version:
1.0
     
Status:
Final
     
Page:
1 of 8
Protocol Amendment
no 3
to Protocol, version 3.0
dated 06 June 2018
Trial ID: NN9536-4376
Effect and safety of semaglutide 2.4 mg once-weekly in subjects with overweight or obesity 
who have reached target dose during run-in period
Trial phase: 3a 
Applicable to all countries
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.

CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol Amendment no 3
CONFIDENTIAL
Date:
04 September 2019
Novo Nordisk
Trial ID: NN9536-4376
Version:
1.0
     
Status:
Final
     
Page:
2 of 8
Table of Contents   
1
Introduction including rationale for the protocol amendment...........................................................3
2
Changes ................................................................................................................................................3
2.1
Section 1 Synopsis ....................................................................................................................3
2.2
Section 2 Flowchart...................................................................................................................3
2.3
Section 4 Objectives and endpoints ...........................................................................................3
2.3.1
4.2.2.1 Confirmatory secondary endpoints................................................................3
2.3.2
4.2.2.2 Supportive secondary endpoints....................................................................4
2.3.3
4.2.3 Exploratory endpoints .....................................................................................4
2.4
Section 9 Trial assessments and procedures...............................................................................4
2.4.1
9.2.1 Time period and frequency for collecting AE and SAE information.................4
2.4.2
Table 9-1 AEs requiring additional data collection (via specific form) and 
events for adjudication.............................................................................................4
2.4.3
9.2.7 Pregnancies and associated adverse events.......................................................5
2.5
Section 10 Statistical considerations..........................................................................................5
2.5.1
10.1 Sample size determination................................................................................5
2.5.2
Table 10-3 Analysis and imputation methods to address the effectiveness and 
efficacy estimands for the primary and confirmatory secondary endpoints in the 
statistical testing hierarchy.......................................................................................5
2.5.3
10.3.2.2 Supportive secondary endpoints..................................................................6
2.5.4
Table 10-4 Analysis and imputation methods to address the effectiveness and 
efficacy estimands for supportive secondary endpoints.............................................7
2.6
Section 11 Appendices ..............................................................................................................8
2.6.1
Appendix 4 Adverse events: definitions and procedures for recording, 
evaluation, follow-up, and reporting.........................................................................8
2.6.2
Appendix 5 Contraceptive guidance and collection of pregnancy information...........8
2.6.3
Appendix 6 Technical complaints: Definition and procedures for recording, 
evaluation, follow-up and reporting..........................................................................8

CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
04 September 2019
Novo Nordisk
Trial ID: NN9536-4376
Version:
1.0
     
Status:
Final
     
Page:
3 of 8
1
Introduction including rationale for the protocol amendment
This protocol is amended for the following reasons:
!
Confirmatory, supportive secondary and exploratory endpoints related to Weight Related Sign 
and Symptom Measure (WRSSM) have been updated. Based on new data from recently 
reported trials, the WRSSM has showed to have substantial ceiling effects and low 
responsiveness within our target population. The measure is therefore unlikely to be able to 
detect a treatment benefit.
!
Minor clarification of contents and correction of minor errors and typos.
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 1 Synopsis
Confirmatory secondary endpoints
Effect endpoints from randomisation (week 20) to week 68
Change in:
!
Waist circumference (cm)
!
Systolic blood pressure (mmHg)
!
Physical functioning score (SF-36)
!
Total score (Weight Related Sign and Symptom Measure (WRSSM))
2.2
Section 2 Flowchart
X added at V25 for ‘Concomitant medication’.
X deleted at V2 for ‘Criteria for discontinuation’.
2.3
Section 4 Objectives and endpoints
2.3.1
4.2.2.1 Confirmatory secondary endpoints
Effect endpoints from randomisation (week 20) to week 68
Change in:
!
Waist circumference (cm)
!
Systolic blood pressure (mmHg)
!
Physical funtioning score (SF-36)
!
Total score (WRSSM)

CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
04 September 2019
Novo Nordisk
Trial ID: NN9536-4376
Version:
1.0
     
Status:
Final
     
Page:
4 of 8
2.3.2
4.2.2.2 Supportive secondary endpoints
Subjects who achieve (yes/no):
!
Responder definition value for SF-36 physical functioning score
!
Responder definition value for WRSSM total score
2.3.3
4.2.3 Exploratory endpoints
Change from randomisation (week 20) to week 68 in:
!
Glycaemic category (normo-glycaemia, pre-diabeted, T2D)
!
Antihypertensive medication (decrease, no change, increase)
!
Lipid-lowering medication (decrease, no change, increase)
!
The Stanford Presenteeism Scale (SPS-6), total score
!
Total score (WRSSM)
2.4
Section 9 Trial assessments and procedures
2.4.1
9.2.1 Time period and frequency for collecting AE and SAE information
Timelines for reporting of AEs including events for adjudication, Section 9.2.1.1, are listed in 
Figure 9-2 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 9-2 9-1.
2.4.2
Table 9-1 AEs requiring additional data collection (via specific form) and events 
for adjudication
Event type 
AE via specific event form
Event for adjudication (Section 
9.2.1.1)
Medication error
Misuse or abuse of trial product*
X
Death
X
Cardiovascular events
      Acute Coronary Syndrome
X
      Cerebrovascular event 
X
      Heart failure
X
      Coronary artery revascularisation
X
Acute pancreatitis
X
X
Acute gallbladder disease
X
Malignant neoplasms
X
Hepatic event 
X
*Additional data for Misuse or abuse of trial product is reported on the medication error event form.

CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
04 September 2019
Novo Nordisk
Trial ID: NN9536-4376
Version:
1.0
     
Status:
Final
     
Page:
5 of 8
2.4.3
9.2.7 Pregnancies and associated adverse events
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 
9-3 9-2 and Appendix 5.
2.5
Section 10 Statistical considerations
2.5.1
10.1 Sample size determination
Table 10-2 Assumptions, marginal power and effective power for each endpoint in the 
hierarchical testing procedure given an anticipated number of 750 randomised subjects
Order
Endpoint
Assumed mean (±SD) for 
completers
Expected mean 
(±SD)
Expected 
difference
Marginal 
power 
(%)
Effective 
power 
(%)
Semaglutide
2.4 mg
Semaglutide 
placebo
Semaglutide
2.4 mg
1
% weight change
-4 (±10)
+5 (±10)
-3.7 (±11)
8.7 %-points
> 99
> 99
2
WC change (cm)
-3 (±10)
+3 (±10)
-2.8 (±11)
5.8 cm
> 99
> 99
3
sBP change (mmHg)
-3.1 (±13)
+1 (±13) 
-3 (±14)
4 mmHg
95
95
4
SF-36 PF score 
change
+6 (±10)
+2 (±10)
+5.9 (±11)
3.9 score-
points
> 99
95
5
WRSSM total score 
change
To be confirmed. Is currently being validated in trials N8022-4272 and -4274
SD = standard deviation; WC = waist circumference; sBP = systolic blood pressure; SF-36 = Short Form 36 v2.0 acute; PF = 
physical functioning; WRSSM = Weight Related Sign and Symptom Measure
All tests in the hierarchy are based on the primary estimand
2.5.2
Table 10-3 Analysis and imputation methods to address the effectiveness and 
efficacy estimands for the primary and confirmatory secondary endpoints in the 
statistical testing hierarchy
Objective
Endpoint
Test 
order
Endpoint 
type
Estimand
Analysis 
set
Statistical 
model
Imputation 
approach
Sensitivity 
analyses
Primary endpoint
From randomisation (week 20) to week 68
Primary
% weight change
1
Continuous
Primary
FAS
ANCOVA
RD-MI
J2R-MI
S1-SI
S2-SI
TP-MI
MMRM
Secondary
FAS
MMRM
-
-
Confirmatory secondary endpoints
From randomisation (week 20) to week 68
Primary
WC change (cm)
2
Continuous
Primary
FAS
ANCOVA
RD-MI
J2R-MI
Secondary
FAS
MMRM
-
-
Secondary
sBP change (mmHg)
3
Continuous
Primary
FAS
ANCOVA
RD-MI
J2R-MI
Secondary
SF-36 PF score change
4
Continuous
Primary
FAS
ANCOVA
RD-MI
J2R-MI
Secondary
WRSSM total score 
change
5
Continuous
Primary
FAS
ANCOVA
RD-MI
J2R-MI
FAS = full analysis set; ANCOVA = analysis of covariance; RD-MI = multiple imputation using retrieved subjects; J2R-MI = jump 
to reference multiple imputation; S1-SI and S2-SI = single imputation as done by Sacks; TP-MI = tipping point multiple imputation;
MMRM = mixed model for repeated measurements; WC = waist circumference; sBP = systolic blood pressure; SF-36 = Short Form 
36 v2.0 acute; PF = physical functioning; WRSSM = Weight Related Sign and Symptom Measure

CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
04 September 2019
Novo Nordisk
Trial ID: NN9536-4376
Version:
1.0
     
Status:
Final
     
Page:
6 of 8
2.5.3
10.3.2.2 Supportive secondary endpoints
Analysis of safety endpoints
Adverse events will be defined as “treatment-emergent” (TEAE), if the onset of the event occurs in 
the on-treatment period (see definition in Section 10.2). TEAEs and SAEs will be summarised by 
descriptive statistics, such as frequencies and rates. No formal statistical inference will be carried 
out based on the number of TEAEs and SAEs. All AEs will be coded using the most recent version 
of the Medical Dictionary for Regulatory Activities (MedDRA).

CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
04 September 2019
Novo Nordisk
Trial ID: NN9536-4376
Version:
1.0
     
Status:
Final
     
Page:
7 of 8
2.5.4
Table 10-4 Analysis and imputation methods to address the effectiveness and 
efficacy estimands for supportive secondary endpoints
Objective
Endpoint
Endpoint 
type
Estimand
Analysis 
set
Statistical 
model
Imputation 
approach
Sensitivity 
analyses
Supportive secondary endpoints (effect related)
From randomisation (week 20) to week 68
Primary
Weight change (kg)
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
FAS
MMRM
-
-
Primary
BMI change (kg/m2)
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
FAS
MMRM
-
-
Secondary
HbA1c change (%, mmol/mol)
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
FPG change (mg/dL)
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
Fasting serum insulin change (mIU/L)
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
dBP change (mmHg)
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
Total cholesterol change (mg/dL)
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
HDL change (mg/dL)
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
LDL change (mg/dL)
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
VLDL change (mg/dL)
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
FFA change (mg/dL)
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
Triglycerides change (mg/dL)
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
SF-36 PF score responders #
Binary
Primary
FAS
LR
RD-MI
-
Secondary
SF-36 RP score change
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
SF-36 BP score change
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
SF-36 GH score change
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
SF-36 VT score change
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
SF-36 SF score change
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
SF-36 RE score change
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
SF-36 MH score change
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
SF-36 PCS score change
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
SF-36 MCS score change
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
WRSSM total score responders ##
Binary
Primary
FAS
LR
RD-MI
-
Primary
Proportion of subjects who gain 
weight
Binary
Continuous
Primary
FAS
ANCOVA 
LR
RD-MI
-
Secondary
FAS
LR
MMRM
-
From week 0 to week 68
Secondary
% weight change
Continuous
Tertiary
FAS
ANCOVA
RD-MI
-
Secondary
Weight reduction <0%
Binary
Tertiary
FAS
LR
RD-MI
-
Secondary
Weight reduction ≥5%
Binary
Tertiary
FAS
LR
RD-MI
-
Secondary
Weight reduction ≥10%
Binary
Tertiary
FAS
LR
RD-MI
-
Secondary
Weight reduction ≥15%
Binary
Tertiary
FAS
LR
RD-MI
-
Supportive secondary endpoints (safety related)
From week 0 to randomisation (week 20)
Secondary
Number of TEAEs
Continuous
-
SAS
-
-
-
Secondary
Number of SAEs
Continuous
-
SAS
-
-
-
Secondary
Pulse change (bpm)
Continuous
-
SAS
MMRM
-
-
Secondary
Amylase change (U/L)
Continuous
-
SAS
Descriptive 
statistics
-
-
Secondary
Lipase change (U/L)
Continuous
-
SAS
Descriptive 
statistics
-
-
Secondary
Calcitonin change (ng/L)
Continuous
-
SAS
Descriptive 
statistics
-
-
From randomisation (week 20) to week 68 / 75
Secondary
Number of TEAEs
Continuous
-
SAS
-
-
-
Secondary
Number of SAEs
Continuous
-
SAS
-
-
-
Secondary
Pulse change (bpm)
Continuous
-
SAS
MMRM
-
-
Secondary
Amylase change (U/L)
Continuous
-
SAS
Descriptive 
statistics
-
-
Secondary
Lipase change (U/L)
Continuous
-
SAS
Descriptive 
statistics
-
-
Secondary
Calcitonin change (ng/L)
Continuous
-
SAS
Descriptive 
statistics
-
-
FAS = full analysis set; ANCOVA = analysis of covariance; RD-MI = multiple imputation using retrieved subjects; 
MMRM = mixed model for repeated measurements; BMI = body mass index; HbA1c = Hemoglobin A1c; FPG = 
fasting plasma glucose; dBP = diastolic blood pressure; HDL = high density lipoprotein; LDL = low density 
lipoprotein; VLDL = very low density lipoprotein; FFA = free fatty acids; LR = logistic regression; SF-36 = Short Form 

CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
04 September 2019
Novo Nordisk
Trial ID: NN9536-4376
Version:
1.0
     
Status:
Final
     
Page:
8 of 8
36 v2.0 acute; PF= Physical Functioning; RP = Role-Physical; BP = Bodily Pain; GH = General Health; VT = Vitality; 
SF = Social Functioning; RE = Role-Emotional; MH = Mental Health; PCS = Physical component summary; MCS = 
Mental component summary; WRSSM = Weight Related Sign and Symptom Measure; TEAEs = treatment emergent 
adverse events; SAEs = serious adverse events; # responder value = 4.3; ## responder value to be validated in trials 
NN8022-4272 and -4274
2.6
Section 11 Appendices
2.6.1
Appendix 4 Adverse events: definitions and procedures for recording, evaluation, 
follow-up, and reporting
Description of AEs requiring additional data collection (via specific event form) and events 
for adjudication
Medication error:
A medication error concerning trial products is defined as:
!
Administration of wrong drug.
!
Note: Use of wrong dispensing unit number (DUN) is not considered a 
medication error unless is results in a confirmed administration of wrong 
drug.
!
Wrong route of administration, such as intramuscular instead of subcutaneous.
!
Accidental administration of more than 2.4 mg/week or a higher dose than intended 
during dose escalation, 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.
!
Administration of an overdose with the intention to cause harm, misuse or abuse of 
trial product.
Misuse or abuse of 
trial product*
Misuse is when the trial product is intentionally and inappropriately used. Abuse of trial 
product is persistent or sporadic, intentional excessive use, which is accompanied by 
harmful physical or psychological effects (e.g. overdose with the intention to cause harm).
*Additional data for Misuse or abuse of trial product is reported on the medication error event form.
2.6.2
Appendix 5 Contraceptive guidance and collection of pregnancy information
Table 11-5 Highly effective contraceptive methods
Bullet added for ‘Implantable progestogen only hormonal contraception associated with inhibition 
of ovulation’.
Female subjects who become pregnant
!
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be reported as an AE or SAE.
2.6.3
Appendix 6 Technical complaints: Definition and procedures for recording, 
evaluation, follow-up and reporting
All technical complaints are handled by Customer Complaint Center, Novo Nordisk. Only technical 
complaints related to adverse events will be included in the CTR.

CONFIDENTIAL

SAP_001.pdf: 
Cover Page for Statistical Analysis Plan 
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT03548987 
Sponsor trial ID: 
NN9536-4376 
Official title of study: 
Effect and safety of semaglutide 2.4 mg once-weekly in 
subjects with overweight or obesity who have reached target 
dose during run-in period 
Document date: 
25-June-2020 
 


Link
Link
List of contents
Statistical analysis plan......................................................................................................................
MedDRA searches..............................................................................................................................
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
Semaglutide s.c. 2.4 mg once weekly
Trial ID: NN9536-4376 (STEP 4)
Clinical Trial Report
Appendix 16.1.9
25 JunH 2020
1.0
Final
16.1.9 Documentation of statistical methods
CONFIDENTIAL
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Includes redaction of personal identifiable information only. 
. 


Statistical Analysis Plan
CONFIDENTIAL
Date:
31 March 2020
Novo Nordisk
Trial ID: NN9536-4376
Version:
1.0
UTN: U1111-1201-0898
Status:
Final
EudraCT No.: 2017-003473-34
Page:
1 of 24
Statistical Analysis Plan
Trial ID: NN9536-4376
STEP 4
Effect and safety of semaglutide 2.4 mg once-weekly in 
subjects with overweight or obesity who have reached target 
dose during run-in period
Author
Camilla Jensen
Biostatistics Obesity
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.

CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Statistical Analysis Plan
CONFIDENTIAL
Date:
31 March 2020
Novo Nordisk
Trial ID: NN9536-4376
Version:
1.0
UTN: U1111-1201-0898
Status:
Final
EudraCT No.: 2017-003473-34
Page:
2 of 24
Table of contents   Page
Table of contents.........................................................................................................................................2
List of abbreviations ...................................................................................................................................3
1
Introduction .........................................................................................................................................5
1.1
Trial information.......................................................................................................................5
1.1.1
Objective(s) .............................................................................................................5
1.1.1.1
Primary objective...............................................................................5
1.1.1.2
Secondary objectives..........................................................................5
1.1.2
Estimands ................................................................................................................5
1.1.3
Endpoints.................................................................................................................6
1.1.3.1
Primary endpoint................................................................................6
1.1.3.2
Secondary endpoints ..........................................................................7
1.1.4
Type of trial.............................................................................................................8
1.2
Scope of the statistical analysis plan..........................................................................................8
2
Statistical considerations .....................................................................................................................9
2.1
Sample size determination.........................................................................................................9
2.2
Definition of analysis sets........................................................................................................11
2.3
Statistical analyses ..................................................................................................................12
2.3.1
Primary endpoint ...................................................................................................12
2.3.2
Secondary endpoints ..............................................................................................17
2.3.2.1
Confirmatory secondary endpoints ...................................................17
2.3.2.2
Supportive secondary endpoints .......................................................18
2.3.3
Exploratory endpoints............................................................................................22
2.3.4
Other analyses .......................................................................................................22
2.4
Pharmacokinetic and/or pharmacodynamic modelling .............................................................22
3
Changes to the statistical analyses planned in the protocol..............................................................23
3.1
Trial specific changes..............................................................................................................23
3.2
Changes applied across STEP trials.........................................................................................23
4
References ..........................................................................................................................................24
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Statistical Analysis Plan
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Date:
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Trial ID: NN9536-4376
Version:
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UTN: U1111-1201-0898
Status:
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List of abbreviations
AD
available but discontinued
ANCOVA
analysis of covariance
AT
available on randomised treatment
BMI
body mass index
BP
bodily pain
CI
confidence interval
dBP
diastolic blood pressure
ECG
electrocardiogram
FAS
full analysis set
FFA
free fatty acid
FPG
fasting plasma glucose
GH
general health
HbA1c
glycated haemoglobin
HDL
high density lipoprotein
LAO-OT
last available observation during the on-treatment period
LDL
low-density lipoprotein
MCS
mental component summary
MD
missing and discontinued
MedDRA
Medical Dictionary for Regulatory Activities
MH
mental health
MMRM
mixed model for repeated measurements
MT
missing on randomised treatment
PCS
physical component summary
PF
physical functioning
PYE
patient years of exposure
PYO
patient years of observation
RE
role-emotional
RP
role-physical
SAE
serious adverse event
SAP
statistical analysis plan
SAS
safety analysis set
sBP
systolic blood pressure
s.c.
subcutaneus
SD
standard deviation
SF
social functioning
SF-36
Short Form-36
TEAE
treatment-emergent adverse event
VLDL
very low density lipoprotein
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Statistical Analysis Plan
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Date:
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Trial ID: NN9536-4376
Version:
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UTN: U1111-1201-0898
Status:
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VT
vitality
WC
waist circumference
WRSSM
Weight Related Sign and Symptom Measure
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Date:
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Trial ID: NN9536-4376
Version:
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UTN: U1111-1201-0898
Status:
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1
Introduction
1.1
Trial information
1.1.1
Objective(s)
1.1.1.1
Primary objective
Effect-related: randomisation (week 20) to week 68
To compare the effect of semaglutide s.c. 2.4 mg once-weekly versus semaglutide placebo as an 
adjunct to reduced-calorie diet and increased physical activity in subjects with overweight or 
obesity who have reached target dose of semaglutide during the run-in period, on body weight. 
1.1.1.2
Secondary objectives
Effect-related: randomisation (week 20) to week 68
To compare the effect of semaglutide s.c. 2.4 mg once-weekly versus semaglutide placebo as an 
adjunct to reduced-calorie diet and increased physical activity in subjects with overweight or 
obesity who have reached target dose of semaglutide during the run-in period, on 
!
cardiovascular risk factors
!
clinical outcome assessments
!
glucose metabolism
Effect-related: week 0 to week 68
To investigate the effect of semaglutide s.c. 2.4 mg once-weekly as an adjunct to reduced-calorie 
diet and increased physical activity in subjects with overweight or obesity who have reached target 
dose during the run-in period, on body weight. 
Safety and tolerability: week 0 to randomisation (week 20)
To investigate the safety and tolerability of semaglutide s.c. 2.4 mg once-weekly as an adjunct to 
reduced-calorie diet and increased physical activity in subjects with overweight or obesity during 
the run-in period.
Safety and tolerability: randomisation (week 20) to week 75
To compare the safety and tolerability of semaglutide s.c. 2.4 mg once-weekly versus semaglutide  
placebo as an adjunct to reduced-calorie diet and increased physical activity in subjects with 
overweight or obesity who have reached target dose of semaglutide during the run-in period. 
1.1.2
Estimands
Primary estimand 
The estimand will quantify the average treatment effect of semaglutide relative to semaglutide 
placebo after 48 weeks’ treatment with semaglutide at the target dose, as an adjunct to reduced-
calorie diet and increased physical activity, in all randomised subjects regardless of adherence to
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Statistical Analysis Plan
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Trial ID: NN9536-4376
Version:
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UTN: U1111-1201-0898
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treatment provided that the subjects are able to reach the target dose of semaglutide during 20 
weeks run-in with escalating semaglutide doses and regardless of initiation of other anti-obesity 
therapies (i.e. weight management drugs or bariatric surgery) (”treatment policy” estimand).
The primary estimand will cover all effect-related objectives except the secondary objective 
addressing ‘Effect-related: week 0 to week 68’.
Secondary estimand  
The estimand will quantify the average treatment effect of semaglutide relative to semaglutide 
placebo after 48 weeks’ treatment with semaglutide at the target dose, as an adjunct to reduced-
calorie diet and increased physical activity, in all randomised subjects had they remained on their 
randomised treatment for the entire 48 weeks after reaching the target dose of semaglutide during 
the 20 weeks run-in with escalating semaglutide doses and not initiated other anti-obesity therapies
(i.e. weight management drugs or bariatric surgery) (”hypothetical” estimand). 
The secondary estimand will cover all effect-related objectives except the secondary objective 
addressing ‘Effect-related: week 0 to week 68’.
Tertiary estimand 
The estimand will quantify the average treatment effect of semaglutide after 68 weeks, as an adjunct 
to reduced-calorie diet and increased physical activity, in all randomised subjects regardless of 
adherence to treatment and regardless of initiation of other anti-obesity therapies (i.e. weight 
management drugs or bariatric surgery) (“treatment policy” estimand).
The tertiary estimand will cover the secondary objective addressing ‘Effect-related: week 0 to 
week 68’.
Quarternary estimand  
The estimand will quantify the average treatment effect of semaglutide after 68 weeks, as an adjunct 
to reduced-calorie diet and increased physical activity, in all randomised subjects had they remained 
on their randomised treatment for the entire 68 weeks and not initiated other anti-obesity therapies
(i.e. weight management drugs or bariatric surgery) (”hypothetical” estimand). 
The quarternary estimand will cover the secondary objective addressing ‘Effect-related: week 0 to 
week 68’.
1.1.3
Endpoints
1.1.3.1
Primary endpoint
Change from randomisation (week 20) to week 68 in body weight (%)
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1.1.3.2
Secondary endpoints
Confirmatory secondary endpoints
Effect endpoints from randomisation (week 20) to week 68 
Change in:
!
Waist circumference (cm)
!
Systolic blood pressure (mmHg)
!
Physical functioning score (SF-36)
Supportive secondary endpoints
Effect endpoints from randomisation (week 20) to week 68 
Change in:
!
Body weight (kg)
!
BMI (kg/m2)
!
Haemoglobin A1c (HbA1c) (%, mmol/mol)
!
Fasting plasma glucose (FPG) (mg/dL)
!
Fasting serum insulin (mIU/L)
!
Diastolic blood pressure (mmHg)
!
Lipids (mg/dL)
o
Total cholesterol
o
High-density lipoproteins (HDL)
o
Low-density lipoproteins (LDL)
o
Very low-density lipoproteins (VLDL)
o
Free fatty acids
o
Triglycerides
!
SF-36:
o
Role-Physical score
o
Bodily Pain score
o
General Health score
o
Vitality score
o
Social Functioning score
o
Role-Emotional score
o
Mental Health score
o
Physical component summary
o
Mental component summary
Subjects who achieve (yes/no):
!
Responder definition value for SF-36 physical functioning score
Subjects who gain weight (yes/no)
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Statistical Analysis Plan
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Trial ID: NN9536-4376
Version:
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Effect endpoints from week 0 to week 68 
Change in body weight (%)
Subjects who achieve (yes/no): 
!
Body weight reduction < 0%
!
Body weight reduction ≥ 5%
!
Body weight reduction ≥ 10%
!
Body weight reduction ≥ 15%
!
Body weight reduction ≥ 20%
Safety endpoints from week 0 to randomisation (week 20)
Number of treatment-emergent AEs 
Number of serious adverse events (SAEs) 
Change in:
!
Pulse (bpm)
!
Amylase (U/L)
!
Lipase (U/L)
!
Calcitonin (ng/L)
Safety endpoints from randomisation (week 20) to week 75
Number of treatment-emergent AEs 
Number of SAEs 
Safety endpoints from randomisation (week 20) to week 68
Change in:
!
Pulse (bpm)
!
Amylase (U/L)
!
Lipase (U/L)
!
Calcitonin (ng/L)
1.1.4
Type of trial
This is a 68-week, randomised, double-blind, placebo-controlled, two-armed multi-centre, 
multinational withdrawal clinical trial1 comparing once-weekly semaglutide s.c. 2.4 mg with 
semaglutide placebo in subjects with overweight or obesity.
1.2
Scope of the statistical analysis plan
This statistical analysis plan (SAP) is based on the updated protocol for trial NN9536-4376 “Effect 
and safety of semaglutide 2.4 mg once-weekly in subjects with overweight or obesity who have 
reached target dose during run-in period”, version 4.0 (04 September 2019) including amendment 
no. 3 (global), and includes more detailed procedures for executing the statistical analyses of the 
primary and secondary endpoints. Statistical analyses and a number of clarifications additional to 

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Statistical Analysis Plan
CONFIDENTIAL
Date:
31 March 2020
Novo Nordisk
Trial ID: NN9536-4376
Version:
1.0
UTN: U1111-1201-0898
Status:
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EudraCT No.: 2017-003473-34
Page:
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those specified in the trial protocol are pre-specified with this SAP. All changes to the statistical 
analyses planned in the trial protocol are documented in section 3.
2
Statistical considerations
Taxonomy of week 68 assessments
For each subject a given assessment at week 68 may be available or missing and Table 2-1
describes the taxonomy for this. Note, this is done per assessment and per subject; subjects may be 
a different type for different assessments (a subject may have “available on randomised treatment 
(AT)” for body weight but “missing on randomised treatment (MT)” for waist circumference).
Table 2-1
Taxonomy for subjects based on week 68 assessments
Assessment
at week 68
Subjects on 
randomised 
treatment at 
week 68
Type description
Type
Abbreviation
Available
Yes
Available on randomised treatment:
Subjects who complete the trial on randomised treatment with an assessment at week 68: 
Includes those that stop and restart trial product
AT
No
Available but discontinued
Subjects who discontinued randomised treatment prematurely but returned to have an 
assessment at week 68. These are also called retrieved subjects
AD
Missing
Yes
Missing on randomised treatment:
Subjects who complete the trial on randomised treatment without an assessment at week 
68: Includes those that stop and restart trial product
MT
No
Missing and discontinued:
Subjects who discontinued randomised treatment prematurely and did not return to have 
an assessment at week 68. These are also called non-retrieved subjects
MD
2.1
Sample size determination 
The sample size and thereby the power for this trial is primarily defined to support safety. However,
no formal statistical inference is planned based on number of adverse events. Given the trial sample 
size, the power of statistical tests for effect endpoints is described below.
The tests of superiority of semaglutide 2.4 mg to semaglutide placebo for the primary and 
confirmatory secondary endpoints are performed using the fixed-sequence statistical strategy. This 
strategy tests the endpoints using a predefined hierarchical order, all at the significance level of 5%, 
moving to test the next endpoint only after a statistically significant superiority result (p-value < 
5%) on the previous endpoint. The test hierarchy is given in Table 2-2 with underlying assumptions, 
marginal power and effective power. The effective power is calculated under the assumption of 
independence of endpoints by multiplying the respective marginal powers successively.
In the analysis approach addressing the primary estimand, week 68 assessments from retrieved 
subjects (AD) are used. These data are also used to impute missing measurements at week 68 for 
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Statistical Analysis Plan
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Trial ID: NN9536-4376
Version:
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UTN: U1111-1201-0898
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non-retrieved subjects (MD). The imputation is done separately within each treatment arm (see 
description below). However, for the power calculations missing values (MT and MD), regardless 
of treatment arm, are assumed to be similar to semaglutide placebo subjects. These assumptions are 
likely conservative with respect to the power, and correspond to the jump to reference sensitivity 
analysis planned below.
Assumptions
The common assumptions for the power calculations are
!
The significance level is 5%
!
The randomisation ratio is 2:1
!
For continuous endpoints the t-test on the mean difference assuming equal variances is used
!
Based on data from NN9536-4153
o
5% of subjects discontinue permanently between randomisation (week 20) and week
68 and
o
60% of these are retrieved (AD) at week 68
!
All subjects in the semaglutide placebo arm are assumed to have same effect as subjects who
complete the trial on semaglutide placebo (AT)
!
Retrieved subjects (AD) in the semaglutide 2.4 mg arm are assumed to have an effect
corresponding to half the treatment difference (compared to semaglutide placebo) of
subjects who complete the trial on semaglutide 2.4 mg (AT)
!
Non-retrieved subjects (MD) in the semaglutide 2.4 mg arm are assumed to have an effect
corresponding to semaglutide placebo
Further assumptions made to calculate the power for each of the primary and confirmatory 
secondary endpoints are based on findings from other projects conducted by Novo Nordisk 
(NN8022 (SCALE), NN9535 (SUSTAIN), NN9924 (PIONEER)), and trial NN9536-4153 and are 
presented in Table 2-2. 
Given these assumptions, the sample size of 750 subjects (500 in the semaglutide 2.4 mg once 
weekly and 250 in the semaglutide placebo arm), gives an effective power (marginal powers 
multiplied) of 95% for the four endpoints in the hierarchical testing procedure. Under the additional 
assumption that minimum 80% of subjects will be eligible for randomisation a total of 900 subjects 
will be started on trial product. As sample size is primarily driven by safety, additional scenarios for 
assumptions are not included due to the overall high power.
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Statistical Analysis Plan
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Date:
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Trial ID: NN9536-4376
Version:
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UTN: U1111-1201-0898
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Table 2-2
Assumptions, marginal power and effective power for each endpoint in the 
hierarchical testing procedure given an anticipated number of 750 randomised 
subjects
Order
Endpoint
Assumed mean (±SD) for 
completers
Expected mean 
(±SD)
Expected 
difference
Marginal 
power 
(%)
Effective 
power 
(%)
Semaglutide
2.4 mg
Semaglutide 
placebo
Semaglutide
2.4 mg
1
% weight change
-4 (±10)
+5 (±10)
-3.7 (±11)
8.7 %-points
> 99
> 99
2
WC change (cm)
-3 (±10)
+3 (±10)
-2.8 (±11)
5.8 cm
> 99
> 99
3
sBP change (mmHg)
-3.1 (±13)
+1 (±13)
-3 (±14)
4 mmHg
95
95
4
SF-36 PF score 
change
+6 (±10)
+2 (±10)
+5.9 (±11)
3.9 score-
points
> 99
95
SD = standard deviation; WC = waist circumference; sBP = systolic blood pressure; SF-36 = Short Form 36 v2.0 acute; PF = 
physical functioning
All tests in the hierarchy are based on the primary estimand
2.2
Definition of analysis sets
Two analysis sets are defined:
!
The full analysis set (FAS) includes all randomised subjects according to the intention-to-
treat principle. Subjects in the FAS will contribute to evaluation “as randomised”.
!
The safety analysis set (SAS) includes all subjects exposed to at least one dose of trial
product. Subjects in the SAS will contribute to evaluation “as treated”.
Any observation excluded from the analysis will be documented before database lock with the 
reason for exclusion provided.
Two observation periods are defined for each subject:
!
In-trial: The in-trial period is defined as the uninterrupted time interval from date of week 0
to date of last contact with trial site.
!
On-treatment (with trial product): A time-point is considered as ‘on-treatment’ if any dose
of trial product has been administered within the prior 2 weeks (14 days). The on-treatment
period is defined as all times which are considered on-treatment.
o
In general, the on-treatment period will therefore be from the date of first trial
product administration to date of last trial product administration (+14 days)
excluding potential off-treatment time intervals triggered by at least two consecutive
missed doses.
o
For the evaluation of adverse events the lag time for each on-treatment time interval
is 7 weeks (49 days) applicable to all subjects treated with trial product including
those who are not eligible for randomisation.
The in-trial and on-treatment periods define the patient years of observation (PYO) and patient 
years of exposure (PYE), respectively, as the total time duration in the periods.
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2.3
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 
database lock.
Effect endpoints will be analysed using the FAS; safety endpoints will be analysed using the SAS.
Results from statistical analyses will generally be accompanied by two-sided 95% confidence 
intervals and corresponding p-values. Superiority will be claimed if p-values are less than 5% and 
the estimated treatment contrasts favours semaglutide 2.4 mg. 
Handling of missing baseline data
The last available and eligible observation at or before randomisation is used as the baseline 
(randomisation) value. If no assessments are available during the run-in period, the mean of 
baseline (randomisation) values across all subjects is used as the baseline (randomisation) value. 
For endpoints evaluating the change from week 0, the last available and eligible observation at or 
before the week 0 visit is used as the baseline (week 0) value. If no assessments are available, the 
mean of baseline (week 0) values across all subjects is used as the baseline (week 0) value.
2.3.1
Primary endpoint
Definition of primary endpoint: % weight change
Change from baseline (randomisation/week 20) to week 68 in body weight (%) is defined as
% weight change = (body weight at week 68 – body weight at baseline)
body weight at baseline
×100.
Analyses addressing the primary estimand
The following statistical analysis and imputation methods are designed to address the primary 
estimand, i.e. to assess the effectiveness of semaglutide 2.4 mg. 
The analysis model for % weight change is a linear regression (ANCOVA) of % weight change 
with randomised treatment as a factor and baseline body weight (kg) as covariate. The estimated 
treatment difference between semaglutide 2.4 mg and semaglutide placebo will be reported together 
with the associated two-sided 95% confidence interval (CI) and corresponding p-value.
The superiority tests of semaglutide 2.4 mg vs. semaglutide placebo will be carried out as follows.
Let μsemaglutide and μsemaglutide placebo denote the true mean of % weight change for semaglutide 2.4 mg 
and semaglutide placebo group, respectively. The null and alternative hypotheses tested are
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Statistical Analysis Plan
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: 	
 ≥	
 
 
: 	
 < 	
 
.
The hypothesis will be rejected and superiority claimed, if the upper limit of the estimated two-
sided 95% CI is below 0.
Handling of missing week 68 values for the primary estimand
All available data at week 68 (AT and AD) are used and missing values (MT and MD) at week 68 
will be imputed and the endpoint will be derived from the imputed values. Several approaches for 
imputation will be applied. First, a description of the primary imputation approach to address the 
primary estimand for the primary endpoint is given followed by a description of the sensitivity 
analyses used to assess the robustness of the primary analysis results. The sensitivity analyses 
investigate how assumptions on body weight development after discontinuation of randomised 
treatment impact the estimated treatment contrasts between semaglutide 2.4 mg and semaglutide 
placebo. An illustration of all imputation approaches for the primary estimand is given in 
Figure 2-1.
Primary imputation approach for the primary estimand
Multiple imputation approach using retrieved subjects (RD-MI): The primary imputation approach 
for the primary estimand is a multiple imputation similar to the one described by McEvoy.2 Missing 
body weight measurement at week 68 for non-retrieved subjects (MD) are imputed using 
assessments from retrieved subjects (AD) in each randomised treatment arm. This will be done 
according to the timing of last available observation on-treatment (LAO-OT) of body weight prior 
to week 68. Missing body weight measurements at week 68 for subjects on randomised treatment 
(MT) are imputed in a similar way by sampling from available measurements at week 68 from 
subjects on randomised treatment (AT) in the relevant randomised treatment arm. The multiple 
imputation approach is done in three steps:
1. Imputation: Defines an imputation model using retrieved subjects (AD) from FAS and done
within groups defined by randomised treatment. The model will be a linear regression of body
weight (kg) at week 68 with gender (male/female), baseline BMI (kg/m2) (in categories ≤35, 35-
<40, ≥40) and timing of the LAO-OT of body weight as factors and baseline (randomisation)
body weight (kg) and LAO-OT of body weight (kg) as covariates. No interactions will be
included. The grouping of timing will be done by quarters (intervals of 12 weeks for endpoints
evaluating the change from randomisation, intervals of 17 weeks for endpoints evaluating the
change from week 0). If timing by quarters is too restrictive, halves (intervals of 24 weeks for
endpoints evaluating the change from randomisation, intervals of 34 weeks for endpoints
evaluating the change from week 0) or excluding timing will be used. The timing by quarters or
halves is defined as too restrictive if the imputation model cannot be fit due to inadequate
numbers of retrieved subjects in 1 or more groups. If the imputation model still cannot be fit
after excluding timing then the model will be further reduced until the model can be fit.
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Statistical Analysis Plan
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Date:
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Trial ID: NN9536-4376
Version:
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UTN: U1111-1201-0898
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Reduction will be done in a fixed order by first removing gender, then collapsing the two highest 
baseline BMI-groups into one (≥35) and finally removing baseline BMI-groups. If no LAO-OT 
exists post-baseline then the LAO-OT will be the baseline body weight and the timing will be the 
first interval. If any subjects are MT, an imputation model for missing body weight 
measurements at week 68 for MT subjects will also be defined using AT subjects in a similar 
way. The estimated posterior distribution for the parameters (regression coefficients and 
variances) in the imputation models are then used to impute missing week 68 body weight values 
for each randomised treatment arm. This will be done 1,000 times and results in 1,000 complete 
data sets.
2. Analysis: Analysis of each of the 1,000 complete data sets, using the analysis model
(ANCOVA) results in 1,000 estimations.
3. Pooling: Integrates the 1,000 estimation results into a final result using Rubin’s formula.
Based on NN9536-4153 phase 2 results 1,000 copies should be sufficient to establish stable results. 
If 1,000 copies are insufficient, 10,000 copies will be used. The multiple imputations will be 
generated using Novo Nordisk trial number 95364376 as seed number. In addition to the seed 
number, it is specified that the dataset is sorted by subject ID.
Sensitivity analyses
Jump to reference multiple imputation approach (J2R-MI): Missing values of body weight at week 
68 (MT and MD) for both the semaglutide 2.4 mg and semaglutide placebo group are imputed by 
sampling among all available assessments at week 68 in the semaglutide placebo group (AT and 
AD). This approach makes the assumption that subjects instantly after discontinuation lose any 
effect of randomised treatment beyond what can be expected from semaglutide placebo treatment as 
adjunct to reduced-calorie diet and increased physical activity.3 The multiple imputation approach is 
done as above with the first step replaced by
1. Imputation: Defines an imputation model using semaglutide placebo subjects from FAS with a
week 68 measurement (AT and AD). The model will be a linear regression of body weight (kg)
at week 68 with gender (male/female), BMI (kg/m2) (in categories 27-<35, 35-<40, ≥40) as
factors and baseline (randomisation) body weight (kg) as covariate. No interactions will be
included. If the imputation model cannot be fit due to inadequate numbers of retrieved subjects
in 1 or more groups, then the imputation model will be reduced until the model can be fit.
Reduction will be done in a fixed order by first removing gender, then collapsing the two highest
baseline BMI-groups into one (≥35) and finally removing baseline BMI-groups. The estimated
posterior distribution for the parameters (regression coefficients and variances) in the imputation
models are then used to impute missing week 68 body weight values for each randomised
treatment arm. This will be done 1,000 times and results in 1,000 complete data sets.
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Statistical Analysis Plan
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Date:
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Trial ID: NN9536-4376
Version:
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UTN: U1111-1201-0898
Status:
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The jump to reference approach is the basis for the sample size calculations. 
A single imputation approach as done by Sacks4 (S1-SI and S2-SI): Missing weight measurements 
at week 68 for non-retrieved subjects (MD) are imputed using a weight regain rate of 0.3 kg/month 
after LAO but truncated at no change from baseline whenever the extrapolation would lead to a 
positive weight gain relative to baseline. If a subject's weight at drug discontinuation represented a 
gain in weight relative to baseline, no additional gain will be imputed, and the unfavourable gain is 
carried forward to week 68. The weight regain imputation will be done for both randomised arms 
(S1-SI). Additionally, a version where only the semaglutide 2.4 mg arm uses the regain rate while 
the semaglutide placebo arm uses last available observation (corresponding to a weight regain rate 
of 0 kg/month) will be performed (S2-SI). For both versions, missing weight measurements at week 
68 for subjects on randomised treatment (MT) are imputed by using LAO.
Tipping-point multiple imputation analysis (TP-MI): First, missing data are imputed according to 
the primary multiple imputation approach. Then, a penalty is added to the imputed values at week 
68. The approach is to explore a range of penalties for both treatment groups, and the impact these 
would have on the study conclusions. The 2-dimensional space of penalties covering the range from 
-30% to 30% will be explored for both treatment groups. This sensitivity analysis evaluates the 
robustness of the superiority conclusions to departures from the observed change in body weight in 
both treatment groups.
Mixed model for repeated measurements (MMRM): This ‘MMRM for effectiveness’ will use all 
assessments regardless of adherence to randomised treatment, including assessments at week 68 for 
retrieved drop-outs (AD). The MMRM for effectiveness will be fitted using the same factor and 
covariate as for the primary analysis all nested within visit. An unstructured covariance matrix for 
measurements within the same subject will be employed, assuming that measurements for different 
subjects are independent.

CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
31 March 2020
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Trial ID: NN9536-4376
Version:
1.0
UTN: U1111-1201-0898
Status:
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EudraCT No.: 2017-003473-34
Page:
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Figure 2-1
Illustration of imputation approaches for the primary estimand

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Statistical Analysis Plan
CONFIDENTIAL
Date:
31 March 2020
Novo Nordisk
Trial ID: NN9536-4376
Version:
1.0
UTN: U1111-1201-0898
Status:
Final
EudraCT No.: 2017-003473-34
Page:
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Analysis addressing the secondary estimand
The secondary estimand for % weight change addresses the efficacy of semaglutide 2.4 mg and will 
be assessed using a ‘MMRM for efficacy’. Week 68 assessments for retrieved drop-outs (AD) are 
not used in this analysis. The MMRM for efficacy will use assessments only from subjects who are 
taking the randomised treatment until end of treatment or until first discontinuing of randomised 
treatment. The derived date of the second consecutive missed dose will be used as the latest date for 
using assessments in this MMRM. The assessment closest in time and before the derived date of the 
second consecutive missed dose will be used as last assessment on randomised treatment. For 
subjects who initiate rescue interventions before completion or first discontinuing of randomised 
treatment, the date of starting weight management drugs or undergoing bariatric surgery will be 
used as latest date for using assessments in this MMRM. Similarly, the assessment closest in time 
and before the date of starting weight management drugs or undergoing bariatric surgery will be 
used as last assessment on randomised treatment. The MMRM for efficacy will be fitted using % 
weight change and the same factor and covariate as for the primary analysis all nested within visit. 
An unstructured covariance matrix for measurements within the same subject will be employed, 
assuming that measurements for different subjects are independent. 
An overview of all analysis and imputation methods to address the primary and secondary
estimands for the primary endpoint is given in Table 2-3.
2.3.2
Secondary endpoints
2.3.2.1
Confirmatory secondary endpoints
Confirmatory secondary endpoints are listed in Section 4.2.2.1 in the protocol and are all included 
in the fixed-sequence statistical strategy, see above. All tests are tests of superiority of semaglutide 
2.4 mg to semaglutide placebo. 
Analyses addressing the primary estimand
All confirmatory secondary endpoints will be analysed using the same imputation approach as used 
for the primary endpoint and to address the primary estimand. The imputation model is the same as 
for the primary endpoint with body weight replaced by assessments of the endpoint to be analysed. 
The statistical model for continuous endpoints will be ANCOVA with factor and covariate as for 
the primary endpoint % weight change with baseline (randomisation) body weight replaced by the 
baseline (randomisation) assessment of the endpoint to be analysed. 
Analyses addressing the secondary estimand
The confirmatory secondary endpoints will be analysed to address the secondary estimand using the 
same MMRM for efficacy described for the primary endpoint.
Sensitivity analyses for confirmatory secondary endpoints
For all continuous confirmatory secondary endpoints a sensitivity analysis using jump to reference 
as imputation approach will be carried out. 

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Statistical Analysis Plan
CONFIDENTIAL
Date:
31 March 2020
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Trial ID: NN9536-4376
Version:
1.0
UTN: U1111-1201-0898
Status:
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EudraCT No.: 2017-003473-34
Page:
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An overview of all analysis and imputation methods to address the primary and secondary
estimands for confirmatory secondary endpoints is given in Table 2-3.
Table 2-3
Analysis and imputation methods to address the primary and secondary
estimands for the primary and confirmatory secondary endpoints in the 
statistical testing hierarchy
Objective
Endpoint
Test 
order
Endpoint 
type
Estimand
Analysis 
set
Statistical 
model
Imputation 
approach
Sensitivity 
analyses
Primary endpoint
From randomisation (week 20) to week 68
Primary
% weight change
1
Continuous
Primary
FAS
ANCOVA
RD-MI
J2R-MI
S1-SI
S2-SI
TP-MI
MMRM
Secondary
FAS
MMRM
-
-
Confirmatory secondary endpoints
From randomisation (week 20) to week 68
Primary
WC change (cm)
2
Continuous
Primary
FAS
ANCOVA
RD-MI
J2R-MI
Secondary
FAS
MMRM
-
-
Secondary
sBP change (mmHg)
3
Continuous
Primary
FAS
ANCOVA
RD-MI
J2R-MI
Secondary
FAS
MMRM
-
-
Secondary
SF-36 PF score change
4
Continuous
Primary
FAS
ANCOVA
RD-MI
J2R-MI
Secondary
FAS
MMRM
-
-
FAS = full analysis set; ANCOVA = analysis of covariance; RD-MI = multiple imputation using retrieved subjects; 
J2R-MI = jump to reference multiple imputation; S1-SI and S2-SI = single imputation as done by Sacks; TP-MI = 
tipping point multiple imputation; MMRM = mixed model for repeated measurements; WC = waist circumference; sBP 
= systolic blood pressure; SF-36 = Short Form 36 v2.0 acute; PF = physical functioning; 
Test order refers to the order of the endpoint in the statistical test hierarchy outlined in Table 2-2
2.3.2.2
Supportive secondary endpoints
Supportive secondary endpoints are listed in Section 4.2.2.2 in the protocol. All tests are tests of 
superiority of semaglutide 2.4 mg to semaglutide placebo. 
Analyses addressing the primary estimand
The effect-related supportive secondary endpoints will be analysed using the same imputation 
approach as used for the primary endpoint and to address the primary estimand. The imputation 
model is the same as for the primary endpoint with body weight replaced by assessments of the 
endpoint to be analysed. The statistical model for continuous endpoints will be ANCOVA with 
factor and covariate as for the primary endpoint % weight change with baseline (randomisation) 
body weight replaced by the baseline (randomisation) assessment of the endpoint to be analysed. 
The statistical model for responder endpoints relating to clinical outcome assessments will be 
logistic regression with randomised treatment as a factor and the baseline (randomisation) 
assessment of the endpoint to be analysed as covariate.
The supportive secondary endpoint subjects who gain weight from randomisation (week 20) to 
week 68 (yes/no)’ is used to describe weight maintenance. It will be analysed using logistic 
regression with randomised treatment as a factor and body weight (kg) at baseline (randomisation) 
as covariate.

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Statistical Analysis Plan
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Trial ID: NN9536-4376
Version:
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UTN: U1111-1201-0898
Status:
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EudraCT No.: 2017-003473-34
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For lipids and fasting serum insulin a multiplicative model will be used, i.e. the ratio between post 
randomisation measurements and baseline (randomisation) will be calculated instead of differences, 
and both the dependent variable and covariate will be log-transformed.
Analyses addressing the secondary estimand
The supportive secondary endpoints will be analysed to address the secondary estimand using the 
same MMRM for efficacy described for the primary endpoint.
The secondary estimand for weight gain responders will be assessed using the same MMRM for 
efficacy except that body weight (kg) will be used as response variable in the model. For subjects 
with missing body weight at week 68, individual values for body weight will be predicted from the 
MMRM and used to classify each subject as weight gain responder or not. This classification will 
then be analysed using a logistic regression model with randomised treatment as a factor and 
baseline (randomisation) body weight (kg) as covariate.
The secondary estimand for responder endpoints relating to clinical outcome assessments will be 
analysed using the same MMRM for efficacy as described for weight gain responders, where 
baseline (randomisation) body weight (kg) is replaced by baseline (randomisation) assessment of 
the endpoint to be analysed.
Analyses addressing the tertiary estimand
The effect-related supportive secondary endpoints addressing the tertiary estimand will be analysed 
using the same imputation approach as used for the primary endpoint, where baseline 
(randomisation) body weight (kg) is replaced by baseline (week 0) body weight (kg). The 
continuous endpoint on body weight will be analysed using ANCOVA with factor and covariate as 
for the primary endpoint % weight change with the baseline (randomisation) value replaced with 
baseline (week 0). The binary endpoints on body weight will be analysed using logistic regression 
with randomised treatment as a factor and baseline (week 0) assessment of body weight as 
covariate.
Analyses addressing the quaternary estimand
The effect-related supportive secondary endpoints addressing the quaternary estimand will be 
analysed using the same MMRM for efficacy described for the primary endpoint, where baseline 
(randomisation) body weight (kg) is replaced by baseline (week 0) body weight (kg).
The quarternary estimand for bw responders will be assessed using the same MMRM for efficacy
described for the secondary estimand for the weight gain responders, where baseline 
(randomisation) body weight (kg) is replaced by baseline (week 0) body weight (kg).
Sensitivity analyses for supportive secondary endpoints
For supportive secondary endpoints no sensitivity analysis will be carried out.

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Statistical Analysis Plan
CONFIDENTIAL
Date:
31 March 2020
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Trial ID: NN9536-4376
Version:
1.0
UTN: U1111-1201-0898
Status:
Final
EudraCT No.: 2017-003473-34
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Additional considerations for statistical analyses 
To evaluate the predictive value of short-term weight changes for long-term benefit of the use of 
semaglutide 2.4 mg, subjects will be categorised based on the weight change achieved in the run-in 
phase. If the weight change from week 0 to week 20 exceeds a certain pre-specified threshold 
subjects are classified as early “responders” whereas subjects are classified as early “non-
responders” if the weight has changed less than the pre-specified threshold. Different thresholds of 
3%, 4% and 5% will be investigated. These sub-group analyses will be done using the primary 
endpoint and the statistical model described for the primary endpoint. These analyses will be 
presented in a report separate from the Clinical Trial Report.
Analysis of safety endpoints
The safety endpoint pulse from randomisation (week 20) to week 68 will be analysed using an 
MMRM for efficacy as described in Section 2.3.1. For pulse from week 0 to randomisation (week 
20), amylase, lipase and calcitonin descriptive statistics will be provided. The analysis of calcitonin 
will be stratified by gender.
Adverse events will be defined as “treatment-emergent” (TEAE), if the onset of the event occurs in 
the on-treatment period (see definition in Section 2.2). TEAEs and SAEs will be summarised by 
descriptive statistics, such as frequencies and rates. No formal statistical inference will be carried 
out based on the number of TEAEs and SAEs. All AEs will be coded using the most recent version 
of the Medical Dictionary for Regulatory Activities (MedDRA).
An overview of all analysis and imputation methods to address the primary, secondary, tertiary and 
quaternary estimands for supportive secondary endpoints is given in Table 2-4.

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Statistical Analysis Plan
CONFIDENTIAL
Date:
31 March 2020
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Trial ID: NN9536-4376
Version:
1.0
UTN: U1111-1201-0898
Status:
Final
EudraCT No.: 2017-003473-34
Page:
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Table 2-4
Analysis and imputation methods to address the primary, secondary, tertiary
and quaternary estimands for supportive secondary endpoints
Objective
Endpoint
Endpoint 
type
Estimand
Analysis 
set
Statistical 
model
Imputation 
approach
Sensitivity 
analyses
Supportive secondary endpoints (effect related)
From randomisation (week 20) to week 68
Primary
Weight change (kg)
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
FAS
MMRM
-
-
Primary
BMI change (kg/m2)
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
FAS
MMRM
-
-
Secondary
HbA1c change (%, mmol/mol)
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
FAS
MMRM
-
Secondary
FPG change (mg/dL,mmol/mol)
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
FAS
MMRM
-
Secondary
Fasting serum insulin change 
(mIU/L, pmol/mol)
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
FAS
MMRM
-
Secondary
dBP change (mmHg)
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
FAS
MMRM
-
Secondary
Total cholesterol change (mg/dL, 
mmol/mol)
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
FAS
MMRM
-
Secondary
HDL change (mg/dL, mmol/mol)
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
FAS
MMRM
-
Secondary
LDL change (mg/dL, mmol/mol)
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
FAS
MMRM
-
Secondary
VLDL change (mg/dL, mmol/mol)
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
FAS
MMRM
-
Secondary
FFA change (mg/dL, mmol/mol)
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
FAS
MMRM
-
Secondary
Triglycerides change (mg/dL, 
mmol/mol)
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
FAS
MMRM
-
Secondary
SF-36 PF score responders #
Binary
Primary
FAS
LR
RD-MI
-
Secondary
FAS
LR
MMRM
Secondary
SF-36 RP score change
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
FAS
MMRM
-
Secondary
SF-36 BP score change
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
FAS
MMRM
-
Secondary
SF-36 GH score change
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
FAS
MMRM
-
Secondary
SF-36 VT score change
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
FAS
MMRM
-
Secondary
SF-36 SF score change
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
FAS
MMRM
-
Secondary
SF-36 RE score change
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
FAS
MMRM
-
Secondary
SF-36 MH score change
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
FAS
MMRM
-
Secondary
SF-36 PCS score change
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
FAS
MMRM
-
Secondary
SF-36 MCS score change
Continuous
Primary
FAS
ANCOVA
RD-MI
-
Secondary
FAS
MMRM
-
Primary
Proportion of subjects who gain 
weight (%)
Binary
Primary
FAS
LR
RD-MI
-
Secondary
FAS
LR
MMRM

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Statistical Analysis Plan
CONFIDENTIAL
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Trial ID: NN9536-4376
Version:
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UTN: U1111-1201-0898
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From week 0 to week 68
Secondary
% weight change
Continuous
Tertiary
FAS
ANCOVA
RD-MI
-
Quarternary
FAS
MMRM
-
Secondary
Weight reduction <0%
Binary
Tertiary
FAS
LR
RD-MI
-
Quarternary
FAS
LR
MMRM
Secondary
Weight reduction ≥5%
Binary
Tertiary
FAS
LR
RD-MI
-
Quarternary
FAS
LR
MMRM
Secondary
Weight reduction ≥10%
Binary
Tertiary
FAS
LR
RD-MI
-
Quarternary
FAS
LR
MMRM
Secondary
Weight reduction ≥15%
Binary
Tertiary
FAS
LR
RD-MI
-
Quarternary
FAS
LR
MMRM
Secondary
Weight reduction ≥20%
Binary
Tertiary
FAS
LR
RD-MI
-
Quarternary
FAS
LR
MMRM
Supportive secondary endpoints (safety related)
From week 0 to randomisation (week 20)
Secondary
Number of TEAEs
Continuous
-
SAS
-
-
-
Secondary
Number of SAEs
Continuous
-
SAS
-
-
-
Secondary
Pulse change (bpm)
Continuous
-
SAS
Descriptive 
statistics
-
-
Secondary
Amylase change (U/L)
Continuous
-
SAS
Descriptive 
statistics
-
-
Secondary
Lipase change (U/L)
Continuous
-
SAS
Descriptive 
statistics
-
-
Secondary
Calcitonin change (ng/L)
Continuous
-
SAS
Descriptive 
statistics
-
-
From randomisation (week 20) to week 68 / 75
Secondary
Number of TEAEs
Continuous
-
SAS
-
-
-
Secondary
Number of SAEs
Continuous
-
SAS
-
-
-
Secondary
Pulse change (bpm)
Continuous
-
SAS
MMRM
-
-
Secondary
Amylase change (U/L)
Continuous
-
SAS
Descriptive 
statistics
-
-
Secondary
Lipase change (U/L)
Continuous
-
SAS
Descriptive 
statistics
-
-
Secondary
Calcitonin change (ng/L)
Continuous
-
SAS
Descriptive 
statistics
-
-
FAS = full analysis set; ANCOVA = analysis of covariance; RD-MI = multiple imputation using retrieved subjects; 
MMRM = mixed model for repeated measurements; BMI = body mass index; HbA1c = Hemoglobin A1c; FPG = 
fasting plasma glucose; dBP = diastolic blood pressure; HDL = high density lipoprotein; LDL = low density 
lipoprotein; VLDL = very low density lipoprotein; FFA = free fatty acids; LR = logistic regression; SF-36 = Short Form 
36 v2.0 acute; PF= Physical Functioning; RP = Role-Physical; BP = Bodily Pain; GH = General Health; VT = Vitality; 
SF = Social Functioning; RE = Role-Emotional; MH = Mental Health; PCS = Physical component summary; MCS = 
Mental component summary; TEAEs = treatment emergent adverse events; SAEs = serious adverse events; # responder 
value = 4.3
2.3.3
Exploratory endpoints
Exploratory endpoints are listed in Section 4.2.3 in the protocol. Observed data for exploratory 
endpoints will be summarised by descriptive statistics. 
2.3.4
Other analyses
All collected data that were not defined as endpoints will be summarised by descriptive statistics. 
2.4
Pharmacokinetic and/or pharmacodynamic modelling
Not applicable for this trial. 

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Statistical Analysis Plan
CONFIDENTIAL
Date:
31 March 2020
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Trial ID: NN9536-4376
Version:
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UTN: U1111-1201-0898
Status:
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EudraCT No.: 2017-003473-34
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3
Changes to the statistical analyses planned in the protocol
The main analyses were described in the protocol for the trial NN9536-4376. However, 
clarifications and more detailed descriptions of endpoints and analyses are provided in this SAP. 
The changes from the protocol of NN9536-4376 are summarised below:
3.1
Trial specific changes
!
Quaternary estimand has been defined to account for analyses based on the hypothetical 
estimand for weight related endpoints from week 0 to week 68.
!
Description of the MMRM for efficacy for weight gain responders has been added.
!
It has been clarified that the safety endpoint pulse from week 0 to randomisation (week 20) 
will not be analysed but reported with descriptive statistics.
!
It has been clarified that the “early responder” analyses will not be presented in the Clinical 
Trial Report, but in a separate report.
3.2
Changes applied across STEP trials
!
The supportive secondary endpoint “Body weight reduction ≥ 20% from baseline at week 0” 
was added.
!
It was clarified that subjects in the FAS/SAS will be evaluated “as randomised”/“as treated”.
!
In the text describing that “In general, the on-treatment period will therefore be from the 
date of first trial product administration to date of last trial product administration” the 
following has been added “(+14 days)” to emphasize that the lag-time after last trial product 
administration is included in the on-treatment period.
!
All AEs will be coded using the most recent version of the Medical Dictionary for
Regulatory Activities (MedDRA).
!
The text explaining how to handle missing baseline values has been changed to make it clear 
that if no eligible observation at or before randomisation is available then the mean of 
baseline values across all subjects is used as baseline value.
!
It is clarified that RD-MI imputation is performed according to the timing of last available 
observation during the on-treatment period (LAO-OT). This is true for all endpoints. This is 
to clarify that the grouping of subjects according to timing is as in McEvoy2. Furthermore it 
is clarified that the LAO-OT must be prior to the landmark visit (week 68)
!
BMI group “27-<35” in the RD-MI imputation has been updated to “≤35” to reflect that 
some subjects loose weight between screening and randomisation and therefore can have a 
BMI < 27 kg/m^2 at the randomisation visit.
!
In grouping of retrieved subjects by timing of LAO-OT in the RD-MI procedure, it is 
clarified that timing by quarters or halves is defined as too restrictive if the imputation 
model cannot be fit due to inadequate numbers of retrieved subjects in 1 or more groups.
Furthermore it is described how a model reduction will be performed if needed.
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Statistical Analysis Plan
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Trial ID: NN9536-4376
Version:
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UTN: U1111-1201-0898
Status:
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EudraCT No.: 2017-003473-34
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!
It is clarified that if no post-baseline LAO-OT exist, then LAO-OT will be the baseline 
value and the timing of LAO-OT will be the first interval.
!
In all multiple imputation procedures, in addition to the seed number, it is specified that the 
dataset is sorted by subject ID.
!
The TP-MI procedure has been updated to be a 2-way tipping point analysis in which 
penalties are applied to both treatment groups (semaglutide 2.4 mg and placebo).
o
The rational for the changed TP-MI procedure is as follows: “To confirm the 
robustness of superiority conclusions using a tipping point analysis, we believe that 
a 2-way tipping point analysis represents the real-world situation for missing data 
from the both treatment arms (semaglutide and placebo). We would like to see 
departures from the treatment difference by varying both treatment arms rather than 
only adding a penalty to the active treatment arm (semaglutide). Additionally, please 
include interpretations for the varying scenarios and how likely they would be seen 
in a real-world setting.” (from FDA response letter 17 May 2018).
!
It is specified that fasting serum insulin will be log-transformed and analysed using a 
multiplicative model.
!
It is specified that lipids, FPG and fasting serum insulin will also be analysed in SI-units.
!
Text and tables have been updated to reflect that analyses for all non-weight related 
endpoints based on the secondary estimand and analyses for all weight related endpoints 
based on the quaternary estimand are to be done.
4
References
1. International Conference on Harmonisation. ICH Harmonised Tripartite Guideline. Topic E10: 
Choice of control group and related issues in clinical trials, 20 July 2000.
2. McEvoy BW. Missing data in clinical trials for weight management. J Biopharm Stat. 
2016;26(1):30-6.
3. Carpenter JR, Roger JH, Kenward MG. Analysis of longitudinal trials with protocol deviation: a 
framework for relevant, accessible assumptions, and inference via multiple imputation. J 
Biopharm Stat. 2013;23(6):1352-71.
4. Sacks FM, Bray GA, Carey VJ, Smith SR, Ryan DH, Anton SD, et al. Comparison of weight-
loss diets with different compositions of fat, protein, and carbohydrates. N Engl J Med. 
2009;360(9):859-73.

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Semaglutide s.c. 2.4 mg once weekly
CONFIDENTIAL
Date:
17 April 2020
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Trial ID: NN9536-4376 (STEP 4)
Version:
1.0
Clinical Trial Report
Status:
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MedDRA searches
Page:
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Clinical Trial Report
Trial ID: NN9536-4376 (STEP 4)
MedDRA searches within safety focus areas
Author
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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disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
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Semaglutide s.c. 2.4 mg once weekly
CONFIDENTIAL
Date:
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Trial ID: NN9536-4376 (STEP 4)
Version:
1.0
Clinical Trial Report
Status:
Final
MedDRA searches
Page:
2 of 7
Table of contents   
Page
Table of contents.........................................................................................................................................2
List of abbreviations and definitions of terms............................................................................................3
1
MedDRA searches for safety focus areas in project NN9536 .............................................................4
2
Abuse and misuse.................................................................................................................................4
3
Acute renal failure ...............................................................................................................................4
4
Allergic reactions .................................................................................................................................4
5
Cardiovascular disorders.....................................................................................................................4
6
Drug-related hepatic disorders............................................................................................................5
7
Gallbladder-related disorders .............................................................................................................5
8
Gastrointestinal disorders....................................................................................................................5
9
Hypoglycaemia.....................................................................................................................................5
10
Injection site reactions .........................................................................................................................5
11
Malignant tumours ..............................................................................................................................6
12
Medication errors ................................................................................................................................6
13
Neoplasms ............................................................................................................................................6
14
Overdose...............................................................................................................................................6
15
Pancreatitis...........................................................................................................................................7
16
Psychiatric disorders............................................................................................................................7
17
Rare events...........................................................................................................................................7
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Semaglutide s.c. 2.4 mg once weekly
CONFIDENTIAL
Date:
17 April 2020
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Trial ID: NN9536-4376 (STEP 4)
Version:
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Clinical Trial Report
Status:
Final
MedDRA searches
Page:
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List of abbreviations and definitions of terms
AE
adverse event
HLT
high level term
MedDRA
Medical Dictionary for Regulatory Activities
NEC
not elsewhere classified
NNMQ
Novo Nordisk MedDRA query
PT
preferred term
SMQ
standardised MedDRA query
SOC
system organ class
CONFIDENTIAL


Semaglutide s.c. 2.4 mg once weekly
CONFIDENTIAL
Date:
17 April 2020
Novo Nordisk
Trial ID: NN9536-4376 (STEP 4)
Version:
1.0
Clinical Trial Report
Status:
Final
MedDRA searches
Page:
4 of 7
1
MedDRA searches for safety focus areas in project NN9536
The MedDRA search strings in this document (ordered alphabetically) were used for the NN9536
submission documents. The same search strings were used for the STEP 1‒4 clinical trial reports. 
The MedDRA version used was 22.1.
2
Abuse and misuse
Custom query (NNMQ Abuse and Misuse):
!
SMQ Drug abuse and dependence, narrow terms only
!
HLT Intentional product misuses 
!
Additional PTs: 
o
Poisoning deliberate
o
Intentional dose omission
o
Performance enhancing product use
o
Completed suicide
o
Intentional self-injury
o
Suicide attempt
o
Assisted suicide
o
Suspected suicide attempt
o
Suspected suicide.
3
Acute renal failure
SMQ Acute renal failure, narrow terms only
4
Allergic reactions
Custom Query (NNMQ Allergic reactions) – only narrow terms from the following:
!
SMQ Anaphylactic reaction 
!
SMQ Angioedema 
!
SMQ Severe cutaneous adverse reactions 
!
SMQ Anaphylactic/anaphylactoid shock conditions 
!
SMQ Hypersensitivity
5
Cardiovascular disorders
Custom query (NNMQ Cardiovascular disorders). Broad and narrow terms from the following:
!
SMQ Central nervous system vascular disorders 
!
SMQ Vasculitis 
CONFIDENTIAL


Semaglutide s.c. 2.4 mg once weekly
CONFIDENTIAL
Date:
17 April 2020
Novo Nordisk
Trial ID: NN9536-4376 (STEP 4)
Version:
1.0
Clinical Trial Report
Status:
Final
MedDRA searches
Page:
5 of 7
!
SMQ Ischaemic heart disease 
!
SMQ Cardiac arrhythmias 
!
SMQ Cardiac failure 
!
SMQ Cardiomyopathy 
!
SMQ Embolic and thrombotic events 
!
SMQ Shock 
!
SMQ Torsade de pointes/QT prolongation
6
Drug-related hepatic disorders
SMQ Drug related hepatic disorders - comprehensive search
7
Gallbladder-related disorders
Custom query (NNMQ Gallbladder-related disorders). Narrow terms from the following:
!
SMQ Functional, inflammatory and gallstone related biliary disorders
!
SMQ Infectious biliary disorders
8
Gastrointestinal disorders
Custom query (NNMQ Gastrointestinal disorders SOC):
!
SOC Gastrointestinal disorders, primary terms only
9
Hypoglycaemia
SMQ Hypoglycaemia, narrow terms only
10 Injection site reactions
Custom query (NNMQ Injection site reactions), both primary and secondary terms from the 
following:
!
HLT Administration site reactions NEC 
!
HLT Application and instillation site reactions 
!
HLT Infusion site reactions 
!
HLT Injection site reactions 
CONFIDENTIAL


Semaglutide s.c. 2.4 mg once weekly
CONFIDENTIAL
Date:
17 April 2020
Novo Nordisk
Trial ID: NN9536-4376 (STEP 4)
Version:
1.0
Clinical Trial Report
Status:
Final
MedDRA searches
Page:
6 of 7
11 Malignant tumours
SMQ Malignant tumours
12 Medication errors
SMQ Medication errors.
13 Neoplasms
Custom query (NNMQ Neoplasms)
!
SOC Neoplasms benign, malignant and unspecified (incl cysts and polyps), primary and 
secondary terms
!
SMQ Biliary neoplasms
!
SMQ Breast neoplasms, malignant and unspecified
!
SMQ Liver neoplasms, benign (incl cysts and polyps)
!
SMQ Liver neoplasms, malignant and unspecified
!
SMQ Malignancies
!
SMQ Malignant lymphomas
!
SMQ Oropharyngeal neoplasms
!
SMQ Ovarian neoplasms, malignant and unspecified
!
SMQ Premalignant disorders
!
SMQ Prostate neoplasms, malignant and unspecified
!
SMQ Skin neoplasms, malignant and unspecified
!
SMQ Uterine and fallopian tube neoplasms, malignant and unspecified
14 Overdose
Custom query (NNMQ Overdose):
!
HLT Overdoses NEC
!
Additional PTs:
o
Accidental overdose
o
Completed suicide
o
Suicide attempt
o
Suspected suicide attempt
o
Suspected suicide
CONFIDENTIAL


Semaglutide s.c. 2.4 mg once weekly
CONFIDENTIAL
Date:
17 April 2020
Novo Nordisk
Trial ID: NN9536-4376 (STEP 4)
Version:
1.0
Clinical Trial Report
Status:
Final
MedDRA searches
Page:
7 of 7
15 Pancreatitis
Custom query (NNMQ Pancreatitis), narrow terms from the following:
!
SMQ Acute pancreatitis
!
HLT Acute and chronic pancreatitis, primary and secondary terms
16 Psychiatric disorders
Custom query: 
!
SOC Psychiatric disorders, primary terms only 
17 Rare events
Custom query (NNMQ Rare events) excluding events that are included in other safety focus areas:
!
SMQ Agranulocytosis, narrow terms only
!
SMQ Guillain-Barre syndrome, narrow terms only
!
SMQ Haematopoietic cytopenias affecting more than one type of blood cell, broad and narrow 
terms
!
SMQ Haematopoietic leukopenia, broad and narrow terms
!
SMQ Haematopoietic thrombocytopenia, narrow terms only
!
SMQ Interstitial lung disease, narrow terms only
!
SMQ Neuroleptic malignant syndrome, narrow terms only
!
SMQ Pseudomembranous colitis, narrow terms only
!
SMQ Retroperitoneal fibrosis, narrow terms only 
!
SOC Congenital, familial and genetic disorders, (all terms are primary PTs) 
!
HLT Angioedemas, primary and secondary routed PTs
!
HLT Glomerulonephritis and nephrotic syndrome, primary and secondary routed PTs
!
HLT Nephritis NEC, primary and secondary routed PTs
!
Additional PTs: 
o
Disseminated intravascular coagulation
o
Hepatic lymphocytic infiltration
o
Multiple organ dysfunction syndrome
CONFIDENTIAL